Male and Female Sexual Dysfunction-072343266X

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The eld of medical studies which we now call sexual
medicine is one of the newest in the panoply of medical
subspecialties. While most lay people think they know
a lot about sex, in fact our scientic knowledge about
human sexuality was very limited until the last quarter
of the 20th century. Prior to then, repressive social
attitudes and sexual taboos made investigation into
human sexuality off-limits to most medical researchers.
The result was a limited pool of basic scientic knowl-
edge in sexual medicine and few treatment options for
the many millions of women and men who suffer from
sexual dysfunction. Then in the 1960s and 1970s,
several social and medical developments in the Western
world produced a so-called sexual revolution. These
developments included oral contraception for women,
the rise of feminism, the abortion rights movement
and the Hippie culture with its anti-establishment
activism. They resulted in liberalized attitudes towards
sexuality and they made research in sexual medicine
a respectable medical pursuit. As a result, in the last
25 years, we have seen the blossoming of important
new basic science ndings in sexual medicine. Sub-
stantial clinical advances in diagnosis and treatment
flowed from the improved basic understanding of
sexual medicine.
Now sexual medicine has matured into an almost
full-fledged subspecialty of the medical sciences.
Sexual medicine is a truly multidisciplinary eld, which
does not belong to either sex or to one specialty area
of medicine. It deals with one of the most common
international human maladies. It has strong clinical
elements from urology, gynecology, psychiatry,
psychology, internal medicine, diabetology, endocrin-
ology, primary care medicine, neurology and
epidemiology and it has equally strong basic science
elements from molecular biology, physiology,
anatomy, biochemistry and genetics. It has a sound
foundation in sophisticated basic sciences, important
clinical applications and treatments, commonly used
and effective classes of pharmacologic treatments and
an important surgical component. It also has an
excellent journal dedicated to the eld, a very active
international professional society, progressive regional
and national professional societies, academic programs
at important medical schools which are dedicated to
both male and female sexual medicine and signicant
overall health implications for both sexes. And sexual
medicine approaches a set of problems which draw
intense interest not only from afflicted individuals but
from the general populace as well. For these reasons,
sexual medicine is ready to become a highly respected
subspecialty, fully integrated into the array of medical
sciences.
A vital new eld of medicine such as this deserves to
have a state-of-the-art textbook to be its reference
work. Male and Female Sexual Dysfunction is the
state-of-the-art textbook for the eld of sexual
medicine. Edited by one of the worlds most respected
leaders in sexual medicine, Dr. Allen D. Seftel, it is a
very important addition to the eld because it gathers
into one book both the basics as well as the latest
trends in sexual medicine. Dr. Seftel has assembled an
all-star cast of contributors who have written the most
current treatises in their areas of special expertise. For
example, the fresh chapters on ejaculatory dysfunction,
female sexual dysfunction, psychogenic sexual dys-
function, gene therapy for erectile dysfunction and
cardiovascular safety of sexual activity represent the
best recent writing on these hot topics. This text
deserves to be on the bookshelf of any primary care
practitioner or specialist who sees patients with sexual
dysfunction, and that is most of us who are in the
practice of medicine or psychology.
Ira D. Sharlip
January 2004
Foreword
Some books are to be tasted, others to be swallowed,
and some few to be chewed and digested: that is, some
books are to be read only in parts, others to be read,
but not curiously, and some few to be read wholly, and
with diligence and attention.
Sir Francis Bacon (15611626)
Yet another book on sex. Has sex changed so
dramatically over the past few years that another book
is required? Should such a book be devoured, or just
politely sniffed and set aside?
It is sometimes difcult to understand why a book
was created. It is not always clear, and may never be
so. Yet, the work is done and the requisite preface must
now be created to complete the process.
Yes, another book on sex. And yes, this book is
needed. Sexual medicine continues to evolve from its
embryonic state into a bona de discipline. This text
was created to bridge the gap in a eld wherein there
is constant scientic data added to the literature at an
alarming rate. It seems that new data or novel concepts
are introduced almost daily. This poses a tremendous
challenge to the average practitioner interested in
sexual medicine. The chapters were chosen based on
current information presented at various scientic
forum; recent provocative and timely scientic papers,
consensus conferences and other high-level and high-
prole venues. The chapters span the breadth of sexual
medicine, and capture the essence of the novel areas.
Ejaculatory dysfunction, male hormonal issues, novel
therapies for male erectile dysfunction, such as the
PDE5 inhibitors, and female sexual dysfunction, to
name a few are reviewed. Cardiac safety is discussed in
depth, a topic that should become familiar to every
reader.
The goals of this book are to update the practitioner
interested in sexual medicine on the latest and most
current concepts in the eld. The chapters are written
by internationally recognized authorities in their
respective sexual medicine disciplines. This book may
be a bit advanced for the medical student or for those
who dabble lightly in the eld of sexual medicine. They
may wish to taste this book, and digest a small part.
This text is to be read wholly, and with diligence and
attention by those who have a vested interest in the
eld of sexual medicine.
Special thanks are hereby given to the wonderful
publishing group at Elsevier, who continued to push
this project forward, in spite of my overwhelming
schedule. Kudos to Dr. Martin Resnick, my chairman at
Case Western Reserve University, University Hospitals
of Cleveland, for his constant inspiration and support;
to my dear friends Dr. Donald Bodner and Dr. Stan
Althof, for their guidance and understanding; and to
my secretary, Ellen Holly, who continues to save me
from drowning. The late Robert J. Krane, M.D., former
Professor and Chair of Urology, Boston University,
was a mentor who shall not be soon forgotten, and
remains sorely missed.
Finally, deep love and overwhelming gratitude to my
wife Carol, who continues to tolerate my endless
academic pursuits, with a warm smile, devotion,
caring, love and understanding. To my sons Bennett,
Jeremy and Rocky, I ask their indulgence, patience and
forgiveness. I teach the sons and daughters of others to
better us all; a noble mission that carries great sacrice
as its partner.
Allen D. Seftel, M.D.
January 2004
Preface
Julien Allard
Pelvipharm
CNRS
BAT 5
91190 Gif-sur-Yvette
France
Stanley E. Althof PhD
Professor of Psychology
Department of Urology
Case Western Reserve University
School of Medicine
Co-director Center for Marital and
Sexual Health
Beachwood
Ohio
USA
Aristotelis G. Anastasiadis MD
The Department of Urology
College of Physicians and
Surgeons of Columbia
University
New York
USA
Debra L. Bemis
c/o Ridwan Shabsigh
Associate Professor of Urology
Surgeons of Columbia University
New York
USA
Gerald B. Brock MD FRCSC
Associate Professor of Surgery
Division of Urology
University of Western Ontario
London
Ontario
Canada
Dominick J. Carbone MD
Assistant Professor
Wake Forest University School of
Medicine
Medical Centre Boulevard
Winston-Salem NC 27157
USA
Dinamarie C. Garcia-Banigan
MD MPH
Department of Endocrinology
Center for Sexual Function
Lahey Clinic Northshore
Peabody
USA
Franois Giuliano MD PhD
Urologist, Associate Professor of
Therapeutics
Academic Hpital Bicetre
94270 Le Kremlin Bicetre
Cedex
France
Irwin Goldstein MD
Director
Institute for Sexual Medicine;
Professor of Urology and
Gynecology
Institute for Sexual Medicine
Boston University School of
Medicine
Boston
USA
Andre T. Guay MD
Assistant Clinical Professor of
Medicine
Howard Medical School Boston
Boston;
Director
Center for Sexual Function
Lahey Clinic Northshore
Peabody
USA
Wayne J. G. Hellstrom MD FACS
Chief, Section of Andrology and
Male Infertility
Tulane University Health Sciences
Center
New Orleans
USA
Joel M. Kaufman MD
Associate Clinical Professor of
Urology
Urology Research Options
Aurora
Colorado
USA
Noel N. Kim PhD
Research Assistant Professor of
Urology
Institute for Sexual Medicine
Medicine
Boston
USA
Louis Kuritzky MD
Clinical Assistant Professor
University of Florida
Gainesville
USA
Sheryl A. Kingsberg PhD
Associate Professor of
Reproductive Biology and
Psychiatry
School of Medicine
Cleveland
Ohio
USA
Robert A. Kloner MD PhD
Director of Research
The Heart Institute
Good Samaritan Hospital;
Professor of Medicine
Keck School of Medicine
Division of Cardiovascular Medicine
University of Southern California
Los Angeles
California
USA
Contributors
Chris G. McMahon MB BS FACSHP
Director
Australian Centre for Sexual Health
Berry Road Medical Centre
St Leonards
NSW
Australia
Ricardo Munarriz MD
Assistant Professor of Urology
Boston Medical Center
Boston
USA
Harin Padma-Nathan MD FACS FRCS
Clinical Professor of Urology
Keck School of Medicine University
of Southern California
Director, The Male Clinic
Beverly Hills
California
USA
Hossein Sadeghi-Nejad MD FACS
Associate Professor of Surgery and
Urology
Department of Surgery
Division of Urology
UMD New Jersey Medical School;
Director, Center for Male
Reproductive Medicine
Hackensack University Medical
Center
Hackensack
New Jersey
USA
Allen D. Seftel MD
Associate Professor of Urology and
Reproductive Biology
University Hospitals of Cleveland
Cleveland VA Medical Center
Cleveland
Ohio
USA
Ridwan Shabsigh MD
Director, The New York Centre for
Human Sexuality
New York;
Surgeons of Columbia
University
New York
USA
Ira D. Sharlip MD
Secretary General
International Society for Sexual and
Impotence Research
San Francisco
California
USA
Brian C. Stisser
c/o Ridwan Shabsigh
New York
USA
Suzette E. Sutherland MD
Urologist
Metropolitan Urologic Specialists,
P.A
Court International Building
St Paul
Minnesota
USA
Abdul Traish BSc MBA PhD
Professor of Biochemistry and
Urology
Centre for Advanced Biomedical
Research
Medicine
Boston
Massachusetts
USA
J. C. Trussell MD
New York
USA
Mustafa F. Usta MD
Fellow of Andrology
Tulane University Health Sciences
Center
New Orleans
USA
Marcel D. Waldinger MD PhD
Associate Professor on Sexual
Psychopharmacology
Department of
Psychopharmacology
Utrecht Institute for Pharmaceutical
Services and Rudolf Magnus
Institute for Neurosciences
Utrecht University
Utrecht
The Netherlands
xii Contributors
INTRODUCTION
Penile erection is caused by blood lling the sinusoidal
spaces (the trabeculae) of the corpora cavernosa, whose
arterial blood supply arises from helicine arterioles
issuing from cavernosal arteries and which are drained
by the emissary veins. Penile erection requires the
vasodilation of cavernosal and helicine arteries and
the relaxation of trabecular smooth-muscle bers,
expanding the lacunar spaces and tunica albuginea.
The subsequent elongation and compression of sub-
tunical venules reduce their diameter and increase
resistance to outflow (for review, see
1
). The simul-
taneous occurrence of increased inflow and reduced
outflow is the cornerstone of penile erection, allowing
penile rigidity to occur. A shift of predominantly
sympathetic tone in favor of parasympathetic tone to
the penis and pelvic area triggers a peripheral cascade
of events, leading to penile erection. The tone of the
corpus cavernosum smooth-muscle bers is ultimately
dependent on the intracellular calcium concentration,
which is regulated by a set of intracellular transduction
pathways controlled by the release of neurotransmitters
from nerves and endothelial cells within the penis.
Several compounds aim to treat erectile dysfunction
by acting directly on the smooth-muscle tone of the
penile arteries and trabeculae. Such compounds can
induce smooth-muscle relaxation by acting on smooth-
muscle cell transmembrane receptors (e.g., prosta-
glandin E
1
)
2
or directly within the smooth-muscle cell
at some points on the transduction pathways, eventually
leading to smooth-muscle relaxation (e.g., sildenal).
3
The development of apomorphine for the treatment
of erectile dysfunction exemplied the possibility of
enhancing penile erection by acting upstream on the
central nervous system (CNS) pathways that control
inhibitory sympathetic and facilitator parasympathetic
tone to the penis.Therefore, the CNS, and more speci-
cally the structures and neurotransmitters involved in
the control of penile erection, represent a valuable
alternative to drugs targeting the corpus cavernosum
smooth muscle. The aim of this chapter is to present a
non-exhaustive view of the central structures and
neurotransmitters involved in the generation of penile
erection.
ORGANIZATIONAL PRINCIPLE
Experimental evidence has demonstrated that the
spinal cord contains all the neural circuitry involved in
the generation of penile erection. This spinal circuitry
is in turn controlled by the brain, which processes
interaction with the milieu extrieur. This led to the
idea that the brain is eventually the master of sexual
function. Whatever the stimulus, it is eventually the
brain that assigns or does not assign an erotic
content to it. Penile erection is one of the end results
of sexual motivation, which is subserved by the limbic
system, integrating information from higher associative
cortical centers and intimately related to the process
of reward and expectation. The limbic system is in
constant interplay with the hypothalamus, which plays
a central role in regulating homeostasis and the complex
behaviors of higher organisms, for instance, food or
water intake.The hypothalamus is a coordinating center
that integrates various inputs to ensure well-organized,
coherent, and appropriate set of autonomic and somatic
responses, including penile erection. Nuclei in the
brainstem participate in the control of penile erection
together with the limbic system and hypothalamus.
THE SPINAL CORD AND PERIPHERAL
INNERVATION OF THE PENIS
Peripheral innervation
The penis receives autonomic innervation from
sympathetic and parasympathetic nuclei located in the
spinal cord (Fig. 1.1). The spinal cord also contains the
motoneurons, innervating perineal striated muscles.
The gross innervation of the penis is similar in different
mammalian species and the following references refer
to comprehensive anatomical data obtained in human,
monkey, or rat.
The parasympathetic nervous system represents the
major proerectile input to the penis. The preganglionic
parasympathetic neurons are located at the sacral level
in the intermediolateral cell column of the spinal cord,
in the so-called sacral parasympathetic nucleus (Fig.
1.2). In humans, they arise mainly from the S3 seg-
ment, with a contribution from the S2 and S4 segment.
Central Neurophysiology of Penile Erection
Julien Allard and Franois Giuliano
CHAPTER 1
Parasympathetic axons run in the pelvic nerve to the
pelvic plexus, and then synapse with postganglionic
neurons whose axons are conveyed by the cavernous
nerve (Fig. 1.1).
4
Although the cavernous nerve may
contain some sympathetic antierectile bers, its
electrical stimulation is responsible for the occurrence
of erectile responses in various animal species. Also
in humans, intraoperative electrical stimulation of the
cavernous nerve elicits penile erection.
5
Sympathetic bers to the penis are mostly antierec-
tile, but some sympathetic bers may be considered as
proerectile as they participate in pelvic vasoconstriction,
thus redistributing pelvic blood flow to the penis upon
erection. The sympathetic nuclei are located in the
intermediolateral cell column and the dorsal gray
commissure at the thoracolumbar level of the spinal
cord.
6
Preganglionic sympathetic axons arise from the
T11L2 segments of the spinal cord in humans and
join the sympathetic paravertebral chain ganglia. Then,
some axons travel in the lumbar splanchnic nerves
to the inferior mesenteric and superior hypogastric
plexuses, from where they travel in the hypogastric
nerves and join the pelvic plexus to relay with the
postganglionic neuron bers traveling in the cavernous
nerves. Sympathetic axons also run in the paravertebral
sympathetic chain to the sacral ganglia, where they
synapse with postganglionic neurons joining the pelvic
or pudendal nerves (Fig. 1.1).
Axons of motoneurons running in the pudendal
nerve arise from the dorsolateral (DL) and dorso-
medial (DM) nucleus located in the ventral horn of the
sacral spinal cord, to innervate the ischiocavernosus
and bulbospongiosus muscles respectively.
7
Contrac-
tions of the bulbospongiosus and ischiocavernosus
striated muscles enhance penile rigidity in mammals,
and contractions of the bulbospongiosus muscles are
necessary for the expulsion of semen.
In turn, the spinal autonomic nuclei controlling
penile erection receive afferent information conveyed
by afferent sensory bers originating from the penis
and perigenital area. The dorsal nerve of the penis
(DNP) contains almost all of the sensory afferents
from the penis.
8
In the proximal part, the afferent
bers in the DNP constitute the pudendal nerve, which
arises in the S2S4 segments of the spinal cord in
humans (Fig. 1.1).
4 Central Neurophysiology of Penile Erection
Figure 1.1 Peripheral control of
penile erection. The main
proerectile pathway (continuous
line), originating from the sacral
parasympathetic nuclei (SPN) at
the sacral level (S), travels in the
pelvic nerve (PN), relaying in the
pelvic ganglion (PG), and
coursing to the penis in the
cavernous nerve (CN).
Antierectile bers (dashed line)
originate from the dorsal gray
commissure (DGC) and
intermediolateral column (IML) at
the thoracolumbar (TL) level, and
run in the hypogastric nerve (HN)
and paravertebral sympathetic
chain (PSC). Some of these
bers join the CN to reach the
erectile tissue. Antierectile bers
also run in the pudendal nerve
(PdN), which contains the axons
of the motoneurons issued from
the dorsolateral (DL) and
dorsomedial (DM) nucleus
controlling the bulbospongiosus
(BS) and ischiocavernosus (IC)
muscles. Sensory afferents from
the glans (dotted line) are
conveyed in the dorsal nerve of
the penis and join the dorsal horn
of the spinal cord at the sacral
level (S). Some sensory bers
(not represented) likely join the
TL level after running in the HN.
PSC
HN
DNP
CN
IC
BS
PdN
PG
PN
IML
DGC
TL
SPN
DL
DM
S
Spinal reflex
In agreement with the peripheral nervous network
described above, experimental and clinical data
support the theory that penile erections are controlled
by a spinal reflex. Distally, the afferent limb of this
reflex is constituted by DNP, and the efferent limb by
the cavernous nerve (Fig. 1.1). Penile erections can be
generated by electrical stimulation of the DNP in anes-
thetized rats spinalized at the T8 level.
9
Interestingly,
mechanical stimulation of the urethra and/or the glans
penis was also shown to trigger a spinal reflex in
spinalized anesthetized rats, consisting in penile
erection and activation of the bulbospongiosus and
ischiocavernosus muscles.
10
Penile erections are also
known to occur in response to local stimulation in
patients with complete spinal cord injury at the thora-
columbar level, supporting the hypothesis that the
spinal cord contains a neural machinery sufcient
for generating penile erection. As mentioned earlier,
spinalization at the T8 level is necessary to obtain
erectile responses to electrical stimulation of the DNP
in anesthetized rats. This supports the existence of an
inhibitory tone exerted by supraspinal projections on
spinal nuclei, and more generally of an interplay,
mediated by reciprocal nervous connections, between
the spinal circuitry controlling penile erection and the
brain.
SUPRASPINAL CONTROL OF SEXUAL
BEHAVIOR AND PENILE ERECTION
Introduction to the limbic system and
its role in penile erection
The idea of the limbic system providing the anatomical
substratum for emotions was rst proposed by James
Papez in 1937 and later extended by Paul McLean
(Fig. 1.3A).
11,12
The basis for the limbic system concept
comes from brain lesion experiments suggesting that
emotional expression was governed by the hypo-
thalamus, since emotion reaches consciousness and,
conversely, the hypothalamus must communicate
reciprocally with higher cortical centers. In the limbic
system, the cingulate gyrus, connected to the prefrontal
cortex, projects to the hippocampus, and the hippo-
campus projects to the hypothalamus through the
fornix, thus allowing connection of the prefrontal
cortex with the hypothalamus. In turn hypothalamic
impulses reach the cortex relayed in the anterior
thalamic nuclei. The amygdala, the bed nucleus of the
stria terminalis (BST), and the nucleus accumbens
were later included in the original circuit constituted
by the prefrontal cortex, the hippocampal formation,
and the hypothalamus.
There is experimental evidence that the cortical
and medial amygdala (MeA), the BST, the nucleus
accumbens, and nuclei within the hypothalamus are
concerned with the control of penile erection and
sexual behavior. The MeA and the BST are currently
thought to be involved in the processing of sexually
relevant olfactory stimuli. The nucleus accumbens is
devoted to sexual motivation. In the hypothalamus,
the paraventricular nucleus (PVN) is involved in the
control of penile erection, whereas the medial preoptic
Supraspinal Control of Sexual Behavior and Penile Erection 5
Figure 1.2 Parasympathetic neurons projecting to the
penis in the rat spinal cord. Pseudorabies virus (PRV) was
used as a transynaptic retrograde marker. PRV was
injected in the rat corpus cavernosum. After a 4-day
survival period, the rat was sacriced and the lumbosacral
spinal cord removed and cut into 20-m-thick coronal
sections. Sections were then processed for PRV
immunochemistry to reveal the neurons infected by the
virus. Dense labeling was observed in the sacral
parasympathetic nucleus (SPN), and, to a lesser extent, in
the dorsal gray commissure (DGC) above the central canal
(CC) and the intermediomedial gray matter (IMM). Note
that, by extending the survival period (i.e., further
replication, neural infection, and retrograde transport of the
virus), this technique allows visualization of the neurons
located in the brain which send projections to the spinal
autonomic centers controlling penile erection. (Reproduced
with permission from Veronneau-Longueville F, Rampin O,
Freund-Mercier M.J, et al. Oxytocinergic Innervation of
Autonomic Nuclei Controlling Penile Erection in the Rat.
Neuroscience 1999; 93(4):143747.)
area (MPOA) is crucial for the display of sexual
behavior. None of these nuclei is specically devoted
to the control of sexual behavior and penile erection.
It is the general participation of the limbic system in
the processes of motivation and reward that makes it
essential for sexual behavior. Moreover, the involve-
ment of hypothalamic nuclei in the control of penile
erection is but one illustration of its implication in the
control of stereotyped responses. The different nuclei
evoked in this chapter are represented in Figure 1.4 as
they would appear on a stereotaxical atlas of the rat
brain.
The medial amygdala and the bed
nucleus of the stria terminalis
The MeA receives information of olfactory origin from
the olfactory bulbs and vomeronasal organ, and sends
projections to the BST and MPOA.
13
Lesions of the
MeA severely impair non-contact erections (NCE, a
paradigm in which the male rat can have olfactory and
visual access to a female in heat, but no contact),
14
while having less effect on copulatory behavior. The
less deleterious effect of MeA lesions on copulatory
behavior than on NCE was explained by the primary
importance of olfactory input for the generation of
NCEs, in agreement with experiments demonstrating
that volatile odors from estrus females are the critical
stimuli for evoking NCE.
Lesions of the BST severely impaired NCE and, to a
lesser extent, copulatory behavior. Liu and colleagues
stressed that lesions of the BST had a more moderate
effect on NCEs than lesions of the MeA.
15
One expla-
nation may be the existence of direct projections from
the MeA to the MPOA, notably through the amyg-
dalofugal pathway. This direct pathway should allow
the olfactory inputs necessary for the generation of
NCEs to reach the hypothalamus, and thus to circum-
vent the lesioned BST. The BST is innervated by the
mesolimbic dopaminergic neurons originating in the
ventral tegmental area, which play a fundamental role
in incentive, motivational, and reward processes in
general, and in sexual motivation and reward in
particular.
16
Therefore, the MeA can be considered as
a site of entry for sexual olfactory inputs, and the BST
as a relay or processing site toward the hypothalamus.
The MeA and the BST are integrated in the more
complex circuitry of the limbic system, giving an
opportunity for the olfactory sensory afferents to be
modulated by other afferents. This also suggests that
Figure 1.3 The limbic system and the control of penile erection. (A) The control of penile erection is intimately related to
the limbic system and the hypothalamus. Major connections of the limbic system are represented in gray. The limbic
system, substratum for emotion, allows communication of higher cortical centers, here the prefrontal cortex (Pf) with the
hypothalamus, a coordinating center for complex autonomic responses. Nuclei of the hypothalamus include the
mammillary bodies (MM), the paraventricular nucleus (PVN), and the median preoptic area (MPA). The cortex influences
the hypothalamus by connecting the cingulate gyrus (not represented) with the hippocampal formation (Hi) and the
amygdala (A). The hypothalamus in turn provides informations to the cingulate gyrus after relaying the anterior thalamic
nuclei (ATN). The hypothalamus is a source of major output to the autonomic centers. BST, bed nucleus of the stria
terminalis; PAG, periaqueductal gray. (B) Many nuclei involved in the control of penile erection receive aminergic afferents
from the brainstem and midbrain. Dopaminergic projections (green) arise from the ventral tegmental area (VTA) in the
midbrain, the median zona incerta (MZI), and periventricular zone (Pe). There are also dopaminergic projections from the
hypothalamus to the spinal cord. Serotoninergic afferents (yellow) to the brain originate from the dorsal and median raphe
nuclei (DR + MR). Serotoninergic nuclei in the rostroventral medulla (RVM) project to the spinal cord. Noradrenergic
projections (red) are issued from the locus ceruleus and lateral tegmentum.
Pf
ATN
Hi
Pf
Hi
MM
BST Acb
Acb
MPA PVN
PAG
RVM
A
MPA
PVN
BST
A
LC+LT
RVM
DR
+
MR
VTA
MZI+Pe
A B
the MeA, BST, and MPOA should not be considered as
a simple input/output pathway.
The nucleus accumbens
The nucleus accumbens is part of the limbic system,
and is innervated by the mesocortical/mesolimbic
pathway constituted by the dopamine cell bodies that
lie medial to the substantia nigra (ventral tegmental
area, A10). The mesocorticolimbic dopamine tract is
essential for motivation and reward processes as well
as for locomotor behavior. The nucleus accumbens has
been involved in the control of sexual behavior, and
dopamine was found to be essential in its function.
Radiofrequency lesions of the nucleus accumbens did
not prevent NCE but increased their latencies, and did
not affect copulations.
17
A likely explanation is that the
nucleus accumbens is involved in the anticipatory phase
of sexual behavior, a nding which cannot be evidenced
in classical copulation experiments.
16
The median preoptic area of the
hypothalamus
The MPOA plays a key role in the display of sexual
behavior in every vertebrate species studied to date
(for review, see
18
), without being critical for the display
of penile erection. Lesions of the MPOA abolished the
display of copulatory behavior, without affecting the
expression of NCEs.
15
When male animals are trained
to seek for an estrous female presented in an operant
chamber under a second-order schedule of reinforce-
ment by pressing a lever, MPOA lesions abolished
mounts, intromissions, and ejaculation, but did not
disrupt instrumental responses, investigation of the
female, or abortive mounting attempts.
16
Therefore,
the MeA and BST on the one hand and the MPOA on
the other hand differ fundamentally in their partici-
pation in the control of sexual behavior. The MeA and
BST specically affect the process of olfactory inputs
related to sexual behavior. In contrast, the MPOA is
very likely involved in the display of copulatory
behavior. The major efferent projections of the MPOA
are to hypothalamic, midbrain, and brainstem nuclei
that regulate autonomic or somatomotor patterns and
motivational state. It has been postulated that the
MPOA removes tonic inhibition on these patterns and
thereby allows sensory stimuli to elicit a motor
response.
The paraventricular nucleus of the
hypothalamus
The PVN is innervated by dopamine neurons that
belong to the incertohypothalamic system, which is
part of the intrinsic dopamine innervation of the
hypothalamus. An involvement of the PVN of the
hypothalamus in the direct control of penile erection
is supported by a wide range of experimental data
gathered in the quest to understand the proerectile
effect of the dopaminergic agonist apomorphine. In
rats, the integrity of the PVN is a sine qua non condition
for apomorphine to display its proerectile activity (see
section on dopamine, below). Nevertheless, destruction
Supraspinal Control of Sexual Behavior and Penile Erection 7
Figure 1.4 Illustration of brain nuclei of the limbic system in the rat brain. Frontal sections of the rat brain, showing the
location of the different nuclei, mentioned earlier. Nuclei are shaded in gray. Hippocampal formations project to the
hypothalamus via the fornix (f). The stria terminalis (st), issued from the amygdala, innervates the bed nucleus of the stria
terminalis, the nucleus accumbens, and the hypothalamus. Many of the aminergic projections from the brainstem and
midbrain run in the median forebrain bundle (mfb). BST, bed nucleus of the stria terminalis; MeA, medial amygdala;
Acb, nucleus accumbens; MPA, median preoptic area; ACo, amygdala, nucleus anterior cortical; Hi, hippocampal
formation; Pa, paraventricular nucleus; VTA, ventral tegmental area; MM, mammillary bodies; Gi, gigantocellular reticularis
nucleus; R, red nucleus.
Acb
BST
MPA mfb PA mfb MM R Gi VTA Mea
st
f
Hi
st
f
of the PVN only slightly impaired copulatory behavior
or NCEs in male rats,
19
suggesting that, at least in the
rat, the PVN is not essential for penile erection or
copulatory behavior. One explanation may be that
several independent pathways could induce penile
erection.
Regardless of the results obtained with dopaminergic
agonists, glutamatergic agonists or oxytocin delivered
in the PVN, as well as electrical stimulation of the
PVN, induced penile erections in rats, supporting the
presence of proerectile neurons in the PVN.
20,21
One
way in which the PVN could affect penile erection is
by directly activating the parasympathetic proerectile
neurons in the sacral parasympathetic nucleus (SPN)
through direct oxytocinergic projections from the
PVN to the SPN. Although currently proposed, this
hypothesis should be handled cautiously as there is no
experimental pharmacological evidence supporting this
hypothesis at this time. Another attractive hypothesis
is that neurons in the PVN project to brain structures
involved in the control of penile erection, such as the
nucleus paragigantocellularis.
22
THE AMINERGIC CONTROL OF
SEXUAL BEHAVIOR
Serotonin
There is a widespread occurrence of serotonin
(5-HT)-positive nerve terminals throughout the CNS.
As shown in Figure 1.3B, the amygdala, the hippo-
campus, the hypothalamus, and the prefrontal cortex
receive serotoninergic innervation from either the
serotoninergic nuclei raphe dorsalis or centralis
superior, or both; these are located in the midbrain and
upper pons. Both the sacral parasympathetic nucleus
and the motoneurons innervating the ischiocavernosus
and bulbospongiosus muscles receive projections from
the raphe nuclei in the brainstem.
23
Experimental data support an inhibitory activity of
serotoninergic projections on sexual functions. Micro-
stimulation of the serotoninergic nuclei projecting to
the spinal cord depressed the reflex response of
pudendal motoneurons to dorsal penile nerve stimu-
lation, suggesting an involvement of serotoninergic
descending projections in the spinal processing of
sensory informations.
24
Behavioral experiments point
to an overall inhibitory effect of 5-HT on male sexual
functions. Intrathecal infusion of 5-HT inhibited intro-
missions and ejaculatory behavior during copulation.
25
An inhibitory control might also be exerted at the
supraspinal level by ascending projections from the
raphe nuclei in the midbrain, which project notably
to the nucleus accumbens and the hypothalamus. In
normal, sexually active male rats treated systemically
with parachlorophenylalanine (p-CPA, an inhibitor of
5-HT synthesis), a reduction in the ejaculation latency
and in the number of intromissions necessary to
achieve ejaculation was observed.
26
Further, in a popu-
lation of non-copulator rats, p-CPA treatment increased
the percentage of rats that copulated to ejaculation.
Conversely, systemic administration of the 5-HT pre-
cursor 5-hydroxytryptophan (5-HTP, which crosses the
bloodbrain barrier) results in an increase in time to
ejaculation together with an increased in number of
intromissions.
27
A plethora of 5-HT receptors have been identied,
divided into seven classes (5-HT17), and at least 15
subpopulations have been cloned. The development
of specic agonists and antagonists of the different
5-HT receptors has made it possible to study the effect
of the stimulating single receptor subtypes. A remark-
able nding is that the stimulation of different 5-HT
subtypes can have the opposite effect on sexual
behavior. For example, 5-HT1A receptors are thought
to facilitate sexual behavior. The 5-HT1A agonist
8-hydroxyphenylpiperazine (8-OH-DPAT, which crosses
the bloodbrain barrier) produces a dramatic facili-
tation of the male rat ejaculatory behavior, evidenced
by a decrease in the number of intromissions preceding
ejaculation (Fig. 1.5)
28
The facilitation of sexual
behavior by 8-OH-DPAT injected systemically has
been explained by a preferential effect on 5-HT1A
autoreceptors present on serotoninergic neurons
within the raphe nuclei. It is assumed that stimulation
of 5-HT1A receptors on serotoninergic neurons leads
to an overall decrease in 5-HT transmission in the
nervous system, as injection of 8-OH-DPAT in the
median raphe decreased limbic forebrain 5-HTP
accumulation and facilitated male sexual behavior.
29,30
In conflict with these data, 8-OH-DPAT displayed the
same facilitatory effect when injected in animals
pretreated with p-CPA or pretreated with intra-
cerebroventricular or intraraphe administration of the
serotonergic neurotoxin, 5,7-dihydroxytryptamine
(5,7-DHT) in rats in which an effect on autoreceptor
would be unexpected, as they lost the ability to release
5-HT.
31
Furthermore, the effects of 8-OH-DPAT might
not be restricted to 5-HT1A receptors, as 8-OH-DPAT
injected into the MPOA produced a facilitation of male
rat sexual behavior, which was antagonized by the con-
comitant injection of the D2 antagonist raclopride.
32
Thus, direct action of 8-OH-DPAT at D2 receptors
could explain some of its effect, although dopamine
release might be an indirect consequence of stimu-
lation of 5-HT1A receptors.
In contrast to the 5-HT1A receptor, the 5-HT1B
receptor is thought to be inhibitory on ejaculatory
behavior. The increased ejaculation latency produced
by 5-HTP was fully antagonized by treatment with the
5-HT1B receptor antagonist isamoltane.
33
In addition,
whereas the 5-HT1A antagonist WAY-100635 fully
reversed the facilitatory effect of 8-OH-DPAT on ejacu-
latory behavior, WAY-100635 enhanced the 5-HTP-
induced inhibition of ejaculatory behavior, supposedly
by indirectly reinforcing the inhibitory effect of 5-HT1B
stimulation.
33
The effect of 5-HT2C receptor stimulation on penile
erection is another example of the versatile effect of
5-HT agonists. Systemic delivery of m-chlorophenyl
piperazine (mCPP) induced penile erections in
conscious rats, and the use of selective 5-HT2 receptor
agonists and antagonists demonstrated that the pro-
erectile effect of mCPP was due to the selective acti-
vation of 5-HT2C receptors.
34
Double-labeling studies
showed that all neurons in the sacral parasympathetic
nucleus and the dorsal gray commissure of the L6S1
segments retrogradely labeled from the corpus caver-
nosum with a retrograde marker displayed 5-HT2C
receptor immunoreactivity.
35
It is commonly accepted
that 5-HT2C receptors are involved in the proerectile
effects of trazodone, an antidepressant with -
adrenoceptor, 5-HT receptor, and dopaminergic
blocking actions, on the basis that mCPP is one of its
metabolites. Nevertheless, trazodone induced penile
erection upon intracorporeal injection in monkeys,
but failed to do so when injected intravenously.
36
In addition, trazodone impaired in vitro corporeal
smooth-muscle contractions elicited by exogenous
norepinephrine (noradrenaline).
37
Therefore, it is
suggested that the proerectile effect of trazodone may
be of peripheral origin.
Local delivery of 5-HT agonists within the brain has
been little studied. The MPOA receives an important
serotoninergic innervation from the raphe nuclei.
Accordingly, local application of serotonin in the
MPOA increased mount latency,
38
which would be in
agreement with the overall inhibitory effect of 5-HT
on sexual behavior. The local application of 5-HT into
the nucleus accumbens was found to inhibit male rat
sexual behavior, as evidenced by an increase in number
of intromissions preceding ejaculation and in time
to ejaculation. Injections into other striatal areas,
including the DL, the ventromedial, and the posterior
neostriatum, as well as the olfactory tubercle, had no
effect. On the other hand, the application of 5-HT into
the dorsal or median raphe nucleus facilitated male rat
sexual behavior, as evidenced by a decrease in time to
ejaculation, and in number of intromissions preceding
ejaculation.
39
Such facilitation is likely due to stimu-
lation of inhibitory autoreceptors on the serotoninergic
neurons of the raphe nuclei, resulting in decreased
serotoninergic release at the previously mentioned
target sites (MPOA and nucleus accumbens).
The Aminergic Control of Sexual Behavior 9
Figure 1.5 Facilitation of
ejaculatory behavior with
8-hydroxyphenylpiperazine (8-OH
DPAT). The chemical structure
of the 5-HT1A agonist 8-OH DPAT
is given in A. Behavioral
experiments in rats (adapted
from
93
) have shown that 8-OH
DPAT signicantly increases the
time for the male to mount the
female for the rst time during a
copulation experiment, and
decreases the time necessary to
achieve ejaculation (B). The
reduction in ejaculation latency is
mainly due to a decrease in the
number of mounts necessary to
achieve ejaculation (C). In
contrast with these results,
obtained with a more or less
specic stimulation of 5-HT1A
receptor, clinical reports of
patients treated with fluoxetine
(A), a specic serotonin reuptake
inhibitor, demonstrated that
increasing serotonin level often
resulted in decreased libido and
delayed or anejaculation. These
apparent discrepancies illustrate
the complex role of the
serotoninergic system in the
control of sexual function.
*P<0.05, t-test.
1st ejaculation 1st mount
Saline
8-OH DPAT 0.4 mg/kg
*
*
L
a
t
e
n
c
y

(
s
)
0
1000
200
400
600
800
Number of intromissions
*
N
u
m
b
e
r
0
25
5
10
15
20
CH
3
F
3
C
O N
H
N
OH
A
B C
8-OH DPAT Fluoxetine
Norepinephrine (noradrenaline)
Basic anatomical data support an implication of the
noradrenergic system in the control of penile erection.
In rats, axons from neurons in the locus ceruleus (the
source of central norepinephrine) course anteriorly
through the medial forebrain bundle to innervate the
entire cerebral cortex and hippocampus. The more
ventrally located noradrenergic cell bodies send bers
that innervate the brainstem and hypothalamus. They
are also dense noradrenergic projections from these
nuclei to the spinal cord (Fig. 1.3B).
Using transsynaptic axonal transport from the corpus
cavernosum, it has been shown that sympathetic and
parasympathetic preganglionic neurons innervating
the penis are in close apposition with neural termi-
nations immunoreactive for
2
a and c adrenoreceptor
subtypes in rats.
40
Apposition between dopamine
-hydroxylase immunoreactive bers (DBH, the
enzyme transforming dopamine to norepinephrine,
thus characterizing noradrenergic neurons in the CNS)
and neurons retrogradely labeled from the major
pelvic ganglion (the source for postganglionic bers
for pelvic viscera, including the penis) has also been
demonstrated.
41
Retrograde axonal transport com-
bined with DBH-immunohistochemistry demonstrated
specic DBH-positive innervation of the motoneurons
of the bulbospongiosus and ischiocavernosus muscles.
These precise anatomical data support a direct modu-
lation of the proerectile neurons in the SPN by
norepinephrine.
There is evidence that epinephrine (adrenaline) and
norepinephrine can exert an antierectile activity at the
peripheral level by acting on
1
-adrenoceptors.
42
A role
for
1
-adrenoceptors on sexual behavior at the CNS
level was also suggested from animal experiments, in
which the
1
-antagonist prazosin increased latencies to
initiation of copulation, to ejaculation, and to reinstate-
ment of copulation following ejaculation.
43
This can be
related to the presence of
1
and adrenoceptors in
the MPOA and PVN, two nuclei involved in the control
of penile erection. Nevertheless, no signicant central
effects on sexual behavior were reported following the
clinical use of
1
-blocking agents for the treatment of
hypertension or benign prostate hyperplasia.
In contrast to
1
-adrenoceptors, there is likely a
central involvement of
2
-adrenoceptors in the control
of sexual behavior. In mating tests, the centrally acting
2
-agonist clonidine induced a profound decit in intro-
missive and ejaculatory behavior.
43
In contrast, a polar
analog of clonidine, which does not readily enter the
CNS, had no effect on male sexual behavior. Con-
versely, yohimbine, an
2
-antagonist with serotonergic
activity, which has long been used as an aphrodisiac
in humans (for review, see
44
) was shown to stimulate
sexual motivation in male rats. Similar facilitating
effects on sexual behavior were obtained with other
2
-antagonists, idazoxan and imiloxan. The central
origin of the prosexual effect of yohimbine was best
demonstrated by Sala and coworkers, who showed that
the most efcient dose delivered within the cerebral
ventricles facilitating sexual behavior was more than
one order of magnitude lower than the most efcient
dose delivered intraperitoneally.
45
It is noteworthy that
immunoreactivity associated with both
2
a and c
adrenoceptors was widely distributed within the brain,
including the hypothalamic nuclei involved in the
control of penile erections. The more selective
2
-
antagonist delequamine also increased sexual behavior
in mating experiments in a dose-related manner (for
example, it increased the percentage of naive male
rats intromitting and ejaculating), but, in contrast to
yohimbine, it did not decrease ejaculation latency.
Indeed, a combination of delequamine and 8-OH-
DPAT reproduced the effect of yohimbine, suggesting
that yohimbine also acts as a 5-HT1A receptor
agonist.
46
Although two metaanalyses concluded that yohim-
bine was superior to placebo in the treatment of erec-
tile dysfunction, yohimbine is much less efcient as a
proerectile drug in humans than in rats.
47
The exact
mechanism by which yohimbine can increase sexual
motivation is unknown at this time. It has been
postulated that such an
2
-antagonist would overall
increase noradrenergic transmission, which would
result in increased arousal. In a relevant context, this
would favor sexual arousal. An implication of central
-adrenoceptors in the antierectile role of -blockers
cannot be ruled out. For example, the mixed
1
- and
2
-adrenergic antagonists propranolol and pindolol
profoundly reduced ejaculatory behavior and other
parameters of sexual behavior in rats.
48
Dopamine
The prosexual effect of dopamine in humans was rst
suggested by the observation of increased sexual
activity in Parkinsons patients treated with dopamine
agonists.
49
Since then, double-blind placebo-controlled
studies have shown that 24 mg doses of apomorphine
delivered sublingually could increase the likelihood of
penile erections in men with erectile dysfunction.
50
It
is noteworthy that, whereas in rats, apomorphine is a
strong inducer of penile erection, it has only a facili-
tatory effect in humans, so that a sexually relevant
context is necessary to increase the likelihood of penile
erection occurring. Projections of dopaminergic nuclei
in the rat brain are represented in Figure 1.3B.
Nucleus accumbens
In mating experiments, injections of apomorphine in
the nucleus accumbens decreased the latency to begin
copulating, whereas injections of apomorphine in the
striatum had no effect. Conversely, injections of apo-
morphine in the ventral tegmental area increased intro-
mission latency, likely by inhibiting the mesolimbic
dopamine pathway by stimulating autoreceptors, and
thus decreasing dopamine transmission at the level of
the nucleus accumbens (Fig. 1.3B).
16
Specic tests have been developed to discriminate
appetitive from consummatory components of sexual
behavior, such as the bilevel chambers test. In this test,
the male rat chases the female from one level to
another after each intromission. The number of level
changes in a xed time before the introduction of the
female is considered a measure of the anticipatory
phase (or motivation) of sexual activity. Such tests
proved that dopamine plays a role in the anticipatory
or appetitive phase of the sexual behavior in male rats,
as bilateral infusions of haloperidol into the nucleus
accumbens reduced the number of level changes (or
appetitive phase) but did not affect consummatory
measures of copulation.
16
Extracellular dopamine increased in the nucleus
accumbens when an estrous female was presented
behind a barrier, as well as during copulation, support-
ing the hypothesis that dopamine plays a positive role
in the anticipatory phase in male rats at the level of
the nucleus accumbens in physiological conditions.
51
Control experiments indicate that neither novelty nor
locomotor activity can account for the increased extra-
cellular dopamine concentrations observed in the
nucleus accumbens of male rats during the presentation
of a sexually receptive female and during copulation.
Moreover, exposure to a non-estrous female did not
elicit dopamine release in the nucleus accumbens in
male rat.
Median preoptic area
The MPOA receives dopaminergic innervation from
the incertohypothalamic pathway, originating from the
A13 cell group, and from the periventricular A14 cell
group. In mating experiments, injection of apomorphine
in the MPOA displayed clear prosexual effects. Injec-
tions of dopamine antagonist (cis-flupentixol) had the
opposite effect (increased intromission and ejaculation
latency, decreased number of rats that copulate and
ejaculate) and prevented the effects of apomorphine
injected in this area.
52
In the bilevel-chamber paradigm,
infusion of haloperidol in the MPOA reproduced all
the effects of its systemic administration, i.e., decrease
of the anticipatory/preparatory and consummatory
phase of copulatory behavior.
16
The stimulatory role of
dopamine in the MPOA in physiological conditions
has been conrmed, as dopamine and 3,4-
dihydroxyphenylacetic acid (DOPAC) were shown
to be increased during the precopulatory phase and
during copulation, and declined after ejaculation.
53
Hull and coworkers reported a consistent relationship
between precopulatory dopamine release in the MPOA
and the ability to copulate subsequently.
54
Further-
more, microinjections of a dopamine agonist into the
MPOA of animals with lesions of the amygdala restored
the copulatory behavior affected by the lesions.
55
Paraventricular nucleus of the
hypothalamus
Injection of doses of apomorphine as low as 5 ng in the
PVN can induce penile erections in a freely moving rat
without the presence of a female. Similar responses are
obtained when the selective D2-like agonist LY171555
is injected in place of apomorphine, but not with the
D1-like agonist SKF38393. Erections induced by
apomorphine injections in the PVN are abolished by
systemic pretreatment with the central D1-like antag-
onist, SCH23390, and D2 antagonist, sulpiride.
56
In
anesthetized rats (Fig. 1.6), penile erections induced by
peripheral delivery of apomorphine are antagonized
by a preceding injection in the PVN of SCH23390
or sulpiride.
57
It is noteworthy that apomorphine
injection in other hypothalamic structures, such as the
ventromedial and DM nucleus, the preoptic area, or the
nucleus accumbens, did not induce penile erection.
56
Conversely, lesions of the PVN strongly reduced the
proerectile activity induced by apomorphine in male
rats.
58
Those experiments therefore strongly suggest
that activation of dopaminergic receptor in the PVN are
responsible for the proerectile effect of apomorphine.
Nevertheless, dopamine is not the sole neurotrans-
mitter exogenously applied which is able to activate
proerectile neurons: injection of glutamate receptor
agonists as well as oxytocin in the PVN was also
shown to induce penile erection in anesthetized rats.
Altogether, activation of neurons in the PVN can be
considered as a sine qua non condition for the pro-
erectile effect of apomorphine to occur. According to
the available data, it cannot be determined whether
this effect is mediated by either dopamine D1-like and
D2-like receptors, or both. The measurement of some
dopamine release within the PVN concomitant to
penile erection during copulation would be a denite
argument for the physiological implication of dopamine
in the PVN in the induction of penile erection but, to
our knowledge, it has not yet been performed before,
during, or after copulation.
Spinal cord
It has recently been demonstrated that apomorphine
delivered at the lumbosacral level with an intrathecal
catheter, or systemically in spinalized animals, elicited
erectile activity in anesthetized rats.
59
The proerectile
activity of apomorphine was also shown to be con-
served in conscious spinalized rats.
60
These results
suggest that there may be a dopamine spinal component
The Aminergic Control of Sexual Behavior 11
in the control of penile erection. Accordingly, there
are dopamine projections from the A11 cell group to
the spinal cord as well as an intrinsic dopamine
innervation within the spinal cord.
61
Immunocyto-
chemical studies revealed that dopamine bers and
terminals exist in virtually all laminae throughout the
spinal cord.
62
Furthermore, studies using ligand-
binding techniques have shown the presence of D1
and D2 receptors in the spinal cord.
63
In male rats, D2
receptors identied with immunochemistry and in situ
hybridization have been located in the parasympathetic
nucleus of the lumbosacral spinal cord, which contains
the cellular bodies of the proerectile autonomic
neurons innervating the penis. D2 receptors have also
been found to be particularly abundant in the DM and
DL nucleus, which innervate the bulbospongiosus and
ischiocavernosus striated muscles involved in penile
rigidity in the rat.
64
OTHER NEUROTRANSMITTERS
INVOLVED IN THE CONTROL OF
SEXUAL BEHAVIOR
Nitric oxide
NO has been involved as an important proerectile
messenger in the CNS, and especially within the PVN.
An increase in NO production in the paraventricular
nucleus of the hypothalamus seems to be the primary
condition for the proerectile effect of apomorphine, n-
methyl aspartic acid and oxytocin, centrally delivered.
Dopaminergic agonists crossing the bloodbrain
barrier injected systemically induced penile erection
and increased the reaction products of NO with O
2
,
NO
2
and NO
3
measured in the dialysate collected

from the PVN.
65
Conversely, systemic pretreatment
with haloperidol or sulpiride (D2-like antagonists)
prevented a PVN increase in NO
2
-
and penile erection
induced by systemic apomorphine.
65
The excitatory
amino acid N-methyl-D-aspartic acid (NMDA) injected
in the PVN induced penile erection and an increase in
NO
2
and NO
3
in dialysate obtained at this site.

66
Morphine injected before NMDA inhibited both the
increase in NO
2
and NO
3
and penile erection. N

G
-
nitro-L-arginine methyl ester (L-NAME, a competitive
inhibitor of NO synthase), injected in the PVN prior to
apomorphine, NMDA, or oxytocin, prevented their
proerectile activity. Accordingly, NO donors delivered
in the PVN induce penile erection in both conscious
and anesthetized rats.
67
In support of a physiological role for NO within the
PVN in sexual behavior, signicant increases in NO
2
and NO
3
were observed in dialysate obtained from

the PVN of copulating rats or rats displaying non-
contact penile erection.
68
Injection of L-NAME (20 g)
in the PVN abolished NCEs and dramatically increased
mount, intromission, and ejaculation latencies.
68
Altogether, these results support a role for NO in the
control of penile erection within the PVN. However,
the importance of the PVN/NO pathway in the control
of penile erection should not be overestimated. Again,
radiofrequency lesions of the PVN did not reduce the
incidence of NCEs compared to sham-operation. In
copulation tests, radiofrequency lesions of the PVN
had an overall inhibitory effect but did not prevent
male rat from copulating to ejaculation.
19
Time (s)
P
r
e
s
s
u
r
e

(
m
m
H
g
)
0
0 600 1200 1800
120
A B
30
60
90
Figure 1.6 Illustration of the proerectile activity of apomorphine. Rats were anesthetized with urethane and blood
pressure (upper line) and intracavernous pressure (ICP: lower line) were continuously measured during the experiment.
The rat was mounted on a stereotaxic frame to perform injection of 0.5 g apomorphine in the paraventricular nucleus of
the hypothalamus (in red in B). Time of injection is indicated by the arrow in abscissa. Note the occurrence of a transient
rise in ICP (arrows) soon after the injection of apomorphine, which corresponds to erectile events. Such increases in ICP
were not observed after injection of the corresponding vehicle.
Oxytocin
Penile erections induced by NO delivery in the PVN
were antagonized by intracerebroventricular delivery
of an oxytocin antagonist, whereas the delivery of
the same antagonist in the PVN was without effect.
67
This is also true for penile erections induced by apo-
morphine or NMDA delivered in the PVN. The PVN
contains the majority of the oxytocinergic neurons
projecting to the extrahypothalamic area, and notably
the septum and hippocampus. Oxytocin induces penile
erection when bilaterally injected in the CA1 eld of
the hippocampus
69
and electrolytic lesion of the medial
septum were shown to prevent erections induced by
apomorphine injection in the PVN, but not erections
induced by oxytocin delivered intracerebro-
ventricularly.
70
Therefore, penile erections could be
generated by activation of oxytocinergic neurons
projecting to extrahypothalamic areas.
The existence of a descending oxytocinergic pathway
from the PVN to the lumbosacral spinal cord has long
been known. Oxytocinergic synapses on preganglionic
parasympathetic neurons projecting to the corpus
cavernosum have been demonstrated and oxytocin
delivered at the lumbosacral level has been shown to
be a powerful inducer of penile erection in anesthetized
rats.
71
Despite the spectacular proerectile effect of
oxytocin delivered intrathecally, the physiological
importance of the oxytocinergic paraventriculospinal
pathway may be relative, again because PVN destruc-
tion only slightly impaired copulations in rats.
ACTH and MSH
The ability of adrenocorticotropin (ACTH) and -
melanocyte-stimulating hormone (-MSH) to cause
sexual excitation has been established in different
species, such as monkeys, rabbits, and rats. Both
peptides are derived from a common precursor,
proopiomelanocortin, which is expressed in the
pituitary, in the arcuate nucleus of the hypothalamus
and the commissural nucleus of the brainstem. -MSH
is constituted by the rst 13 amino acids of ACTH; it
is N-acetylated and C-amidated, and consequently,
resistant to most peptidases.
In a number of reports, intracerebroventricular
injections of ACTH (124) in the range of 110 g
were shown to induce penile erection and yawning
(see, for example,
72
). -MSH displayed similar potency.
ACTH-induced penile erection recruits a circuit
independent of the one used by oxytocin and apo-
morphine. Intracerebroventricular injection of an
oxytocin antagonist can prevent the erectile activity
induced by systemic apomorphine or intracerebro-
ventricular oxytocin, but cannot prevent the erectile
activity induced by ACTH (124).
73
Moreover, destruc-
tion of the PVN does not affect the erectile activity
induced by intracerebroventricular ACTH (124).
However, a common point in these three drugs is the
participation of NO in their proerectile effect, as penile
erections induced by ACTH (124) were prevented
by pretreatment with the NO synthase inhibitor
L-NAME.
74
In situ hybridization demonstrated the presence of
two different melanocortin receptors (MCRs) in the
brain, MC3R and MC4R receptors. Expression of the
MC3R mRNA is restricted to regions in the hypo-
thalamus and limbic system, whereas the MC4R mRNA
was found in virtually every brain region, including the
cortex, thalamus, hypothalamus, and brainstem, and
also in the spinal cord. The sites of injection within the
brain for -MSH to induce penile erection were the
PVN, the DM nucleus, the ventromedial nucleus,
and the anterior hypothalamic area. However, the
involvement of the PVN in mediating the proerectile
effect of ACTH is unlikely, as PVN lesions prevent the
yawning and penile erection induced by apomorphine
(or oxytocin), but not by ACTH (124).
58
In contrast,
hypophysectomy prevented ACTH-induced and
apomorphine-induced penile erection in rats, although
the specicity of such operations should be
determined.
72
Using the selective MC4R receptor antagonist HS104,
it has been suggested that grooming, stretching, and
yawning induced by ACTH and -MSH were mediated
by MC4R, whereas penile erection was not.
75
The use
of other selective MCR antagonists will be required
to quantify precisely this crucial issue. However, a
specic MC4R agonist was shown to facilitate sexual
behavior and enhance penile erection induced by
electrical stimulation of the cavernous nerve in mice.
76
Melanotan II is an -MSH analog which underwent
clinical trials for the treatment of erectile dysfunction.
Preliminary double-blind, placebo-controlled studies
demonstrated the efcacy of melanotan in inducing
penile erection in men with erectile dysfunction,
although in a very restricted population (Fig. 1.7).
77
Unfortunately, there are no experimental data on the
mode of action of melanotan II, as melanotan II is
the rst -MSH agonist inducing penile erection when
injected peripherally.
THE INFLUENCE OF ANDROGENS
Adult sexual function and testosterone
Castration results in a decrease in male sexual activity
in all species studied so far. In rats, castration leads to
failure to achieve ejaculation, followed by a loss of
mounts with intromission, with the animal eventually
ceasing to mount the female.
18
Castration also decreased
penile reflexes, revealed by elevated response latency
The Influence of Androgens 13
and eventually decreased number of erections.
78
Thus,
androgens influence not only sexual motivation, but
also the general integrity of the circuitry involved in
the control of penile erection in male rats. The situation
is not as clear-cut in humans. Indeed, there are no clear
correlations between testosterone level and erectile
function.
79
Although castration is often accompanied
by impotence in men, some men reported sexual
intercourse for up to 20 years after castration.
80
On the
other hand, not all hypogonodal men undergo resto-
ration of erection after androgen supplementation.
81
One explanation may be that very small amounts of
androgen, such as that made by the adrenal gland, may
be sufcient to preserve some erectile function.
Several studies have demonstrated a signicant
improvement in sexual behavior (i.e., spontaneous
erections, nocturnal penile tumescence, sexual thoughts,
and frequency of masturbation or intercourse) in
hypogonadal men treated with testosterone.
82
In fact,
it seems that, whereas sleep erections were signi-
cantly improved by androgen replacement in hypo-
gonodal men, erections when watching erotic lms
were not.
83
Central effect of androgens
In animals, the effects of castration on sexual behavior
are reliably reversed by supplementation with testos-
terone (see
18
for review). Within the CNS in rats,
testosterone is enzymatically converted into the non-
aromatizable androgen dihydrotestosterone by 5a
reduction and into estradiol by aromatization
84
(Fig.
1.8). In rats, numerous studies have demonstrated that
the conversion of testosterone to estradiol is necessary
for the effects of testosterone on sexual behavior.
For example, the non-aromatizable androgen dihydro-
testosterone was ineffective in restoring copulation in
castrated rats and other species, whereas estradiol
effectively maintains or restores copulation (at least in
castrated male rats).
18
On the other hand, it was
demonstrated that penile reflex restoration in rats
required dihydrotestosterone, whereas estradiol was
ineffective.
85
As mentioned earlier, testosterone
treatment reliably improves some aspects of sexual
behavior in hypogonadal men, the most consistent of
which is libido. In contrast, there has been no demon-
stration yet supporting a role for the production of
the reductive pathway or conversion to estradiol in
the sexual effects of androgens in humans. Steroids
resistant to reductase activity were as effective as
testosterone in hypogonadal men.
86
Non-aromatizable
androgens may be less effective than testosterone, but
some data on dihydrotestosterone suggest that the
conversion of testosterone to estrogen is not necessary
for the central sexual effect of testosterone in
humans.
87
Androgen-binding sites are expressed in discrete
nuclei within the brain. Autoradiographic studies of
testosterone-binding sites demonstrated considerable
labeling in the MPOA, BST, medial and cortical
amygdala.
88
Many nuclei within the hypothalamus were
found to be heavily labeled, such as the ventromedial
nucleus, arcuate nucleus, and ventral premammillary
nucleus. The ability of testosterone delivered within
5
A
15
5
B
15
5
C
15
0
100
0
100
0
100
5
15
5
15
5
15
0
100
0
100
0
100
Figure 1.7 Illustration of the proerectile effect of melanotan II (MT-II) in humans. Placebo (A) or MT-II (B, 25 g/kg and C,
133 g/kg) was injected subcutaneously in patients and RigiScan recording was performed from 6 h. Apparent erections
developed in 8 of 10 men treated with MT-II. (Reproduced with permission from Wessells H et al. Effect of an alpha-
melanocyte stimulating hormone analog on penile erection and sexual desire in men with organic erectile dysfunction.
Urology 2000; 56:641646.)
the brain to impact sexual behavior at doses too low to
display a peripheral effect was demonstrated in male
rats. The MPOA and the anterior hypothalamus were
the most effective sites for testosterone implants to
restore sexual behavior in male rats.
89
There is evidence
that androgens influence aminergic systems controlling
sexual behavior. Using castrated rats supplemented
with testosterone propionate or vehicle at different
time postoperation, Hull and colleagues have shown
that there was a correlation between dopamine release
in the MPOA during the precopulatory phase and the
ability to copulate subsequently.
54
Further investi-
gations showed that the extracellular concentration
of dopamine was profoundly decreased in castrated
males in the MPOA.
90
NO was proposed to be the link
between testosterone withdrawal and decreased
dopamine level in the MPOA on the basis that (1) NO
synthesis inhibitor, administered through a dialysis
probe, prevented the increase of dopamine in the
MPOA seen in controls during copulation;
91
and (2)
long-term, but not short-term, castration signicantly
decreased the number of brain NO synthase immuno-
reactive neurons in the MPOA.
90
Thus, one consequence
of androgen would be to facilitate dopamine release at
the level of the MPOA by upregulating NO synthase
activity.
Androgens also likely to interfere with the
serotoninergic system. Castration of male rats signi-
cantly reduced the density of 5-HT2A binding sites in
the frontal cortex, olfactory tubercle, and nucleus
accumbens.
92
Accordingly, it reduced the expression of
5-HT2A mRNA (measured by in situ hybridization
with a
35
S-labeled riboprobe) in the dorsal raphe.
Castration also reduced the number of cells expressing
the 5-HT transporter mRNA in the dorsal raphe
nucleus and the number of 5-HT transporter binding
sites in higher centers of the brain. Treatment with
testosterone or estradiol benzoate but not dihydro-
testosterone restores the density of binding sites or
labeling of cells to control level. The causal relation-
ship, if any, between these changes in serotoninergic
transmission and sexual behavior is not clear. However,
these results demonstrate the ability of testosterone,
after conversion to estradiol, to modify aminergic
transmission in regions involved in cognition, mood,
and mental state, i.e., with psychological parameters
able to influence sexual behavior.
CONCLUSIONS
Penile erection results from the activation of auto-
nomic spinal nuclei by descending projections from
the brain. Several brain nuclei participating in the
control of penile erection have been identied in the
limbic system. Nuclei in the brainstem also participate
in the control of penile erection. At this time, there is
no specic structure known to be devoted to penile
erection. Clinical and experimental data have showed
that manipulations of the aminergic system can impact
positively or negatively on sexual function. This led to
the use of apomorphine as a proerectile agent and
SSRIs for the treatment of rapid ejaculation. Results of
further clinical trials with melanocortin agonists are
expected in the near future.
H
O
O
Testosterone
5-Dihydrotestosterone
17-Estradiol
H
O
O
H
H
O
HO
Figure 1.8 Metabolization of
testosterone within the brain.
Testosterone can be
metabolized in brain cells as
5-dihydrotestosterone by
5-reductase. Aromatization
converts testosterone into
estradiol. 5-dihydrotestosterone
and 17-estradiol differentially
affect sexual behavior. Male rat
sexual behavior is facilitated by
estradiol, and testosterone
facilitation of male rat sexual
behavior can be blocked by
steroidal inhibitors of
aromatization. Not all mammals
display this exclusive sensitivity to
estradiol. Male sexual behavior of
guinea pig and rhesus monkey is
restored by the non-aromatizable
androgens androstenedione and
dihydrotestosterone.
Conclusions 15
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88. Sar M, Stumpf WE. Autoradiographic localization of
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89. Kierniesky NC, Gerall AA. Effects of testosterone
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62:881891.
INTRODUCTION
Erectile dysfunction (ED) was rst described by the
Egyptians about 2000 BC. While Hippocrates also
described many cases of male impotence, it was da
Vinci who in the early sixteenth century rst noted the
role of blood in the creation of male erection. His
writings, however, were kept secret, and it was not
until 1585 that Ambroise Par gave the rst accurate
description of penile anatomy and erection.
Currently, according to the National Institutes of
Health consensus development panel of impotence,
1
ED is dened as the persistent inability to attain and/or
maintain penile erection sufcient to permit statis-
factory sexual intercourse. Perhaps the key phrase in
this denition is the term satisfactory; by denition,
ED must cause at least some degree of personal distress
to either the patient himself or to the couple before
medical therapy is indicated. In other words, ED is at
least to some degree a subjective condition.
This chapter will review the epidemiology and patho-
physiology of ED. Since sexual function and sexual
problems have only recently been discussed openly in
most societies and cultures, few epidemiologic data
exist until the middle of the twentieth century. Recent
studies, however, have given us a more accurate picture
of the prevalence and incidence of ED. Similarly, most
of the current understanding of the pathophysiology of
ED was not developed until the 1980s and 1990s. The
changes in the smooth muscle, endothelium, and bro-
elastic tissues of the penis associated with aging,
diabetes, and atherosclerosis that produce ED are
discussed in detail in this chapter.
EPIDEMIOLOGY
Prevalence
Epidemiological studies on the prevalence of ED have
demonstrated a clear association between aging and
impotence.
2
The largest population-based study of
normative data on male sexual behavior was published
by Kinsey and coworkers in 1948.
3
They estimated that
only 2% of men had ED at age 40 years, but this gure
increased to 25% by age 65 and 75% in men over the
age of 80. Diokno and associates
4
also documented
that the prevalence of ED increased with age. In their
study of 296 marrried men older than 60, they found
that the incidence of impotence increased from 29%
between the ages of 60 and 64 to 64% in men over the
age of 80.
One of the most important epidemiological studies
on ED is the Massachussetts Male Aging Study
(MMAS),
5
in which 1709 men between the ages of 40
and 70 were rst surveyed between 1987 and 1989 and
then again between 1995 and 1997. This evaluation
included a private self-administered questionnaire on
sexual function and activity, and represents the rst
multidisciplinary, community-based, random-sample
epidemiologic survey on ED and its psychosocial cor-
relates in the USA. Overall, the mean probability of
some degree of ED was 52%. From age 40 to 70, the
probability of complete ED nearly tripled, from 5.1%
to 15%, while the probability of moderate ED doubled,
from 17% to 34%.The likelihood of mild ED remained
constant throughout the study, at 17%. In the MMAS,
age proved to be the most powerful predictor of impo-
tence; whenever age was tested by multivariate linear
regression or multivariate analysis of variance in con-
junction with another risk factor for ED, it invariably
proved to be statistically signicant at P < 0.0001.
Other studies yield similar results. Another more
recent population-based study conrmed the ndings
of the MMAS. Blanker and associates
6
showed that the
likelihood of severe ED increased from 3% in men
aged 5054 years old to 26% in men aged 7078. In
addition, the percentage of men who reported being
sexually active declined signicantly with increased
age. In one Swedish study, Malmsten and associates
7
demonsrated a clear decrease in sexual activity with
increasing age. While 76.1% of men 45 years of age
were sexually active, only 16.7% of men aged 80 years
were. Finally, in Solstad and Hertofts study
8
of 411
men responding to a questionnaire and 100 men who
were subsequently interviewed by a professional, about
40% of men suffered from some degree of ED.
In addition, newer data estimate the prevalence of
sexual dysfunction in both men and women. Lauman
and coworkers
9
noted that sexual dysfunction is actually
more prevalent for women (43%) than men (31%), and
is associated with various demographic characteristics,
Pathophysiology of Male Erectile Dysfunction
Dominick J. Carbone and Allen D. Seftel
CHAPTER 2
including age and marital status. For example, among
men, the oldest cohort (age 5059 years) was more
than three times as likely to experience erection
problems, while among women, non-married females
were roughly 1.5 times as likely to have climax pro-
blems and sexual anxiety. In addition, high educational
attainment was negatively associated with experience
of sexual problems for both men and women, and the
disparity was particularly profound among women.
After controlling for other demographic characteristics,
women who graduated from college in the study were
approximately half as likely to experience low sexual
desire, problems achieving orgasm, sexual pain, and
sexual anxiety as women who had not graduated from
high school.
Incidence
Johannes
10
recent follow-up to the MMAS has allowed
for the rst estimation of the incidence of ED in the
USA. One subgroup of the study included 847 men who
had not had ED at baseline (19871989) who were
available for follow-up in 19951997. From this group
of patients, the incidence rate of impotence in white
males in the USA was found to be 25.9 cases/1000
person-years. As expected, the annual incidence rates
increased with each decade of age: 12.4 cases/1000
person-years for men aged 4049; 29.8 cases/1000
person-years for men aged 5059; and 46.4 cases/
1000 person-years for men aged 6069.
Diabetes, treated heart disease, and treated hyper-
tension all increased the risk of ED. For diabetes, the
risk increased to 50.7 cases/100 person-years; for treated
heart disease, the risk increased to 58.3 cases/1000
person-years; and for treated hypertension, the risk
increased to 42.5 cases/1000 person-years. By extra-
polating these data to the known population of the
USA, Lewis et al.
11
estimated that the incidence of
new cases of ED in white men age 4069 years old
would be 617 715 per year.
The clear nding from a review of the epidemiologic
data, then, is an obvious link between impotence and
aging.The importance of this trend is further heightened
by the fact that the US population is aging. Current
conservative estimates suggest that, by the year 2030,
20% of the population will be over the age of 65;
due to changes in life expectancy, this number rises
inexorably upward. Review of the epidemiologic data
shows that a clear understanding of the pathophysiolgy
of ED will be critical to the well-being of an aging
population.
PATHOPHYSIOLOGY
Recently, with the advent of effective oral therapy for
the treatment of ED, patients with impotence have
frequently been treated without any regard for their
underlying pathophysiology. Indeed, some observers
suggest that men with ED do not require evaluation for
any underlying pathophysiology, and that the patient
may proceed directly to treatment with any work-up.
Unfortunately, as the ensuing discussion demonstrates,
men with ED frequently have complex disease processes
that can affect them systemically, and therefore a
thorough understanding of the underlying patho-
physiologic mechanism of ED is essential. ED can in
fact be a harbinger of signicant systemic illness.
Overview of erectile function
Although a thorough discussion of normal penile
physiology is included elsewhere in the text, a brief
review of normal physiology is useful before moving
to a detailed discussion of pathophysiology. In essence,
penile erection is a neurologic and hemodynamic event
under psychological control.
Three types of erection exist: central, reflexogenic,
and nocturnal. In central erections, the initial stimulus
begins in the supraspinal centers, travels through the
spinal cord, and then reaches the corpora cavernosa
by traveling along the cavernous nerves. Terminal
branches of the cavernous nerves release a variety of
neurotrasmitters that are involved in initiating the
erectile process. In addition, the endothelial lining
cells of the cavernosal sinusoids also release active
mediators. Specically, nitric oxide (NO), vasoactive
intestinal peptide (VIP), acetylcholine, and a number
of prostaglandins (PGs) are considered to be the most
important erectogenic neurotransmitters. Relaxation
of the intracavernosal sinusoids allows blood to enter
the corpora cavernosa, with resultant compression of
the subtunical and emissary veins, resulting in rigidity.
With ejaculation and orgasm, norepinephrine (nor-
adrenaline) released by neural adrenergic bers in the
corpora cavernosa mediates smooth-muscle contrac-
tion and subsequent penile detumesence.
A similar cascade of events is noted in reflexogenic
erections, but in this case the triggering event is
mechanical stimulation of the dorsal nerve of the
penis, which in turn sends signals to the lumbosacral
cord. Here, synapses with parasympathetic bers
traveling back to the corpora cavernosa take place.
Reflexogenic pathways play an important role in sexual
intercourse, since the continuous stimulation of the
penis that naturally occurs during intercourse will
maintain the activation of the descending neural path-
ways to the corpora cavernosa.
Nocturnal erections occur during rapid eye movement
(REM) sleep from the time of intrauterine life, but they
are poorly understood. However, it is postulated that
these erections represent a spontaneous mechanism
for delivering blood to the penis and thus oxygenating
20 Pathophysiology of Male Erectile Dysfunction
the corpora, thus maintaining the viability of caver-
nosal tissue, which is exquisitely sensitive to changes
in oxygen tension. As Montorsi et al. have suggested,
17
this type of erection may be at risk for deterioration
in the aging male, thus contributing to the increased
incidence of ED in this population.
Classication
Many classication systems of the various etiologies
of ED have been proposed. One of the most useful is
the classication recommended by the International
Society of Impotence Research.
11
Broadly, ED may be categorized as either organic
or psychogenic. Until recently, it was assumed that
psychogenic impotence was by far the most common
type; we know now that most men with ED have
a mixed condition with at least some degree of
organic dysfunction. Lues functional classication of
impotence
12
highlights the overlapping nature of many
of the causes of impotence and shows that it is
uncommon for a given patients ED to derive strictly
from one source.
In this chapter, rst consideration will be given to the
the major organic pathophysiologies vasculogenic,
endocrinologic, and neurogenic. Next, ED associated
with therapeutic drugs and systemic disease will be sum-
marized. Finally, psychogenic ED will be considered.
Vasculogenic
Arteriogenic
The classic arterial supply of the cavernous bodies of
the penis begins with the internal iliac arteries, then
runs via the pudendal artery to the branching of the
penile arteries, the dorsal and cavernous arteries. This
classic arterial supply will vary considerably in indi-
vidual patients.
In men with arteriogenic ED, reduced penile
perfusion impairs flow to the cavernous tissue and the
sinusoidal spaces. This deciency in turn decreases
rigidity of the erect penis while increasing time to
maximal erection. Most men with arteriogenic ED
suffer from generalized atherosclerotic disease, although
trauma to the cavernous arteries may also result in
arteriogenic ED, particularly in younger patients.
The link between atherosclerotic disease and
arteriogenic ED is clear from a consideration of the
literature. As early as 1980, Michal and Ruzbarsky
14
showed that the incidence and age at onset of coronary
disease and ED are parallel. Arteriography has demon-
strated diffuse bilateral disease of the internal pudendal,
common penile, and cavernous arteries in impotent
men with atherosclerosis, and Shabsigh et al.
15
have
shown that abnormal penile vascular ndings increased
along with the number of risk factors for ED. Egashira
and coworkers
16
have specically linked atherosclerosis
of the pudendal and cavernosal arteries to ED. Finally,
Montorsi et al.
17
have shown that the severity of ED
correlates with the severity of coronary artery occlusive
disease on coronary angiography.
Others have theorized that, since impaired caver-
nosal blood flow secondary to arteriogenic disease
reduces intracavernosal blood pO
2,
arteriogenic disease
may also be injurious to the cavernosal tissue itself,
ultimately causing corporeal brosis, impairing penile
NO synthase activity, and resulting in a vicious circle
that exacerbates impotence.
In an animal model, Nehra and associates
18
showed
that hypoxia-induced overexpression of transforming
growth factor (TGF-1), a pleotrophic cytokine,
decreased the smooth muscle to connective tissue ratio
by inducing the expression of collagen, bronectin,
and proteoglycans, while inhibiting the growth of
smooth-muscle cells and the activity of collagenase.
This cavernosal expandability correlated with smooth-
muscle content and could be used to predict trabecular
histology. In addition, impaired cavernosal oxygen
tension resulting from arteriogenic disease may affect
prostanoid production in the corpora cavernosa; as
noted above, PGs are key mediators of normal erectile
function. Morisaki and coworkers have shown that
low oxygen tension results in decreased basal and
stimulated levels of PGI
2
, thromboxane A
2
, PGF
2
, and
PGE
2
. Finally, Kim and associates
19
have shown that,
when conditions of hypoxia are produced in organ
bath strips of human corpora cavernosa, NO-mediated
responses, including relaxation and cyclic guanosine
monophosphate synthesis, are impaired. It has been
theorized that chronic hypoxia due to reduced arterial
inflow may result in similar changes in the human
penis.
Venogenic (cavernosal)
Rajfer et al.
20
have suggested that inadequate venous
occlusion failure to store blood in the penis may be
the most common cause of vasculogenic ED. Venous
occlusion is a complex and incompletely understood
process that begins with relaxation of the broelastic
component of the cavernous smooth muscle and con-
comitant expansion of the penile sinusoids. In addition
to allowing for the inflow of blood, this process results
in compression of the subtunical and emissary veins
against the intact tunica albuginea. This phenomenon
in turn results in a state where intracavernosal pressure
exceeds systolic blood pressure, and ultimately, a rigid
erection is achieved. Derangement and dysfunction of
any of these entities the broelastic component, the
cavernosal smooth muscle, and the tunica albuginea
may result in venogenic ED.
The rst and most easily understood mechanism of
venogenic ED is alteration of the tunica albuginea.This
Pathophysiology 21
tough coating tissue of the cavernous bodies is critical
for the venoocclusive mechanism, and degenerative
changes such as those seen in Peyronies disease, aging,
and traumatic injury may result in failure of this
process. Metz et al.
21
have shown that the inelastic
tunica albuginea resulting from the changes of
Peyronies disease results in inadequate compression
of the subtunical and emissary veins adjacent to the
tunica, causing venogenic ED. In addition, Dalkin and
Carter
22
have shown that surgery for Peyronies
disease can also result in failure of compression of the
subtunical and emissary veins, and thus venogenic
ED. Finally, Iacono and coworkers
23
have shown that
loss of the elastic bers in the tunica albuginea with
resultant changes in the microarchitecture, as seen in
the aging male, can result in injury to the venoocclusive
mechanism and ED.
Loss of compliance of the broelastic component
of the penile sinusoids with increased deposition of
collagen and decreased elastic bers is another patho-
physiologic mechanism of venogenic ED. Sattar and
coworkers
24
have demonstrated a signicant difference
in the mean percentage of elastic bers between normal
men and those with venous leakage. Specically, the
mean percentage of elastic bers in normal men was
9%; this number was reduced to 5.1% in men with
venogenic ED.
Finally, because corporeal smooth muscle is the key
factor in controlling the hemodynamic processes that
lead to erection, change in smooth-muscle content
and damage to the smooth muscle itself can lead to
venogenic ED. In another biopsy study, Sattar and
coworkers
25
also demonstrated a signicant difference
between the mean percentage of cavernous smooth
muscle in normal potent men compared to those with
venous leak impotence. Specically, in normal potent
men, the mean percentage of cavernous smooth muscle
stained with antidesmin or antiactin was 38.5% and
45.2%, respectively; these gures were reduced to
27.4% and 34.2% in the men with venous leak impo-
tence. Similarly, Pickard and coworkers
26
have shown
reduced muscle content in men with venous or mixed
venous/arterial impotence.
In addition, injury to the smooth muscle itself can
also exacerbate ED through a variety of mechanisms.
In a recent rodent study, Bakircioglu and coworkers
27
looked at the effect of aging on both the smooth-
muscle content and caveolin-1 protein expression in
penile smooth-muscle cells. Caveolae are specialized
invaginations of the plasma membrane of most cells
and are involved in transporting macromolecules across
capillary endothelial cells by transcytosis. In addition,
caveolae contain various signal transduction molecules,
including subunits of G protein and G protein-coupled
receptors. These molecules appear to be involved in
intracellular calcium homeostasis and in regulating the
endothelial isoform of NO synthase, both key deter-
minants of erectile function. Specically, three subtypes
of caveolin have been identied; suggested functions
of caveolin-1 include endothelial NO synthase
regulation. In Bakircioglus study,
27
the percentage of
smooth muscle positive for caveolin-1 was reduced in
aged rats; this nding was paralleled by a decrease in
the expression of caveolin-1 protein on Western blot
analysis, which suggests that a reduced expression of
caveolin-1 may contribute to ED in aged rats through
a venogenic mechanism.
In addition to decreased caveolin-1 expression,
another mechanism of smooth-muscle dysfunction
that may promote ED is derangement of ion channels.
Ion channels regulate the biochemical events of muscle
function, and alteration of these channels can pro-
foundly affect function. Fan et al.
28
have reported that
impotent patients may have changes of the maxi-K
+
channel in smooth-muscle cells. This derangement of
the potassium channels might contribute to decreased
hyperpolarizing ability, altered calcium hemostasis, and
ultimately, impaired smooth-muscle relaxation in men
with impotence, resulting in venoocclusive dysfunction.
Endocrinologic
Testosterone production is regulated via the
hypothalamicpituitary axis. Any abnormality of the
hypothalamicpituitary axis can result in hypo-
gonadism. Hyopogonadotropic hypogonadism may
be congenital, as in Kallmans syndrome, or it could
be caused by a pituitary tumor or injury. Hyper-
gonadotropic hypogonadism may also be genetic, as in
Klinefelters syndrome, or it too could be the result of
a tumor or injury. Finally, testicular failure, whether
caused by injury, surgery, or disease such as mumps
orchitis, may result in testicular failure.
The endocrine milieu plays a signicant role in regu-
lating erectile function, and androgen deciency has
long been known to contribute to, but not necessarily
be the only cause of, ED. In their review of the literature
from 1975 to 1992, Mulligan and Schmitt
29
concluded
that testosterone enhances sexual interest, increases
the frequency of sexual acts, and increases the
frequency of nocturnal erections. This last nding is
especially critical, for, as noted above, it has recently
been postulated that normal nocturnal erections are
essential for maintaining normal corporeal oxygen
tension and function. Granata and coworkers
30
recently
reported that the threshold testosterone level for
normal nocturnal erections is about 200 ng/ml. Men
with lower serum testosterone levels had abnormal
nocturnal erection parameters, while those with
normal tesosterone levels did not. Thus, it appears that
an adequate testosterone level may be essential for
maintaining normal penile health.
Testosterone may be a particularly important con-
tributor to ED in the aging male; this gradual decrease
in bioactive hormone has been termed andropause. In
his review, Vermeulen
31
showed that there is a gradual
decline in serum total and bioavailable testosterone,
due to a decrease in the number and function of
testicular Leydig cells, as well as by an age-related
decrease in episodic and stimulated gonadotropin
secretion. Morley and coworkers
32
cross-sectional
study has shown that, even in healthy males, mean
serum total testosterone levels decrease by about 30%
between the ages of 25 and 75, while mean serum-free
testosterone levels decrease by about 50% over the
same period. As Ferrini and Barret-Connor
33
have
noted, this discrepancy can be explained by an age-
associated increase in sex hormone-binding globulin
binding capacity. In addition to testosterone, other
related sex hormones also change over time. Herbert
34
demonstrated that serum estradiol and estrone decrease
with age, while Morley and coworkers
35
have also
shown that dihydroepiandrosterone and its sulfate also
gradually decrease with aging.
While evidence of abnormal testosterone levels in
men with ED is abundant, the precise mechanism of
androgens effect on erectile physiology is poorly
understood. Beyer and Gonzales-Mariscal
36
have
reported that testosterone and dihydrotestosterone are
responsible for normal male pelvic thrusting during
coitus. In addition, Mills et al.
37
and Pensen et al.
38
have
demonstrated a number of hemodynamic changes in
the penis of castrated rats, including decreased arterial
flow, increased venous leakage, and decreased response
to stimulation by the cavernous nerve. All of these
changes could obviously ultimately lead to ED. These
studies also showed that treatment with flutamide,
estradiol, or a gonadotropin-releasing hormone antag-
onist along with castration further amplied the
impairment of the erectile response. Finally, and
perhaps most signicantly, penile NO synthase activity
was reduced in these animals, suggesting a clear link
between endocrinologic dysfunction and erectile
activity. Traish and coworkers
39
demonstrated that
castration reduced trabecular smooth-muscle content
in the rabbit model, thus implying that reduced testos-
terone levels could result in or exacerbate preexisting
venoocclusive dysfunction. Finally, Fujimoto et al.
40
showed that androgen induces proliferation of cultured
smooth-muscle cells isolated from rat aorta. These cells
have androgen receptors and possess 5-alpha reductase
activity. As Cunningham and Hirshkowitz
41
have
suggested, it is probable that testosterone and its
metabolite dihydrotestosterone have signicant effects
on endothelium and vascular smooth muscle in man.
Other hormonal abnormalities apart from abnor-
malities of testosterone may contribute to the patho-
physiology of ED. Hyperprolactinemia is one example.
Hyperprolactinemia, most commonly the result of a
tumor or medication, is known to result in both sexual
and reproductive dysfunction. Symptoms may include
galactorrhea, gynecomastia, loss of libido, ED, and
infertility. Hyperprolactinemia causes inhibited
secretion of gonadotropin-releasing hormone via a
negative-feedback mechanism, resulting in low levels
of testosterone, and potentially, ED.
Finally, both the hyperthyroid and hypothyroid state
can result in ED. In hypothyroidism, elevated prolactin
levels and resulting low testosterone secretion can result
in a hypogonadal state and subsequent impotence. In
hyperthyroidism, the most common sexual disorder is
decreased libido, which is thought to be secondary to
the increase in circulating estrogen levels associated
with this condition. Occasionally, ED may result.
Neurogenic
As noted earlier, erectile function is a hemodynamic
and neurologic event under psychological control.
With the advent of effective oral therapy to improve
penile hemodynamics, most of the recent interest in
the study of erectile physiology has been directed
toward the vasculogenic component. Nevertheless,
neurologic dysfunction remains an important cause of
impotence.
As Sachs and Meisel
42
have noted, the medial
preoptic area, the paraventricular nucleus, and the
hippocampus have been regarded as critical inte-
gration centers for sexual drive and penile erection.
Not surprisingly, central nervous system disease
affecting these areas, such as stroke, encephalitis,
temporal lobe epilepsy, and Parkinsons, may result in
ED. Parkinsonisms effect may be caused by imbalance
of the dopaminergic pathways, as dopaminergic
agonists are known to improve erectile function. Other
lesions in the brain which can result in ED are tumors,
Alzheimers, ShyDrager, and trauma.
Spinal cord injury is also an important etiology in
the pathophysiology of ED. In the man with spinal
cord injury, the precise nature of the ED is determined
by the extent and location of the lesion. As noted
earlier, reflexogenic erections result from stimulation
of the dorsal nerve of the penis, which in turn sends
signals to the lumbosacral cord. Here, synapses with
parasympathetic bers traveling back to the corpora
cavernosa take place, and erection can occur. Eardley
and Kirby
43
have noted that reflexogenic erections are
preserved in approximately 95% of patients with com-
plete upper cord lesions, whereas only about 25% of
men with complete lower cord lesions can obtain an
erection. Thus, it appears that sacral parasympathetic
neurons are instrumental in reflexogenic erections.
However, as Courtois and coworkers
44
have noted,
synaptic connections through the thoracolumbar
Pathophysiology 23
pathway may be adequate to compensate for a sacral
lesion. Obviously, trauma is the most common cause of
spinal cord disease leading to ED, but other disorders
at the spinal level, including spina bida, syringomyelia,
tumor, transverse myelitis, and multiple sclerosis, may
result in neurogenic ED. Also, it is important to
remember that, particularly in younger men, herniation
of a lumbar disk may result in injury to the sacral
nerve roots and can in fact cause sudden-onset ED.
One of the most common causes of neurogenic
ED is injury to the cavernous nerves during radical
pelvic surgery. Incidence of iatrogenic impotence from
various radical pelvic procedures is summarized
in.
4448
The close relationship of the cavernous nerves and
the pelvic organs explains the historically high inci-
dence of ED following radical pelvic surgery. However,
an improved understanding of the neuroanatomy
of the pelvic and cavernous nerves has resulted in
modied, nerve-sparing surgery for cancer of the
rectum, bladder, and prostate, producing a signicantly
lower incidence of iatrogenic impotence than had been
reported previously.
After exiting the hypogastric plexus, the cavernous
nerves descend inferiorly to run along the lateral wall
of the rectum. From there, they turn sharply upward
and adhere tightly to the capsule of the prostate under
the leaves of the lateral pelvic fascia as the neuro-
vascular bundles. Identication of the nerves is possible
during radical retropubic prostatectomy with careful
dissection between the capsule of the prostate and the
lateral pelvic fascia, and, once they are identied, the
neurovascular bundles may be preserved and pushed
safely out of the way with blunt dissection. From there,
the cavernous nerves run along the urethra at the 3
and 9 oclock positions before entering the penis itself.
Again, with careful dissection that does not extend
beyond the urethral wall itself, as well as with
meticulous hemostasis of the dorsal venous complex
so as to optimize visualization of the structures, pre-
servation of the neurovascular bundle and erectile
function may be achieved. Finally, isolation of the
seminal vesicles after meticulous dissection of
Denonvilliers fascia as well as careful ligation of the
lateral pedicles of the prostate will optimize post-
perative erectile function.
Moreover, it is important to remember that,
particularly in younger patients, one need not save
both nerves in order to achieve postoperative potency.
Preservation of a single neurovascular bundle will
typically be adequate to permit satisfactory post-
operative sexual function; this is particularly useful in
patients with prostate cancer localized to one side of
the gland. As both Catalona and Bigg
50
and Walsh and
Donker
45
have shown, the introduction of these nerve-
sparing techniques for radical prostatectomy has
reduced the incidence of impotence from nearly 100%
to 3050% a major advancement in urologic surgery.
Similar improvements, though not as dramatic, have
also been noted for radical surgery for cancer of the
bladder and rectum.
However, as Martin and coworkers have demon-
strated,
52
potency following nerve-sparing radical
prostatectomy may involve more than nerve preser-
vation. In their recent study, 27 patients underwent
nerve-sparing radical prostatectomy with the aid of
a CaverMap device, an instrument which provides
objective, intraoperative conrmation of nerve preser-
vation. Seven patients suffered from persistent ED
despite conrmation of nerve preservation with the
CaverMap device; all of these individuals underwent
duplex studies to evaluate penile blood flow. All seven
patients had abnormal penile blood flow; six had
evidence of venous leak impotence, and one had
evidence of arteriogenic impotence. These data suggest
that, despite careful intraoperative preservation of
normal cavernous nerve anatomy, patients may well
have vasculogenic causes for postprostatectomy
impotence.
Pelvic fracture can also result in ED as a result of
neurogenic injury. For example, in cases of posterior
urethral disruption associated with pelvic fracture, the
unforgiving attachment of the prostate to the pubic
symphysis via the puboprostatic ligaments results in
a tremendous shearing force during injury that will
dislodge the prostate from the membranous urethra.
This same force will also result in disruption or injury
to the cavernous nerves that run along the lateral wall
of the prostate and then to the 3 and 9 oclock
positions of the urethra, with resultant neurogenic ED.
In fact, it is generally the injury itself, and not the
surgery performed to correct it, that results in ED in
cases of pelvic fracture and urethral disruption. These
injuries are a particularly troubling etiology of ED, as
they tend to occur in younger patients, and can lead
to lifelong ED that responds poorly to current oral
therapies.
Finally, neurogenic ED can also involve loss of
sensory input and reflexogenic erections.This phenom-
enon is an extremely common complaint in the elderly
population. Recall that reflexogenic erections in
particular are dependent upon stimulation of the dorsal
nerve and the intact delivery of this stimulation to the
lumbosacral cord. Both of these functions appear to be
substantially decreased in older patients. In one study,
Bemelmans and coworkers
53
performed somatosensory
evoked potentials as well as sacral reflex latencies on
impotent patients with no clinically identiable neuro-
logic disease. They noted that 47% of patients had at
least one abnormal neurophysiologic measurement,
and that the likelihood of an abnormality tended to
increase signicantly with the patients age. Similarly,
Rowland and colleagues
54
also showed a marked
decrease in penile tactile sensitivity as men age. The
importance of these ndings is further heightened
when one considers that, particularly in older men, the
reflexogenic erection resulting from adequate process-
ing of sensory input from the genitalia is crucial to
achieving and maintaining normal sexual function.
Since psychogenic erection tends to decrease with age,
the reflexogenic erection takes on added importance.
Thus, sensory etiologies should always be considered
in men with ED with or without an overt neurologic
disorder, particularly in the elderly population, and
sensory testing should be part of the evaluation of ED.
Drug-induced
As Carbone and Seftel have noted,
55
a large number
of therapeutic drugs can cause ED as an unwanted
side-effect.
54
The tendency of certain pharmaceuticals
to induce ED may result in decreased patient com-
pliance, and thus familiarity with these side-effects is
mandatory for any practicing clinician. Indeed, it is not
uncommon for men with cardiovascular conditions that
cause ED to take drug holidays from these agents in
order to avoid their tendency to cause ED. Ironically,
the patients poor compliance will often exacerbate
the underlying condition responsible for the erectile
failure.
While the large number of agents that can cause ED
defy simple classication, generally, pharmaceuticals
induce ED by interfering either with central neuro-
endocrine or local neurovascular control of penile
smooth-muscle tissue. A brief characterization of some
of the most common classes of medications known to
induce ED follows, as well as an elucidation of the
mechanism through which these agents are thought to
cause impotence.
Antipsychotics and antidepressants are widely
associated with sexual dysfunction. These agents
tend to induce ED by interfering with the 5-
hydroxytryptaminergic, noradrenergic, and dopaminergic
central neurotransmitter pathways involved in ED.
Antipsychotics also tend to decrease libido, thereby
exacerbating the erectile failure and sometimes inducing
ejaculatory dysfunction as well. Specic mechanisms
through which the antipsychotics induce ED include
anticholinergic actions, a central antidopaminergic
effect, and the release of prolactin. With the exception
of trazodone and bupropion, nearly all of the four
major classes of antidepressants (tricyclic, heterocyclic,
selective serotonin reuptake inhibitors, and monoamine
oxidase inhibitors) can also induce ED and ejaculatory
disorders. Mechanisms are thought to include increased
sensitivity to 5-hydroxytryptamine (5-HT) and adren-
ergic receptors in the postsynaptic neurons.
Other central-acting drugs that can induce ED include
centrally acting sympatholytics such as methyldopa
and clonidine. These drugs are thought to impair
erectile activity by inhibiting the hypothalamic center
through
2
-receptor stimulation. Another medication
that may cause ED through a central mechanism is
reserpine, which depletes the stores of catecholamines
and 5-HT by blocking vesicular monoamine trans-
porters I and II.
Antihypertensives in particular tend to cause ED by
disrupting local neurovascular control of penile smooth
muscle. Calcium-channel blockers are one such example,
and -adrenergic blockers such as phenoxybenzamine
are another. -Adrenergic blockers also appear to act to
cause ED through a predominantly local mechanism,
but they are also known to have central side-effects,
including sedation, sleep disturbances, and depression,
that could contribute to their tendency to cause ED.
Another class of antihypertensives, the thiazide
diuretics, have been reported to have a deleterious
effect on potency, and potassium-sparing diuretics such
as spironolactone have also been reported to cause ED
in 430% of patients. Spironolactone may also cause
decreased libido, gynecomastia, and mastodynia.
Cimetidine, an H
2
-receptor antagonist, has also been
associated with decreased libido and ED. Wolfe
56
has
shown that that the drug may act as an antiandrogen
and can increase prolactin levels. Other drugs that may
induce ED through antiandrogenic effects and a resultant
endocrinologic etiology include estrogens, ketoconazole,
and cyproterone acetate.
Cigarette smoking is another well-recognized cause
of ED, and in fact, the link between ED and tobacco
abuse is now included in the surgeon generals warning
against smoking. Obviously, cigarette smoking is linked
to atherosclerotic disease and vasoconstriction; these
conditions restrict penile inflow and result in
arteriogenic dysfunction. In addition, Junemann and
coworkers
57
demonstrated that cigarette smoking may
have a directly injurious effect on the smooth muscle
of the corpora cavernosa, potentially inducing veno-
occlusive dysfunction and venous leak impotence.
Moreover, Hishkowitz and colleagues demonstrated an
adverse impact of cigarette smoking on nocturnal
erections; men smoking more than two packs per day
had the weakest nocturnal erections. This decrease in
nocturnal erections may in turn reduce oxygen tension
in the corporeal tissue, thus inducing endothelial cell
dysfunction and ultimately penile brosis.
While alcohol in small amounts may improve
erection due to its vasodilatory effect as well as its
well-described suppression of anxiety and enhance-
ment of sexual drive, chronic alcoholism appears to
have a deleterious impact on sexual function. Chronic
alcoholism may result in liver dysfunction, with
resulting decreases in serum testosterone as well as
Pathophysiology 25
increases in serum estrogen levels, resulting in
endocrinologic ED. In addition, as Miller and Gold
58
have pointed out, the polyneuropathy that can
accompany chronic alcoholism may also affect penile
nerves; thus, chronic alcoholism could potentially
induce ED through a neurogenic mechanism as well as
an endocrinologic one.
Systemic disease
A number of systemic diseases are known to be
associated with ED and play a clear role in the patho-
physiology of erectile failure. Perhaps the most
important are diabetes mellitus, hyperlipidemia and
atherosclerosis, hypertension, and chronic renal
failure.
Diabetes mellitus
A brief review of the epidemiologic data regarding ED
and diabetes quickly demonstrates the profound impli-
cations that diabetes has on normal erectile function.
Overall, ED has been estimated to occur in approxi-
mately 3575% of men with diabetes mellitus. In
addition, impotence tends to occur at an earlier age in
men with diabetes mellitus. Oftentimes, ED is the rst
sign of diabetic disease; it has been estimated that ED
is the presenting symptom in up to 12% of men with
diabetes. Finally, the incidence of ED in diabetes has
been shown to be age-dependent, rising from 15% at
age 30 years to 55% at age 3460 years.
As Jevtich and colleagues noted in 1982,
59
studies
in animal models of diabetes, as well as in human
subjects, demonstrate penile arterial narrowing and
arteriolar disease. In a duplex study, Wang and
colleagues
60
showed an extremely high prevalence
(>75%) of penile arterial insufciency among men
with diabetes. Moreover, penile biopsy studies in
diabetics have demonstrated ultrastructural changes in
corporeal smooth muscle consistent with arteriogenic
dysfunction, as well as impaired endothelium-
dependent relaxation of the corporeal smooth muscle.
Thus, it is thought that microvascular changes and
arteriogenic ED represent the likely endpoint of the
pathophysiology of ED in the diabetic male.
In addition, nerve dysfunction also likely plays a role
in the development of ED in the diabetic. Bemelmans
and his colleagues
61
applied a similar technique to the
one cited earlier in a study of the somatosensory nerve
function of men with diabetes and erectile failure.They
demonstrated that diabetic men had longer latencies of
somatosensory-evoked potentials of the pudendal
nerves and of the bulbocavernous reflexes than normal
controls. This in turn puts the reflexogenic erection
at risk, and helps explain why ED is often the earliest
and most common clinical sign of diabetic autonomic
neuropathy. In addition to these ndings, Sullivan and
coworkers
62
have demonstrated evidence of NO-
dependent selective nitrergic nerve degeneration in
diabetes mellitus in a rabbit model.
Diabetes has also been associated with signicant
derangements in the local mediators of erectile
function in both human studies and animal models.
For example, Vernet and colleagues
63
showed that
genetically diabetes-prone rats have lower penile
neuronal NO synthase activity than control animals.
Keegan and colleagues
64
have suggested that ED may
result in diabetic animals from mechanisms including
impaired NO synthesis, increased endothelin B
receptor-binding sites and ultrastructural changes, and,
nally, increased levels of oxygen free radicals with
resulting oxidative stress injury. In addition, Seftel and
coworkers
65
showed that elevated levels of advanced
glycosylation endproducts may be implicated in the
development of ED in human subjects with diabetes.
Abnormalities in levels of VIP, prostaglandins, and
endothelins all important mediators of normal erectile
function have also been demonstrated in both animal
models and human subjects with diabetes mellitus and
erectile failure.
Hyperlipidemia and atherosclerosis
Obviously, hyperlipidemia and atherosclerosis result
in the deposition of lipid in the arteriolar walls of
the vessels. These lesions can encompass the internal
pudendal or cavernosal arteries as well, reducing inflow
and resulting in arteriogenic ED.
While the propensity of hyperlipidemia and athero-
sclerosis to effect impotence via an arteriogenic
mechanism and reduced inflow is well established,
newer data suggest that hyperlipidemia may also cause
direct dysfunction of the cavernous smooth muscle
and the endothelial cells that release NO. Azadzoi
and coworkers
66
have shown that, in a rabbit model,
atherosclerosis and hypercholesterolemia resulted in
decreased NO synthase activity and increased produc-
tion of contractile prostaglandins and thromboxane,
thus impairing smooth-muscle relaxation and erectile
function. Similarly, Ahn and colleagues
67
have pro-
posed that the impaired NO-mediated smooth-muscle
relaxation associated with hypercholesterolemia may
in fact be caused by the contractile effect of oxidized
low-density lipoprotein.
Hypertension
Hypertension represents another well-recognized risk
factor for ED. Interestingly, although in this condition
the increased blood pressure itself does not impair
erectile activity, the associated arterial stenotic lesions
are thought to be the cause, resulting in impaired
inflow and arteriogenic disease.
None the less, newer data show that hypertension
may also mediate erectile failure by affecting local
vasodilators and constrictors. A recent paper from
Taddei et al. has shown that NO availability is
impaired in hypertension because of the production of
cyclooxygenase-derived vasocontrictor substances as
well as reduced endothelin B-receptor-mediated NO
activation.
Chronic renal failure
Chronic renal failure is also associated with ED, and
it has been estimated that approximately 50% of
patients entering dialysis are impotent. The ED
associated with chronic renal insufciency is likely a
multifactorial phenomenon. Kaufman and colleagues
69
showed that 78% of patients with ED and renal failure
had cavernous artery occlusive disease and 90% had
venoocclusive dysfunction. In addition, chronic renal
failure can result in considerable derangements of the
hormonal milieu, resulting in decreased libido in
addition to erectile failure. Decreased levels of serum
testosterone as well as elevations of serum prolactin
have been demonstrated in men with chronic renal
failure. Finally, the fact that many of these patients are
managed with multiple medications means that they
are also at risk for drug-induced ED.
Psychogenic
Until recently, it was believed that approximately 90%
of impotent men had pure psychogenic ED. Though
most observers have moved away from this concept
and now favor a mixed approach that emphasizes
organic factors, it cannot be denied that at least some
men suffer from a signicant psychogenic component
to their ED.The growing awareness of organic etiologies
should not mean that consideration of pychogenic
factors should be discarded, however, and therefore,
the chapter concludes with a brief summary of the
pathophysiology of psychogenic ED.
A number of well-dened precipitants of acquired
psychogenic ED have been described.These include but
are not limited to relationship deterioration, divorce,
death of the partner, vocational failure, and loss of
personal or partner health.
As Althof and Levine
70
have counseled, each of these
etiologies must be considered in the man with psycho-
genic ED. As they have noted, the alienation, mutual
hostility, lack of intimacy, and partner unreceptivity
that accompany relationship deterioration can result in
psychogenic ED in spite of the mans expectations that
he can function in the face of these problems. Similarly,
they have noted that many divorced and divorcing
men are surprised by their suddenly unreliable erectile
function, and that the clinician treating these indi-
viduals should remember that issues such as the
patients continuing love for his divorced wife, his con-
cern about his ability to love again, his worry over his
childrens situation, and his fear that his new relation-
ship might deteriorate as well may in fact be at the
root of the patients ED. Similarly, death of a spouse
may result in unresolved grief, confusion, discomfort,
and guilt that can impair erectile activity. Vocational
failure can result in feelings of despair, hopelessness,
and worthlessness that attack the patients self-esteem
and result in psychogenic ED. Finally, loss of personal
or partner health is an important consideration in
treating men with ED, particularly in this era of effec-
tive oral therapy. Nearly all clinicians have encountered
patients who, despite all assurances to the contrary,
are reluctant to resume sexual activity because of fear
of major health events or even death. Conversely,
deterioration of his partners health, as well as issues
including female sexual arousal and lubrication, can
result in signicant psychogenic ED. Ignoring these
factors and focusing only on organic etiologies can
doom therapy for ED from the outset.
Moreover, there is evidence to suggest that psycho-
genic ED can in fact result from underlying physiologic
mechanisms. Steers
71
has suggested that psychogenic
ED may result from direct inhibition of the spinal
erection center by the brain as an exaggeration of the
normal suprasacral inhibition. In addition, it has been
postulated that excessive sympathetic outflow or
elevated peripheral catecholamine levels due to stress
may have a direct constrictive effect on penile smooth
muscle, increasing smooth-muscle tone and preventing
the relaxation necessary for normal penile function.
Kim and Oh
72
have shown that patients with psycho-
genic ED have higher levels of serum norepinephrine
than do normal controls or even patients with vasculo-
genic ED.
Finally, a consideration of psychogenic ED must
include mention of the phenomenon of psychological
resistance, or drop-out from effective therapy, whether
the therapy is a pill, an injection, or even an implant.
During the period of sexual inactivity, the couples
behavior may be transformed, resulting in emotional
distance and anger. Simply restoring erection does not
necessarily restore sexual function, and obviously, it is
restoration of sexual function that is the true goal of
therapy.
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References 29
INTRODUCTION
For many decades premature ejaculation has been
considered a psychological disorder that had to be
treated with psychotherapy. However, psychological
treatments and underlying theories mostly relied on
case reports and the opinions of some leading psycho-
therapists and sexologists and were not based on
controlled studies a typical example of authority- or
opinion-based medicine. In spite of the availability of
clomipramine,
1
an efcacious ejaculation-delaying
tricyclic antidepressant, in the early 1970s, possible
secondary medical use with clomipramine to treat pre-
mature ejaculation remained unrecognized. In contrast
to authority-based medicine, evidence-based medicine
2
has been accepted today as the hallmark for clinical
research and medical practice. Particularly in the last
decade, randomized clinical trials with clomipramine
3,4
and some selective serotonin reuptake inhibitors
(SSRIs)
59
have repeatedly demonstrated the efcacy of
serotonergic antidepressants in delaying ejaculation. In
spite of these studies, it is still believed in sexology
that premature ejaculation is a psychological disorder.
In order to unravel this dichotomy, it is important to
apply the principles of evidence-based medicine to
both the psychological and neurobiological approach
to premature ejaculation and its treatment.
HISTORICAL DEVELOPMENT OF
THEORIES
Waldinger
10
distinguishes four periods in the approach
to and treatment of premature ejaculation. Throughout
these periods premature ejaculation has been con-
sidered from both a medical and a psychological view,
resulting in contrasting psychotherapeutic and drug
treatment approaches.
The rst period (18871917):early
ejaculation
In 1887 Gross
11
described the rst case of early ejacu-
lation in the medical literature. A second report written
by von Krafft-Ebing
12
followed in 1901. Although
publications were rare, it is of note that during the rst
30 years of its existence in the medical literature, early
ejaculation was viewed as an abnormal phenomenon
and not particularly as a psychological disturbance.
The second period (19171950):
neurosis and psychosomatic disorder
In 1917 Abraham
13
described rapid ejaculation as
ejaculatio praecox and stated that it was a symptom of
a neurosis caused by unconscious conflicts. Treatment
should consist of classic psychoanalysis. On the other
hand some physicians stated that premature ejaculation
was due to anatomical urological abnormalities, such
as too short a foreskin frenulum or changes in the
posterior urethra, which had to be treated by incising
the foreskin or electrocauterizing the verumontanum.
In 1943, Schapiro
14
argued that premature ejaculation
was neither a pure psychological nor a pure somatic
disorder, but a psychosomatic disturbance caused by a
combination of a psychologically overanxious consti-
tution and a weak ejaculatory system. Schapiro decribed
two types of premature ejaculation: type B, in which
early ejaculation existed from the rst experience of
intercourse, and type A, which led to erectile dysfunc-
tion. Many years later both types were distinguished as
the primary (lifelong) and secondary (acquired) forms
of premature ejaculation.
15
The third period (19501990): learned
behavior
The biological component of premature ejaculation and
therefore also drug treatment, advocated by Schapiro,
was ignored by most sexologists who advocated
psychoanalytic treatment. This neglect became even
more pronounced after Masters and Johnson
16
claimed
high success rates of behavioral therapy in the form of
the squeeze technique, an adaptation of the stopstart
technique published by Semans
17
in 1956. Masters and
Johnson stated that men with premature ejaculation
had learnt by themselves rapidity because their rst
experiences of sexual intercourse were performed in
a hurry.
Premature Ejaculation: Cause and Treatment
According to Evidence-based Medical Research
Marcel D. Waldinger
CHAPTER 3
The fourth period (1990 to present):
neurobiology and genetics
Although behavioral treatment has prevailed in
sexology until today, hardly any study has been
performed to investigate its effectiveness. In contrast,
since the 1990s there has been an increasing number
of publications on the efcacy of SSRIs, clomipramine,
and topical anesthetic creams in delaying ejaculation.
At the same time, a new neurobiological view has been
developed arguing that premature ejaculation is related
to a disturbance of serotonin (5-HT) metabolism in
specic areas of the central nervous system, and a
possible genetic vulnerability has been postulated.
10,18
SEROTONIN NEUROTRANSMISSION
AND 5-HT RECEPTORS
To understand better the neurobiology of premature
ejaculation and its treatment, a basic knowledge of
what is happening in serotonergic neurons in the
central nervous system is required.
Serotonergic neurons originate in the raphe nuclei
and adjacent reticular formation in the brainstem.
There is a clear dichotomy in the serotonergic (5-
hydroxytryptamine; 5-HT) system neuronal cell
groups:
19
a rostral part with cell bodies in the midbrain
and pons projecting to the forebrain and a caudal
part with cell bodies predominantly in the medulla
oblongata with projections to the spinal cord. In the
forebrain and spinal cord the serotonergic neurons
contact other serotonergic neurons. The place of
connection is the synapse, in which the neurotrans-
mitter 5-HT provides information from one neuron to
another. After it is made in the cell body, 5-HT runs
through the serotonergic neuron to the presynaptic
membrane, from which it is released into the synapse.
In the synapse 5-HT proceeds to receptors at the
opposite neuron (postsynaptic receptors) and, after it
has contacted these receptors, 5-HT runs back to the
presynaptic membrane. Through the activity of 5-HT
transporters (5-HTT) in the presynaptic membrane,
5-HT is brought back into the presynaptic neuron. The
process of 5-HT release and its action on postsynaptic
receptors is called serotonergic neurotransmission.
Usually there is a sort of equilibrium in the
serotonergic neurotransmission system due to remark-
able mechanisms. If 5-HT release from the presynaptic
neuron into the synapse becomes too high, the so-called
5-HT
1B/1D
autoreceptors, located in the presynaptic
membrane, become activated. Their activation results
in a dimininished release of 5-HT in the synapse.
Consequently, equilibrium is restored. This feedback
mechanism of the cell, where the released 5-HT inhibits
its own release, is a frequently occurring principle in
neurotransmitter regulation and provides the system
with the possibility of preventing overstimulation of
postsynaptic receptors.
19
However, serotonergic neurotransmission becomes
seriously disturbed by the action of serotonergic anti-
depressants. SSRIs block the 5-HT transporters, both
in the presynaptic membrane and around the cell-
body. As a consequence, 5-HT concentration increases
outside the cell body and in the synapses. Due to
increased 5-HT levels, 5-HT
1A
autoreceptors at the
surface of the cell body and 5-HT
1B/1D
autorreceptors
in the presynaptic membrane become activated. The
activation of both the somatodendritic 5-HT
1A
auto-
receptors and the presynaptic 5-HT
1B/1D
autoreceptors
results in inhibition of 5-HT release into the synaptic
cleft. Consequently 5-HT concentration in the synapse
diminishes but usually remains mildly increased due to
the blockade of the 5-HT transporters, leading to some
stimulation of all postsynaptic 5-HT receptors. After
some days the 5-HT
1A
and 5-HT
1B/1D
autoreceptors
become desensitized, resulting in a diminished inhibi-
tory action of these receptors to 5-HT release. Con-
sequently, 5-HT is again released into the synapse.
However, due to the SSRI-induced continuous blockade
of the 5-HT transporters, 5-HT cannot move back into
the presynaptic neuron and as a consequence 5-HT
levels in the synapse rise. This increased serotonergic
neurotransmission exerts a stronger effect on all post-
synaptic receptors. It is the action of these postsynaptic
receptors that determines the clinical effects of the
SSRIs.
Translated into clinical terms, this means that after
acute treatment (on-demand treatment) there is only a
mild increase of 5-HT in the synapse and mild acti-
vation of postsynaptic receptors, whereas during
chronic treatment there is a strong increase of 5-HT in
the synapse with strong effects on all postsynaptic
neurons.
THE EFFECTS OF DRUGS ON
EJACULATION
Animal studies
Male rat studies have demonstrated that 5-HT and
5-HT receptors are involved in the ejaculatory process.
As far as is currently known, 5-HT
2C
and 5-HT
1A
receptors determine the speed of ejaculation. For
example, studies with D-lysergic acid diethylamide and
quipazine, which are non-selective 5-HT
2C
agonists,
suggest that stimulating 5-HT
2C
receptors delays
ejaculation.
20
However, 2,5-dimethoxy-4-iodophenyl-
2-aminopropane, which equally stimulates 5-HT
2A
and
5-HT
2C
receptors, also increases ejaculation latency,
21
whereas the selective 5-HT
2A
receptor agonist 2,5-
dimethoxy-4-methylamfetamine does not have this
effect.
20
On the other hand, activation of postsynaptic
32 Premature Ejaculation: Cause and Treatment According to Evidence-based Medical Research
5-HT
1A
receptors by the selective 5-HT
1A
receptor
agonist 8-hydroxy-2-(di-n-propylaminotetralin) in male
rats resulted in shorter ejaculation latency.
20
Adminis-
tration of SSRIs results in higher levels of 5-HT in the
synapse due to active blockade of 5-HT transporters in
the presynaptic membrane.
19
Initially, the 5-HT level is
only mildly increased, but due to desensitization of the
5-HT
1A
and 5-HT
1B/1D
autoreceptors, 5-HT levels in the
synapse greatly increase. The higher levels of 5-HT
consequently activate the postsynaptic 5-HT
2C
and
5-HT
1A
receptors.
19,22
Acute administration of clom-
ipramine and SSRIs does not lead to a signicant
change in the sexual behavior of male rats.
23
However,
chronic administration with fluoxetine
24
and paroxetine
25
signicantly delays ejaculation latency time in male
rats. Chronic administration of fluvoxamine however
exerts only a mild change in male rat sexual
behavior.
25
Human studies
Based on 5-HT
2C
and 5-HT
1A
receptor interaction data
in animals,Waldinger et al.
10,19,26
formulated the hypo-
thesis that in men with premature ejaculation there is
a hyposensitivity of the 5-HT
2C
and/or hypersensitivity
of the 5-HT
1A
receptor. The hypothesis that activation
of postsynaptic 5-HT receptors delays ejaculation is
supported by numerous studies in humans with differ-
ent SSRIs. However, in these studies it is not obvious
whether similar receptor subtypes, that is, 5-HT
2C
and
5-HT
1A
receptors, are also involved in human ejacu-
lation, since SSRI treatment activates many different
postsynaptic subtype receptors. To nd an answer, two
human studies with the 5-HT
2C
-blocking antidepressants
nefazodone
27
and mirtazapine
28
were performed. In a
double-blind placebo-controlled study with the 5-HT
2C
/
5-HT
2A
receptor antagonist and 5-HT/norepinephrine
(noradrenaline) reuptake inhibitor nefazodone, 400 mg
nefazodone daily did not exert any ejaculation delay,
in contrast to a signicant delay after 20 mg paroxetine
daily and 50 mg sertraline daily. In a similar study the
5-HT
2C
/5-HT
3
receptor antagonist and noradrenergic
and specic serotonergic antidepressant mirtazapine
did not induce ejaculation delay compared with the
signicant delay resulting from 20 mg paroxetine daily.
In both studies nefazodone and mirtazapine did not
delay ejaculation. Further studies with selective 5-HT
2C
and 5-HT
1A
agonists and antagonists are encouraged to
elucidate still undiscovered pharmacological mech-
anisms underlying the ejaculatory process.
EVIDENCE-BASED MEDICINE
Evidence-based medicine means that it is not enough
to formulate a seemingly attractive hypothesis of the
cause of a disease for it to be scientically accepted.
Instead one has to come up with empirical evidence,
preferably replicated in various controlled studies.
Evidence-based research:
psychotherapy
The psychoanalytic idea of unconscious conflicts as
the cause of premature ejaculation has never been
investigated in a manner that allowed generalization,
as only case reports on psychoanalytic therapy have
been published.
But this is also true for behavioral therapy. Masters
and Johnson
16
deliberately refuted a denition of pre-
mature ejaculation in terms of a mans ejaculation time
duration. Instead, they insisted on dening premature
ejaculation in terms of the female partner response,
e.g., as the mans inability to inhibit ejaculation long
enough for his partner to reach orgasm in 50% of inter-
course. It is obvious that their denition is inadequate
because it implies that any male partner of a woman
who has difculty in reaching orgasm on 50% of inter-
courses suffers from premature ejaculation.
Masters and Johnson argued that premature ejacu-
lation was conditioned by having ones rst sexual
contact in a rapid way (for example, in the back seat
of a car or with an impatient prostitute). However,
Masters and Johnson, and sexologists who followed
their ideas, have never provided any evidence-based
data for this assumption. Regarding their proposed
behavioral squeeze technique treatment, Masters and
Johnson claimed a 97% success for delaying ejacu-
lation. However, this very high percentage of success
has never been replicated by others.
Usually, a lack of reproducible data leads to critical
comments. This is one of the basic principles of
evidence-based medicine. The effects of treatment
intervention should be reproducible by others. How-
ever, critical comments were not appreciated in
traditional sexological thinking of the late twentieth
century. This non-scientically supported and uncritical
belief in behavioral treatment still exists today, despite
clear evidence-based medical research in favor of the
neurobiological view. But the criticism is justied. The
methodological insufciencies of Masters and Johnsons
report are very serious. Their report on the efcacy of
the squeeze method contains numerous biases.
First, there was a bias in the selection and allocation
of the subjects: patients were not randomized to the
new squeeze technique, the older stopstart technique,
or a nonsense behavioral technique. Second, the treat-
ment design was open and not double-blinded. Further,
the diagnosis of premature ejaculation was not
quantied and therefore inaccurate, particularly since
Masters and Johnson used an obscure denition of
premature ejaculation. Baseline data were not reported
Evidence-based Medicine 33
and inclusion and exclusion criteria were lacking. The
assessment of success was subjectively reported with-
out quantication or scoring scales. In addition, Masters
and Johnson did not provide any information on their
data processing. In spite of all these methodological
flaws, their behavioral technique has been accepted
uncritically worldwide and promoted as the rst choice
of treatment. Even the very poor results of two
studies
29,30
on behavioral therapy (which were also
poorly designed) could not prevent sexologists from
continuing to claim the squeeze technique as the rst
choice of treatment. Not only the squeeze technique,
but also all sorts of psychotherapy, including thought
prevention, gestalt therapy, transactional analysis, group
therapy, and bibliotherapy, have been proposed as
being effective.
3134
Also the efcacy of these psycho-
therapies has only been suggested in case reports and
has never been investigated in well-designed controlled
studies.
How can we explain the uncritical acceptance of
the squeeze technique as rst-choice treatment? In
the 1960s, Masters and Johnson were highly esteemed
professionals who worked with patients with sexual
disorders.Their formulated focused treatment approach
to sexual dysfunction was indeed revolutionary at
that time. In a very short time they became experts in
the eld and were considered as authorities. Clearly,
the uncritical acceptance of their squeeze method
as the ideal treatment is an example of opinion- or
authority-based medicine.
67
Evidence-based research: drug
treatment
In contrast to the easy acceptance of behavioral treat-
ment by sexologists, it was much more difcult for
drug treatment to be accepted in the face of its
rejection by professionals in the eld. Only a few
physicians have tried to develop drug strategies to
treat premature ejaculation. Currently, in spite of still
ambiguous attitudes of many sexologists, drug treat-
ment with serotonergic antidepressants is accepted as
efcacious therapy. Despite all circumstantial evidence,
it should be emphasized that it is obligatory to main-
tain a scientic approach to investigating empirical
evidence.
35
Investigating the extent to which differences
in methodology may have an influence on the clinical
outcome of drug treatment studies, Waldinger and
coworkers conducted a systematic review and meta-
analysis of all drug treatment studies published since
1943.
36
In this study several methodological evidence-based
criteria were compared, such as study design (open
versus double-blind), tools for diagnostic testing (stop-
watch versus subjective reporting or questionnaire),
and ways of assessment (prospective versus retrospec-
tive). The results revealed that, of 79 publications on
drug treatment, 43 studies involved serotonergic anti-
depressants. It was clearly demonstrated that single-
blind or open studies and studies using a questionnaire
or subjective report on the ejaculation time led to a
higher variability in ejaculatory delay. Only eight
studies
3,6,8,27,28,3739
fullled all criteria of evidence-
based medicine, e.g., prospective double-blind studies
using real-time stopwatch assessments at each inter-
course both at baseline and during the drug trial. For
daily treatment similar efcacy for paroxetine, clom-
ipramine, sertraline, and fluoxetine has been demon-
strated, whereas that for paroxetine was found to be
clearly stronger than all aforementioned drugs. Based
on this metaanalysis paroxetine appears to have the
strongest ejaculation delaying effects.
36
OPERATIONAL DEFINITION OF
PREMATURE EJACULATION
For evidence-based research it is of utmost importance
to have a denition of premature ejaculation. How-
ever, due to conflicting ideas about the essence of pre-
mature ejaculation, sexologists have never reached an
agreement on a denition.
DSM-IV
40
denes premature ejaculation as per-
sistent or recurrent ejaculation with minimal sexual
stimulation before, upon, or shortly after penetration
and before the person wishes it. Until recently, any
scientic basis for the DSM-IV denition was lacking.
For instance, the meaning of persistent, recurrent,
minimal, and shortly after is vague and certainly
needs further qualication. In order to get an empiri-
cally operationalized denition, Waldinger et al.
investigated 110 consecutively enrolled men with life-
long premature ejaculation.
41
In this study, men and
their female partners were instructed to use a stop-
watch at home during each coitus for a period of
4 weeks (Fig. 3.1). It was found that 10% of these men
ejaculated between 1 and 2 min but that most
(90%) ejaculated within 1 min of intromission: 80%
actually ejaculated within 30 s, whereas 60% ejaculated
within 15 s. The age of the men and duration of their
relationship did not correlate with the ejaculation time.
Based on this study, Waldinger and coworkers empiri-
cally dened lifelong premature ejaculation as ejacu-
lation that is less than 1 min in more than 90% of
episodes of sexual intercourse, independent of age and
duration of relationship.
41
It must be noted that this
denition denes premature ejaculation as being an
early ejaculation that is independent of psychological
or relationship distress. Thus, assessment by stopwatch
revealed that premature ejaculation is a matter of
seconds and not of minutes. In this respect the ICD-10
denition (ejaculation before or within 15 s) seems
more appropriate than the DSM-IV denition, but both
need to be adapted to these recent data.
NEW THEORY OF PREMATURE
EJACULATION
Waldinger and Olivier
10,26
formulated a new theory on
the etiology and genesis of lifelong premature ejacu-
lation. Waldinger postulated that lifelong early ejacu-
lation is not an acquired disorder due to habituation
of initial hurried intercourses, as has been suggested
by Masters and Johnson. Instead, early ejaculation is
postulated to be part of a normal biological variability
of the intravaginal ejaculation latency time (IELT) in
men, with a possible familial genetic vulnerability.
10,18,26
The IELT is dened as the time between vaginal
penetration and intravaginal ejaculation.
5,6
According
to Waldinger, early ejaculation is primarily a neuro-
biological phenomenon, that may or may not lead
secondarily to psychological or psychosocial distress.
Dependent of intra- and interpersonal and probably
also cultural factors, early ejaculation may be perceived
as premature ejaculation. Both animal and large-scale
human epidemiological stopwatch studies are needed
to demonstrate the existence of a biological continuum
of the IELT.
Based on animal and human psychopharmacological
studies, Waldinger and coworkers further postulated
that lifelong premature ejaculation is related to
decreased central serotonergic neurotransmission, and
5-HT
2C
receptor hyposensitivity and/or 5-HT
1A
receptor
hypersensitivity.
10,19,42
Treatment should therefore
consist of 5-HT
2C
receptor stimulation and/or 5-HT
1A
receptor inhibition.
Evidence for the role of the 5-HT
2C
receptor has
been found in four stopwatch studies in men with
premature ejaculation.
6,27,28,37
It was demonstrated that
5-HT
2C
receptor-stimulating and 5-HT
2C
-blocking anti-
depressants exerted an ejaculation delay and absence
of ejaculation delay, respectively.
EJACULATION THRESHOLD
HYPOTHESIS
In order to understand the suggested biological vari-
ation in IELT in relation to the serotonergic system,
delaying effects of SSRIs, and suggested genetics,
Waldinger et al. have proposed the existence of a
threshold of the IELT.
10,26
Where the threshold setpoint is low, men only sustain
little sexual arousal prior to ejaculation.Whatever these
men do or fantasize during intercourse, any control of
ejaculation remains marginal and these men ejaculate
easily, even when they are not fully aroused. The low
threshold is assumed to be associated with a low 5-HT
neurotransmission and probably a hypofunction of the
5-HT
2C
receptor and/or hyperfunction of the 5-HT
1A
receptor, as mentioned earlier.
Where the setpoint is higher, men experience more
control over their ejaculation time. They can sustain
more sexual arousal before ejaculating. In these men
5-HT neurotransmission varies around a normal or
averaged level and the 5-HT
2C
receptor functions
normally. The mean and range values of the setpoints
that are considered to be normal or averaged are not
known. These men have the neurobiological ability
voluntarily to decide to ejaculate quickly or after a
longer duration of intercourse.
Ejaculation Threshold Hypothesis 35
Figure 3.1 Intravaginal
ejaculation latency time (IELT)
measured with a stopwatch in
110 men with lifelong premature
ejaculation. Ninety percent of
men ejaculated within 1 min of
vaginal penetration: 80%
ejaculated within 30 s.
(Reproduced with permission
from Waldinger MD, Hengeveld
MW, Zwinderman AH et al. An
empirical operationalization study
of DSM-IV diagnostic criteria for
premature ejaculation. Int J
Psychiatry Clin Pract 1998;
2:287293.)
IELT (s)
N
o
.

o
f

s
u
b
j
e
c
t
s
0
010
1120
2130
3140
4150
5160
6170
7180
8190
91100
101110
111120
121130
131140
141150
151160
161170
171180
30
5
10
15
20
25
Where the setpoint is high or very high, men may
experience difculty in ejaculating or cannot ejaculate
even when fully sexually aroused. At a high setpoint
5-HT neurotransmission is supposed to be increased,
5-HT
2C
receptor sensitivity is enhanced, and/or 5-HT
1A
receptor sensitivity is decreased.
According to this threshold hypothesis, it appears to
be the level of 5-HT
2C
and 5-HT
1A
receptor activation
that determines the setpoint and associated ejaculation
latency time of an individual man. In case of men with
premature ejaculation or any man using serotonergic
antidepressants, the SSRIs and clomipramine activate
the 5-HT
2C
receptor and therefore switch the setpoint
to a higher level, leading to a delay in ejaculation. The
effects of SSRIs on the setpoint appear to be individu-
ally determined; some men respond with an intense
delay while others experience only a small delay at the
same drug dose. Moreover, stopping treatment results
in uniform resetting of the setpoint within 35 days to
the lower individually determined reference level, that
is assumed to be genetically determined.
It is speculated that the threshold is mediated by
5-HT neurotransmission and 5-HT receptors in the
brainstem or spinal cord and may consist of serotonergic
bers that inhibit neurons conveying somatosensory
information from the genitals. It is suggested that SSRIs
enhance the inhibitory effects of these serotonergic
neurons. However, the cerebral cortex may also mediate
inhibitory impulses, but this has not yet been demon-
strated. Apart from a suggested SSRI-induced increased
inhibition of sensory input, the SSRIs may also delay
ejaculation by interfering with spinal cord motoneurons
of peripheral neurons that inhibit the internal genitals.
Further studies are needed to unravel this important
and intriguing question.
COURSE OF RAPIDITY
It is generally believed that aging delays ejaculation.
This assumption may be true for men with a normal or
average ejaculation time but has never been inves-
tigated in men with premature ejaculation. In a stop-
watch study
41
of 110 consecutively enrolled men (aged
1865 years) with lifelong premature ejaculation, 76%
reported that, throughout their lives, their speed of
ejaculation had remained as rapid as at their rst
sexual contacts in puberty and adolescence; 23%
reported that it had even become gradually faster with
age and only 1% reported that it had become slower.
From these data it is questioned whether the xed
rapidity and even paradoxical shortening of the ejacu-
lation latency time while getting older should be recog-
nized as part of the pathogenetic process of premature
ejaculation. According to Waldinger, early ejaculation
is part of a normal biological variation in IELT in men,
but its paradoxical or xed course through life is
considered as pathological. Chronic premature ejacu-
lation appears to be the clinical syndrome of primary
(lifelong) premature ejaculation.As yet, there is no real
cure for lifelong premature ejaculation, although drugs
may alleviate the symptoms, but only as long as they
are being taken.
NEUROANATOMY
Together with an increasing number of clinical studies
on the psychopharmacological treatment of premature
ejaculation, there has been an increasing amount of
evidence from animal neuroanatomical and neuro-
pharmacological studies that (early) ejaculation is
regulated by various areas in the central nervous
system, and that the rapidity of ejaculation is controlled
by neurotransmitters, such as 5-HT and dopamine, in
specic areas in the central nervous system.
Most knowledge of the functional neuroanatomy of
ejaculation is derived from male rat studies.With regard
to male rat copulatory behavior, one has to distinguish
between brain, brainstem, and spinal cord regions that
become activated before and after ejaculation, when
sensory information returns from the genitals (Fig. 3.2).
The medial preoptic area (MPOA) in the rostral hypo-
thalamus and the nucleus paragigantocellularis (nPGi)
in the ventral medulla
43,44
are suggested to play an
important role in the process leading to ejaculation.
Electrical stimulation of the MPOA promotes ejacu-
lation.
45
It is hypothesized that ejaculation is tonically
inhibited by serotonergic pathways descending from
the nPGi to the lumbosacral motor nuclei. The present
hypothesis is that the nPGi itself is inhibited by inhibi-
tory stimuli from the MPOA. Disinhibition of the nPGi
is supposed to lead to ejaculation. The discovery of
serotonergic neurons in the nPGi and the well-known
ejaculation delay induced by serotonergic anti-
depressants suggests an action of the SSRIs on the
nPGi. However, the precise location in the central
nervous system on which SSRIs act to inhibit ejacu-
lation has not yet been demonstrated.
On the other hand, brain areas activated as a result
of the occurrence of one or more ejaculations have
been observed in several mammals.
46
Using expression
of the immediate early gene, c-fos, as a marker for
neural activity in male rats, Coolen and coworkers
4650
demonstrated the presence of distinct ejaculation-
related neural activation in several brain regions
following ejaculation; the posteromedial part of the
bed nucleus of the stria terminalis (BNSTpm), a lateral
subarea in the posterodorsal part of the medial
amygdala (MEApd), the posterodorsal preoptic nucleus
(PD) and the medial part of the parvicellular sub-
parafascicular nucleus (SPFp) of the thalamus. These
brain regions containing ejaculation-induced acti-
vation are extensively interconnected and reciprocally
connected with the MPOA,
49
forming an ejaculation-
related subcircuit within the larger brain circuits under-
lying male sexual behavior.
49
The functional signicance
of this ejaculation subcircuit is still poorly understood
but it may be that these areas play a role in satiety
and thus mediating the postejaculatory interval.
Recently an important study by Truitt and Coolen
50
highlighted the role of the lumbar spinal cord in the
processing of ejaculation. They identied a group of
lumbar spinothalamic cells (LSt) that are specically
activated after ejaculation and provide direct genital
sensory inputs to the SPFp in the thalamus and the
ejaculation-related subcircuit in the brain. The LSt
cells also project to sympathetic and parasympathetic
neurons related to the genitals. It is suggested that the
LSt cells contribute to triggering the ejaculatory reflex
and to the sensation of ejaculation, i.e., orgasm.
These and other animal studies have clearly shown
the existence of a neural circuitry for ejaculation in
mammals. The role of the recently identied LSt cells
for premature ejaculation remains to be elucidated.
Data of fundamental animal research remain basic for
understanding the neurobiological underpinnings of
early ejaculation.
Interestingly, a neurophysiological study
51
showed
shorter latencies and greater amplitudes of somato-
sensory evoked potentials from the (glans) penis in
men with lifelong premature ejaculation compared to
matched normal controls. This study and studies with
sacral evoked potentials
5254
may suggest a sensoric
hyperexcitability. Currently, a key issue for research is
the question of whether early ejaculation is due to a
higher excitability in the genital part of the somato-
sensoric cortex (sensoric input side) or due to an
inability to delay ejaculation (motoric output side), or
both.
Brain imaging studies (e.g., positron emission
tomography scan studies) in humans are needed to
unravel the neural substrate of the ejaculatory process
in men and may contribute to a better understanding
of which part of the neural circuitry is disturbed in
premature ejaculation.
PREMATURE EJACULATION AND
GENETICS
In 1943 Schapiro noted that men with premature ejacu-
lation seemed to have family members with similar
complaints.
14
Remarkably, this interesting observation
has never been cited. To investigate the potential
familial occurrence of premature ejaculation I routinely
asked 237 consecutively enrolled men with premature
ejaculation about the family occurrence of similar
complaints.
18
Due to embarrassment only 14 men con-
sented to ask male relatives about ejaculation latency.
These 14 men reported a total of 11 rst-degree male
relatives with information available for direct personal
interview. In fact, 10 relatives fullled our strictly
Premature Ejaculation and Genetics 37
Figure 3.2 Medial preoptic area
(MPOA). Areas in the central
nervous system that are involved
prior to, during, and after
ejaculation. Somatosensory bers
reach the somatosensory cortex.
Efferent pathways run from the
hypothalamus down to the sacral
spinal cord and genitals. After
ejaculation, information is
conveyed from the genitals to
the spinal cord and various
areas in the cerebrum. MEApd,
posterodorsal part of the medial
amygdala; PD, posterodorsal;
BNSTpm, posteromedial part of
the bed nucleus of the stria
terminalis; SPFp, parvicellular
subparafascicular nucleus; nPGi,
nucleus paragigantocellularis;
LSt, lumbar spinothalamic cells.
Somatosensory cortex
MEApd PD
Thalamus
SPFp
Motor output
Sensory input
after ejaculation
Hypothalamus
MPOA (rostral area)
Brainstem
nPGi
BNSTpm
Lumbosacral spinal cord
Genitals
Glans penis
Pudendal nerve Sympathetic nerve
Dorsal nerve
Ejaculation Tactile stimulus
LSt-cells
S
o
m
a
t
o
s
e
n
s
o
r
y

t
a
c
t
i
l
e

i
n
p
u
t
dened criterion of an ejaculation time of 1 min or
less. In this small select group of men the calculated
risk of having a rst relative with premature ejaculation
was 91% (condence interval 5999). Therefore, the
odds of family occurrence is much higher than the
suggested population prevalence rate of 439%. More-
over, the high odds ratio indicates a familiar occur-
rence of the syndrome which is far higher than of
chance alone. Based on this preliminary observation
the influence of genetics gains substantial credibility.
18
TREATMENT
Drug treatment for early ejaculation
In 1943 Bernard Schapiro
14
described the use of
topical anesthetic ointment to delay ejaculation. The
use of anesthetics to diminish the sensitivity of the
glans penis is probably the oldest treatment for pre-
mature ejaculation.
In 1973 the rst report of successful ejaculation
delay by clomipramine was published.
1
However, in
the 1970s and 1980s, drug treatment of premature
ejaculation was not very popular. The introduction of
the SSRIs meant a revolutionary change in the approach
to and treatment of premature ejaculation. SSRIs
encompass ve compounds (citalopram, fluoxetine,
fluvoxamine, paroxetine, and sertraline) with a similar
pharmacological mechanism of action. In 1994 the rst
double-blind study was reported on the ejaculation-
delaying effect of paroxetine.
5
In the last decade all
other SSRIs and clomipramine have repeatedly been
investigated in their propensity to delay ejacu-
lation.
39,3739,5566
There is some evidence that
fluvoxamine and citalopram have less effect in
delaying ejaculation than paroxetine, sertraline, and
fluoxetine.
6,37
Although the methodology of the initial drug treat-
ment studies was rather poor, later double-blind and
placebo-controlled studies replicated the genuine effect
of clomipramine and SSRIs in delaying ejaculation.
In spite of a development towards more evidence-
based drug treatment research, most studies still lack
adequate design and methodology.
35,36,41,42,67
For the
interpretation of drug treatment studies it is important
to bear in mind that the outcome values of the ejacu-
lation time are dependent on both gender (e.g., assess-
ment by the male or his female partner) and method
(e.g., assessment by subjective reporting, questionnaire,
or stopwatch).
35,36,41,42,67
A recent systematic review
and metaanalysis of all drug treatment studies
36
per-
formed since 1943 clearly demonstrated that single-
blind and open design studies and studies using
subjective reporting or questionnaires showed a higher
variability in ejaculation delay than double-blind
studies in which the ejaculation delay was prospectively
assessed with a stopwatch. Of all 79 studies, only
12 studies (14.4%)
3,6,8,27,28,3739,6870,82
have been
performed according to the established criteria of
evidence-based medicine.
36
Nevertheless, in spite of the inaccuracy of most drug
treatment studies in assessing the delay accurately,
there are three drug treatment strategies for treating
premature ejaculation: (1) daily treatment with
serotonergic antidepressants; (2) as-needed treatment
with antidepressants; and (3) anesthetic topical
ointments.
Daily treatment with serotonergic
antidepressants
Daily treatment can be performed with paroxetine
(2040 mg), clomipramine (1050 mg), sertraline
(50100 mg), and fluoxetine (2040 mg). The recent
metaanalysis of all drug treatment studies has demon-
strated that paroxetine exerts the strongest ejaculation
delay.
36
Paroxetine, sertraline, and fluoxetine may give
rise to side-effects such as fatigue, yawning, mild
nausea, loose stools, or perspiration. These side-effects
often start in the rst week after intake and gradually
disappear within 23 weeks. Ejaculation delay with
daily treatment usually manifests itself at the end of
the rst or second week and sometimes even earlier.
With the exception of fluoxetine, it is advised not to
stop the SSRIs acutely but gradually within 34 weeks,
in order to avoid withdrawal symptoms. Side-effects of
clomipramine may consist of nausea, dry mouth, and
fatigue. Sometimes clomipramine and the SSRIs may
give rise to reversible feelings of diminished libido or
moderate decreased rigidity of the penis. It is advised
to inform patients about all aforementioned side-
effects when starting treatment.
As-needed treatment with antidepressants
Since 1993 only eight studies
4,7177
have been published
on as-needed (on-demand) treatment. Due to this
limited number of studies and to inadequate designs, a
metaanalysis was insufciently powered to provide
nal conclusions with regard to the difference in efcacy
and dose relationships.
36
In spite of these scientic
limitations it has been found that clomipramine
(1050 mg) taken minimially 46 h before intercourse
may be efcacious, lasting for at least 15 h. Another
strategy is the daily use of paroxetine, sertraline, and
fluoxetine in a low dose combined with as-needed
higher doses shortly before intercourse.
As-needed treatment with anesthetic
topical ointments
Only a few controlled studies have been performed
with anesthetic ointments. In one study, the results of
lidocaine (lignocaine)prilocaine cream 10 min before
intercourse have been reported.
78
In the Far East, good
results according to evidence-based studies were
published with SS-cream, a regionally manufactured
cream consisting of various herbs, taken 12 h before
intercourse.
69,7983
NEW DRUG DEVELOPMENTS
Currently, in spite of the very efcacious ejaculation-
delaying effect of paroxetine and clomipramine, these
drugs are not ofcially registered for the treatment of
premature ejaculation. The pharmaceutical companies
fabricating these antidepressants have never been
interested in obtaining such registration, as the
ejaculation-delaying effects were considered to be
unwanted sexual side-effects harming the marketing of
these drugs for the treatment of depression, anxiety
disorders, or obsessivecompulsive disorder. However,
currently some pharmaceutical companies have
become interested in developing new drugs to treat pre-
mature ejaculation. Such pharmaceutical involvement
is much welcomed as premature ejaculation has been
a neglected disorder in sexology for much too long.
There is a noticeable trend for on-demand treatment.
However, as 5-HT neurotransmission is lower after
acute SSRI administration than after chronic adminis-
tration, it is predicted that acute treatment with
selective 5-HT reuptake inhibitors is less effective in
delaying ejaculation than chronic treatment. The
challenge for new drug development is to manufacture
a drug that after acute administration will have an
equal or even stronger ejaculation-delaying effect than
is induced by chronic paroxetine treatment.
SUMMARY
Historically, four periods can be distinguished in the
approach to and treatment of lifelong premature ejacu-
lation. Although drug treatment has been an option for
many decades, psychotherapy has prevailed as rst-
choice of treatment. However, the application of
evidence-based medicine principles shows that there is
hardly any evidence to support the psychological
approach and efcacy of behavioral treatment. In
contrast, controlled trials with SSRIs, clomipramine,
and anesthetic ointments have repeatedly demonstrated
the efcacy of both daily and as-needed drug treat-
ment to delay ejaculation. Currently, an evidence-based
medical approach is gradually replacing the authority-
based medical attitude that characterized the view
of premature ejaculation. Based on pharmacological
studies there is evidence that premature ejaculation is
related to a diminished serotonergic neurotransmission,
and 5-HT
2C
or 5-HT
1A
receptor disturbances. More-
over, animal studies have demonstrated the presence
of a distinct ejaculation-related neural circuit in the
central nervous system. Its role in premature ejacu-
lation remains to be elucidated.
The rst choice of treatment should be drug treat-
ment. Metaanalysis has demonstrated that paroxetine
exerts the strongest delay. Psychotherapy is only
indicated for those men or couples who cannot cope
with or cannot accept early ejaculation.
10
In contrast
to the classical psychological view, the purpose of
psychotherapy, whether psychodynamic or cognitive,
is not how to delay ejaculation but how to cope with
early ejaculation.
10
Animal and large-scale human
epidemiological studies are needed to investigate the
hypothesis that early ejaculation is part of a normally
distributed biological continuum of the IELT in the
general male population.
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INTRODUCTION
Orgasm and ejaculation constitute the nal phase of
the sexual response cycle. Ejaculation is a reflex com-
prising sensory receptors and areas, afferent pathways,
cerebral sensory areas, cerebral motor centers, spinal
motor centers and efferent pathways. The ejaculatory
reflex is predominantly controlled by a complex inter-
play between central serotonergic and dopaminergic
neurons with secondary involvement of cholinergic,
adrenergic, oxytocinergic, and GABAergic neurons.
PHYSIOLOGY OF EJACULATION
There are three basic mechanisms involved in normal
ante-grade ejaculation emission, ejection and orgasm
(Table 4.1).
1
Ejaculatory dysfunction can result from
disruption at any point in this cascade of events.
Emission is the result of a sympathetic spinal cord
reflex initiated by genital and/or cerebral erotic stimuli.
Emission involves the sequential contraction of
accessory sexual organs and the sensation of emission
is due to distension of the posterior urethra. There is
considerable voluntary control of emission. As the sen-
sation of ejaculatory inevitability increases, voluntary
control progressively decreases until a point at which
ejaculation cannot be stopped is reached.
Ejection also involves a sympathetic spinal cord
reflex upon which there is limited voluntary control.
Ejection involves bladder neck closure to prevent retro-
grade flow, rhythmic contractions of bulbocavernous,
bulbospongiosus and other pelvic floor muscles, and
relaxation of the external urinary sphincter. Inter-
mittent contraction of the urethral sphincter prevents
retrograde flow into the proximal urethra.
2
Orgasm is
the result of cerebral processing of pudendal nerve
sensory stimuli resulting from increased pressure in
the posterior urethra, sensory stimuli arising from the
veramontanum and contraction of the urethral bulb
and accessory sexual organs.
The ejaculate can be divided into several fractions
by serial biochemical analysis.
3
It comprises secretions
from the seminal vesicles, prostate and bulbourethral
(Cowpers) glands, and spermatozoa. It is produced
when the combining the secretions of the prostate and
the contents of the ampullary parts of the vasa
deferentia, are washed out by fluid from the seminal
vesicles and expelled from the urethra.
4
The sperma-
tozoa are stored in the tails of the epididymides and
the vas deferens ampullae. Approximately 5080% of
the entire ejaculatory volume is contributed by the
seminal vesicles, 1530% by the prostate gland and a
small contribution is derived from the bulbourethral
(Cowpers) glands which is rich in enzymes and
plasminogen activator.
5
Spermatozoa normally consti-
tute less than 0.1% of the ejaculatory volume. The rst
fraction of the ejaculate contains the maximum number
of spermatozoa, and subsequent fractions contain
sequentially less. Acid phosphatase, citric acid and
zinc, emanating from the prostate, are also in highest
concentration in the initial fractions of the ejaculate.
Subsequent fractions contain fructose from the seminal
vesicles, which increases in concentration towards the
The Ejaculatory Response
Chris G. McMahon
CHAPTER 4
TABLE 4.1 The three mechanisms of normal
antegrade ejaculation.
Emission Sympathetic spinal cord reflex
Considerable voluntary control
Genital and/or cerebral erotic stimuli
Sequential contraction of accessory
sexual organs
Sensation due to distension of
posterior urethra
Ejection Sympathetic spinal cord reflex
Limited voluntary control
Bladder neck closure
Rhythmic contractions of
bulbocavernosus/pelvic floor muscles
Relaxation of external urinary sphincter
Orgasm Smooth-muscle contraction of
accessory sexual organs
Build-up and release of pressure in
posterior urethra
Contraction of urethral bulb
Cerebral processing of pudendal nerve
sensory stimuli
end of the ejaculatory process. The pH of the ejaculate
increases in successive fractions as the acid component
provided by the prostate is serially mixed with the
more alkaline contribution of the fructose-rich fluid
from the seminal vesicles.
NERVOUS CONTROL OF
EJACULATION AND ORGASM
The ejaculatory reflex comprises sensory receptors
and areas, afferent pathways, cerebral sensory areas,
cerebral motor centers, spinal motor centers and
efferent pathways (Fig. 4.1).
6
Sensory receptors and areas
The mucosa of the glans penis contains specialised
sensory receptors, KrauseFinger corpuscles. They dis-
charge along afferent nerves to the spinal cord and
brain when repetitive and cumulative stimulation
applied to the glans penis exceeds the excitation
threshold. Sensory information from the penile shaft,
perineum, testes and from variable extragenital
erogenic organs e.g., nipples, anal sphincter, modulates,
usually enhancing, afferent information from the
KrauseFinger corpuscles.
Afferent pathways
Sensory information from the glans penis travels along
somatic and autonomic afferent pathways to the spinal
cord. Sensory bers of the pudendal nerve, contained
within the dorsal nerve of penis extend to the S4 level
and autonomic bers within the hypogastric plexus
transmit information to the sympathetic ganglia
located along the spinal cord.
Cerebral control of ejaculation and
orgasm
Seminal emission and ejaculation are controlled by
the paraventricular nucleus (PVN) of the anterior
hypothalamus and the medial preoptic area (MPOA;
Fig. 4.2).
7
The medial preoptic area (MPOA) is located
rostral to the anterior hypothalamus and appears to
have a pivotal role in augmenting copulatory behavior.
7
Electrical stimulation of the MPOA can elicit seminal
emission or ejaculation in monkeys
8
and rats.
9
Electrical stimulation of the MPOA, also elicits the
urethrogenital reflex in rats, which may mimic orgasm
in humans.
10
This occurs in the absence of genital stimu-
lation. This reflex is usually elicited in anesthetized,
spinally transected rats by distending the urethra with
saline and then suddenly releasing the pressure. This
results in rhythmic ring of the hypogastric, pelvic,
and motor pudendal nerves and rhythmic contractions
of the perineal muscles, similar to those seen during
orgasm in humans.
Microinjection of moderate doses of a mixed D1/D2
dopamine agonist (apomorphine)
11
or of a pure D1
agonist (thienopyridene),
12
into the MPOA, promotes
erections and copulation of male rats, apparently by
44 The Ejaculatory Response
Figure 4.1 The ejaculatory reflex
comprises sensory receptors
and areas, afferent pathways,
cerebral sensory areas, cerebral
motor centers, spinal motor
centers and efferent pathways.
MPOA, medial preoptic area;
PVN, paraventricular nucleus;
nPGi, nucleus
paragigantocellularis.
Thalamus
Postejaculatory
sensory input
nPGi
MPOA
PVN
Sensory
Cortex
Cerebral
receptor areas
Cerebral
motor areas
S4
level
Dorsal nerve
of penis
Glans penis, genitals,
extragenital areas,
centers, spinal motor
centers and efferent
pathways
Afferent
pathways
Sensory
receptor areas
Sympathetic
nerves
Lumbosacral
spinal cord
Spinal motor
center
Efferent
pathways
Ejaculation
increasing parasympathetic tone. Higher doses of a
mixed D1/D2 agonist, or of a selective D2 agonist,
favour seminal emission and ejaculation.
12
Reduced
libido during the ejaculatory refractory period may
result from decreased dopamine release in the nucleus
accumbens, a major terminal of the mesolimbic
dopamine tract.
13
Dopamine is released in the MPOA
of male rats in the presence of an estrous female, and
increases more during copulation.
14
The levels of
extracellular dopamine in the MPOA may regulate the
phases of copulation, with high levels triggering
ejaculation.
There are no neurons that extend from the MPOA to
the lumbosacral spinal cord. Its facilitative effects are
possibly mediated by the periaqueductal gray (PAG) of
the midbrain, which receives input from the MPOA
and sends efferents to the lumbar spinal cord, and
by the PVN, which has direct reciprocal connections
to the MPOA. Stimulation of mixed D1 and D2
receptors
11, 15
or specically of D2 receptors
16
in the
PVN also increases the number of ex copula erections
and seminal emissions.
Neurons that contain a marker (neurophysin)
associated with oxytocin descend from the PVN to
the lumbosacral spinal cord,
17
where they may elicit
seminal emission/ejaculation.
In a series of elegant rat experiments involving selec-
tive pharmacologic and/or radiofrequency lesions, Liu
et al.
18
demonstrated that the parvocellular neurons of
the hypothalamic PVN mediates erectile function in
rats, whereas the magnocellular PVN neurons mediate
ejaculation. Oxytocinergic PVN neurons possibly
modulate the male sexual response as evidenced by
increased cerebrospinal fluid concentrations of oxytocin
after ejaculation, augmented male sexual behavior
following intraventricular administration of oxytocin
and decreased seminal emission in rats with lesions of
the parvocellular PVN neurons.
19
The MPOA is also of importance to the cholinergic
influence on sexual behavior. Injections of the cholin-
ergic agonists oxotremorine and carbachol cause a
stimulation of sexual behavior in male rats seen as a
reduced number of intromissions preceding ejacu-
lation, whereas injection of scopolamine reduces the
number of animals intromitting and ejaculating.
20
The paragigantocellular (nPGi) reticular nucleus in
the ventral medulla is a supraspinal locus of descend-
ing inhibitory influence on spinal nuclei mediating
ejaculatory reflexes in the male rat.
21
Approximately
78% of the descending neurons from nPGi are
serotonergic.
22
Lesions of the nPGi facilitate both the
elicitation of the urethrogenital reflex and reflexive
penile erections.
23
Selective serotonin neurotoxin
lesions of the nPGi or transection of the spinal cord
released the urethrogenital reflex from this tonic
inhibition allowing the reflex to be elicited by urethral
distension. However, stimulation of the MPOA can
elicit the reflex, even if the nPGi and spinal cord are
intact, suggesting that the MPOA may inhibit the
nPGi, as well as stimulating an excitatory site.
Spinal motor centers
Emission is controlled by the sympathetic nervous
system. The cell bodies of the sympathetic neurons are
located in the lateral columns of the gray matter in the
thoracolumbar segments of the spinal cord. Efferent
sympathetic nerves emerge from the ventral roots of
the spinal column at Th12L2 to reach the sympathetic
chains bilaterally (Fig. 4.3).
Nervous Control of Ejaculation and Orgasm 45
Preoptic
nucleus
Supraoptic
nucleus
Posterior
nucleus
Dorsomedial
nucleus
Ventromedial
nucleus
Mammillary
nuclei
Paraventricular
nucleus
Figure 4.2 The hypothalamus.
The nerves proceed via the thoracic sympathetic
chain to the caudal (inferior) enteric plexus, the major/
minor splanchnic nerves, the celiac/cranial mesenteric
plexuses, and the intermesenteric nerves. Descending
nerves from these ganglia encircle the aorta on each
side before joining in the midline to form the hypo-
gastric plexus just below the bifurcation of the aorta.
The nerves proceed via the lumbar sympathetic chain
and the lumbar splanchnic nerves to the caudal mesen-
teric plexus. The intermesenteric nerves and all lumbar
splanchnic nerves merge into the inferior mesenteric
and superior hypogastric plexuses. The former plexus
mainly innervates the colon via the colonic nerve and
from the latter arise paired hypogastric nerves. The
junction of the hypogastric nerve and the pelvic nerve
constitutes the pelvic plexus in the pelvis, which is
an integration of sympathetic and parasympathetic
nervous systems. The branches from this plexus inner-
vate the epididymis, vas deferens, seminal vesicle,
prostate, bladder neck, and urethra (Fig. 4.4).
24
Norepinephrine is released from the axon terminal
of the postganglionic neurons of the seminal tract in
response to sympathetic signals passing through the
hypogastric nerves. Norepinephrine activates smooth
muscle 1-adrenergic receptors causing a rise in intra-
cellular calcium, actinmyosin interaction, vas deferens
Figure 4.3 The pelvic sympathetic and parasympathetic nervous systems.
L5
L3
L4
White and gray
communicants
Gray ramus
communicans
Lumbrosacral
plexus
Pelvic nerves
(nerve 1 organizes)
sacral parasympathetic
Pudendal nerve
(somatic)
2nd lumbar sympathetic ganglion
Aortic plexus
Inferior mesenteric ganglion
Inferior mesenteric
artery and plexus
Hypogastric plexus
Superior hemorrhoidal
artery and plexus
Right pelvis plexus
Vasical plexus
Rectal plexus
Cavernous plexus
Corpus penis
smooth muscle contraction, a marked elevation of intra-
luminal pressure in the cauda epididymis/proximal vas,
and propulsion of spermatozoa out to the ampulla.
This ampullary wall distension and nerve signals trigger
contraction of the ampulla to emit the content into the
posterior urethra. Many substances including acetyl-
choline and neuropeptide-Y might modulate neuro-
transmitter release and/or the resting tone of the
smooth muscle of the vas deferens. Both nerve signal
and distention of the wall of the ampulla might trigger
contraction of the ampulla to emit the content into the
posterior urethra.
Retrograde axonal tracing methods demonstrate
that the majority of postganglionic neurons distributed
in the vas deferens originate from the pelvic plexus.
25
The pelvic plexus receives neural input from both the
hypogastric and pelvic nerves. Electrical stimulation
of the hypogastric nerve elicited contraction of the
vas deferens,
26,27
while stimulation of the pelvic nerve
caused no detectable motor responses.
27,28
Histo-
chemical studies of the vas deferens have also shown
that the adrenergic bers mainly innervate the smooth
muscle layers, whereas cholinergic bers chiefly inner-
vate the subepithelial layer.
1
Nervous Control of Ejaculation and Orgasm 47
Figure 4.4 The nerve supply to the bladder, vas deferens, and external genitals.
Great saphenous
nerve
Lesser splanchnic
nerve
Least splanchnic
nerve
Celiac ganglion
Superior mesenteric ganglion
Aorticorenal ganglion
Intramesenteric nerves
(aortic plexus)
Inferior mesenteric
ganglion
Informal spermatic
artery and plexus
Pelvic nerve
(nervus angens)
Sacral plexus
Dorsal nerve of penis
Epididymis
Testis
T10
T11
T12
L1
L2
L3
L4
S1
S2
S3
S4
S5
Hypogastric plexus
Pudendal nerve
Pelvic
plexus
Vesical
plexus
Prostatic plexus
Cavernous plexus
Vas deferens
Sympathetic
preganglions
Parasympathetic
preganglions
Afferent and
somate nerves
Sympathetic
postganglions
Parasympathetic
postganglions
Almost all the lumbar splanchnic nerves originate
from L2 and/or L3 lumbar sympathetic ganglia
(corresponding to L1L2 spinal levels).
24
Preservation
of the L2 and/or L3 lumbar splanchnic nerve in retro-
peritoneal lymph node dissection of testicular cancer
allows preservation of ejaculatory function.
29
Partial
interruption of the pathway from the spinal cord to the
seminal tract would be expected to cause insufcient
closure of bladder neck and retrograde ejaculation.
Complete interruption of the pathway is likely to
cause failure of emission.
The anatomical architecture of the peripheral
sympathetic nervous system suggests probable cross-
innervation and has been conrmed in the dog and
rat.
30
Some signals in the lumbar splanchnic nerve
cross to the other side of the body at the level of the
caudal mesenteric plexus and/or the pelvic plexus.
Preganglionic axons in the hypogastric nerve probably
provide a bilateral innervation to postganglionic
neurons in the pelvic plexuses, which also exhibit
crossing to the bilateral vasa deferentia.
30
The pudendal nerve arises from the S2S4 segments
of the sacral spinal cord and does not enter the pelvic
plexus, but exits the pelvis through the greater sciatic
foramen, re-enters it through the lesser sciatic foramen,
and innervates the perineal striated muscles (Fig. 4.1).
Rhythmic contractions of these perineal striated
musculature including the bulbocavernosus and ishio-
cavernosus muscles, propels the seminal fluid. Sacral
spinal cord injury patients usually show dribbling
ejaculation due to the lack of contribution of the
musculature.
Ejection is controlled by the parasympathetic
nervous system. Efferent somatic bers emerge from
the anterior horn of the S2S4 spinal segments (Onufs
nucleus), and travel in the motor branch of the pudendal
nerve to innervate the pelvic floor striated muscles
including the bulbospongiosus and bulbocavernosus
muscles. Rhythmic contractions of the bulbocavernosus,
ishiocavernosus and other pelvic floor striated muscles
propels seminal fluid into the urethra. These muscles
are innervated by the pudendal nerve and show excite-
ment during ejaculation. Shak measured the electro-
myographic (EMG) response of the bulbocavernosus,
ischiocavernosus muscles and the external urethral
sphincter during ejaculation induced by glans penis
vibration and demonstrated that the ejaculatory
mechanism consists of two distinct reflexes.
31
The
glansvasal reflex is responsible for the emission phase
and the urethromuscular reflex is responsible for the
ejection phases of ejaculation. In a further study in
dogs, Shak reported increased electrical activity of
the pelvic floor muscles and external anal (EAS) and
urethral sphincters (EUS) during electroejaculation.
32
He suggested that the increased puborectalis muscle
activity might express the prostatic secretions into the
posterior urethra, that levator ani contraction elevates
the prostate and partially straightens the prostato-
membranous urethral kink that might occur during
erection and that the EAS and EUS contractions are
believed to abort the urge to defecate or urinate and
prevent leak of faeces, flatus, or urine during coitus.
The rhythmic EUS contraction at ejaculation might act
as a suction ejection pump, sucking the genital fluid
into the posterior urethra while being relaxed and
ejecting it into the bulbous urethra upon contraction.
The marked elevation of blood pressure, tachy-
cardia, tachypnoea and perspiration that accompanies
ejaculation are probably elicited by catecholamines
secreted from the adrenal medulla. The adrenal
medulla receives sympathetic nerves via the thoracic
sympathetic chain and the major/minor splanchnic
nerves.
NEUROCHEMICAL CONTROL OF
EJACULATION
Dopamine and serotonin are important neurotrans-
mitters in the brain. Many studies have been conducted
to investigate the role of the brain in the development
and mediation of sexuality, and dopamine and
serotonin have been identied as essential neuro-
chemical factors.
Dopaminergic control
It has been known for a long time that treatment with
dopaminergic drugs has a signicant effect on the
sexual behavior of rodents. Kimura et al.
33
attributed
the dopaminergic system, particularly that in the
anterior hypothalamus, with a sexual facilitatory role.
Gessa and Tagliamonte
34
proposed the dopamine
positive/serotonin negative hypothesis. However,
dopamine/serotonin balance is more complex as
evidenced by the paradoxical hypersexuality of
spontaneous involuntary orgasm reported with some
members of the selective serotonin reuptake inhibitor
(SSRI) class of antidepressant drugs.
Five types of dopaminergic receptors have been
identied. On a pharmacological basis, these subtypes
have been divided into two families: the D1- and D2-
family. The D2 family has the most important thera-
peutic role and the D1- family might have an
important modulating effect on the D2-receptors. A
possible sexual response regulatory role of dopamine
is suggested by the observation that dopamine is
released in the MPOA of male rats in the presence of
an estrous female, and progressively increases during
copulation
13
eventually triggering ejaculation. In
addition, electrical stimulation of the MPOA, even in
the absence of genital stimulation, also elicits the
urethrogenital reflex in rats, resulting in sequential
ring of the hypogastric, pelvic, and motor pudendal
nerves and rhythmic contractions of the perineal
muscles, similar to those seen during orgasm in
humans.
Serotonergic control
Whereas dopamine, via D2 receptors, promotes
seminal emission/ejaculation, serotonin is inhibitory.
A potent vasoconstrictor, subsequently identied as
serotonin, was rst identied in the blood more than
100 years ago. An endogenous factor, enteramine was
found in the enterochromafn cells of the gut by
Erspamer in 1940.
35
This factor was subsequently
structurally identied as 5-hydroxytryptamine (5-HT),
found to be identical to the serum vasoconstrictor and
called serotonin.
36,37
Eighty percent of the total body serotonin is found
in the enterochromafn cells in the gastrointestinal
tract.
38
Peripheral 5-hydroxytryptamine acts as a vaso-
constrictor, platelet aggregator when released from
platelets, a neurotransmitter in he enteric plexuses of
the gut and as an autocrine hormone when secreted by
the enterochromafn cells in the gastrointestinal tract,
pancreas and elsewhere.
39
Circulating 5-HT is unable
to enter the brain as it cannot cross the bloodbrain
barrier.
The serotonergic system of the brain was initially
localized in the 1960s using FalckHillarp histo-
chemical techniques. More recently, the development
of antibodies against 5-HT and autoradiographic
techniques have permitted identication of detailed
5-HT receptor locations.
40
In 1979, Peroutka and
Snyder
41
rst identied different 5-HT receptors using
radioligand binding technology. Currently, at least
16 different receptors have been characterised, e.g.,
5-HT1a, 5-HT1b, 5-HT2a, 5-HT2b, etc. Although the
function and localization of many of these receptors is
becoming increasingly clear, much remains unknown.
Serotonergic neurons are widely distributed in brain
and spinal cord and are predominantly found in the
brainstem, raphe nuclei and the reticular formation.
There are two different groups of serotonergic neurons.
A rostral group with cell bodies located in the mid-
brain and rostral pons project their axons into the
forebrain. A second caudal group of serotonergic
neurons with cell bodies in medulla project their axons
into spinal cord.
The rostral part of the 5-HT system comprises the
caudal linear nucleus, the dorsal and median raphe
nuclei and the reticular formation of the pons and
midbrain. The caudal system contains the nuclei raphe
magnus, pallidus and obscurus, the adjacent reticular
formation, solitary nucleus and the nucleus
subcoeruleus.
42
The ascending projections from the rostral 5-HT
neurons comprises two parallel but functionally and
morphologically distinct pathways.
42
Projections that
arise from the median raphe nucleus and are called the
basket-axon system, comprise thick bers (M-bers)
that branch into short, thin bers and form multiple,
large, round boutons (varicosities) and extensive
synapses. The second system arises from the dorsal
raphe nucleus and has thin bers (D-bers) which
branch extensively and are characterized by multiple
fusiform-like boutons (varicosities) which do not seem
to contain any synaptic structures. Both systems are
extensively distributed throughout the brain. In the
cerebral cortex, both M- and D-bers coexist whereas
the striatum receives only ne D-bers and the gyrus
dentatus primarily receives the thick M-bers.
The caudal raphe nuclei project to the caudal brain
stem and spinal cord. The raphe magnus nucleus pre-
dominantly projects to the dorsal horn of the spinal
cord. The nuclei pallidus and obscurus project to the
ventral horn, intermediate zone and the intermedio-
lateral cell column of the thoracolumbar and sacral
spinal cord. Most of the afferent projections to the
caudal raphe nuclei arise from the mesencepthalic
periaqueductal grey area and the medial cell groups of
the hypothalamus and preoptic area, the so called
limbic system.
43
Serotonergic neurons use a variety of different
mechanisms to self-regulate their own activity. Synaptic
cleft 5-HT and 5-HT neurotransmission are regulated
by somatodendritic 5-HT1a autoreceptors, presynaptic
5-HT1B 1D autoreceptors and a 5-HT transporters
reuptake system (Fig. 4.5). Each of these mechanisms
is a negative-feedback system which reduces synaptic
cleft 5-HT and prevents over-stimulation of the
postsynaptic receptors. Somatodendritic 5-HT1a auto-
receptors are found in high concentrations on the cell
bodies and dendrites of serotonergic neurons in raphe
nuclei. They are activated by endogenous 5-HT and
cause a reduction in ring rate of 5-HT neuron and
reduced 5-HT neurotransmission. This endogenous
5-HT probably originates from somatodendritic release
as opposed from synaptic release. Administration of
the selective 5-HT1A receptor agonist, 8-OH-DPAT, to
rats lowers central 5-HT levels and causes male rats to
ejaculate at the rst or second intromission. Activation
of 5-HT1A receptors is attenuated or blocked by acti-
vation of 5-HT2C receptors. Presynaptic 5-HT1B 1D
autoreceptors also inhibit 5-HT release into synaptic
cleft.This receptor is linked to an inhibitory (GI protein)
transaction mechanism which blocks the release of
5-HT and blocks the release of 5-HT from axonal
vesicles, the exact mechanism of which has yet to be
identied.
Large numbers of 5-HT transporters (5-HTT) are
located predominantly on axonal terminals but also on
Neurochemical Control of Ejaculation 49
the serotonergic cell bodies and its dendrites and glial
cells. As 5-HT is released into the synaptic cleft from
presynaptic axonal vesicles, 5-HT transporters reuptake
and remove 5-HT from the synaptic cleft, preventing
overstimulation of the postsynaptic receptors. After
blockage of 5-HT transporters by selective serotonin
reuptake inhibitor class drugs (SSRIs), synaptic cleft
5-HT increases but is counteracted by activation of
5-HT1A autoreceptors which inhibit further 5-HT
release.
The cerebral serotonergic (5-HT) system exerts an
inhibitory role on ejaculation and male sexual activity
in the rat model. Serotonin is released in the anterior
lateral hypothalamus (LHA) of male rats at the time of
ejaculation.
44
In 1969, Tagliomonte et al.
45
reported
that the serotonin depletor, p-chlorophenylamine
(PCPA) promoted aggression, insomnia and aberrant,
often compulsive hypersexual behavior in rats suggest-
ing that the cerebral serotoninergic (5-HT) system
exerts an inhibitory role on male sexual activity in the
rat model. Microinjection of a SSRI into the LHA
delayed both the onset of copulation and also delayed
ejaculation after copulation had begun.
44
This parallels
the reported adverse effects of the SSRI class of anti-
depressant drugs, which include decreased libido and
delayed ejaculation/orgasm. Kondo and Yamanouchi
46
localized this inhibitory action to serotonergic neurons
in the median raphe nucleus. Lorrain et al.
44
suggested
that the observed increase in extracellular 5-HT in
both the anterior lateral hypothalamus and MPOA of
male rats following ejaculation, may inhibit subsequent
ejaculation and is responsible for the ejaculatory
refractory period. The postejaculatory decrease in
libido may result in part from decreased dopamine
release in the nucleus accumbens, a major terminal of
the mesolimbic dopamine tract.
14
Dopamine in the
nucleus accumbens has been related to motivation
and/or reward related to numerous behaviors, including
eating, drinking, copulation, and drug addiction. There-
fore, one site at which SSRI drugs may inhibit both
libido and ejaculation is the LHA.
While the nucleus accumbens probably mediates the
SSRI-induced decrease in libido, it probably does not
influence ejaculation directly. The structure mediating
that effect is not known; however, neurons from the
LHA do descend to the lumbar spinal cord, where the
neurons controlling genital reflexes reside.
Different 5-HT receptor subtypes may have
opposing effects on sexual function. In 1997, Ahlenius
and Larsson
47
reported that activation of 5-HT1a
receptors in male rats with a selective agonist shortens
the ejaculatory latency time. Hillegaart and Ahlenius
48
conrmed this but also reported that activation of
5-HT1b receptors inhibited male rat ejaculatory
behavior. Berendsen and Broekkamp
49
demonstrated
that activation of 5-HT1a receptors is attenuated or
blocked by activation of 5-HT2c receptors. More
recently, Rehman et al.
50
suggested that 5-HT1a
Figure 4.5 Synaptic cleft 5-HT
and 5-HT neurotransmission are
regulated by somatodendritic
5-HT1a autoreceptors,
presynaptic 5-HT1B 1D
autoreceptors and a 5-HT
transporters reuptake system.
Axon
Axonal
terminal
5-HTT
Synaptic cleft
Postsynaptic neuron
5-HTT
1F
1G
1Db
1Da
1B
1A 1F
7
6
1B
1D
1D
5
4
2B
2A 1E
2C
5-HT
5-HT
receptors at different locations (brain, raphe nuclei,
spinal cord, and autonomic ganglia) may modulate rat
sexual behavior in opposing ways.
GABAergic control
Several studies have identied an inhibitory and
regulatory role in sexual functioning in rats of gamma-
aminobutyric acid (GABA). Administration of GABA
or compounds that induce elevated levels of GABA
in the cerebrospinal fluid inhibits sexual behavior.
Elevated CSF GABA levels have been demonstrated
during the postejaculatory interval in male rats and
during weaning in female rats also suggesting an
inhibitory role (a). Benzodizepines, used in the treat-
ment of anxiety, are believed to exert their effect
through enhancement of GABAergic neurotrans-
mission. Diazepam inhibits sexual behavior in male
rats, suggesting a possible mechanism for anxiety
induced psychogenic sexual dysfunction.
51
It is estimated that 3040% of neurons in the CNS
use GABA as their primary neurotransmitter. GABA-
receptors are divided into two classes on a pharma-
cological basis: GABA
A
and GABA
B
. GABA-receptors
are distributed throughout the CNS, and it is estimated
that 3040% of neurons in the CNS use GABA as
their primary neurotransmitter. GABA
A
receptors are
probably tonically (and constantly) activated, while
GABA
B
receptors are activated only under certain
physiological situations.Activation of a GABA receptor
has an inhibitory effect on the target neuron, such that
a higher concentration of other neurotransmitters
(e.g., dopamine, serotonin) is required to achieve a
neurotransmission of the same intensity.
GABA
A
agonists inhibitory sexual behavior as
evidence by a reduced number of mounts and intro-
missions when these drugs are administered systemi-
cally or locally in to the medial preoptic area.
52
GABA
A
antagonists, on the contrary, have no effect on sexual
behavior when administered systemically but when
administered by microinjection direct in to the medial
preoptic area have a positive sexual effect and reduce
the ejaculatory latency time (as above). Male rats that
are non-copulators also achieve benet from GABA
antagonists. The GABA
B
receptor subtype also have
an important role in mediating GABAs inhibition of
sexual behavior. Systemic injection of the GABA
B
agonist, Baclofen results in a decrease in the number of
rat mounts, intromissions and erections.
51,52
Cholinergic control
Cholinergic receptors are divided into two classes:
muscarinic and nicotinic receptors. Although both are
found in almost all parts of the human body, the
nicotinic receptor is seen in particularly high concen-
trations at the neuromuscular junction, autonomic
ganglions and in the brain. Through its effect on
cognition and blood flow via its action on the
cholinergic system of the forebrain, nicotine regulates
and/or coordinates a large array of central nervous
system functions.
Administration of nicotinic receptor agonists such
as nicotine or carbachol or physostigmine, anticholin-
esterase inhibitor, potentiates cholinergic neurotrans-
mission and results in a reduction of sexual behavior
in rats. Low doses of nicotine have been reported to
cause elevated levels of serotonin in the brain. As
previously described, enhanced serotonergic neuro-
transmission most often results in an inhibition of
sexual behavior. Cholinergic antagonists such as
atropine or scopolamine, exert an inhibitory effect on
sexual behavior. Microinjection of scopolamine into
the ventricles of the brain, prolongs initiation of copu-
lation and reduces the number of intromissions and
ejaculation in rats.
51
Microinjection of the cholinergic
agonists oxotremorine or carbachol into the MPOA
causes a stimulation of sexual behavior in male seen as
reduced ejaculatory latency time.
Adrenergic control
The wide distribution of adrenergic receptors through-
out the peripheral and central nervous system makes
the adrenergic nervous system an essential part of the
mechanism that controls many different physiological
functions including sexual function. In the CNS, alpha-
adrenergic receptors are present throughout the brain,
while beta-1 and -2 receptors are found only in the
cortex and cerebellum. Although norepinephrine
effects both erection and ejaculation, it is difcult to
conclude whether peripheral or central neurotrans-
mission is essential in determining the direction of the
effect. It is reasonable to conclude that a cholinergic
adrenergic balance is essential to keeping sexual func-
tions in balance.As such priapism has been reported as
an adverse effect of alpha-adrenergic blockade with the
alpha-1 antagonists prazosin especially if cholinergic
activity is reduced or eliminated at the same time.
53
Prazosin has also been shown to increase the ejacu-
latory latency time and the postejaculatory interval in
both rats and humans.
THE ROLE OF NITRIC OXIDE
Nitric oxide (NO) is becoming recognized as one
of the important intracellular messengers in the
brain.
54,55
Several authors have reported that NO
might be involved in the regulation of emotional and
behavior.
5658
There is a possibility that brain NO is
involved in regulating male rat sexual behavior. Melis
et al. reported the role of NO in a specic brain
Neurochemical Control of Ejaculation 51
area on male copulatory behavior, especially penile
erection.
59,60
Sato et al. investigated the influence of
the extracellular nitric oxide (NO) level on male rat
copulatory behavior.
61
Microinjection of the NO pre-
cursor, L-arginine into the MPOA, induced signicant
elevations of extracellular NO and a increased male
copulatory behavior with signicant increase in mount
rates. Microinjection of the NO synthase inhibitor
N-monomethyl-L-arginine (L-NMMA) signicantly
reduced NO levels and inhibited copulatory behavior.
These ndings suggested that the elevation of extra-
cellular NO in the MPOA facilitates male copulatory
behavior of rats, whereas the decrease of NO reduces
their copulatory behavior.
There is a possibility that NO facilitates male
copulatory behavior through acceleration of dopamine
release. Lorrain and Hull
62
reported that micro-
injection of the NO precursor, L-arginine, into the
MPOA, increased the extracellular dopamine level.
Moreover, they showed the possible role of CGMP/NO
pathway in the control of dopamine release during
copulation.
63
They suggested that NO may play a role
in control of male copulatory behavior and tempera-
ture regulation through the modulation of monoamine
release. L-Glutamate elicits an intracavernous pressure
increase in the MPOA.
64
It increases NO production
by activation of NMDA receptors. This suggest that NO
in the MPOA directly promotes penile erection, and
supports a biological role of NO in the MPOA for
positive mediation of male sexual behavior
Hull et al. demonstrated that microinjection of the
NO synthase inhibitor, N-nitro-L-arginine methyl ester
(NAME) decreased the number of ex copula erections,
but also increased the number of ex copula seminal
emissions and decreased the latency to the rst
seminal emission.
65
The results indicate that not only
does nitric oxide promotes erection in intact male rats,
but may also inhibit seminal emission, probably by
decreasing sympathetic nervous system activity.
Kriegsfeld et al. reported that mice homozygous for
eNOS gene deletion have striking ejaculatory
anomalies.
66
A signicantly higher percentage of eNOS
gene deletion mice than normal controls ejaculated
during the testing period, requiring less stimulation
and few mounts and intromissions.
Intraperitoneal injection of pilocarpine caused a
dose-related seminal emission adult male rats.
67
The
seminal emission response to pilocarpine was greatly
reduced in atropinized animals, suggesting a cholinergic
effect. NAME, a nitric oxide synthesis inhibitor,
inhibited the pilocarpine-induced seminal emission,
which was reversed by L-arginine or by coinjection of
sodium nitroprusside. These results suggest that nitric
oxide mediates the inhibitory neurotransmission
responsible for seminal emission in pilocarpine-
stimulated rats.
Consistent with this, Giuliani et al. have demonstrated
that the specic type V isoenzyme phophodiesterase
inhibitor, sildenal, modies central DA-mediated
behavior in rats.
68
They also reported that sildenal
diminished both the ejaculation latency and the
inter-intromission interval in normal rats.
69
Following
castration, the effect of sildenal on copulatory func-
tion was not observed but as restored following testo-
sterone replacement.
It is also known that testosterone is fundamental for
a normal mating pattern, which is totally disrupted by
castration and can be restored by the replacement of
the hormone. It has been suggested that testosterone-
induced activation is linked to increased synthesis
and/or release of DA in the brain
70
and NO could be
the bridge between testosterone and DA for copulatory
behavior.
FUNCTIONAL BRAIN IMAGING
DURING SEXUAL AROUSAL
The recent develop of functional brain imaging tech-
niques such as positron emission tomography (PET)
and more recently, functional magnetic resonance
imaging (fMRI) have made it possible to investigate the
cerebral events that occur during sexual arousal,
erection and ejaculation.
In spite of the limited amount of research into the
vents that occur during sexual arousal. First, electro-
encephalographic (EEG) studies of healthy right-
handed volunteers presented with visual sexual stimuli
demonstrated an increased right-to-left temporal
activity asymmetry, i.e., a pattern of right temporal
activation.
71
Similarly, greater right-hemisphere
involvement was demonstrated on EEG in right-hand-
dominant method actors able to generate feelings of
sexual arousal and depression under laboratory
conditions.
72
A similar increased right-to-left hemi-
spheric activity asymmetry was also found during
nocturnal penile tumescence (NPT) during rapid eye
movement (REM) sleep.
73
Second, a study using single
photon emission computed tomography (SPECT) to
image the brain during orgasm in right-handed men,
demonstrated an increased regional cerebral blood
flow (rib) limited to the right prefrontal cortex.
74
Third,
there have been multiple studies of various kinds of
epileptic seizures accompanied by diverse sexual mani-
festations. In partial epileptic seizures with bilateral
genital sensations accompanied by fear or pleasure,
the discharge was located through stereo electro-
encephalography in the right or left temporal regions
and in limbic structures (amygdala, hippocampus,
pararhinal region). In another type of seizure, the
clinical signs are essentially motor with the patient
grasping his genitals and initiating pelvic thrusting.This
kind of seizure has been related to a discharge arising
in the anterior part of the cingulate cortex.
75
Fourth,
neurosurgical or pathological lesions of the brain have
provided a limited understanding of the cerebral cor-
relates of human sexual behavior. Neurosurgery, like
EEG studies, has demonstrated the involvement of
temporal lobes in the control of human sexual
behavior. Following the bilateral removal of temporal
lobes in a case of temporal epilepsy in a 19-year-old
male, the patient presented with hypersexuality,
exhibitionistic behavior, masturbation in front of
others, emergence of homosexual behavior, but a loss
of heterosexual desire.
76
Frontal lobes have been
reported to exert an inhibitory control on sexual
arousal, as indicated by an increased sexual desire
after frontal lobotomy
77
and by a disinhibited sexual
behavior after lesions of the orbitofrontal cortex.
In the 1960s and 1970s, neurosurgical unilateral
destructions of hypothalamic nuclei were performed in
West Germany in male volunteers with the purpose of
suppressing sexual behaviors such as pedophilia and
rape. Such lesions were placed in areas extending from
the medial preoptic area (MPOA) rostrally to the
ventromedial nucleus caudally. In animal studies, the
MPOA has been implicated in the male copulatory
pattern of mounting and pelvic thrusting, whereas the
ventromedial nucleus has been found to be involved in
lordosis, a sexual behavior typical of female animals.
After these operations, several men, showed not only
a decreased sexual behavior but also a decreased sexual
desire and less sexual fantasy. However, the results of
these studies are difcult to interpret, given the purely
psychological impact of the neurosurgical procedure.
78
Furthermore, in animals unilateral lesions have been
ineffective. Finally, the involvement of septal nuclei has
also been implicated in the control of sexual arousal in
human males; however, the evidence remains limited.
79
Although the studies mentioned above have
provided useful insights into the cerebral correlates of
human sexual behavior, they suffer from the use of
comparatively imprecise technology (such as EEG) or
from the difculty to extrapolate from complex patho-
logical conditions (such as epileptic seizures) to healthy
cerebral functioning.
Stoleru et al. rst reported on the role of PET to
identify brain areas activated in healthy males in
healthy males experiencing visually evoked sexual
arousal.
80
Eight male subjects underwent six measure-
ments of regional brain activity as they viewed three
categories of lm clips: sexually explicit clips, emotion-
ally neutral control clips, and humorous control clips
inducing positive but nonsexual emotions. Visually
evoked sexual arousal was characterized by a threefold
pattern of activation: the bilateral activation of the
inferior temporal cortex, a visual association area; the
activation of the right insula and right inferior frontal
cortex, which are two paralimbic areas relating highly
processed sensory information with motivational
states; and the activation of the left anterior cingulate
cortex, another paralimbic area known to control
autonomic and neuroendocrine functions.
Redoute et al. used PET to investigate responses of
regional cerebral blood flow (rCBF) in nine healthy
males presented with visual sexual stimuli of graded
intensity.
81
The claustrum, a region whose function had
been unclear, displayed one of the highest activations.
Additionally, activations were recorded in paralimbic
areas (anterior cingulate gyrus, orbitofrontal cortex),
in the striatum (head of caudate nucleus, putamen), and
in the posterior hypothalamus (Fig. 4.6). By contrast,
decreased rCBF was observed in several temporal
areas. Based on these results, we propose a model of
the brain processes mediating the cognitive, emotional,
motivational, and autonomic components of human
male sexual arousal.
Bocher et al. reported similar ndings with acti-
vation of bilateral, predominantly right, inferoposterior
extrastriate cortices, the right inferolateral prefrontal
cortex and the midbrain.
82
Regional blood flow cor-
related well with the patients subjective assessment of
the level of sexual arousal.
Functional Brain Imaging During Sexual Arousal 53
A B
Figure 4.6 Regional cerebral
blood flow (rCBF) determined by
positron emission tomography
(PET) during sexual arousal.
(A) Parasagittal section (4 mm
left of midline) showing increased
regional cerebral blood flow
(rCBF) in the left anterior cingulate
gyrus. (B) Coronal section
demonstrating increased rCBF in
(a) Anterior cingulate gyrus;
(b) head of caudate nucleus
(c) claustrum (d) putamen.
81
Copyright 2000 John Wiley &
Sons Inc. Reprinted by permission
of Wiley-Liss, Inc., a subsidiary of
John Wiley & Sons, Inc.
Compared with PET, fMRI is non-invasive, has
superior spatial resolution; permits focus on single
subject ndings where appropriate as opposed to
reliance on pooled data and most importantly has
substantially higher signal-to-noise ratios enabling
superior temporal correlation between brain activation
and peripheral response.
The importance of olfactory sexual stimulation was
demonstrated in a fMRI in male common marmoset
monkeys presented with the scents of both ovari-
ectomized and ovulating monkeys.
83
The sexually
arousing odors of the ovulating monkeys enhanced
signal intensity in the preoptic area and anterior hypo-
thalamus compared to the doors of ovariectomized
monkeys.
Park et al. investigated relationships between brain
activation and sexual response using fMRI.
84
This study,
which used a 1.5T scanner and blood oxygenation
level-dependent (contrast) (BOLD) fMRI, involved 12
males with normal sexual function (mean age 23 years)
and two hypogonadal males. Erotic and nonerotic lm
clips were alternated. Findings included activation in
seven of the 12 healthy subjects associated with erotic
segments in the inferior frontal lobe, cingulate gyrus,
insula, corpus callosum, thalamus, caudate nucleus,
globus pallidus and inferior temporal lobe (Fig. 4.7).
Hypogonadal men had signicantly lower activation of
these areas, which increased to that seen in normal
controls following testosterone replacement.
Arnow at al. used fMRI to further examine the
relationships between brain activation and sexual
response in a group of young, healthy, heterosexual
males exposed to video material consisting of explicitly
erotic (E), relaxing (R) and sports (S) segments in an
unpredictable order.
85
Data on penile turgidity was
collected using a custom-built pneumatic pressure cuff.
Strong activations specically associated with penile
turgidity were observed in the right subinsular region
including the claustrum, left caudate and putamen,
right middle occipital/middle temporal gyri, bilateral
cingulate gyrus and right sensorimotor and premotor
regions. Smaller, but signicant activation was observed
in the right hypothalamus.
To date, all functional studies have focused on the
identication of the cerebral events that occur during
sexual arousal and erection in both normal and, to a
lesser extent, dysfunctional men. Functional MRI
studies also offer the opportunity to study the specic
cerebral events that occur in late arousal and at
ejaculation/orgasm in normal men and in men with
ejaculatory dysfunction.
CONCLUSION
The key to sexual pharmacology is an indepth under-
standing of the central neurotransmitter mechanisms
responsible for erection and ejaculation. An untapped
opportunity exists for research into the pharmaco-
logical modulation of the ejaculatory threshold and
the treatment of ejaculatory dysfunction.
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References 57
INTRODUCTION
Ejaculatory dysfunction is one of the most common
male sexual disorders. The spectrum of ejaculatory
dysfunction extends from premature ejaculation (PE),
through delayed ejaculation to a complete inability to
ejaculate, anejaculation, and includes retrograde
ejaculation.
PHYSIOLOGY OF EJACULATION
There are three basic mechanisms involved in normal
antegrade ejaculation emission, ejection, and orgasm
(Table 5.1).
1
Ejaculatory dysfunction can result from
disruption at any point in this cascade of events.
Emission is the result of a sympathetic spinal cord
reflex initiated by genital and/or cerebral erotic stimuli.
Emission involves the sequential contraction of
accessory sexual organs and the sensation of emission
is due to distension of the posterior urethra. There is
considerable voluntary control of emission.
1
As the
sensation of ejaculatory inevitability increases, voluntary
control progressively decreases until a point at which
ejaculation cannot be stopped is reached. Ejection also
involves a spinal cord reflex upon which there is
limited voluntary control. Ejection involves bladder
neck closure to prevent retrograde flow, rhythmic
contractions of bulbocavernous, bulbospongiosus, and
other pelvic floor muscles, and relaxation of the
external urinary sphincter (Fig. 5.1). Intermittent
contraction of the urethral sphincter prevents retro-
grade flow into the proximal urethra.
2
Orgasm is the
result of cerebral processing of pudendal nerve sensory
stimuli resulting from increased pressure in the
posterior urethra, sensory stimuli arising from the
verumontanum, and contraction of the urethral bulb
and accessory sexual organs.
PREMATURE EJACULATION
PE is perhaps one of the most common male sexual
disorders and has been estimated to occur in 439% of
men in the general community.
37
The Diagnostic and
Statistical Manual of Psychiatry (DSM-IV) denes it
as persistent or recurrent ejaculation with minimal
sexual stimulation before, on or shortly after penetration
and before the person wishes it which is associated
with marked distress or interpersonal difculty.
8
Most of the community-based epidemiological studies
employed inconsistent and poorly validated denitions
of PE and true normative data are lacking. The true
prevalence of PE cannot be determined without
conducting a large community-based age-ranging
study involving stopwatch timing of the intravaginal
Ejaculatory Dysfunction
Chris G. McMahon
CHAPTER 5
TABLE 5.1 The three mechanisms of normal
antegrade ejaculation.
Emission
Sympathetic spinal cord reflex (T10L2)
Genital and/or cerebral erotic stimuli with
considerable voluntary control
Peristaltic contraction of epididymis and vas
deferens
Contraction of seminal vesicles and prostate
Expulsion of spermatozoa/seminal/prostatic fluid
into posterior urethra
Ejaculatory inevitability sensation resulting from
distension of posterior urethra
Ejection
Parasympathetic spinal cord reflex (S2S4)
Limited voluntary control
Rhythmic contractions of bulbocavernous/pelvic
floor muscles
Bladder neck closure
Relaxation of external urinary sphincter
Orgasm
Build-up and release of pressure in posterior urethra
Smooth-muscle contraction of accessory sexual
organs and urethral bulb
Sensation due to cerebral processing of pudendal
nerve sensory stimuli
ejaculation latency time (IVELT) and regarding PE as
ejaculation within 1 min of intromission.
The rst report of rapid ejaculation in the medical
literature appeared in 1887.
9
In 1901,Von Krafft-Ebing
described a case of abnormally rapid ejaculation.
10
The rst use of the term ejaculatio praecox was
attributed to Abraham in 1917.
11
During the early
decades of the twentieth century PE was generally
regarded as psychogenic and due to unconscious con-
flicts, fear, or psychological trauma.Treatment paralleled
this presumed psychogenic etiology and consisted of
classic psychoanalysis.
12
A small number of authors
suggested a variety of biogenic causes, including glans
penis hypersensitivity, abnormalities of the verumon-
tanum in the prostatic urethra, or a shortened preputial
frenulum. Treatment was etiology-specic and included
topical local anesthesia, electrocautery of the verumon-
tanum, or a frenulectomy/frenuloplasty.
The current classication of PE into primary (life-
long) and secondary (acquired) forms evolved from
the initial suggestion by Schapiro in 1943 that PE
was a psychosomatic disturbance.
13
He proposed that
PE was due to a combination of a psychologically
overanxious personality and an inferior ejaculatory
apparatus as a point of least resistance for emotional
pressure. Schapiro classied PE as either type B, a
continuously present tendency to ejaculate rapidly
from the rst act of intercourse, and type A, which
eventually led to erectile dysfunction. The behavioristic
view that chronic PE was the result of performance
anxiety related to a disturbing initial episode of rapid
ejaculation was rst proposed by Masters and
Johnson.
14
Most of the behavioral treatments currently
used are based on this premise.
Over the past 15 years, an increasing number of
publications have reported the pharmacological
treatment of PE with a variety of different medications
which act either centrally or locally to retard the
psychoneurological control of ejaculation and sub-
sequent orgasm. It is well established that major tran-
quilizers such as the phenothiazine Melleril and the
selective serotonin reuptake inhibitors (SSRIs) retard
ejaculation signicantly and will, in a small percentage
of men, result in anejaculation.
1517
The efcacy of
these drugs in delaying ejaculation combined with the
low side-effect prole made them rst-choice agents
for PE when administered on a daily as well as an on-
demand basis.
18,19
At the same time animal and sexual
psychopharmacological human studies attributed a
serotonergic genesis and possible genetic etiology to
the neurobiological view of PE.
2023
Dening premature ejaculation
Medical literature contains several one-dimensional
and multidimensional operational denitions of PE.
The lack of agreement as to what constitutes PE has
hampered basic and clinical research into the etiology
and management of this condition. Quantitative
measures of intercourse such as the IVELT, the number
of thrusts between penetration and ejaculation, the
extent of partner sexual satisfaction, and the patients
assessment of his voluntary control over ejaculation
have been described. All denitions of PE assume
heterosexual intercourse initiated by the male partner
and are limited to actual sexual intercourse, ignoring
other forms of non-coital sexual expression.
Number of thrusts
Operationalization of PE using the quantiable and
objective number of intravaginal thrusts between
penetration and ejaculation has been reported by
several authors.
2429
Segraves et al.
30
proposed ejacu-
lation prior to eight thrusts as a standard denition of
PE, whereas Fanciullacci et al.
25
suggested 15 thrusts
as a more appropriate dening limit. These denitions
were subjective, had neither a rational nor empirical
basis and no normative data were presented. Thrust
dimensions such as velocity, force, and depth and the
impact of other dimensions such as duration of fore-
play and menopausal status of partner, which might
influence the extent of partner arousal and vaginal
lubrication, were not discussed. Furthermore, thrust-
60 Ejaculatory Dysfunction
Figure 5.1 Nerves involved with emission and ejection.
Sympathetic nerves from T10 to L2 innervate the vas
deferens, prostate, and bladder neck, and contraction
results in emission and bladder neck closure . Somatic
nerve bers in the pudendal nerve arise from S2S4 and
innervate the pelvic floor musculature, the contraction of
which causes forceful ejection .
T10-L2
S2-S4
Vas
deferens
Testis
Ganglion
1
2
Prostate
Bladder
Pelvic
floor
counting and the use of other standards for self-
evaluation of ejaculatory control are likely to alter
baseline sexual behavior by promoting sexual anxiety,
spectatoring, and goal-oriented sexual behavior, all of
which might render the measures inaccurate.
Intravaginal ejaculatory latency time
Operationalizing PE using the length of time between
penetration and ejaculation, the IVELT forms the basis
of most current clinical studies on PE.There is consider-
able variance of the IVELT used to identify men with
PE, ranging from 1 to 7 min, and none of the denitions
offers any supportive rationale for their proposed cut-
off time or normative data.
3139
An average duration
of intercourse of 47 min was reported by Gebhard,
suggesting that ejaculation prior to 4 min after intro-
mission should be considered premature.
40
This
assumes that the average length of intercourse equates
to the preferred length of intercourse. Darling et al.
41
reported a preferred length of intercourse of over 11
min in a survey of over 700 women. Furthermore,
other authors have reported both shorter and longer
average lengths of intercourse.
42,43
Waldinger and Zwinderman reported IVELTs of less
than 30 s and less than 60 s in 77 and 90% of 110 men
with PE respectively.
29
McMahon reported similar
results in 1346 consecutive men with PE and mean
IVELT of 43.4 40.8 s (Fig. 5.2).
44
Ejaculation ante
portas (during foreplay) occurred on the majority of
occasions in 5.6% of men. Lifelong PE was present in
736 men (74.4%) and acquired PE was present in 253
men (25.6%). The average age at presentation for
treatment was 33.1 years and was similar for men
with lifelong and acquired PE (Fig. 5.3). In men with
Premature Ejaculation 61
Figure 5.2 The distribution of
intravaginal ejaculation latency
times (IVELTs) in 1346
consecutive men with premature
ejaculation (PE).
IVELT (s)
%

M
e
n

w
i
t
h

P
E
0
0 20 40 60 80 100 120 140 160 180
100
10
20
30
40
50
60
70
80
90
Figure 5.3 The age of
presentation of 1346 consecutive
men with premature ejaculation.
Age range (years)
%
0
<20
7.5
5.5
2030
18.5
32.4
3040
33.4
37.2
4050
16.2
17.4
5060
11.4
4
6070
9.6
3.2
>70
3.4
0.4
50
10
20
30
40
Lifelong
Acquired
acquired PE, 40.3% presented within 12 months of
the onset of symptoms, 26.2% within 15 years, and
33.5% after 5 years. Younger men with acquired PE
tended to present earlier for treatment, suggesting a
greater degree of bother in younger men.
Partner satisfaction
The inability to control and defer ejaculation until the
female partner was sexually satised on at least 50%
of intercourse attempts was proposed as a denition of
PE by Masters and Johnson.
14
Although the sexual
pleasure of both partners must be considered when
assessing the extent of sexual dysfunction, an inherent
problem exists in dening a man as dysfunctional
based on the sexual responsivity of his partner. What
constituted sexual satisfaction was not dened. Sexual
satisfaction may not always include orgasm and is
more an evaluation of the entire sexual interaction.
45
This denition assumes that sexual pleasure is linked
to the duration of intercourse. No rationale is offered
for the 50% cut-off gure. This denition implies that
any male whose female partner has difculty in reaching
orgasm should be labeled as a premature ejaculator.
Furthermore, it suggests that female partners should
achieve orgasm on 50% of intercourse episodes. This
denition is somewhat at odds with the report that
only 30% of women achieve orgasm during sexual
intercourse, regardless of the extent of their partners
ejaculatory control and latency. Some partners may
never achieve sexual satisfaction regardless of the
extent of their partners ejaculatory control and latency
and even after lengthy intercourse, whilst others may
achieve orgasm after relatively brief intercourse, lead-
ing to a potentially high incidence of false-negative
and positive results.
Voluntary control
Kaplan and other authors have suggested that an
inability to defer ejaculation voluntarily denes
PE.
26,4648
This denition has yet to be adequately
operationalized to allow comparison across subjects or
across studies. Confusion also exists as to exactly what
men must have voluntary control over. Kaplan et al.
regarded control over the actual ejaculatory reflex as
the basis of their denition.
26
Whilst there is little doubt
that ejaculation is the result of a spinal autonomic
reflex, it has yet to be empirically demonstrated that
the ejaculatory reflex can be brought under voluntary
control.
49
Furthermore, there is no clear evidence that
men with ejaculatory control are in fact controlling
their ejaculatory reflex. Contrary to Kaplan, Zilbergeld
took a more global approach to dening control,
regarding it as voluntary control over the entire process
of ejaculation achieved by modication of sexual
technique and behavior.
48
Grenier and Byers failed to
demonstrate a strong correlation between ejaculatory
latency and subjective ejaculatory control.
7,50
They
reported that some men with a brief IVELT reported
adequate ejaculatory control and vice versa, and
concluded that the dimensions of ejaculatory control
and latency are distinct concepts. Contrary to this,
Waldinger et al. reported a moderate correlation
between the IVELT and the feeling of ejaculatory
control.
29
The use of a combination of the control and latency
dimensions was rst reported by Strassberg et al. in
1990 and forms the basis of the DSM-IV denition
of PE.
8,33
Although this approach is somewhat of an
improvement over previous denitions in that it
acknowledges that PE may have aspects of both control
and latency, the lack of operationalization of the
control dimension and the lack of guidelines offering
a rationale for the use of age, novelty, situation, or
frequency of sexual activity diagnosing PE limits its
application.
The lack of a reliable operational denition for PE
severely limits clinical research into the understanding
of PE. Studies that fail to dene PE offer meaningless
or difcult-to-interpret results. In a recent metaanalysis
of 61 studies on PE published since 1963, Rowland
et al. reported that only 45 studies (74%) used a
denition of PE.
51
Quantiable objective or subjective
criteria for dening PE were used in only 22 studies
(36%) and only four studies (6.6%) had employed two
or more criteria. Seventy-eight percent of the subjects
studied had been self-identied as suffering from PE
but only 42% had presented for treatment. The lack
of a universally accepted operationalized denition
makes comparison of different studies difcult or
impossible as experimental group subjects in one study
may very well have been placed in the control group
of a second study.The ability to compare and generalize
study results requires the development of a uniform
operationalized multivariate denition of PE, including
the dimensions of latency and control. Both dimensions
should be dened, measured, and analyzed as con-
tinuous variables without arbitrary cut-off values. The
development of a nomogram of age-specic latency
and degree of ejaculatory control is an integral part of
the development of clinical research in ejaculatory
dysfunction.
THE ETIOLOGY OF RAPID
EJACULATION
Historically, attempts to explain the etiology of PE
have included a diverse range of biogenic and psycho-
logical theories (Table 5.2). Most of these proposed
etiologies are not evidence-based and are speculative
at best. Psychological theories include the effect of
early experience and sexual conditioning, anxiety,
sexual technique, the frequency of sexual activity, and
psychodynamic explanations. Biogenic explanations
include evolutionary theories, penile sensitivity, central
neurotransmitter levels and receptor sensitivity, degree
of arousability, the speed of the ejaculatory reflex, and
the level of sex hormones.The lack of an operationalized
denition for PE and the presence of methodological
problems related to the inadequate denitions used
are common flaws in the majority of these studies.
Anxiety
Anxiety has been reported as a cause of PE by multiple
authors and is entrenched in the folklore of sexual
medicine as the most likely cause of PE despite scant
empirical research evidence to support any causal
role.
26,27,48,52,53
Several authors have suggested that
anxiety activates the sympathetic nervous system and
reduces the ejaculatory threshold as a result of an
earlier emission phase of ejaculation.
26,52
Strassberg et al.
33
used a multivariate denition of
PE incorporating both latency and control dimensions
and failed to demonstrate any difference in sexual
anxiety between a control group of men with normal
ejaculatory control and men with PE. Kockott et al.
reported that men with PE and low levels of sexual
anxiety ejaculated rapidly during both intercourse and
solitary masturbation.
54
Men with PE and high levels
of sexual anxiety, however, ejaculated rapidly only
during sexual intercourse and had superior ejaculatory
control during solitary masturbation. This study
contained several methodological flaws which make
interpretation of results difcult. Anxiety was only
measured during sexual intercourse and not during
solitary masturbation and was subjectively self-
evaluated by the patient and not by an objective
validated inventory. Furthermore, anxiety levels in a
control group of men with normal ejaculatory control
were not examined.
Isolated anecdotal reports suggest a potential role
for anxiolytic medication in the treatment of PE.
Segraves
55
reported the successful treatment of a 71-
year-old man with primary PE with the benzodiazepine
lorazepam, whereas Cooper and Magnus
31
failed to
distinguish any difference in ejaculatory latency times
of men with PE at baseline or following treatment with
the -blocking drug propranolol or placebo.
The possibility that high levels of anxiety and
excessive concerns about sexual performance and
potential sexual failure might distract a man from
monitoring his level of arousal and recognizing the
prodromal sensations that precede ejaculatory inevi-
tability has been suggested as a possible cause of PE by
several authors.
26,48,53,56
The causal link between
anxiety and PE is speculative, is not supported by any
empirical evidence, and is in fact contrary to empirical
evidence from other researchers. No difference in either
subjectively or objectively measured sexual arousal or
sexual sensory awareness was found between men with
PE and men without PE in a laboratory setting.
3234
In
direct contradiction to this theory, Kockott et al. found
that men with severe PE demonstrated higher objec-
tive and subjective measures of arousal than men with
erectile dysfunctions or normal control subjects.
54,57
This study was limited, however, to solitary stimulation
without ejaculation, making extrapolation of results
to ejaculation during sexual intercourse difcult. All
published studies ignore the possibility that the
presence of anxiety in men with PE may just as likely
be the result of PE as the cause, and fail to establish
the direction of the presumed causal relationship.
Early sexual experience
Masters and Johnson were the rst of several researchers
to suggest that early sexual experiences characterized
by anxiety and rush might condition men to develop
a subsequent pattern of rapid ejaculation.
14,58
How-
ever, no empirical evidence was offered to support this
hypothesis and no distinction was made between men
with lifelong PE and men with acquired PE. All
researchers failed to recognize that anxiety and rush
dene the early sexual experiences of most men.
Furthermore, the early sexual histories of a control
group of men with subsequent normal ejaculatory
control were not examined to determine whether early
conditioning experiences are unique to men with PE.
Williams reported a small case series of four men with
acquired PE and suggested that some men might
initially condition themselves to ejaculate quickly due
to their perception that their partner was sexually
The Etiology of Rapid Ejaculation 63
TABLE 5.2 Proposed etiologies of premature
ejaculation.
Psychogenic Anxiety
Early sexual experience
Frequency of sexual intercourse
Ejaculatory control techniques
Evolutionary
Psychodynamic theories
Biological Penile hypersensitivity
Hyperexcitable ejaculatory reflex
Arousability
Endocrinopathy
Genetic predisposition
5-Hydroxytryptamine receptor
dysfunction
uninterested, and remain subsequently unable to
control ejaculation when the initial negative circum-
stances were no longer present.
52
The resultant sexual
anxiety and concern about the legitimacy of the
partners renewed sexual interest might serve to
maintain the PE.
Frequency of sexual intercourse
The evidence to support a link between ejaculatory
control and frequency of sexual activity is conflicting.
Speiss et al.
32
reported that the frequency of sexual
activity in men with PE is lower than age-matched
controls with normal ejaculatory control, whereas
Strassberg et al.
34
failed to demonstrate any relation-
ship. The mechanism of this relationship is yet to be
characterized but may include reduced performance
anxiety, a higher ejaculatory threshold, or superior
ejaculatory control due to earlier and superior recog-
nition of prodromal ejaculatory sensations. Consistent
with these observations, McMahon and Touma, in a
placebo-controlled cross-over study of the efcacy of
paroxetine in treating PE, reported that the pretreat-
ment frequency of sexual intercourse increased from
0.5 to 3.2 times per week with paroxetine but fell to
pretreatment levels with placebo.
19
The observation
that men with PE may develop a pattern of sexual
avoidance may also explain this reduced frequency of
sexual intercourse, indicating that the polarity of the
relationship between PE and frequency of sexual
activity remains undetermined.
57
EJACULATORY CONTROL
TECHNIQUES
Zilbergeld suggested that some men with adequate
ejaculatory control might consciously learn a variety
of effective sexual techniques for deferring ejaculation
during their early sexual experiences and unconsciously
continue to use those techniques subsequently.
48
These
techniques may include thought distraction, pelvic floor
muscle contraction, or alteration of the speed and/or
depth of penile vaginal thrusting. Data to support this
hypothesis are weak and studies to evaluate the use
and effectiveness of control techniques in men with PE
are lacking.
Evolutionary
Hong suggested that PE was the result of evolutionary
natural selection, arguing that rapid intercourse allowed
insemination of more females with transmission of
a possible genetic basis for PE to more offspring.
59
The observation that primate courtship and sexual
contact are often extended is inconsistent with this
hypothesis.
60
Psychodynamic theories
Abraham was the rst to suggest a psychodynamic
basis of PE. He theorized that PE was the adult
manifestation of unresolved and excessive narcissism
during infancy which resulted in exaggerated import-
ance being placed on the penis and the associated
pleasure of urination.
11
He offered no empirical basis
for this theory and subsequent studies by other
authors have failed to demonstrate any evidence for
his narcissism hypothesis.
13
Kaplan et al. initially
theorized but later recanted a link between male anger
and hostility towards women and PE, suggesting that
the man both symbolically soils the woman and
denies her sexual pleasure as a result of an unconscious,
deep-seated hatred of women.
26,56
Penile hypersensitivity
Multiple authors have proposed that men with PE
have a hypersensitive penis and either reach ejacula-
tory threshold more rapidly or have a lower ejacula-
tory threshold than men with normal ejaculatory
control.
13,33,61,62
A limitation of the universal
applicability of this theory is its inability to explain
acquired PE.
Xin et al. demonstrated that men with PE have
lower biothesiometric vibration perception thresholds
and signicantly shorter mean somatosensory evoked
potential latency times of the glans and penile shaft
than controls.
63,64
Paick et al.
65
and Rowland et al.,
66
however, were unable to reproduce these ndings,
reporting no signicant statistical differences between
normal controls and patients with primary PE. Several
authors have reported that penile sensitivity reduces
with aging.
62,67,68
This is probably due to loss of the
fastest conducting peripheral sensory axons from the
third decade, dermal atrophy, myelin collagen inl-
tration, and pacinian corpuscle degeneration.
65
Some
researchers have suggested this observation as the
reason why PE is reported more often in younger
men.
53
However, a more attractive explanation of this
observation is the presence of greater anxiety and less
frequent sexual activity in the absence of a long-term
relationship resulting in fewer sexual opportunities to
learn ejaculatory control. Fanciullacci et al. measured
signicantly higher-amplitude cortical somatosensory
evoked potentials following penile electrical stimulation
in men with severe lifelong PE compared to control
subjects.
25
They hypothesized that men with PE have
a greater representation of the penile sensory nerve
supply in the cerebral cortex than controls, and
suggested this as an indication of an organic basis for
PE. Consistent with this is the report by Yang and
Bradley that the cortical distribution of the dorsal
nerve of the penis is larger in men with lifelong PE.
69
Brain imaging with functional magnetic resonance
imaging and positron emission tomography is required
in humans to identify the central control of the ejacula-
tory process in man.
Research into the relationship between PE and
penile hypersensitivity has effectively excluded the
impact of other factors which may affect the level of
arousal achieved and the time required to reach, and
the level of, the ejaculatory threshold. These factors
include the extent of use of fantasy and other forms of
non-contact stimulation. If penile sensitivity were, in
fact, a cause of PE, men with PE would be expected to
ejaculate more quickly than controls only in situations
where there was direct stimulation of the penis.
Hyperexcitable ejaculatory reflex
Several authors have suggested that PE is due to a
defective and premature ejaculatory reflex with a faster
emission and/or expulsion phase. Several authors have
reported a link between PE and a malfunctioning
bulbocavernosal reflex (BCR). The bulbocavernosus
muscle (BCM) surrounds the urethral bulb and is one
of several muscles responsible for the expulsive phase.
This hypothesis lacks a rm physiological basis, as the
emission phase of the ejaculatory process has already
started by the time the BCM contracts.
Gospodinoff suggested that a faster BCR might
impede the process of learning to control ejaculation.
49
One of the most common treatments for PE, the
squeeze technique, is based on the assumption that PE
is due to a defective ejaculatory reflex.
70
Colpi et al. demonstrated that men with lifelong PE,
dened as ejaculating within 15 thrusts of penetration,
have higher-amplitude sacral evoked potentials
measured through perineal and perineal surface
electrodes compared to age-matched controls.
24
They
concluded that men with PE have a hyperexcitable
BCR. However, the sacral evoked potential latency in
men with lifelong PE did not differ from age-matched
controls, which is inconsistent with this conclusion.
Similar results were reported by Fanciullacci et al.
25
A shorter BCR latency time in men with lifelong PE
compared to men with acquired PE and normal
controls was, however, reported by Gospodinoff.
49
Unlike Colpi et al., Gospodinoffs study groups were
not age-matched and the cohort of men with acquired
PE were 13 years younger than men with lifelong PE,
suggesting that the difference in these two groups could
be due to age-related degeneration of the afferent and
efferent nerves of the BCR. In addition, men with
acquired PE had a longer BCR latency time than
controls, which is at odds with the suggestion that PE
is due to a hyperexcitable ejaculatory reflex.
Arousability
Laboratory studies using solitary stimulation during
audiovisual stimulation have failed to demonstrate
greater, more frequent, or more rapid arousal in men
with PE compared to a control group of sexually non-
dysfunctional men.
32
Abnormal levels of sex hormones
Although there are several reports of a possible link
between PE and levels of sexual hormones, a careful
review of the published literature fails to conrm any
causal link. Pirke et al. failed to demonstrate any
difference in the levels of free and total testosterone
and luteinizing hormone (LH) during serial sampling
between men with PE, erectile dysfunction, or normal
controls.
71
Cohen, however, reported that levels of free
and total testosterone, LH, and follicle-stimulating
hormone (FSH) were reduced in men with PE. He also
reported that four of 12 men with PE had elevated
prolactin levels and suggested that PE may be the
result of a hypothalamicpituitary disorder.
72
He sub-
sequently reported that pharmacological treatment of
PE with an SSRI-class drug improved ejaculatory
latency and elevated androgen and LH levels.
73
Genetic predisposition
A familial predisposition to PE was rst reported by
Schapiro in 1943.
13
Waldinger et al. reported that 10
of 14 rst-degree male relatives of men with lifelong
PE also suffered from PE, with an IVELT of less than
1 min.
23
Based on this small study, the odds ratio of a
familial occurrence of PE far exceeds the incidence in
the general community and supports Schapiros con-
tention that PE may have a genetic basis.
5-Hydroxytryptamine receptor sensitivity
The current understanding of the functional neuro-
anatomy and the role of central serotonin (5-HT) and
dopamine neurotransmission in ejaculation are based
on male rat studies. The hypothalamic medial preoptic
area (MPOA) and the medullary nucleus paragiganto-
cellularis (nPGI) in the ventral medulla have pivotal
roles in the central control of ejaculation.
74,75
Electrical
stimulation of or microinjection of dopamine agonists
into the MPOA promotes ejaculation.
76
It has been
suggested that descending serotonergic pathways from
Ejaculatory Control Techniques 65
the nPGI to the lumbosacral motor nuclei tonically
inhibit ejaculation and that disinhibition of the nPGI
results in ejaculation.
77
The prevalence of serotonergic
neurons in the nPGI and the observation that SSRI-
class drugs inhibit ejaculation suggest that the nPGI is
a possible site of action of these drugs.
78
Coolen et al.
identied ejaculation-initiated neural activation in
several brain regions after ejaculation, including the
posterodorsal medial amygdala, the posteromedial bed
nucleus of the stria terminalis, and the medial parvi-
cellular subparafascicular nucleus of the thalamus.
7981
It is likely that afferent neurons ascend in the spinal
cord to the medial parvicellular subparafascicular
nucleus and the other brain areas mentioned and
activate ejaculation. These areas are extensively and
reciprocally interconnected and probably form the
basis of an ejaculation brain circuit.
81
Multiple dopamine and 5-HT receptor types have
been identied. Studies using highly selective 5-HT
receptor agonists and antagonists have identied a
pivotal role of 5-HT2C and 5-HT1A receptors in the
central control of ejaculation. Stimulation of the
5-HT2C receptors in male rats with non-selective
5-HT2C agonists such as D-lysergic acid diethylamide
and quipazine delays ejaculation.
82
In contrast to this,
activation of postsynaptic 5-HT1A receptors by the
selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-
propylaminotetralin) in male rats facilitates ejaculation.
82
Waldinger et al. hypothesizsed that lifelong PE in
humans may be explained by either hyposensitivity of
the 5-HT2C and/or hypersensitivity of the 5-HT1A
receptor.
83
They suggested that men with low 5-HT
neurotransmission and probable 5-HT2C receptor
hyposensitivity may have their ejaculatory threshold
genetically set at a lower point and ejaculate quickly
and with minimal stimulation, and often prior to reach-
ing their erectile threshold. Men with a genetically
determined higher set point can sustain more prolonged
and higher levels of sexual stimulation and can exert
more control over ejaculation. Finally, men with a very
high set point may experience delayed or absent
ejaculation despite prolonged sexual stimulation and
achieving a full erection.
84
Treatment with an SSRI-
class drug will activate the 5-HT2C receptor, adjust the
ejaculatory threshold set point, and delay ejaculation.
The extent of ejaculatory delay may vary widely in
different men according to the dosage and frequency
of administration of SSRI and the genetically deter-
mined ejaculatory threshold set point. Cessation of
treatment results in reestablishment of the previous set
point within 57 days in men with lifelong PE.
Identication of the specic 5-HT receptor subtypes
involved in PE is only possible by administering
subtype-selective 5-HT2C or 5-HT1A receptor ligands.
Unfortunately these agents are not yet available for
human use.
TREATMENT
Psychosexual counseling
In many marriages PE causes few, if any, problems. In
others, the couple may reach an accommodation of the
problem through various strategies young men with
a short refractory period may often experience a
second and more controlled ejaculation during a sub-
sequent episode of lovemaking while many other men
with PE learn to help their spouse reach an orgasm in
other ways. Frequently, however, PE eventually leads
to signicant problems in the relationship; the spouse
comes to feel the sexual relationship is completely
one-sided, regards her husband as selsh, and develops
a pattern of sexual avoidance. This only worsens the
severity of the prematurity on the occasions when
intercourse does occur. Arguments may ensue, worsen-
ing the mans preexisting anxiety and often leading to
the emergence of secondary erectile dysfunction, with
each partner feeling hurt and rejected as the marriage
begins to crumble. Because of the risk of the develop-
ment of secondary erectile dysfunction due to per-
formance anxiety, it is important to recognize and
treat PE early.
The cornerstone of treatment is the Semans stop
start maneuver.
70
Whilst there is some disagreement
over why it works, the fact that it works is beyond
dispute. It has been theorized that PE occurs because
the man fails to pay sufcient attention to preorgasmic
levels of sexual tension. The Semans maneuver was
designed to teach men with PE to monitor the sensa-
tions immediately premonitory to orgasm and reduce
or slow their thrusting sufciently to allow the sensa-
tions to subside. Treatment unfolds over a period of
several weeks. The wife is instructed to stimulate her
supine partners penis until he signals to her that he is
very close to orgasm. She stops, waits until he signals
signicant reduction in preejaculatory sensation, and
resumes manual stimulation. This process is repeated
through several cycles before the man is permitted to
ejaculate. After several successful practice sessions
without accident, the couple is instructed to use a
lubricant such as a jelly.Through the training experience
the man is instructed to focus only on his penile sensa-
tions, not to worry about whether his wife is tired or
bored, and to avoid fantasy. When he has learned
extravaginal ejaculatory control, insertion is permitted
in the female-superior coital position. Initially she
uses slow thrusting until he signals her to stop. She
remains motionless until he signals readiness to resume
thrusting. Gradually he begins to thrust. Each time he
reaches a level of excitement premonitory to ejacula-
tory inevitability, he is instructed to signal the need for
another pause. After several cycles of this kind he is
permitted to thrust to climax. This process is repeated
on three or more occasions and when substantial
control has been achieved, other coital positions may
be tried, utilizing the same cyclic stopstart process.
It appears crucially important that couples who have
undergone treatment for PE continue to practice the
Semans maneuver from time to time, perhaps for many
years following treatment. A failure to do so may put
the man at high risk of recurrence of symptoms.
The Semans maneuver was modied by Masters
and Johnson, who encouraged the woman to give the
penis a hard squeeze for 34 s at the level of the
frenulum and the coronal ridge when the man signals
awareness of sensations premonitory to orgasm.
27
As
most men with PE are aware of their anxiety and the
sources of that anxiety tend to be relatively supercial,
treatment success with the Semans maneuver or
Masters and Johnsons squeeze technique is relatively
good in the short term. However, convincing long-term
treatment outcome data are lacking.
85,86
Many men decline psychosexual counseling for a
variety of reasons. Men may regard attending a
psychiatrist or psychologist as stigmatizing, may be
unable to devote the time required to attend several
counseling sessions, or may demand a quicker response
than psychosexual counseling is reported to offer.
Optimal results are highly dependent on the partici-
pation of the sexual partner in the counseling sessions
many men do not have a current partner or may
have a non-compliant sexual partner. Clearly, a signi-
cant treatment hiatus exists in the management of
PE which may be lled by pharmacological treatment.
Pharmacological treatment
PE may be treated pharmacologically with a variety
of different medications which act either centrally or
locally to retard the psychoneurological control of
ejaculation and subsequent orgasm. Their mechanism
of action usually involves increased central 5-HT
neurotransmission.
It is well established that major tranquilizers, such
as the phenothiazine Melleril and antidepressants,
particularly members of the SSRI class, will retard
ejaculation signicantly and, in a small percentage of
men, result in anejaculation (Fig. 5.4).
1517
Deveaugh-
Geiss et al. reported a complete failure of ejaculation
in 42% of 520 depressed patients treated with
clomipramine.
16
Monteiro et al. reported a similar
incidence with clomipramine (33%) whilst Patterson
reported a 75% incidence of anejaculation in fluoxetine-
treated depressed men.
17,87
From a chart review, Hsu
and Shen reported that 34 of 80 male patients had
reported loss of libido, ejaculatory dysfunction,
anorgasmia, and delayed ejaculation while receiving
the SSRIs fluoxetine, paroxetine, and sertraline for
depression.
88
SSRI-related delay in ejaculation has also
been reported in patients with anxiety and panic
disorders.
89
Montejo-Gonzalez et al. compared the
incidence of sexual adverse effects with different SSRIs
(fluoxetine, fluvoxamine, paroxetine, and sertraline) in
a longitudinal prospective and multicenter study of
152 depressed men.
90
They reported that paroxetine
provoked the most ejaculatory delay and that sexual
adverse effects tended to persist, with only 5.8% of
patients reporting complete resolution of sexual
adverse effects within 6 months of starting treatment.
Interestingly, there was a signicant increase in the
incidence of sexual adverse effects with direct patient
questioning (58%) versus spontaneously reported
(14%).These reports identify a high incidence of SSRI-
associated sexual adverse effects and underscore the
underreported nature of antidepressant-associated
sexual dysfunction in the drug manufacturers pre-
scribing information, which is due, in part, to the hypo-
active sexual desire of depressed patients, but also to
less than ideal initial clinical trial design.
Clomipramine
In 1979,Ahlenius et al. reported that the antidepressant
clomipramine prolonged ejaculatory latency in rats by
inhibition of central 5-HT uptake.
91
Colpi et al. failed
to demonstrate any signicant difference in values of
either latency times or amplitudes of sacral or dorsal
nerve somatosensory cortical evoked responses in
patients before and after treatment with clomipramine,
but did demonstrate a signicant difference in penile
sensory thresholds after treatment (P < 0.05).
92
Several anecdotal and controlled studies have
reported that clomipramine is efcacious in the treat-
ment of PE. Its efcacy is limited by a reported 515%
incidence of adverse reactions, which include drow-
siness, and less commonly dry mouth, blurred vision,
and other cholinergic side-effects. Steiger demonstrated
a dose-dependent reduction of nocturnal penile
tumescence in men treated with clomipramine, which
exceeded that expected from the observed marked
suppression of rapid eye movement sleep, although no
patients described erectile dysfunction.
93
Painful ejacu-
lation related to clomipramine has been anecdotally
reported.
94
In 1980, Goodman reported improved ejaculatory
control in nine of 16 men with PE following treatment
with clomipramine.
95
Girgis et al. reported similar
results but qualied his reported 51% response rate as
complicated by dose-related anticholinergic adverse
effects, reduced sexual desire, and genital anesthesia.
96
Segraves et al. reported a dose-dependent increase in
IVELT which was superior to placebo.
30
Althof et al. had
similar ndings, reporting 250% and 500% increases
in IVELT with doses of 25 and 50 mg, respectively,
and statistically signicant improvements in male and
female sexual satisfaction scores in a double-blind
placebo-controlled trial of 15 couples.
97
Montorsi et al.
Treatment 67
reported that 10 of 33 responders had maintained
improved ejaculatory control following withdrawal of
the drug.
98
Haensel et al. rst reported that on-
demand clomipramine taken 1224 h before antici-
pated sexual activity is more effective than placebo in
men with primary PE, but is ineffective in men with
both PE and ejaculatory dysfunction.
99
Strassberg et
al. subsequently reported that clomipramine at doses
as low as 25 mg taken on demand 34 h prior to
coitus was more effective than placebo in delaying
ejaculation in a laboratory setting using vibrotactile
stimulation.
100
In a comparative efcacy and safety study of
fluoxetine, sertraline, clomipramine, and placebo, Kim
and Seo reported that clomipramine and sertraline
caused a greater increase in ejaculation latency time
than fluoxetine or placebo, that patient sexual satis-
faction was signicantly higher with clomipramine, but
that the incidence of side-effects with clomipramine
was signicantly higher (P < 0.05) compared to that of
fluoxetine, sertraline, and placebo.
101
Selective serotonin reuptake inhibitors
The SSRIs enhance 5-HT neurotransmission and
activate 5-HT receptors by blocking presynaptic and
somatodendritic 5-HT reuptake transporter receptors.
They are primarily indicated in the treatment of
depression and are often associated with a variety of
sexual adverse reactions, including delayed ejaculation.
Results of several anecdotal case series or controlled
studies, indicating a role for SSRIs in the treatment of
PE, have been reported. Their action is assumed to
be central but Hseih et al. have demonstrated that
serotonin, fluoxetine, and clomipramine can reduce the
pressure response of the seminal vesicle to electrical
nerve stimulation of the lesser splanchnic nerve,
suggesting an additional peripheral action.
102
Figure 5.4 The chemical structure of serotonin and the selective serotonin reuptake inhibitors (SSRIs) clomipramine,
fluoxetine, sertraline, and paroxetine.
Serotonin
Setraline Paroxetine
Clomipramine Fluoxetine
O
O
O
HO
F
NH
Cl
Cl
HN
Me
N
N
O
HN
Me
Ph
Cl
H
NH
2
NMe
2
CF
3
Berendsen and Broekkamp observed that the
responses to SSRIs in rats resembled 5-HT1c receptor
activation and suggested that SSRI-induced inhibition
of male ejaculatory dysfunction results from 5-HT1c
receptor stimulation.
103
In contrast to this, Hillegaart
and Ahlenius suggested that SSRI-induced inhibition
of male ejaculatory dysfunction is due to 5-HT1b
receptor stimulation.
104
However, SSRIs may have
differential effects on the various subpopulations of
serotonin receptors, e.g., fluvoxamine, in contrast to
other SSRIs, has little effect on ejaculatory latency.
Olivier et al. took a more balanced approach and
suggested that fluvoxamine actions are primarily
mediated via 5-HT1a receptors, whilst those of
fluoxetine and paroxetine are primarily mediated via
5-HT2c receptors.
21
After chronic administration of
an SSRI, Waldinger et al. suggested that a number of
adaptive processes, possibly including presynaptic
5-HT1a and 5-HT1b/1d receptor desensitization, may
play a role in achieving the observed greatly enhanced
5-HT neurotransmission (Fig. 5.1).
83
Kim and Seo compared the efcacy and safety of
fluoxetine, sertraline, clomipramine, and placebo in
46 men with PE and reported that clomipramine or
sertraline caused a greater increase in mean IVELT
than fluoxetine or placebo (P <0.01), that patient sexual
satisfaction rate after treatment with clomipramine
was signicantly higher, but that the incidence of side-
effects with clomipramine was signicantly higher
(P <0.05) compared to that of fluoxetine, sertraline,
and placebo.
101
Hsieh et al. evaluated the effect of
several drugs on PE using a rat animal model in which
the seminal vesicle was electrically stimulated via its
lesser splanchnic nerve and changes in the pressure
response were monitored.
102
Like serotonin, fluoxetine
and clomipramine reduced the pressure response of
the seminal vesicle to stimulation.
Fluoxetine
Fluoxetine achieves peak plasma concentrations within
68 h of administration and is metabolized in the liver
predominantly by demethylation to an active metab-
olite, norfluoxetine, which has equivalent potency and
selectivity as an SSRI to its parent molecule. Both
fluoxetine and norfluoxetine are slowly eliminated, the
former having non-linear pharmacokinetics, ensuring
signicant accumulation of both species with chronic
dosing and persistence of active drug for several weeks
after drug withdrawal.
105
In 1986, Renyi reported that fluoxetine signicantly
reduced the ejaculatory response in male rats when
administered 48 h before a non-selective 5-HT receptor
agonist.
106
Yells et al. also described an increase in
both ejaculation latency and postejaculatory interval
consistent with human ndings.
75
Contrary to these
earlier studies, Mos et al. failed to demonstrate any
major inhibitory effects of SSRIs on male rat sexual
behavior at non-sedative doses, observing only slightly
stronger effects with paroxetine and sertraline and, para-
doxically, facilitated sexual behavior with fluoxetine at
low doses.
107
Similar results were reported by Vega
Matuszcyk et al. and both groups concluded that
masculine sexual behavior in rats does not constitute a
suitable model to investigate the differential mechanism
of sexual inhibition of SSRIs that have been described
in human males.
108
As is the case with clomipramine, fluoxetine increased
penile sensory threshold values compared to pretreat-
ment and control groups (P < 0.05) but produced
no change in the amplitudes and latencies of sacral
evoked response and cortical somatosensory evoked
potential tests.
109
Crenshaw rst reported the efcacy
of fluoxetine treatment of PE, describing a dose-related
improvement in ejaculatory control in 46 men, with
some men maintaining improvement after withdrawal
of fluoxetine after 36 months of treatment.
110
Several
other authors have suggested a potential role for
fluoxetine in the treatment of PE.
111115
Graziottin
reported its efcacy in men with severe primary PE
who had never achieved intravaginal ejaculation, and
the occurrence of anxiety as a side-effect, which cleared
with concurrent use of a benzodiazepine.
114
Kindler et al. reported the efcacy of fluoxetine in
the treatment of comorbid panic disorder and PE.
116
Kara et al. in a double-blind placebo-controlled study
of fluoxetine demonstrated a sevenfold increase in the
ejaculatory interval which was noted as early as 1 week
after initiation of treatment.
115
Ejaculatory delay is
clearly an acute adverse effect of fluoxetine consistent
with rapid achievement of peak plasma concentrations
and prompt augmentation of 5-HT synaptic neuro-
transmission. Haensel et al., in a prospective, double-
blind, placebo-controlled, cross-over study of 40 men
with PE, combined PE/ejaculatory dysfunction, ejacu-
latory dysfunction alone, or a control group of normal
men, reported a signicant increase in ejaculation
latency time in the PE group and, in contrast to their
earlier ndings with clomipramine, the PE/ejaculatory
dysfunction group following treatment with fluoxetine,
a subjective but not objective improvement in erectile
function and no major adverse effects.
117
Fluoxetine is generally well tolerated by most
patients: adverse effects include drowsiness, insomnia,
anxiety and nausea and, less commonly, reduced sexual
desire and ejaculatory dysfunction. Anejaculation is a
dose-dependent adverse effect and may persist for
several weeks after drug withdrawal due to the slow
elimination of fluoxetine and its rst active metabolite.
There have been infrequent anecdotal reports of
fluoxetine-related prolonged erection and priapism
and spontaneous involuntary orgasm.
118,119
Treatment 69
Sertraline
Sertraline has a relatively long half-life of 26 h, allow-
ing once-daily dosing, promptly achieves peak plasma
levels within 46 h, and undergoes extensive rst-
pass metabolism to less active desmethylsertraline.
In addition to its selective 5-HT-inhibitory actions,
sertraline also appears to inhibit excitatory responses
through blocking dopamine receptors and effecting
amino acid s-receptors, and by downregulating central
adrenergic receptors.
120
The most common side-effects
are sexual and gastrointestinal, but a very occasional
patient will experience the agitation and tremor seen
with fluoxetine.
In 1994, Swartz rst reported that sertraline at doses
of 2550 mg daily improved the mean ejaculation
latency time to 20 min in a case series of 10 men with
PE.
121
Balbay et al. reported improved ejaculatory
control in 11 of 16 men after 1 week and in a further
three at the end of a second treatment week.
122
McMahon also reported the occurrence of improved
ejaculatory control and improved sexual satisfaction,
as evidence by subsequent increased frequency of
intercourse within 12 weeks, and a direct dose-related
increase in ejaculation latency time which may be
associated with anejaculation with doses of 50 mg
or higher.
123
Similar case series ndings have been
reported by Kaplan
124
and Wise.
125
Mendels et al.,
126
McMahon,
127
and Biri et al.
128
have conrmed superi-
ority to placebo in the treatment of PE in separate
controlled studies. McMahon also demonstrated a dose-
dependent superiority to placebo and reported that
staged drug withdrawal allowed 20 of the 29 patients
(67%) to discontinue treatment after a mean treat-
ment interval of 7.3 months yet maintain improved
ejaculatory control.
127
Waldinger et al., in a well-
designed 6-week placebo-controlled comparative study
of fluoxetine, sertraline, paroxetine, fluvoxamine, and
placebo in 60 men with severe PE, reported signicant
increases in ejaculation latency time compared to
placebo with fluoxetine, sertraline, and paroxetine but
not with fluvoxamine.
129
Paroxetine exerted the
strongest delay in ejaculation, followed by fluoxetine
and sertraline. In a second study which included some
men with less severe PE, they reported that percentage
increase in ejaculation latency time is independent of
the pretreatment ejaculation latency time, suggesting
that ejaculation-delaying side-effects of some SSRIs
may be generalized to men with less severe PE. As
discussed earlier, sertraline causes a greater increase
in ELT than fluoxetine and is better tolerated than
clomipramine.
101
Paroxetine
Paroxetine has a relatively long half-life of 24 h, also
allowing once-daily dosing, and achieves peak plasma
levels within 28 h, with steady-state systemic levels
occurring after 714 days.
130
Paroxetine selectively
inhibits 5-HT uptake in brain neurons, but, unlike
sertraline, has little afnity for dopamine receptors
and central adrenergic receptors. Its adverse-effect
prole parallels that of sertraline and drug interactions
with warfarin, tryptophan, and Dilantin have been
reported.
Waldinger et al. rst reported a signicant improve-
ment in ejaculatory control with paroxetine compared
to placebo in a double-blind study of 17 men with
PE.
18
In a subsequent study, Waldinger et al. demon-
strated that improved ejaculatory control achieved
with paroxetine was dose-related.
131
In an uncontrolled
study of 32 men with PE treated with 20 mg paroxetine
for 2 months, Ludovico et al. reported improved
ejaculatory control in all subjects, with recurrence of
symptoms in 28 men within 3 weeks of drug with-
drawal.
132
Reported adverse effects included sleepiness
(61%) and mild sensory confusion (68%). Giammusso
et al.,
133
McMahon and Touma,
134
and Isaksen
135
have
reported similar efcacy in uncontrolled case series
but fewer adverse effects because of the lower dose of
paroxetine employed (10 mg).
The use of on-demand paroxetine administered
34 h before planned coitus was rst reported by
McMahon and Touma
134
in an uncontrolled case series
of 94 men and later in a cross-over placebo-controlled
study of 42 men.
19
They reported a sevenfold increase
in ejaculation latency time with on-demand
paroxetine, which improved signicantly if patients
were initially treated with daily paroxetine for 3 weeks.
This ejaculatory recruitment is related to the greater
5-HT neurotransmission seen with chronic adminis-
tration and to the non-linear pharmacokinetics of
paroxetine. Paroxetine is a potent inhibitor of the
P450 2D6 enzyme, which is responsible for its rst-
pass metabolism, resulting in prolonged drug clearance
as the paroxetine concentration increases with multiple
dosing, and disproportionately greater increase in its
concentration with every dose.
136138
SSRIs are an effective treatment for 8085% of men
with PE. Most men will notice an increase in their
IVELT within 23 days and this increase will increase
by six- to eightfold and plateau after 34 weeks
treatment. Paroxetine, fluoxetine, sertraline, and clom-
ipramine appear to have similar efcacy in several
short-term and longitudinal studies (Fig. 5.5).
129,139,140
SSRIs are generally well tolerated. Adverse effects are
usually minimal and include minor drowsiness and
gastrointestinal upset. Side-effects usually attenuate and
disappear after 23 weeks treatment. The occasional
patient who experiences anejaculation with inappro-
priately high starting doses or too rapid dose titration
will respond to drug withdrawal and rechallenge at a
lower dose after a brief washout period. Minor hyper-
activity and anxiety are occasionally seen as transient
acute adverse effects; SSRIs are best avoided in patients
with current or controlled bipolar affective disorders
as frank mania may occur.
McMahon reported that men with lifelong PE
respond differently to SSRI drugs than do men with
acquired PE.Treatment with SSRI drugs was associated
with a signicantly lower IVELT in men with lifelong
PE compared to acquired PE after 24 weeks of treat-
ment (Fig. 5.6).
44
Restoration of ejaculatory control
after drug withdrawal occurred in 68.2% of men with
acquired PE within 12 months of treatment with com-
bined paroxetine and ejaculatory control reeducation
using Semans stopstart technique. The average
duration of treatment was 4.7 months and the prospect
of restoration was directly related to the frequency of
intercourse and inversely related to age. Only 17.1%
of men with lifelong PE achieved restoration of ejacu-
latory control within 12 months and rapid ejaculation
recurred in 50% of this group over the following
12 months (Fig. 5.7). This variance in response to treat-
ment suggests that lifelong PE has a different etiology
to acquired PE, consistent with Waldingers hypothesis
that lifelong PE is a biological variance of ejaculatory
function with a lower ejaculatory threshold set point
possibly due to 5-HT receptor malfunction.
84
Phosphodiesterase inhibitors
Nitric oxide (NO) is becoming recognized as one of the
important intracellular messengers in the brain.
141,142
Several authors have reported that NO may be involved
in the regulation of emotion and behavior.
143145
There
is a possibility that brain NO is involved in regulating
male rat sexual behavior. Melis reported the role of
NO in a specic brain area on male copulatory
behavior, especially penile erection.
146,147
Sato et al.
investigated the influence of the extracellular NO level
Treatment 71
Weeks
Paroxetine
Sertraline
Fluoxetine
Clomipramine
M
e
a
n

E
L
T

(
m
i
n
)
0
1
2
3
4
5
6
7
0 1 2 3 4 5 6 7 8 9 10 11 12
8
P = 0.46
Figure 5.5 Effects of paroxetine,
sertraline, fluoxetine, and
clomipramine on the intravaginal
ejaculatory latency time (ELT) in
men with premature ejaculation.
Duration Rx
Lifelong PE
Acquired PE
I
V
E
L
T

(
m
i
n
)
0
1
2
3
4
5
6
7
0 1 2 4 8 12
4.68
6.65
24 36 52
9
8
Figure 5.6 Intravaginal
ejaculation latency times (IVELT)
during long-term treatment with
paroxetine for men with lifelong
and acquired premature
ejaculation (PE) where IVELT-
acquired PE >IVELT lifelong
IVELT >24/52 (P <0.05).
on male rat copulatory behavior.
148
Microinjection of
the NO precursor, L-arginine, into the MPOA, induced
signicant elevations of extracellular NO and an
increased male copulatory behavior with signicant
increase in mount rates. Microinjection of the NO
synthase inhibitor N-monomethyl-L-arginine (L-
NMMA) signicantly reduced NO levels and inhibited
copulatory behavior. These ndings suggested that the
elevation of extracellular NO in the MPOA facilitates
male copulatory behavior of rats, whereas a decrease
in NO reduces their copulatory behavior.
There is a possibility that NO facilitates male
copulatory behavior through acceleration of dopamine
release. Lorrain and Hull reported that microinjection of
the NO precursor, L-arginine, into the MPOA increased
the extracellular dopamine level.
149
Moreover, they
showed the possible role of the cyclic guanosine
monophosphate (cGMP)/NO pathway in the control of
dopamine release during copulation.
150
They suggested
that NO may play a role in control of male copulatory
behavior and temperature regulation through the
modulation of monoamine release. L-glutamate elicits
an intracavernous pressure increase in the MPOA.
151
It increases NO production by activating NMDA
receptors. This suggests that NO in the MPOA directly
promotes penile erection, and supports a biological
role of NO in the MPOA for positive mediation of
male sexual behavior.
Hull et al. demonstrated that microinjection of the
NO synthase inhibitor, N-nitro-L-arginine methyl ester
(NAME), decreased the number of ex copula erections,
but also increased the number of ex copula seminal
emissions and decreased the latency to the rst
seminal emission.
152
The results indicate that not only
does NO promote erection in intact male rats, but also
it may inhibit seminal emission, probably by decreasing
sympathetic nervous system activity. Kriegsfeld et al.
153
reported that mice homozygous for endothelial nitric
oxide synthase (eNOS) gene deletion have striking
ejaculatory anomalies. A signicantly higher percent-
age of eNOS gene deletion mice than normal controls
ejaculated during the testing period, requiring less
stimulation and few mounts and intromissions.
Intraperitoneal injection of pilocarpine caused a
dose-related seminal emission in adult male rats.
154
The seminal emission response to pilocarpine was
greatly reduced in atropinized animals, suggesting a
cholinergic effect. NAME, an NO synthesis inhibitor,
inhibited the pilocarpine-induced seminal emission,
which was reversed by L-arginine or by coinjection of
sodium nitroprusside. These results suggest that NO
mediates the inhibitory neurotransmission responsible
for seminal emission in pilocarpine-stimulated rats.
Consistent with this, Giuliani and Ferrari have
demonstrated that the specic type V isoenzyme
phophodiesterase inhibitor, sildenal, modies central
dopamine-mediated behavior in rats.
155
They also
reported that sildenal diminished both the ejaculation
latency and the interintromission interval in normal
rats.
156
Following castration, the effect of sildenal on
copulatory function was not observed but was restored
following testosterone replacement.
Several authors have reported their experience with
sildenal citrate as a treatment for PE.
157159
Abdel-
Hamid et al. compared the efcacy and safety of on-
demand clomipramine, sertraline, paroxetine, sildenal,
and the pause/squeeze technique in the treatment of
lifelong PE in a prospective randomized double-blind
cross-over study of 31 potent men.
7,157
Treatment with
sildenal was associated with a signicantly higher
IVELT (15 min) and sexual satisfaction score than all
other treatments and sexual satisfaction scores
positively correlated with the IVELT for each treat-
ment. The lack of a placebo group, the estimation of
baseline IVELT by patient recall only, and the use of
the Erectile Dysfunction Inventory of Treatment
Satisfaction (EDITS) treatment response inventory,
which is validated for erectile dysfunction and not PE,
are major limitations of this study. Many men with
entirely normal ejaculatory control will, as a result of
inadequate sexual education and/or unrealistic patient/
partner expectations, incorrectly perceive themselves
as rapid ejaculators.
In an open-label study of 80 potent men, Salonia
et al. compared treatment with paroxetine alone using
initial chronic and then on-demand dosing, with a
combination of paroxetine and sildenal, using the
same dosing regime for paroxetine and sildenal
administered 1 h before intercourse.
158
Both treatments
signicantly improved the ejaculatory latency time and
intercourse satisfaction domain of the International
Index of Erectile Function (IIEF). The combination of
paroxetine and sildenal produced superior results in
Figure 5.7 Restoration of ejaculatory control in men with
lifelong and acquired premature ejaculation (PE) following
withdrawal of selective serotonin reuptake inhibitor (SSRI)
drug treatment.
SSRI drug treatment duration (months)
%

w
i
t
h

r
e
s
t
o
r
e
d
e
j
a
c
u
l
a
t
o
r
y

c
o
n
t
r
o
l
0
12
17.1%
68.2%
24
8.7%
84.4%
36
4.9%
84.6%
100
20
40
60
80
Lifelong PE
Acquired PE
both end points at 6 months treatment and the authors
suggested a possible role of sildenal in the treatment
of rapid ejaculation. Using a validated scoring inven-
tory for the severity of PE, Chen et al. studied 58 men
with PE who were previously refractory to psycho-
sexual counseling and pharmacological treatment.
159
Treatment with sildenal administered 1 h before
sexual intercourse signicantly improved the baseline
inventory score for the severity of PE. The authors
suggest improved erectile function as the possible
mechanism and a potential role of sildenal in the
treatment of rapid ejaculation.
The proposed mechanisms for the effect of sildenal
on ejaculatory latencies include a central effect involving
increased NO and reduced sympathetic tone, smooth-
muscle dilatation of the vas deferens and seminal
vesicles which may oppose sympathetic vasoconstriction
and delay ejaculation, reduced performance anxiety
due to better erections, and downregulation of the
erectile threshold to a lower level of arousal, so that
increased levels of arousal are required to achieve
the ejaculation threshold. None of these studies are
placebo-controlled and the results are confusing and
difcult to interpret. It is unlikely that phosphodi-
esterase inhibitors have a signicant role in the treat-
ment of PE, with the exception of men with acquired
PE secondary to comorbid erectile dysfunction. The
results of a manufacturer-sponsored double-blind
placebo-controlled multicenter study have yet to be
fully reported. Preliminary results show no signicant
difference in the IVELT of sildenal compared to
placebo but do demonstrate signicant improvements
in the ejaculatory control domain and the ejaculatory
function global efcacy question. The latter is possibly
consistent with the erectile response of sildenal.
It is also known that testosterone is fundamental for
a normal mating pattern, which is totally disrupted by
castration and can be restored by the replacement of
the hormone. It has been suggested that testosterone-
induced activation is linked to increased synthesis
and/or release of dopamine in the brain
70
and NO could
be the bridge between testosterone and dopamine for
copulatory behavior.
Topical treatment
Application of topical anesthetic to the penis virtually
abolishes the display of penile reflexes in rats.
160
Sachs
and Liu demonstrated that division of the sensory
branches of the pudendal nerves severely impaired the
ability of male rats to achieve intromission, and hence
ejaculation.
161
Wieder et al. reported that ejaculatory
response to penile vibrotactile stimulation in spinal
cord-injured men requires the presence of intact dorsal
penile nerves.
162
The use of topical local anesthetics such as lidocaine
(lignocaine) and/or prilocaine as a cream, gel, or spray
is well established and they appear moderately
effective in retarding ejaculation, but do so at the price
of possibly causing signicant penile hypoanesthesia,
and possible transvaginal absorption, resulting in
vaginal numbness and resultant female anorgasmia
unless a condom is used.
163166
Atan et al. reported the
combined use of fluoxetine and topical lidocaine in 43
men with PE. Seventy-two percent of the fluoxetine-
treated group improved as opposed to 83.3% of the
fluoxetine/lidocaine group.
167
Xin et al. reported signicantly improved ejacula-
tory control in 89.2% of patients treated with SS-
cream.
168,169
SS-cream is made with extracts from nine
natural herbs, some of which have local anesthetic
properties; it is applied to the glans penis 1 h before
and washed off immediately prior to coitus. Adverse
effects were noted in 5.9% of patients: these included
mild local irritation and delayed ejaculation. Both
the latency and amplitude of somatosensory evoked
potentials measured at the glans penis were increased
over baseline after the application of SS-cream.
170
Conclusion
Pharmacological modulation of ejaculatory threshold
represents a novel and refreshing approach to the
treatment of PE and a radical departure from the
psychosexual model of treatment, previously regarded
as the cornerstone of treatment. It appears to ll a
treatment hiatus produced by both the limitations
and non-acceptance of psychosexual counseling by
some sufferers and by the lack of convincing longi-
tudinal clinical efcacy data. Pharmacological treat-
ment offers patients a high likelihood of achieving
improved ejaculatory control within a few days of
initiating treating, consequential improvements in
sexual desire and other sexual domains and a favorable
adverse effect prole. consequential improvements in
sexual desire and other sexual domains and a favor-
able adverse effect prole. It fails to address directly
causal psychologicalor relationship factors, and data
are either lacking or scarce on the efcacy of com-
bined psychosexual counseling and pharmacological
treatment, and the maintenance of improved ejacula-
tory control after drug withdrawal.
SURGERY
There have been several reports on the role of selec-
tive dorsal nerve neurotomy in the treatment of PE.
All reports recommended restriction of this surgical
approach to patients who have primary PE and who
have proven refractory to a trial of psychosexual
counseling. The surgery is performed under local
anesthetic and involves division of the distal, ventral
branches of the dorsal nerve in an attempt to
Surgery 73
denervate the penis. No controlled studies have been
performed to evaluate the place of dorsal neurotomy
in the management of PE.
DRY EJACULATION
Dry ejaculation is a relatively common complaint in
older men. It can be due to either retrograde ejacu-
lation or true failure of emission and has multiple
causes (Table 5.3).
RETROGRADE EJACULATION
Retrograde ejaculation is due to incompetence of the
bladder neck mechanism, most often due to trans-
urethral resection of the prostate or open prostatec-
tomy. These men may have some antegrade ejaculation
and usually experience orgasmic sensation. This may,
however, be reduced as part of the changes that occur
in the male sexual response as a man ages. Retrograde
ejaculation and failure of emission can be distinguished
by examination of a postmasturbatory specimen of
urine for the presence of spermatozoa and fructose.
Retrograde ejaculation can be surgically treated with
bladder neck reconstruction but results remain con-
sistently poor.
1,171
Drug treatment is the most promising
approach. As mentioned earlier, -adrenergic sympa-
thetic nerves mediate both bladder neck closure and
emission. Several sympathomimetic agents have been
described as useful with mixed results.
172
These drugs
include pseudoephedrine and ephedrine, and phenyl-
propanolamine. These agents work by stimulating the
release of norepinephrine (noradrenaline) from the
nerve axon terminals but may also directly stimulate
both - and -adrenergic receptors. The most useful is
pseudoephedrine, which is administered at a dose of
120 mg 22.5 h precoitally. The tricyclic antidepressant,
imipramine, which blocks the reuptake of nor-
epinephrine by the axon from the synaptic cleft is also
occasionally useful.
173
The usual dose is 25 mg twice
daily. Current feeling is that long-term treatment with
imipramine is likely to be more effective.Whilst medical
treatment may not always produce normal ejaculation,
it may result in some prograde ejaculation. In patients
who do not achieve antegrade ejaculation with either
surgery or medication, sperm retrieval and articial
insemination is an alternative approach. The basic
method of sperm retrieval involves recovery of urine
by either catheter or voiding after masturbation, and
then centrifugation and isolation of the sperm.
FAILURE OF EMISSION/RETARDED
EJACULATION
Any medical disease or surgical procedure which
interferes with the sympathetic nerve supply to the vas
and bladder neck, the somatic efferent nerve supply to
the pelvic floor or the somatic afferent nerve supply to
the penis can result in failed emission or retarded
ejaculation. This can include spinal trauma, especially
above the level of T10, the functional sympathectomy
that can result from diabetic autonomic neuropathy
and surgical sympathectomies following a colectomy,
proctectomy, bilateral sympathectomy, abdominal
aortic aneurysmectomy and other vascular surgical
procedures, open prostatectomy and retroperitoneal
lymph node dissections for testicular tumors (Table
5.3). Ejaculatory dysfunction following retroperitoneal
lymph node dissection is a major concern since it is a
procedure which is usually performed on young men
in the prime of their reproductive years. Fossa et al.,
however, suggest that the use of a modied unilateral
node dissection in patients with stage A tumors lowers
the incidence of postoperative ejaculatory disturbance
without interfering with the excellent survival rates
associated with standard treatment.
174
The progressive loss of the fast conducting peripheral
sensory axons which begins to be apparent in the third
decade of life, and the dermal atrophy, myelin collagen
TABLE 5.3 Causes of failure of emission or
retrograde ejaculation.
171a
Anatomic Transurethral resection of the
causes prostate
Bladder neck incision
Neurogenic Diabetic autonomic neuropathy
causes Spinal cord injury
Radical prostatectomy
Proctocolectomy
Bilateral sympathectomy
Abdominal aortic aneurysmectomy
Retroperitoneal lymph node
dissection
Psychogenic
Endocrine Hypogonadism
Hypothyroidism
Medication -Methyldopa
Thiazide diuretics
Tricyclic and selective serotonin
reuptake inhibitor
antidepressants
Phenothiazine
Alcohol abuse
DeBusk R, Drory Y, Goldstein I et al. Management of
sexual dysfunction in patients with cardiovascular disease:
recommendations of the Princeton Consensus Panel. Am
J Cardiology 2000; 86:175181. With permission from
Excerpta Media Inc.
inltration, and pacinian corpuscle degeneration
observed in older men, may result in a degree of age-
related degenerative penile hypoanesthesia and
difculty in achieving the ejaculatory threshold.
65
This
is anecdotally exaggerated in men with erectile dys-
function treated with intracavernous pharmacotherapy
and is often compounded by the loss of pelvic floor
muscle tone seen in the similarly aged, postmeno-
pausal, and often multiparous sexual partners of these
men. Certain medication can result in a type of
chemical sympathectomy. Included in this category
are -methyldopa and thiazide diuretics.
Whilst retrograde ejaculation can be surgically
treated with bladder neck reconstruction, no surgical
procedure exists for the treatment of failed emission.
As is the case with retrograde ejaculation, drug treat-
ment is the most promising approach. Whilst medical
treatment may not always produce normal ejaculation,
it may convert a patient with lack of emission into one
with retrograde ejaculation and may result in small
amounts of viable sperm, both of which can be com-
bined with standard articial insemination techniques
to produce a pregnancy.
Drug treatment of delayed
ejaculation/anejaculation
There are multiple reports in the literature of the use
of a variety of drugs in the treatment of delayed ejacu-
lation or anejaculation. The drugs facilitate ejaculation
by either a central dopaminergic or antiserotoninergic
mechanism of action. There are no published placebo
controlled studies and most are anecdotal case reports/
series dealing with the treatment of SSRI-induced
ejaculatory dysfunction (Table 5.4).
Several authors have reported that the cerebral
serotoninergic system exerts an inhibitory role on
ejaculation and male sexual activity in the rat model
and that the dopaminergic system, particularly that in
the anterior hypothalamus, has a facilitatory role.
175,176
The ejaculatory dysfunction commonly associated with
the antihypertensive -methyldopa which reduces
cerebral monoamine levels by suppressing the cerebral
dopaminergic system is consistent with these reports.
177
The occurrence of paradoxical hypersexuality, e.g.,
spontaneous orgasm, with clomipramine and fluoxetine,
however, suggests that this balance is more complex
and that different 5-HT receptor subtypes may have
opposing effects on sexual function.
178,179
The antihistamine cyproheptadine, which increases
cerebral 5-HT levels, has been shown to increase male
sexual activity in the rat.
175
The literature contains
several anecdotal case reports and other small case
series of the use of cyproheptadine to reverse the
anorgasmia induced by the SSRI antidepressants but
contains no controlled studies.
180185
These studies
suggest an effective dose range of 216 mg, administered
on a chronic or on-demand basis. McCormick et al.
reported that the use of cyproheptadine to reverse the
anorgasmia induced by the SSRI fluoxetine has been
reported in two patients.
180
Ashton et al. also reported
improvement in 12 of 25 men with SSRI-induced
sexual dysfunction with a mean dose of 8.6 mg, with
efcacy limited by sedation and potential reversal of
antidepressant effect.
181
The authors experience
suggests a role for cyproheptadine in the treatment of
both retarded ejaculation and anejaculation which is
limited to a degree by its sedative effect.
Central dopamine activity can be increased by a
variety of mechanisms, ranging from the provision of
TABLE 5.4 Adjunctive drug therapy for selective serotonin reuptake inhibitor (SSRI)-induced sexual
dysfunction.
Drug Symptom dosage As needed Daily
Amantadine Anorgasmia 100400 mg 75100 mg b.i.d. or t.i.d.
Decreased libido (for 2 days prior to coitus)
Erectile dysfunction
Bupropion Anorgasmia 75150 mg 75 mg b.i.d. or t.i.d.
Buspirone Anorgasmia 1560 mg 515 mg b.i.d.
Decreased libido
Cyproheptadine Anorgasmia 412 mg On demand
Decreased libido
Yohimbine Anorgasmia 5.410.8 mg 5.4 mg t.i.d.
Decreased libido
Failure of Emission/Retarded Ejaculation 75
dopamine synthesis precursors, e.g., L-dopa, to use of
substitute neurotransmitters to stimulate central
dopamine receptors directly (Table 5.5). Amantadine,
an indirect stimulant of dopaminergic nerves both
centrally and peripherally, which is used in the
treatment of Parkinsons disease and has a limited role
as an antiviral agent, has been reported to stimulate
sexual behavior, ejaculation, and other sexual reflexes
in rats.
186,187
Several authors have reported a place for
amantadine in the reversal of SSRI antidepressant-
induced anorgasmia.
181,188192
Ashton et al. reported
improvement in SSRI-induced sexual dysfunction in
eight of 19 men with a mean dose of 200 mg.
181
Balon
reported some efcacy with on-demand amantadine
(100 mg) administered 56 h before coitus in a similar
group of patients.
188
Several authors have reported their experience
with yohimbine, a derivative of the bark of the Yocon
tree, in the management of SSRI induced sexual
dysfunction.
193195
Yohimbine is an
2
-antagonist, an
1
-agonist, a calcium-channel blocker, and inhibits
platelet aggregation. Price and Grunhaus reported
reversal of clomipramine-induced anorgasmia with a
dose of 10 mg administered 90 min before coitus.
193
In a placebo-controlled study of 15 patients with
fluoxetine-induced anorgasmia, Jacobsen reported a
73% response rate to yohimbine.
194
Hollander reported
yohimbine reversal of anejaculation in ve of six men
with intercourse and/or masturbation.
195
The response
to yohimbine is typically delayed, taking up to 8 weeks,
and is often associated with adverse effects, including
nausea, headache, dizziness, and anxiety. Careful dose
titration is important as the extremes of dose have less
prosexual effect.
Buspirone is a benzodiazepine-class anxiolytic
which possesses 5HT-1A receptor agonist activity.
196
Othmer et al. reported normalization of sexual func-
tion in eight of 10 men with a generalized anxiety
disorder and associated sexual dysfunction using a
dose range of 1560 mg daily.
197
Bupropion is a novel
antidepressant which prolongs the action of dopamine
by reducing its uptake from the synaptic cleft.
198
Ashton and Rosen described reversal of SSRI-induced
anorgasmia in 66% of patients studied. An improve-
ment in sexual function was noted by Rowland in 14
non-depressed diabetic men with erectile dysfunction
with on-demand doses of 75150 mg.
199
Several authors have reported induction of pre-
mature ejaculation in rats following administration of
apomorphine, a central and peripheral dopamine-2
receptor agonist, at a dose of 50 g/kg. Dopamine
receptor antagonists block this effect.
200,201
A potential
role for apomorphine in the management of erectile
dysfunction was rst highlighted by Seagraves et al. and
more recently Heaton et al. have reported an efcacy
in excess of 50% in patients with psychogenic erectile
dysfunction when administered sublingually.
202,203
Adverse effects of nausea, vomiting, and dizziness are
minimized with this sublingual route of administration.
Aizenberg et al. examined the effect of the 5-HT2a/
2c and a
2
-antagonist mianserin in the treatment of
patients with sexual dysfunction induced by SSRIs.
204
Nine of the 15 subjects reported a marked improve-
ment in their sexual functioning in the areas of orgasm
and satisfaction, usually within the rst and second
week of mianserin treatment. The authors suggested
that coadministration of low-dose mianserin might
be an additional option in the treatment of sexual
dysfunction induced by SSRIs.
Quinelorane is a highly selective, potent dopamine-
2 agonist, which was extensively studied in animals in
the early part of this decade. Foreman and Hall observed
increased mounting, intromission, and ejaculation in
both sexually inactive and sluggish rats following
administration of quinelorane.
205
Prior administration
of a dopamine antagonist eliminated these stimulatory
effects, conrming that these sexual effects were due
to stimulation of dopamine receptors. They reported
that many rats failed to ejaculate at the extremes of
doses, with low doses causing sedation and high doses
causing hyperactive behavior, such as chewing or
snifng. Animals appears to become more sensitive to
dopamine agonists with increased use, suggesting that
abuse may eliminate any sexual benets. Eaton et al.
TABLE 5.5 Mechanism of action of drugs which increase dopamine neurotransmission.
Mechanism of increasing dopamine neurotransmission Drug
Prolong action by decreasing uptake Bupropion, cocaine
Prolong action by decreasing metabolism L-deprenyl
Increased release of dopamine Amfetamine
Direct stimulation of dopamine receptors with substitute neurotransmitters Bromocriptine, quinelorane,
apomorphine
Increase dopamine synthesis by providing precursors L-dopa
injected quinelorane directly into the rat paraventricular
nucleus and MPOA and reported different responses
with different doses.
206
At extremes, quinelorane could
cause paradoxical PE, reduced sexual desire, and erec-
tile dysfunction.The reduced sexual response observed
at low doses is due to stimulation of dopamine
autoreceptors which decrease dopamine activity
and respond to lower doses than do the stimulatory
dopamine-2 receptors. In theoretical clinical use,
lowering the dose to avoid excess excitement may
result in worse sexual dysfunction than prior to treat-
ment. Human double-blind placebo-controlled clinical
studies of quinelorane were commenced in the late
1980s, involving multiple sites and more than 500
men and women with erectile dysfunction, reduced
sexual desire, and reduced arousal. The US Food and
Drug Administration review of the trial data was
inconclusive and concern was expressed over the more
than 50% incidence of nausea and hypotension and
the indirect negative sexual adverse effects. Clinical
studies were terminated and the results remain con-
dential and unpublished.
In patients who do not achieve antegrade ejaculation
with either surgery or medication, sperm retrieval and
articial insemination is an alternative approach. The
basic method of sperm retrieval involves recovery of
urine by either catheter or voiding after masturbation,
and then centrifugation and isolation of the sperm.
There are several more invasive methods of sperm
retrieval available. Sperm can be harvested directly
from the vas percutaneously or during microsurgical
vasotomy under local anesthetic. Ejaculation can be
produced with the use of vibration or transrectal
electrostimulation. This is most commonly performed
in men with spinal cord damage. Approximately 70%
of spinal cord-injured men can obtain ejaculation with
this method but each man must be closely monitored
for a hypertensive crisis due to autonomic dysreflexia.
Sperm banking can be conducted in men with
testicular cancer prior to surgery. However more than
50% of these men are subfertile at the time of diag-
nosis and this may explain the relatively poor results
from articial insemination with stored sperm in these
patients.
EJACULATORY DYSFUNCTION IN
SPINAL CORD-INJURED PATIENTS
The ability to ejaculate is severely impaired by spinal
cord injury (SCI). Bors and Comarr highlighted the
impact of the level and completeness of SCI on post-
injury erectile and ejaculatory capacity (Table 5.6).
207,208
Unlike erectile capacity, the ability to ejaculate
increases with descending levels of spinal injury. Fewer
than 5% of patients with complete upper motor neuron
lesions retain the ability to ejaculate. Ejaculation rates
are higher (15%) in patients with both a lower motor
neuron lesion and an intact thoracolumbar sympa-
thetic outflow. Approximately 22% of patients with an
incomplete upper motor neuron lesion and almost all
men with incomplete lower motor neuron lesions will
retain the ability to ejaculate. In those patients who
are capable of successful ejaculation, the sensation of
orgasm may be absent and retrograde ejaculation often
occurs.
Several techniques for obtaining semen from spinal
cord-injured men with ejaculatory dysfunction have
been reported. The intrathecal administration of the
anticholinesterase inhibitors neostigmine and subcu-
taneous physostigmine to induce ejaculation is more of
historical interest and is no longer used due to a 60%
risk of autonomic dysreflexia, especially in men with
injuries above the T5 level.
209,210
The use of electro-
ejaculation to obtain semen by electrical stimulation of
efferent sympathetic bers of the hypogastric plexus
is an effective and safe method of obtaining semen.
Brindley reported that 71% of men with SCI who
underwent electroejaculation achieved ejaculation.
211
Ohl et al. reported that sperm density and motility
were higher in those with incomplete lesions.
212
Vibratory stimulation is successful in obtaining
semen in up to 70% of men with SCI.
213
This tech-
nique induces a reflexogenic ejaculation via the sacral
roots and the ejaculatory coordination center in the
upper thoracolumbar spinal cord. It is however
associated with a signicantly higher risk of autonomic
dysreflexia than electroejaculation. Pretreatment with a
fast-acting vasodilator such as nifedipine will minimize
the risk of severe hypertension should autonomic
TABLE 5.6 Correlation of erection, ejaculation, and intercourse with level and severity of spinal cord injury
1
Cord lesion Reflexogenic Psychogenic Successful Ejaculation
erections (%) erections (%) coitus (%) (%)
Upper motor neuron lesion
Complete 92 9 66 1
Incomplete 93 48 86 22
Lower motor neuron lesion
Complete 0 24 33 15
Incomplete 0 1 100 100
Ejaculatory Dysfunction in Spinal Cord-injured Patients 77
dysreflexia occur with either form of treatment.
214
Percutaneous aspiration of semen from the vas deferens
has also been reported as a means of harvesting semen
for use with articial reproductive techniques.
215
Semen collected from men with SCI is often initially
senescent and of poor quality, with a low sperm count
and reduced sperm motility, but may improve with
subsequent ejaculations. This poor semen quality may
be due to chronic urinary tract infection, sperm content
with urine, chronic use of various medications, elevated
scrotal temperature due to prolonged sitting, and stasis
of prostatic fluid. Testicular biopsies in spinal cord-
injured men demonstrate a wide range of testicular
dysfunction, including hypospermatogenesis, maturation
arrest, atrophy of seminiferous tubules, germinal cell
hypoplasia, interstitial brosis and Leydig cell hyper-
plasia. In addition prostatitis secondary to prolonged
catheterization, epididymitis, and epididymoorchitis
can precipitate obstructive ductal lesions and testicular
damage.
INHIBITED MALE ORGASM
Inhibited male orgasm is the psychogenic variant of
retarded ejaculation, also called ejaculatory incom-
petence by Masters and Johnson.
27
It may be dened
as recurrent and persistent inhibition of the male
orgasm as manifested by delay in or absence of ejacu-
lation following an adequate phase of sexual excite-
ment. It may range in severity from very severe forms
in which a man has never been able to experience
waking climax, even with masturbation, to milder
forms in which intravaginal climax occurs, but only
after prolonged thrusting. Clinically it is the least
common sexual disorder and it most often presents as
a primary disorder. In most cases, however, the problem
is situational. Orgasm occurs readily with masturbation
but not during intercourse. Usually only the rare global
case of retarded ejaculation presents any difculty
with differential diagnosis. Secondary retarded ejacu-
lation, when its situational, strongly suggests a
problematic relationship. Global secondary retarded
ejaculation suggests the development of some psycho-
physiologic or pharmacologic cause such as sedative
hypnotic abuse, narcotic or alcohol abuse. In very rare
instances neurologic disease or neurologic trauma may
account for this disorder.
The prevailing wisdom holds that inhibited male
orgasm is analogous to female anorgasmia. According
to this theory, psychogenically mediated reflex
inhibition occurs despite high levels of sexual tension.
Apfelbaum has proposed, however, that the disorder
is best understood as the surface manifestation of an
underlying disorder of sexual desire.
216
He has theorized
that these patients, though they have erections, never
pass from initial penile engorgement to the plateau
level with high levels of sexual tension. There are
patients who typify both of the above perspectives but
Martin believes that the majority of patients do reach
plateau at some point during thrusting, only to
experience reflex inhibition, and subsequently subside
back to preplateau levels of tension.
217
A wide variety
of psychologic factors may be responsible for the
inhibition, including fear of impregnating the partner,
religion, guilt, depressed or repressed hostility towards
the partner, oedipal fears of retaliation, and fears of
soiling or deling the partner with semen.
As a rule, treatment outcome with behavioral sex
therapy tends to be less successful for orgasm
inhibition than for other sexual disorders. The basic
treatment strategy requires that the man move by the
method of successive approximation from extravaginal
ejaculation to ejaculation in the vagina. A treatment
sequence might involve a progression from solitary
masturbation to masturbation with his wife in the next
room, to masturbation in her presence but with her
back turned, to masturbation with her looking on, to
wife-assisted masturbation to orgasm. Once he has
traversed these steps with successful ejaculatory
outcome the patient is asked to insert his penis into
the lubricated vagina just at the point of ejaculatory
inevitability.After several repetitions of this maneuver,
which is designed to desensitize the man to the anxiety
associated with intravaginal orgasm, he is asked to
insert at plateau but before ejaculatory inevitability. If
he can proceed to ejaculation he is given permission to
insert yet earlier in the sexual response cycle. The
couple is encouraged to do everything possible to
enhance the erotic aspects of the sexual experience
and the wife is taught how to cup her husbands
testicles for an extra sensation when he is at high levels
of erotic tension. Liberal use of fantasy is encouraged,
as is the use of commercially available erotica. It is
particularly important that the man should not
attempt insertion until he has reached high levels of
erotic tension during sex play.
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INTRODUCTION
The testes produce spermatozoa and the androgenic
steroid hormones. Both processes are under complex
feedback control by the hypothalamicpituitary system.
Testicular androgen hormones are responsible for the
formation of the basic male phenotype during embryo-
genesis and regulate male sexual function.
Androgens are hormones that are based on the struc-
ture of testosterone, the major male sex hormone, and
are capable of developing and maintaining masculine
sexual characteristics, fertility, and the anabolic status
of somatic tissues. All androgens act through the single
androgen receptor and have similar biological effects.
Their effects in different target tissues are diversied
by metabolism of testosterone to its active metabolites
dihydrotestosterone (DHT) and estradiol.
ANATOMY OF THE TESTES
The testes lie loose within the cavity of the scrotum,
are capable of great mobility, and are suspended by the
spermatic cords. The left testis hangs somewhat lower
than the right (Fig. 6.1). In early fetal life the testes are
located intraperitoneally within the abdominal cavity.
Before birth they descend and enter, pass through and
emerge from the inguinal canal with the spermatic
cord at the external inguinal ring to enter the scrotum.
During their course coverings derived from the serous,
Androgens in Male Sexual Physiology
Chris G. McMahon
CHAPTER 6
Figure 6.1 Anatomy of the male genitals.
Testicular
artery
Testicular
vein
Inguinal ligament
Penis
Superficial
inguinal ring
Spermatic cord
Scrotal septum
Cremaster muscle
Superficial scrotal fascia
Dartos muscle
Scrotal
skin (cut)
Urinary bladder
Inguinal canal
Genitofemoral
nerve
Deferential artery
Ductus deferens
Pampiniform plexus
Testicular artery
Epididymis
Scrotal
cavity
Testis (covered by
visceral layer of
tunica vaginalis)
Raphe
Ureter
muscular, and brous layers of the abdominal parietes
invest them. The average dimensions of the testis are
45 cm in length, 2.5 cm in breadth, and 3 cm in the
anteroposterior diameter; its weight varies from 10.5
to 14 g. Each testis is of an oval form. Lying upon the
lateral edge of this posterior border is a long, narrow,
flattened body, named the epididymis.
The spermatic cord is composed of arteries, veins,
lymphatics, nerves, and the excretory duct of the testis
and is invested by the layers brought down by the
testis in its descent. The arteries of the cord are the
internal and external spermatic artery and the artery
to the ductus deferens. The spermatic veins emerge
from the back of the testis, receive tributaries from the
epididymis, and unite to form a convoluted plexus, the
pampiniform plexus. This forms the chief mass of the
spermatic cord and ascends, eventually uniting in a
single vein as it passes through the inguinal canal to
open into the inferior vena cava on the right side, and
the left renal vein on the left side. The lymphatic
vessels of the testes consist of two sets, supercial and
deep, the former commencing on the surface of the
tunica vaginalis, the latter in the epididymis and body
of the testis. They ascend with the spermatic veins in
the spermatic cord and end in the lateral and preaortic
groups of lumbar glands. The nerves are the spermatic
plexus from the sympathetic thoracolumbar outflow,
joined by laments from the pelvic plexus, which
accompany the artery of the ductus deferens.
The glandular structure of the testis consists of
numerous conical-shaped lobules, the apex being
directed toward the mediastinum (Fig. 6.2). Each lobule
consists of one to three, or more, minute convoluted
tubes, the seminiferous tubules. The total number of
tubules is estimated to be 840, and the average length
of each is 7080 cm. Each tubule consists of a base-
ment layer containing three different groups of epithe-
lial cells arranged in several irregular layers. Among
these cells may be seen the spermatozoa in different
stages of development as spermatogonia, spermatoblasts
or spermatids or spermatozoon, and the supporting
cells or Sertoli cells. In the apices of the lobules, the
tubules unite together to form 2030 larger ducts, the
tubuli recti. The tubuli recti enter the mediastinum to
form a close network of anastomosing tubes, the rete
testis. The rete testis eventually terminates in 1215 or
20 ducts, the efferent ductules, and ultimately in the
epididymis.
REGULATION OF TESTICULAR
FUNCTION
Androgenic steroids are synthesized in the Leydig
cells. Leydig cell function is regulated by the posterior
pituitary gonadotropin, luteinizing hormone (LH).
Spermatozoa are produced in the Sertoli cells of the
spermatogenic tubules. A second posterior pituitary
gonadotropin, follicle-stimulating hormone (FSH),
controls Sertoli cell function and spermatogenesis.
Gonadotropin regulation
The production of the pituitary gonadotropins, LH and
FSH, is regulated by hypothalamic gonadotropin-
releasing hormone (GnRH), or luteinizing hormone-
releasing hormone (LHRH). Plasma concentrations of
LH, FSH, and testosterone fluctuate in a pattern that
parallels the pulsatile release of GnRH (Fig. 6.3). This
pulsatile gonadotropin release is most apparent for
LH due to its short plasma half-life compared to FSH.
Pulses of LH secretion occur every 12 h in adult men.
The pulsatile secretion of testosterone in response to
LH release is dampened and less obvious due to con-
current stimulation of steroid synthesis and secretion
by the Leydig cell. Although testosterone secretion is
primarily regulated by pituitary LH, a FSH stimulated
Sertoli-cell-derived factor may enhance testosterone
production.
1
Testosterone regulates the hypothalamicpituitary
production of LH in a negative-feedback manner. By
decreasing the hypothalamic GnRH pulse frequency
and reducing pituitary sensitivity to GnRH, testos-
terone lowers LH release. Although testosterone is
86 Androgens in Male Sexual Physiology
Figure 6.2 Anatomy of the testis.
Head of
epididymis
Efferent
ductules
Rete
testis
Seminiferous
tubule
Scrotal
cavity
Tunica
albuginea
Spermatic
cord
Body of
epididymis
Ductus
deferens
Tail of
epididymis
Testis
converted to DHT and to estrogens in the pituitary,
pituitary gonadotropin secretion is primarily regulated
by testosterone. LH secretion is exquisitely sensitive
to testosterone negative feedback. Administration of
exogenous androgen that approximates the normal
daily secretory rate of testosterone (~20 mol or 6 mg)
results in almost complete suppression of LH secretion.
However, pituitary sensitivity to testosterone feedback
is reduced in chronic androgen deciency.
Pituitary FSH release is also regulated by the gonadal
peptide inhibins and activins.
2
Gonadal inhibins A and
B are heterodimeric proteins, produced by the Sertoli
cell.
3
They selectively suppress FSH without affecting
LH and provide feedback control of FSH production.
Activins, which are also produced by the pituitary,
are homodimeric proteins that selectively stimulate
FSH production through an autocrineparacrine
mechanism.
4
In summary, hormonal feedback signals from Leydig
cells and the spermatogenic tubules feedback and
precisely regulate the hypothalamicpituitary release
of LH/FSH and thereby their own function.
Synthesis of testosterone
About 95% of plasma testosterone in men is produced
by the Leydig cells of the testes from cholesterol and
the remainder is derived from conversion of adrenal
androgens, largely androstenedione. The biochemical
pathway by which the cholesterol is converted to
androgens and estrogens is depicted in Figure 6.4.
Cholesterol is synthesized either de novo in the Leydig
cell or derived from plasma lipoproteins, and is
converted to testosterone as the result of ve enzy-
matic reactions: (1) cholesterol side-chain cleavage
(CYP11A1); (2) 3-hydroxysteroid dehydrogenase/
isomerase 2 (3-HSD2); (3) 17-hydroxylase (CYP17);
(4) 17,20-lyase (CYP17); and (5) 17-hydroxysteroid
dehydrogenase 3 (17-HSD3). The rst four reactions
occur in the adrenal gland as well as the testis. The
presence of enzyme cofactors and posttranslational
modication (phosphorylation) of the enzyme confers
17,20-lyase activity, allowing androgen synthesis in
both the testis and zona reticularis of the adrenal
gland.
Delivery of cholesterol by the steroid acute
regulatory (StAR) protein to the inner mitochondrial
membrane for side-chain cleavage by CYP11A1 to
form pregnenolone is the rate-limiting step in testos-
terone synthesis. LH stimulates the activity of StAR
protein and the enzymes in the steroid pathway. Small
amounts of other steroid hormones including estradiol
are synthesized in the Leydig cell.
Transport of testosterone
The testes of a healthy young man secrete 1720 mol
(56 mg) of testosterone into the plasma each day.
Almost all testosterone is transported in plasma bound
to protein, largely to albumin and to a specic trans-
port protein, sex hormone-binding globulin (SHBG).
Approximately 12% of testosterone is unbound in the
plasma and circulates as free testosterone. The bound
and unbound fractions are in dynamic equilibrium.
5
Testosterone binds strongly to SHBG, whereas its
afnity for albumin is weak.
6
Testosterone rapidly
dissociates from albumin, adding to the fraction of
circulating testosterone available for entry into tissues
(bioavailable testosterone).
7
Whether non-SHBG-
bound testosterone is truly the fraction that is available
to all androgen target tissues is not clear, however.
Non-SHBG-bound testosterone does appear to be
available to the brain and the prostate.
8
However,
DHT, which is converted from testosterone via
Regulation of Testicular Function 87
Figure 6.3 Hypothalamic
pituitary regulation of
testosterone and
spermatogenesis.
Hypothalamus
Pituitary
Leydig cells
Testes
GnRH (+)
Sperm
Seminiferous
tubules
LH (+)
FSH (+)
T ()
Inhibitin
()
Activin
(+)
5-reductase locally in the androgen target tissue, is
the predominant androgen in most androgen target
organs, including the prostate. Furthermore, bone
mineral density measurements in older men correlate
signicantly better with free testosterone levels than
they do with total testosterone levels.
9
Metabolism of androgens
Testosterone is a precursor hormone which is converted
into two other hormones, DHT and estrogens. These
two hormones mediate most of the peripheral androgen
physiologic actions. DHT is synthesized by 5-reduction
of testosterone in androgen target tissues. It is respon-
sible for most of the differentiative, growth-promoting,
and functional aspects of male sexual differentiation
and virilization. Estrogens are principally synthesized
in adipose tissue and to a lesser extent in other extra-
glandular tissues, from circulating plasma testosterone
by the action of aromatase enzyme (CYP19).
10
Extra-
glandular estrogen formation increases with age and
with increased mass of adipose tissue. Estrone is
Figure 6.4 The biochemical pathway for the synthesis of testosterone.
Cholesterol
Pregnenolone
A
d
r
e
n
a
l

a
n
d

t
e
s
t
e
s
T
e
s
t
e
s
P
e
r
i
p
h
e
r
a
l

t
i
s
s
u
e
s
Progesterone
17OHProgesterone
17,20 lyase
CYP10 (aromatase)
CYP17
CYP17
CYP11A1
Cholesterol side-chain
cleavage enzyme
Androstendione
Testosterone
3-HSD3
(5-reductase)
3-HSD2
(17-hydroxysteroid
dehydrogenase)
17-hydroxylase
(3-hydroxysteroid
dehydrogenase/isomerase2)
Dihydrotestosterone Estradiol
HO
OH
HO
OH
HO
HC
HO
H
OH
CH
3
CH
3
CH
3
CH
2
CH CH
2
CH
2
produced from circulating precursors. Estradiol pro-
duction is derived directly from estrone (50%), from
circulating testosterone (35%), and from direct
synthesis in the testis (15%).
Testosterone and its active metabolites are
catabolized in the liver and excreted predominantly in
the urine as the 17-ketosteroids, androsterone and
etiocholanolone, or as the polar metabolites, diols,
triols, and conjugates. As opposed to testosterone,
estradiol secretion by the testes increases when
pituitary gonadotropin levels increase. Peripheral
androgen effects are the result of the combined actions
of testosterone and its active androgen and estrogen
metabolites. These androgen and estrogen metabolites
of testosterone exert local (paracrine) actions in the
tissues in which they are formed or enter the circu-
lation and act as hormones at other sites.
Actions of androgens
Androgens are responsible for the formation of the
male phenotype during sexual differentiation, regu-
lation of LH secretion, and induction of sexual
maturation at puberty. The cellular process by which
androgens perform these functions is schematized in
Figure 6.5. Testosterone passively diffuses into the
target tissue cell and is converted to DHT predomi-
nantly by steroid 5-reductase 2 and to a lesser extent
by steroid 5-reductase 1.Androgen-receptor proteins of
the cell nucleus bind testosterone or DHT. The formed
hormonereceptor complex binds to specic DNA
sequences and regulates messenger RNA transcription
to synthesize specic cellular proteins. The androgen
receptor, which is encoded by a gene on the long arm
of the X chromosome, contains 917 amino acids and
has a molecular mass of about 110 kDa. The poly-
morphic region in the amino terminus, which contains
a variable number of glutamine repeats, regulates the
activity of the receptor. The androgen receptor has
distinct hormone-binding, DNA-binding, and transcrip-
tional regulatory domains. Estradiol acts by a similar
mechanism on its own distinct estrogen receptors.
The testosteronereceptor complex regulates LH
secretion, spermatogenesis, and the virilization of the
wolfan ducts during sexual differentiation. The DHT
receptor complex is responsible for external virilization
during embryogenesis and for most androgen actions
during sexual maturation and adult sexual life. The
process by which two hormones can bind to the same
receptor but have different physiologic effects is
unknown. However, DHT appears to bind to the
receptor much more tightly than does testosterone,
which serves to amplify its hormonal signal.
Spermatogenesis
The normal adult testes produce in excess of 100
million sperm each day. Both androgen production by
the Leydig cells and pituitary release of FSH effect
spermatogenesis.The Sertoli cell, which regulates germ
cell proliferation and maturation in the seminiferous
tubules, is the major site of FSH action. FSH, whilst
not essential for spermatogenesis, increases the number
and maturation of sperm. Androgen, acting through
receptors in the seminiferous tubules, is essential for
spermatogenesis. The Sertoli cells are unable to syn-
Regulation of Testicular Function 89
Figure 6.5 The cellular mechanism of action of androgens. LH, luteinizing hormone.
Gonadotropin
regulation
Sexual
differentiation
Testis
Testosterone
Receptor
5-reductase
Dihydrotestosterone
Androgen target tissue
Estradiol
LH
Wolfian stimulation
External virilization
Sexual maturation
at puberty
thesize steroid hormones de novo but can convert
testosterone that diffuses from adjacent Leydig cells to
DHT and estradiol. Spermatogenesis is also regulated
by several paracrine and autocrine mechanisms
involving multiple cytokines and growth factors, some
of which are produced by the Sertoli cell itself.
EVALUATION OF TESTICULAR
FUNCTION
The diagnosis of androgen deciency involves the
recognition of appropriate clinical features of absent or
diminished androgenization, with conrmation by bio-
chemical testing.
11
The assessment of androgen status
should include specic enquiry about the reproductive
history, including the presence of developmental
abnormalities of the urogenital tract and the extent of
sexual maturation at puberty.
Reduced androgen action during embryogenesis
may result in hypospadias, cryptorchidism, or micro-
phallus. Sexual maturation will not occur with pre-
pubertal Leydig cell failure and the features termed
eunuchoidism will occur. These include an infantile
amount and distribution of body hair, poor develop-
ment of skeletal muscles, and delayed closure of the
epiphyses. Postpubertal Leydig cell failure is associated
with changes in sexual function, including hypoactive
sexual desire and erectile/ejaculatory dysfunction,
reductions in fertility, beard and body hair growth and
distribution, testicular volume, musculature, strength
and energy, and the presence of gynecomastia.
12
Evaluation of the testes is an essential part of the
physical examination. The prepubertal testis measures
about 2 cm in length and 2 ml in volume and grows
during puberty to reach the adult proportions by age
1617 years. Testes in adult men average 4.6 cm in
length (range 3.55.5 cm), corresponding to a volume
of 1225 ml. Approximately 60% of testicular mass is
contributed by the the seminiferous tubules. The testes
of prepubertal seminiferous tubular damage are small
and rm, whereas postpubertal damage is associated
with testes that are soft as the capsule, once enlarged,
does not contract to its previous size. Testicular size
remains unchanged as men age, even in advanced age.
The presence of a varicocele should be sought by
palpation with the patient standing.
The diagnosis of postpubertal androgen deciency
requires a high index of suspicion and appropriate
laboratory assessment because some androgen func-
tions regress very slowly and other functions may
remain unchanged.
Plasma testosterone levels
Plasma testosterone is measured by immunoassay. The
plasma testosterone level in normal adult men ranges
from 10 to 35 nmol/l (310 ng/ml). Testosterone
secretion is pulsatile and occurs every 6090 min in
response to pulsatile hypothalamicpituitary LH
secretion. Men with prolonged intervals between LH
pulses may have testosterone levels that transiently fall
below the normal range. Furthermore, plasma testos-
terone levels also vary throughout the day and at dif-
ferent times of the year, and may be as much as 30%
higher in the morning than in the evening. As such, a
single random testosterone sample is unreliable in the
diagnosis of androgen deciency. A pool of two or
three samples spaced 1520 min apart on at least two
separate days and preferably in the morning minimizes
the effects of random and laboratory fluctuations and
diurnal rhythms and provides a more accurate
assessment.
13
Measurements of free testosterone by immunoassay
may assist in the diagnosis of androgen deciency, but
require extensive validation. Indirect measurements
of free testosterone, such as the free androgen index
(testosterone/SHBG ratio), correspond poorly with
direct measurements and lack empirical validation as a
diagnostic test.
DHT can also be measured by immunoassay. In
young men the plasma DHT level is about one-tenth the
value for testosterone, averaging ~2 nmol/l (0.6 ng/ml).
In older men with benign prostatic hyperplasia (BPH),
plasma DHT levels average ~3 nmol/l (0.9 ng/ml).
Testicular function cannot be assessed by the measure-
ment of urinary 17-ketosteroids as most of the urinary
17-ketosteroids in men is derived from adrenal
androgens and only approximately 40% is derived
from the testes.
Plasma LH levels
Plasma LH is also measured by immunoassay. Because
LH secretion is pulsatile in fashion, assay of a pool of
two or three samples drawn 1520 min apart, as is the
case with testosterone, provides a more accurate assess-
ment. In early puberty, sleep-related nocturnal gonado-
tropin surges result in levels of plasma testosterone
and LH which are higher at night than during the day.
By the age of 17, the pulsatile LH secretion is of similar
magnitude during sleep and waking periods and
daytime levels of plasma testosterone have gradually
increased to reach adult levels. The presence of hypo-
gonadism can only be assessed by the simultaneous
interpretation of a low plasma testosterone level and
the plasma LH. A low plasma testosterone level
associated with an elevated LH level implies primary
testicular insufciency or primary hypogonadism
whereas a low plasma testosterone level and a reduced
LH level suggests hypothalamic or pituitary disease
or secondary hypogonadism (hypogonadotropic
hypogonadism).
Response to gonadotropin stimulation
Leydig cell capacity in prepubertal boys where both
LH and testosterone levels are low can be evaluated
by measuring the plasma testosterone response to
gonadotropin stimulation. Normal prepubertal boys
respond within 35 days of injection of human chorionic
gonadotropin (hCG) with an increase in the plasma
testosterone level to ~7 nmol/l (2 ng/ml). This response
increases with the start of puberty and peaks in early
puberty.
Response to GnRH
In prepubertal boys, acute administration of GnRH
produces a minimal increase in plasma LH and FSH as
the pituitary has not been primed by previous expo-
sure to GnRH or gonadal steroids. The LH response to
acute administration of GnRH increases after puberty,
while the FSH response is less robust.The extent of the
LH response to GnRH challenge reflects the amount of
LH stored in the pituitary. The extent of LH response
is broad but most men demonstrate a four- to vefold
increase in LH levels with the peak level at 30 min,
following either subcutaneous or intravenous GnRH
challenge.
The determination of testosterone and basal LH is
usually sufcient for the diagnosis of primary testicular
failure, and the assessment of GnRH response is rarely
required. Men with secondary hypogonadism due to
either pituitary failure or hypothalamic disease can
have either a normal or an abnormal LH response to
GnRH challenge.Although a normal response does not
clearly distinguish these causes of hypogonadism, a
suboptimal response indicates that an abnormality
exists but fails to characterize the site of the defect.
The presence of a normal LH response after pulsatile
or daily GnRH challenge for a week suggests that
hypothalamic disease is present.
SEMEN ANALYSIS
The ejaculate can be divided into several fractions by
serial biochemical analysis.
14
It comprises secretions
from the seminal vesicles, prostate and bulbourethral
(Cowpers) glands, and spermatozoa. It is produced
when the combination of the secretions of the prostate
and the contents of the ampullary parts of the vasa
deferentia is washed out by fluid from the seminal
vesicles and expelled from the urethra.
15
The sperma-
tozoa are stored in the tails of the epididymides and
the vas deferens ampullae. Approximately 5080% of
the entire ejaculatory volume is contributed by the
seminal vesicles, 1530% by the prostate gland, and a
small contribution is derived from the bulbourethral
(Cowpers) glands; this is rich in enzymes and plasmin-
ogen activator.
16
Spermatozoa normally constitute less
than 0.1% of the ejaculatory volume. The rst fraction
of the ejaculate contains the maximum number of
spermatozoa, and subsequent fractions contain
sequentially less. Acid phosphatase, citric acid, and
zinc, emanating from the prostate, are also in highest
concentration in the initial fractions of the ejaculate.
Subsequent fractions contain fructose from the seminal
vesicles, which increases in concentration towards the
end of the ejaculatory process. The pH of the ejaculate
increases in successive fractions as the acid component
provided by the prostate is serially mixed with the
more alkaline contribution of the fructose-rich fluid
from the seminal vesicles.
Seminal fluid, obtained by masturbation and after
ejaculatory abstention for 12 days on at least three
separate occasions, should be examined within an hour
of collection. The normal ejaculate volume is 26 ml.
Sperm density should exceed 20 million per ml. At
least 60% of the sperm should be motile and of normal
morphology. What denes an adequate sperm count is
unclear and some men with low sperm counts are
fertile. The confusion surrounding the lower limit of
normal sperm density, motility, and morphology
relates to the presence of multiple factors that produce
temporary aberrations in sperm count and the absence
of any true measure of sperm functional capacity in
routine semen analysis.
Plasma FSH levels
Plasma FSH is measured by immunoassay. When
damage to the germinal epithelium of the seminiferous
tubules is severe, plasma levels of Sertoli cell inhibin B
fall and plasma levels of FSH increase.
TESTICULAR BIOPSY
Open or percutaneous needle testicular biopsy is an
aid to diagnosis in some men with oligospermia and
azoospermia. The presence of a normal testicular
histology on biopsy and a normal FSH level in an
azoospermic man suggests obstruction of the vas
deferens. Sperm harvesting can be performed during
testicular biopsy for intracytoplasmic sperm injections
(ICSI) into oocytes.
17
PLASMA ESTROGEN LEVELS
Estrogens are principally synthesized in adipose tissue
and to a lesser extent in other extraglandular tissues,
from circulating plasma testosterone by the action of
aromatase enzyme. Extraglandular estrogen formation
increases with age and with increased mass of adipose
tissue.
18
Estrone is produced from circulating precursors.
Plasma Estrogen Levels 91
Estradiol production is derived directly from estrone
(50%), from circulating testosterone (35%), and
from direct synthesis in the testis (15%). The plasma
level of estradiol is usually <180 pmol/l (50 pg/ml) in
normal men whereas the plasma estrone level is some-
what higher but is usually <300 pmol/l (80 pg/ml).
Abnormally high estrogen production and elevated
plasma estrogen levels can be due to increased pro-
duction or reduced metabolism of plasma precursors
in liver failure or adrenal disease, to increased extra-
glandular aromatization seen in adipose tissue of
obese men, or to increased production by the testes
due to hormone-secreting testicular tumors, androgen
resistance, or gonadotropin stimulation.
PHASES OF NORMAL TESTICULAR
FUNCTION
Testicular production of testosterone in the male
embryo commences at about 78 weeks of gestation
and is partly stimulated by placental hCG. A high level
of plasma testosterone is maintained until late
gestation, at which stage the level falls and is only
slightly greater in males than in females at birth. The
plasma testosterone level in the male infant is
transiently raised for the rst 3 months of life due to a
short-lived increase in pituitary gonadotropins, but
again falls to low levels by age 6 months to 1 year and
remains low until puberty. After puberty, the plasma
testosterone level progressively increases to reach adult
levels by the age of 17 years. The level of bioavailable
testosterone declines at a rate of approximately 1%
per year after the age of 40 years. However, there is a
negligible decline in total testosterone until the later
decades of life, as the level of SHBG increases by
approximately 1% per year in parallel with the decline
in bioavailable testosterone.
19
ABNORMALITIES OF TESTICULAR
FUNCTION
Puberty
The hypothalamicpituitary system, the testes, or the
adrenals are probably responsible for the control of
puberty.
20
Before the onset of puberty, gonadotropin
secretion by the pituitary is low, but prepubertal
castration causes a rise in plasma gonadotropin levels.
The small amount of circulating plasma testosterone
present before puberty exerts sensitive negative-
feedback control of pituitary gonadotropin, resulting
in low secretion of gonadotropins. Sleep-related
nocturnal gonadotropin surges occur in early puberty
and result in levels of plasma testosterone and LH
which are higher at night than during the day. As
puberty proceeds, gonadotropin secretion increases
due to an increase in both GnRH secretion and pituitary
sensitivity to GnRH and the hypothalamicpituitary
system becomes less sensitive to negative-feedback
control. By the age of 17, the pulsatile LH secretion is
of similar magnitude during sleep and waking periods,
and daytime levels of plasma testosterone have
gradually increased to reach adult levels.
The onset, duration, and sequence of normal male
puberty are highly variable.
21
Testicular enlargement
forecasts puberty at the age of 1112 years. The rise in
plasma testosterone is responsible for the growth of
the testes, penis, the prostate, the seminal vesicles, and
the epididymides. Muscle and connective tissue growth,
particularly androgen-sensitive muscles of the pectoral
region and the shoulder, occurs. The pitch of the voice
lowers as the larynx and vocal cords enlarge. Growth
of the beard, regression of the scalp hair line, and the
development of truncal, limb, axillary, and pubic hair
occur as part of the typical hair growth of male
puberty.
Precocious puberty
Precocious puberty is sexual development before the
age of 9. It may be either complete with virilization and
premature activation of the hypothalamicpituitary
system with resultant spermatogenesis, or incomplete
with virilization only and hypothalamicpituitary
activity appropriate for age.
Virilizing syndromes are associated with plasma
testosterone which is inappropriately elevated for age
and can occur with Leydig cell tumors, Leydig cell
hyperplasia, hCG-secreting tumors, adrenal tumors,
congenital adrenal hyperplasia (most commonly 21-
hydroxylase deciency), or androgen administration.
Precocious puberty with asymmetric-sized testes
suggests the presence of a Leydig cell tumor. The local
androgen production seen in Leydig cell tumors may
result in limited localized spermatogenesis.
Virilizing adrenal tumors predominantly secrete
androstenedione and dehydroepiandrosterone, which
are partly converted to testosterone. Levels of 17-
hydroxyprogesterone and, as a result, androgen levels
are elevated in congenital adrenal hyperplasia.Although
both congenital adrenal hyperplasia and adrenal
tumors are associated with increased 17-ketosteroid
excretion, treatment with glucocorticoid administration
will promptly decrease the 17-ketosteroid excretion
of the former to normal but fails to normalize 17-
ketosteroid excretion in the latter.
Autonomous Leydig cell hyperplasia results in adult
levels of testosterone and virilization by the age of
2 years, and occurs either sporadically or can be
inherited as a male-limited autosomal disorder. LH
receptor mutations result in premature receptor acti-
vation in the absence of LH due to receptor mutations.
LH levels and the LH response to GnRH are
prepubertal.
Premature activation of the hypothalamicpituitary
system can be due to brain tumors, brain injury, or
infection but is most often idiopathic. It is associated
with the normal physical, hormonal, and biochemical
features of puberty, including sleep-related nocturnal
gonadotropin surges, elevated plasma LH levels, and
enhanced LH response to GnRH.
Management of sexual precocity is etiology-specic.
The elevated plasma testosterone levels seen in Leydig
cell hyperplasia can be partly lowered by treatment with
either medroxyprogesterone acetate or ketoconazole,
or its androgen action partly reduced with spirono-
lactone.The gonadotropin production and testosterone
synthesis of idiopathic precocious puberty and
precocious puberty due to inoperable central nervous
systems lesions is best treated with long-acting GnRH
analog therapy.
Delayed or incomplete puberty
The onset, duration, and sequence of normal male
puberty are highly variable and distinguishing delayed
or failed puberty from variants of normal develop-
ment can be problematic. Separating failure of puberty
from variants of normal development is one of the
most difcult problems in endocrinology. Most boys
fail to demonstrate a normal spurt of growth and sexual
development at 1213 years of age but a small number
of boys may not commence puberty until 16 years of
age or older, continue slow pubertal development until
age 2022, and may have a family history of delayed
puberty.
Pubertal failure is seen in prepubertal hypo-
thyroidism and panhypopituitarism. Absent puberty in
the presence of low plasma testosterone levels and
elevated FSH and LH levels suggests primary testicular
disease. Hereditary androgen resistance, in which both
plasma testosterone and LH levels are high, often
causes male pseudohermaphroditism but in a mild
form may present as absent or incomplete puberty.
The majority of boys with absent puberty have low
plasma levels of testosterone and gonadotropins and
must be distinguished from idiopathic hypogonado-
trophic hypogonadism (Kallmann syndrome) or
isolated gonadotropin deciency. Cryptorchidism and
microphallus are features of hypogonadotrophic hypo-
gonadism. Anosmia or hyposmia is common in hypo-
gonadotropic hypogonadism and is due to abnormal
development of the olfactory tracts which share
progenitor cells with GnRH neurons.
22
Several distinct
abnormalities of GnRH formation or action are
involved in the pathogenesis of hypogonadotropic
hypogonadism. An X-linked recessive trait associated
with defects in a neural cell adhesion molecule (KAL)
involved in the migration of GnRH neurons into the
olfactory bulb may be inherited. An autosomal domi-
nant trait with variable expression or rare autosomal
recessive traits may impair the GnRH receptor. The
plasma testosterone level is low for age, plasma FSH
and LH levels are usually below the normal male
range, and the secretion of other pituitary hormones is
normal. In patients with GnRH deciency, endocrine
abnormalities are corrected and spermatogenesis is
initiated following pulsed GnRH treatment.
Hypogonadotropic hypogonadism, due to decient
GnRH production and abnormal gonadotropin func-
tion, and primary adrenal insufciency are features of
X-linked adrenal hypoplasia congenita. The extent of
LH and/or FSH deciency varies in isolated gonado-
tropin deciency and clinical features can range from
eunuchoidal features and prepubertal-sized testes to
a degree of testicular enlargement and pubertal
development in boys with only partial LH and/or FSH
deciency.
Adult males
Androgen production and spermatogenesis can be
influenced by a variety of factors at testicular and
hypothalamicpituitary levels.
23,24
An increase in scrotal
temperature due to a varicocele, a transient increase
in either core or peripheral temperature, as might
occur in a hot bath, diet, drugs, alcohol, environmental
agents, and psychological stress may be associated
with a temporary decrease in spermatogenesis.
Hypothalamicpituitary disorders, testicular defects,
or abnormalities of sperm transport may affect Leydig
cell function or spermatogenesis jointly or selectively,
and lead to chronic abnormalities of testicular func-
tion. Most often, androgen production and fertility are
jointly affected due to dependence of spermatogenesis
on androgens.
HYPOTHALAMICPITUITARY
DISORDERS
Impaired gonadotropin secretion can occur in either
generalized anterior pituitary disease or as an isolated
defect. In hypogonadotropic hypogonadism, secretion
of both LH and FSH is impaired. Gonadotropin secre-
tion can also be affected by several external factors.
The elevated plasma cortisol of Cushings disease can
suppress LH secretion. Patients with untreated
congenital adrenal hyperplasia have elevated levels of
adrenal androgens, suppressed gonadotropin secretion,
and consequent infertility. Critical illness also sup-
presses plasma gonadotropin levels. Androgen misuse
or abuse in eugonadal men can inhibit gonadotropin
secretion and impair spermatogenesis. Hyperpro-
lactinemia due to a pituitary adenoma or as an adverse
Hypothalamicpituitary Disorders 93
effect of drugs such as spironolactone or phenothiazines
can inhibit LH and FSH secretion and cause combined
Leydig cell and seminiferous tubule dysfunction.
Elevated prolactin can occasionally be associated with
normal gonadotropin and androgen levels but still
impair fertility by a direct action of spermatogenesis.
Hemochromatosis usually impairs testicular function
as the result of effects on the pituitary; less often it
affects the testis directly. Morbid obesity is associated
with reduced levels of SHBG and of total and bio-
available testosterone but normal LH levels, which
return toward normal with weight loss. Obesity may
also contribute to the decreased testosterone levels in
the subset of such men with Pickwickian syndrome.
TESTICULAR DISORDERS
Developmental defects
The diagnosis of Klinefelter syndrome (XXY) and the
XX male syndrome is not usually made until the
recognition that puberty is delayed. Varicocele, crypt-
orchidism, germinal cell aplasia, and deletions or muta-
tions of the azoospermia factor (AZF) genes on the Y
chromosome may cause infertility in the presence of
normal androgen production.
2527
Varicocele occurs in approximately 10% of men, most
often on the left side (90%), and may be the causative
factor in as many as 30% of couples with infertility.
A varicocele is due to dilation of the pampiniform
plexus of veins that surrounds the testis and is caused
by incompetence of the venous valve between the
internal spermatic vein and the renal vein, allowing
retrograde flow of blood into the internal spermatic
vein. Varicocele occurs in ~1015% of men in the
general population and in 2040% of men with
infertility. The testes are normally 12C cooler than
the core body temperature. A varicocele increases the
blood flow and consequently the temperature of both
testes as a result of the extensive anastomoses of the
venous systems and may impair spermatogenesis, non-
specically affecting all sperm parameters. Open ligation
or percutaneous transfemoral balloon embolization of
the internal spermatic vein restores fertility in 50%
of men whose preoperative sperm counts exceed 10
million per milliliter.
Unilateral cryptorchidism, even when corrected
before puberty, is often associated with impaired
spermatogenesis, demonstrating that both testes can be
abnormal in unilateral cryptorchidism. Some patients
with germinal cell aplasia have absent germinal
epithelium and resultant azoospermia, elevated FSH
levels, but normal plasma testosterone and LH levels.
28
Kartagener syndrome is an autosomal recessive defect
associated with situs inversus, chronic sinusitis, and
bronchiectasis due to absent or impaired motility of
the cilia of the airways and of the sperm. Electron
microscopic studies demonstrate structural defects in
the dynein arms, spokes, or microtubule doublets of the
cilia of the epithelia of the airways and of the sperm.
Acquired testicular disorders
Viral orchitis caused by the mumps virus, echovirus,
lymphocytic choriomeningitis virus, and group B
arboviruses is a common cause of testicular failure.
Mumps orchitis occurs in approximately 2025% of
mumps, is usually unilateral but may be bilateral
(3035%), and develops 23 days after the onset of
parotitis. The testes are swollen and painful and will
either return to normal size within 710 days or
undergo atrophy over the next 26 months. Unilateral
atrophy occurs in approximately 30% of cases and
bilateral atrophy occurs in about 1015%. Atrophy is
thought to be due to ischemia secondary to pressure
and edema within the tunica albuginea and to the
direct effects of the virus on the seminiferous tubules.
Normal seminiferous tubular function is restored in
70% of men with unilateral mumps orchitis but in only
30% of men with bilateral orchitis.
Testicular torsion and direct, severe testicular
trauma in contact sports and in men with hazardous
occupations can cause testicular atrophy. Testicular
irradiation reduces testicular blood flow and secretion
of testosterone, and spermatogenesis in a dose-
dependent fashion. Plasma levels of FSH and LH are
increased and azoospermia may develop as the ger-
minal epithelium is progressively destroyed. Recovery
of sperm density is also dose-related, may require as
long as 45 years, and may be incomplete despite
shielding of the testes. Cryopreservation and banking
of sperm are vital in men who wish to father children
prior to further radiotherapy or chemotherapy.Although
direct testicular radiation therapy for boys with acute
lymphoblastic leukemia causes permanently low
plasma testosterone levels, lifelong androgen deciency
is uncommon in adult men after radiotherapy.
Testicular function can be impaired by prescribed or
recreational drugs by a variety of mechanisms. Testos-
terone synthesis can be inhibited by spironolactone
and ketoconazole, which interferes with the nal steps
in androgen synthesis. Spironolactone and cimetidine
also block androgen target organ actions by compe-
titive inhibition of androgen receptor site binding.
The cirrhosis of long-term alcohol abuse is associated
with feminization, including testicular atrophy and
gynecomastia due to impaired hepatic catabolism of
estrogens. Long-term alcohol abuse also decreases
plasma testosterone levels in the absence of liver
disease. Marijuana, heroin, or methadone abuse may
be associated with low plasma testosterone and elev-
ated estradiol levels through unknown mechanisms.
Treatment with digitalis may occasionally cause
increased plasma estradiol and decreased plasma
testosterone levels.
Chemotherapeutic agents often impair spermato-
genesis. Cyclophosphamide often causes azoospermia
within a few weeks of starting therapy and return of
spermatogenesis occurs in 50% of men within 3 years
of ceasing chemotherapy. Leydig cell function and
androgen synthesis may also be damaged with com-
bination chemotherapy containing alkylating agents.
This is manifested by reduced plasma testosterone and
elevated LH levels in prepubertal boys, and normal
plasma testosterone levels but an enhanced LH
response to GnRH in adult men.
Occupational and recreational exposure to chemicals
or agents toxic to spermatogenesis such as lead, cad-
mium, microwaves, or ultrasound may cause infertility.
Increased exposure to environmental antiandrogens
or estrogens may be responsible for the 40% decline
in sperm density observed over the past 50 years.
Testicular abnormalities associated with
systemic disease
Androgen synthesis and spermatogenesis are decreased
in chronic renal failure despite the high plasma LH
level caused by both increased production and reduced
clearance but does not restore normal testosterone
production. Furthermore, hyperprolactinemia is present
in 30% of men with renal failure and decreases testos-
terone production. Gynecomastia, erectile dysfunction
(ED), and hypoactive sexual desire due to androgen
deciency and increased plasma estrogen levels are
common in chronic renal failure. Successful transplan-
tation and, to a much lesser extent, chronic hemo-
dialysis may return testicular function to normal.
In cirrhosis of the liver, the presence of an elevated
LH level inappropriately lower than that expected for
the degree of androgen deciency probably results
from inhibition of LH secretion by elevated estrogens.
Increased estrogen production results from impaired
hepatic extraction of adrenal androstenedione and
subsequent increased extraglandular conversion by
aromatization to estrone and estradiol. ED, testicular
atrophy, and gynecomastia are common in men with
cirrhosis and successful liver transplantation reverses
these effects of cirrhosis. Advanced metastatic cancer
and Hodgkins disease are often associated with
reduced Leydig cell function characterized by lowered
plasma testosterone levels and normal to increased
plasma LH levels, and reduced spermatogenesis.
Similar non-specic hormone changes occur after
surgery, acute myocardial infarction, and severe burns.
In men with a human immunodeciency virus (HIV)-
related illness, 3550% of men eventually develop low
testosterone levels.
29
Gonadotropins may initially be
elevated as part of a compensated state of hypo-
gonadism prior to the development of overt androgen
deciency. Many of the hormonal changes seen in HIV-
related illness are non-specic and related to severe
illness. Androgen replacement therapy (ART) may
increase muscle and lean body mass.
30
Neurologic diseases associated with altered testicular
function include myotonic dystrophy, spinobulbar
muscular atrophy, and paraplegia. In myotonic
dystrophy, small testes may be associated with both
androgen deciency, due to impaired Leydig cell func-
tion, and impaired spermatogenesis. The function of
the androgen receptor is impaired in spinobulbar
muscular atrophy and reduced androgenization, infer-
tility, and the hormonal features of androgen resistance
are late manifestations. Spinal cord injury may lead
to a temporary decrease in testosterone levels and
persistent defects in spermatogenesis.
Androgen resistance
Androgen receptor defects result in resistance to the
action of androgen in target organs and may be
associated with a spectrum of symptoms, ranging from
oligo- or azoospermia with mild resistance, to a
defective male phenotypic development, infertility,
and under androgenization with more severe degrees
of androgen resistance.
Treatment
Oral testosterone preparations have relatively poor
bioavailability. Relatively small amounts reach the
systemic circulation as it is rapidly absorbed into the
portal blood and promptly degraded by the liver.
Parenteral testosterone, unless modied to retard
absorption or degradation, is also rapidly degraded.
Effective ART requires either a slowly absorbed form
such as a transdermal patch system or micronized
oral testosterone, or modied analogs which retard
absorption or degradation, or enhance the androgenic
potency.
Three types of modication have had widespread
clinical application: (1) esterication of the 17-hydroxyl
group; (2) alkylation at the 17 position; and (3) alter-
ation of the ring structure, particularly by substitutions
at the 2, 9, and 11 positions. Most pharmacologic
agents actually have combinations of ring structure
alterations and either 17-alkylation or esterication of
the 17-hydroxyl group.
Esterication of the 17-hydroxyl group decreases
the polarity of the molecule, rendering the steroid
more soluble in the fat injection vehicles and leading to
slower release into the circulation after intramuscular
injection. Absorption is more retarded and drug action
prolonged, if larger acids are esteried. Esters such as
Testicular Disorders 95
testosterone cypionate and testosterone enanthate can
be injected intramuscularly every 2 weeks.
31
Most orally active androgens feature 17-methyl or
-ethyl alkylation which retards hepatic catabolism and
allows the alkylated derivatives to reach the systemic
circulation. Unfortunately, all 17-alkylated steroids
can cause abnormal liver function, and have a limited
role in therapy. Other alterations of the ring structure
have been adopted empirically; some slow the rate of
inactivation, others enhance the potency of a given
molecule, and some alter the conversion to other
active metabolites. For example, the potency of
fluoxymesterone may be due to the fact that, unlike
most androgens, it is a poor precursor for conversion
to estrogens in peripheral tissues.
Three transdermal preparations are available in
which a testosterone-loaded patch is applied to the
skin each day and provides physiologic testosterone
levels that mimic the normal diurnal variation with
higher levels in the morning hours.
3234
One is applied
to a shaved scrotum (Testoderm) and has poor patient
acceptance. The other two systems, Androderm and
Testosterone TTS, contain proprietary skin absorption
enhancers and are applied to the trunk, arms, or
thighs. Androderm is associated with a high incidence
of skin irritation.
Adverse effects of androgens
Adverse effects of physiological androgen doses are
uncommon in adult men. All androgens can induce
virilization in women and children and use in these
settings requires expert management. Acne, coarsening
of the voice, hirsutism, weight gain, gynecomastia,
male-pattern hair loss, and menstrual irregularities
may occur and will slowly resolve once treatment is
discontinued. Gynecomastia is common in children
receiving androgens, due to a greater capacity to con-
vert androgens (aromatized) in extraglandular tissues
to estradiol in childhood. The administration of
testosterone esters to men results in an increase in
plasma estrogen levels, but in men with normal liver
function. Although chronically ART in adult men with
testosterone esters results in high plasma estrogen
levels, gynecomastia only develops in adult men with
abnormal liver function or following treatment with
high doses.With the supraphysiologic doses of androgen
misuse or abuse, gonadotropin secretion is inhibited,
the testes atrophy, and spermatogenesis diminishes,
often for up to 12 months after cessation of the
androgen.
In older men, ART with testosterone ester injections
may cause polycythemia.
35
Symptoms of obstructive
sleep apnea may occur in predisposed men or worsen
in men receiving ART.
3638
Minor sodium retention is
common with ART and may result in edema in men
with controlled or insipient cardiac failure, or when
androgens are administered in large supraphysiological
doses.
The transient supraphysiological peak plasma
testosterone levels of testosterone esters or the high
rst-pass portal testosterone concentrations of oral
testosterone undecanoate increase hepatic testosterone
exposure, and may be associated with reduced levels
of SHBG, high-density lipoprotein cholesterol, and
other hepatic proteins.
39
This is rarely seen with trans-
dermal patches or implants where the plasma testos-
terone level is relatively constant.
All 17-alkylated synthetic androgens (oxandrolone,
fluoxymesterone, danazol) are hepatic and can cause
cholestatic hepatitis, peliosis hepatis, and hepatic
tumors with abnormal liver function tests, including
elevated plasma levels of alkaline phosphatase and
conjugated bilirubin. Although preexisting chronic liver
disease increases the risk of androgen hepatotoxicity,
jaundice may occur in the absence of men with normal
hepatic function. Peliosis hepatis (blood-lled cysts in
the liver) and hepatoma are the most serious compli-
cations of androgens and may either follow a benign
course after cessation of androgens or be rapidly fatal.
Other synthetic androgens, such as 19-nortestosterone
derivatives (nandrolone) and the 1-methyl androgens
(mesterolone, methenolone), are not hepatotoxic.
ART is contraindicated in men with prostate or
breast cancer. Prostate cancer should be excluded in
all men over the age of 40 prior to initiating ART, with
a digital rectal examination and determination of
prostate-specic antigen. In men with an elevated
prostate-specic antigen level, further investigation
with transurethral ultrasonography (TRUS) and biopsy
of the prostate should be performed prior to initiation
of ART. ART should be used cautiously in older men
with symptoms of BPH as it may precipitate urinary
obstruction. These men should also be warned about
the possibility of experiencing unfamiliar increases in
sexual desire. Precautions should also be exercised in
the use of ART in men with bleeding disorders,
androgen-sensitive epilepsy, migraine, sleep apnea or
polycythemia, and in men with cardiac or renal failure
or severe hypertension susceptible to fluid overload
from sodium and fluid retention.
40
Screening for
cardiovascular and prostate disease in men receiving
ART need be no more intensive than for age-matched
men not receiving ART.
41
Androgen replacement therapy
ART is indicated in androgen deciency of any cause
to restore normal male secondary sexual characteristics
and male sexual behavior and to mimic the anabolic
hormonal effects on muscle and bone mass, bone
marrow, nitrogen retention, and other androgen-
responsive tissues. Response to ART in hypogonadal
men is almost always successful.
42
All the clinical
features of androgen deciency, except decreased
spermatogenesis, usually respond within 12 months
of starting ART, although the full effect may take
longer. However, suppression of plasma LH to the
normal range may not occur for many weeks in men
with primary, long-standing hypogonadism. ART, after
puberty, is lifelong as the underlying disorders are
almost always permanent.
Deep intramuscular injections of a long-acting ester
such as testosterone enanthate or mixed testosterone
esters as 250 mg in 1 ml oil at 14-day intervals are
usually given into the upper and outer quadrant of the
buttock, resulting in a sustained increase in plasma
testosterone to the normal male range.
43
Alternatively,
transdermal testosterone patchs, which are available
in different doses and are replaced daily, can be used.
Testosterone and its esters should be used in
preference to 17-alkylated synthetic androgens and
19-nortestosterone derivatives, because of their
established safety and efcacy and ease of dose titration
and monitoring of testosterone levels. ART should
start with injections, but the proven patient preference
for the stable testosterone levels and smoother clinical
effects provided by implants or transdermal formu-
lations as opposed to the wide fluctuations in testos-
terone levels and symptoms during intramuscular
testosterone ester injections offers superior compliance
for long-term treatment.
44,45
Previously untreated elderly men may require lower
starting doses of ART. Poor compliance with dosing
frequency may be associated with more, higher peaks
and lower trough blood testosterone levels, and
exaggerated fluctuations of symptoms. An inadequate
response to ART, indicated by absent or poor sympto-
matic improvement and low trough testosterone levels
with or without persistently elevated LH levels in
primary hypogonadism, may indicate a need for 10-day
injection intervals. Increased dosage of ART is rarely
required, with the exception of men with mild andro-
gen resistance due to androgen-receptor mutations.
Persistently inadequate clinical responses suggest that
recalcitrant symptoms are not due to androgen
deciency.
In prepubertal hypogonadism, commencement of
low-dose ART at the time of puberty (age 1214 years),
followed by gentle dose escalation, results in a normal
progression of the events of puberty. ART should be
designed to replicate normal development and not
shorten the process. If ART is delayed until after the
expected time of puberty, the extent of virilization is
variable but the majority of patients achieve relatively
complete anatomic and functional sexual maturation.
Prepubertal hypogonadal boys with microphallus
require intermittent low-dose androgen therapy to
achieve normal external genitalia, and rarely experience
premature epiphyseal closure and shortened stature.
Although the time frame for the appearance of second-
ary sex characteristics is variable, penile development,
deepening of the voice, and the appearance of other
secondary sexual characteristics usually commence
during the rst year of treatment.
Adequacy of ART can be monitored by clinical
observation for resolution of the major symptoms of
androgen deciency and for improved clinical well-
being, combined with a limited number of hormonal
assays. Restoration of adequate potency and sexual
desire has a low threshold for androgen action and
does not indicate adequate androgen replacement.
The achievement of trough blood testosterone levels
within the normal range can be a valuable guide to the
adequacy of parenteral androgen replacement but is of
limited use in monitoring with oral ART. Suppression
of blood LH levels into the eugonadal reference range
indicates adequate ART in men with primary hypo-
gonadism. ART is either inadequate or the patient is
non-compliant if elevation of LH persists after 46
months of ART. In contrast to this, blood LH levels are
of no use in monitoring the response to ART in hypo-
gonadotropic hypogonadism.
The adequacy of long-term androgen effects on
bone mass can be evaluated by baseline and annual
bone densitometry of vertebral trabecular bone with
dual-photon absorptiometry.
Use of androgens in eugonadal men
The use of androgens has been touted as a treatment
for manifold disorders in eugonadal men. In some of
these disorders, the use of androgen therapy has been
rationalized on the basis that potential non-virilizing
benets, including improved nitrogen retention, muscle
mass, and hemoglobin, might outweigh any deleterious
actions. The proposed benets include improved
nitrogen balance in catabolic states, such as HIV-related
illness, enhanced erythropoiesis in the anemia of renal
failure and other refractory anemias, the treatment of
endometriosis, improved growth in growth retardation
of various etiologies, and self-administration by
athletes to increase muscle mass and consequently
performance.
46,47
These benets are rarely achieved, as
negligible physiologic effects occur in eugonadal men
with normal testicular androgen production unless
extremely high androgen doses are used. Furthermore,
as all androgens act upon a single receptor, the
prospect of the development of a synthetic androgen
that produces only the anabolic and not the virilizing
effects seems remote.
Fewer than 2% of men with ED have an androgen
deciency. In men with ED, androgen deciency should
be excluded with screening plasma testosterone levels
Testicular Disorders 97
and androgens should only be administered to men
with a proven androgen deciency.
At this stage, there is no convincing evidence that
the modest midlife decreases in plasma testosterone
levels have any clinical importance. This progressive
decline in androgen production with aging has been
inappropriately called the male menopause or
andropause but clearly differs from female meno-
pause, when ovarian failure effectively ends reproduc-
tive capacity.These terms are confusing and misleading
and have no basis in evidence-based medicine.
Androgen abuse by male and female athletes is now
epidemic, in the expectation that muscle development
and athletic performance will be improved.
48
In
controlled studies, androgens do improve nitrogen
balance and muscle mass.
49
The androgen doses
frequently taken by athletes may exceed 10 times the
replacement dose, and there are no data to conrm
that athletic performance is enhanced and that increased
muscle mass is sustained.
50
The risks associated with
multiple side-effects of high-dose androgen abuse,
particularly marked virilization in women, far outweigh
the presumed benets.
51
The prescription of androgens
with the sole purpose of enhancing the performance of
elite athletes is regarded as a breach of professional
standards by medical boards in most countries.
TESTOSTERONE SUPPLEMENTATION
IN THE AGING MALE
There is a large amount of clinical evidence to support
the role of hormone replacement therapy (HRT) in
postmenopausal women. Over the past two decades,
the concept of the male menopause or andropause
and the potential role for male HRT in reversing some
aspects of aging and prolonging the quality of life in
older men, by preventing or reducing a variety of age-
related degenerative symptoms, has generated increasing
interest in both physicians and special-interest patient
groups. The major androgen target organs of interest
with regard to the benecial effects of male HRT
include bone, muscle, adipose tissue, the cardiovascular
system, and the central nervous system (libido and
aspects of mood). Serum testosterone levels decline
slowly with normal aging in men and, although all men
are not destined to become hypogonadal as they age,
the prevalence of androgen deciency in the older
male is signicant.
ANDROGEN LEVELS IN THE AGING
MALE
Most recent studies have demonstrated a progressive
decline in plasma levels of total testosterone, free
testosterone and bioavailable testosterone, and an
increase in SHBG plasma levels as men age.
5255
Serum
levels of DHT do not alter as men age. The increase in
SHBG results in a greater rate of decline in serum
levels of bioavailable testosterone than that seen for
total testosterone.
56,57
The circadian rhythm in plasma levels of testos-
terone seen in young men, with peak levels occurring
in the morning, attenuates in older men.
58
Testosterone
declines with age due to decreased production. Leydig
cell mass and the activity of the enzymes in the testos-
terone production pathway reduce as men age.
59,60
The
increase in testosterone production in response to
increased gonadotropin stimulation is also attenuated
in older men.
61
An age-related decline in hypothalamic
pituitary function may also contribute to the decline in
testosterone production. Older men fail to demonstrate
an appropriate increase in LH secretion in response to
a hypoandrogenic state, and many older men with low
testosterone levels have normal LH levels, resulting in
a relative hypogonadotropic hypogonadism.
The rate of testosterone decline among individual
men can vary as men age. There is a wide variation in
the reported prevalence of hypogonadism in older
men in published studies (Table 6.1). This relates to a
general lack of agreement on the criteria for dening
hypogonadism in older men. Well-designed clinical
research involving male HRT is limited and is at least
20 years behind that for HRT in the postmenopausal
female. Most of the current ART in studies of aging
TABLE 6.1 Prevalence of androgen deciency in aging men.
Study Age range n Plasma total % of older men
(years) testosterone (ng/ml) in study
Vermeulen and Kaufman (1996)
95
2000 300 <32 22% (6080 years)
36% (80100 years)
Lunglmayr (1997)
96
5087 817 <30 11.4%
Morley et al. (1997)
55
75101 77 <25 33%
Smith et al. (2000)
97
4069 1660 <32 20.4% (4079 years)
males have enrolled men with testosterone levels either
at or below the lower limit of the normal range for
young adult men and have assessed the responsiveness
of androgen target organ responses to ART.
ANDROGEN TARGET ORGAN
CHANGES IN THE AGING MALE
Age-related degenerative organ changes that occur in
the aging male include a decline in bone mass and an
increased incidence of osteoporosis and minimal-
trauma fractures, a decrease in muscle tissue mass and
a decline in muscle strength, an increase in adipose
mass, particularly in intraabdominal fat, a decline in
sexual desire and erectile function, and a decreased
sense of well-being. All of these changes, with the
exception of increased adipose mass and ED, can be
improved with ART in the younger adult hypogonadal
male.
POTENTIAL BENEFITS OF MALE
HORMONE REPLACEMENT THERAPY
The potential benets and risks of male HRT in the
aging male are listed in Table 6.2.
Bone
The effects of androgen therapy on bone mineral den-
sity or other biochemical parameters of bone turnover
has been reported by several authors in studies lasting
318 months.
6266
Some of these studies included
osteoporotic older men and evaluated androgen
therapy in men undergoing chronic treatment with
glucocorticoids. The majority of these studies demon-
strated that androgen therapy increased bone mineral
density and slowed down the rate of bone degradation.
However, at this stage there are no data as to whether
the increased bone density is maintained in the long
term, the optimal level of testosterone therapy required
to improve bone mass, and whether testosterone
therapy lowers the rate of osteoporotic fractures in
older men.
Muscle mass and strength
The effects of testosterone therapy in older men on
body composition changes and muscle strength have
been evaluated in several published trials.
61,64,6770
Results from these studies are inconsistent and difcult
to interpret (Table 6.3). A decline in body fat was
reported by Marin et al.
67
and Katznelson et al.,
65
but
other authors reported no change. Most studies demon-
strated an increase in lean body mass and muscle
strength.The magnitude of the decline in body fat mass
was similar to that seen with testosterone replacement
in young hypogonadal men. Improvements in lean
body mass and muscle strength were less pronounced,
suggesting that the muscles of older men may be less
responsive to the anabolic effects of testosterone than
are the muscles of young men.Although muscle strength
was improved in most studies, grip strength was the
primary strength measure. One study assessed the
effects of androgen therapy on mobility and function
and demonstrated reductions in stair-climbing and
distance walk times. One study assessed the effects
of androgen therapy on mobility and function and
demonstrated reductions in stair-climbing and distance
walk times.
71
Sexual function and mood
The effect of testosterone therapy on sexual function
in healthy eugonadal older men has not been reported.
The effects of androgen therapy in eugonadal men
with sexual dysfunction has been reported by several
TABLE 6.2 Potential benets and risks of male hormone replacement therapy in the aging male.
Benets Risks
Increased bone mass, reduced osteoporosis and Increased risk of prostate cancer and benign
prevent fractures prostatic hyperplasia
Increased muscle strength Development of gynecomastia
Increased physical capacity Precipitate or worsen sleep apnea
Increased muscle mass Development of polycythemia
Improved libido and sexual function Fluid overload
Improved well-being and mood Increased incidence of cardiovascular disease
Decreased incidence of cardiovascular disease
Potential Benefits of Male Hormone Replacement Therapy 99
authors. ED is seldom improved but men with hypo-
active sexual desire often report improvement.
7275
Several blinded, placebo-controlled testosterone
replacement studies in older men have evaluated effects
on sense of well-being or other aspects of mood.Testos-
terone therapy in older men was associated with an
improved sense of well-being and mood which was
superior to placebo in several blinded, placebo-
controlled studies.
61,67
Neuropsychological performance
scores for visual memory and visuospatial performance
were lower in hypogonadal men, suggesting a possible
relationship between circulating plasma testosterone
levels and cognitive function.
76
Cardiovascular system
The incidence of cardiovascular disease and cardio-
vascular mortality increases as men age. However,
most epidemiological studies demonstrate that higher
serum testosterone levels are associated with a lower
risk of cardiovascular disease in men.
77
There are scant
published data on the effects of testosterone therapy
on cardiovascular risk factors in older men. Decreased
platelet aggregation or decreased vascular smooth-
muscle tone in men receiving androgen therapy has
been reported in some small preliminary studies. In
older men, testosterone administration by intra-
muscular injections or transdermal patch results in a
modest decrease in total or low-density lipoprotein-
cholesterol levels, and no change or a minimal decrease
in high-density lipoprotein-cholesterol levels.
73
Although the impact of these changes on cardiovascular
disease is unknown, one recent study demonstrated
that transdermal patch replacement therapy in hypo-
gonadal men over the age of 65 did not affect brachial
artery vascular reactivity.
78
Dehydroepiandrostenedione
replacement
Testosterone is not the only androgen that declines
with age. Dehydroepiandrostenedione (DHEA) also
declines with age. Serum DHEA levels are highest in
the third decade of life and then decline at a rate of
approximately 2% per year, so that by the eighth
decade, levels might be only 120% of normal values
among young people.
79
Decreased adrenal secretion of
DHEA is responsible for this decline, with the rate of
decline highest before age 60 and then later becoming
more gradual.
80,81
Data on the role of DHEA supplementation in the
aging male are conflicting. Morales et al. reported that
DHEA supplementation in aging men returned levels
of DHEA and DHEA sulfate to normal values and was
associated with signicant improvements in subjects
muscle strength and body fat mass, sense of well-
being, including better sleep, increased energy, and
better ability to handle stress.
82,83
More recently, in a
crossover study of 39 older men given 100 mg per
day of DHEA, there were no changes in measures of
body composition or subjective measurements of well-
being.
84
The effect of DHEA on bone mineral density is also
unclear. Villareal et al. reported an increase in total
bone mineral density (1.6%) and lumbar spine bone
mineral density (2.5%), as well as a decrease in total
and truncal fat and an increase in fat-free mass in men
and women who received 50 mg per day of DHEA for
6 months.
85
Labrie et al. reported similar changes in
women aged 6070 treated with a skin cream contain-
ing DHEA.
86
However, the Morales group did not nd
a change in bone mineral density after 6 months of
DHEA 100 mg/day.
82
There is inadequate evidence to
TABLE 6.3 Body fat, lean muscle mass, and muscle strength in the aging male on hormone replacement
therapy.
Study Treatment Study Body fat Lean body Muscle strength
(months) (n) (%) mass
Tenover (1992)
61
3 13 NC + 3.2% NC (grip)
Morley et al. (1993)
64
3 8 NC + (grip)
Marin et al. (1993)
67
9 31 6.4% NC
Urban et al. (1995)
68
1 6 + (LE)
Katznelson et al. (1996)
65
18 29 14.0% +5.0%
Sih et al. (1997)
69
12 17 NC + (grip)
Brill et al. (2002)
71
10 1 NC + (excluding time)
Ferrando et al. (2002)
70
6 12 + + (LE)
NC, no change; LE, leg extensors.
support the use of DHEA in the prevention or treat-
ment of age-related osteoporosis.
The relationship between cognition and DHEA has
been reported in a limited number of studies. The
Rotterdam study found that the ratio of free cortisol
over DHEA sulfate was signicantly related to cogni-
tive impairment, as measured by the Mini-Mental
State Examination healthy elderly subjects.
87
However,
no studies have demonstrated that DHEA supplemen-
tation improves cognition. Although short-term supple-
mentation produced mild changes in event-related
potentials, an improvement in memory or mood was
not demonstrated.
88
Claims that DHEA can prevent
memory loss and slow the progression of age-related
conditions such as Alzheimers or Parkinsons disease
are not supported by available scientic evidence.
DHEA sulfate concentration is independently and
inversely related to death from any cause and death
from cardiovascular disease in men over age 50.
89
The
Massachusetts Male Aging Study also suggests that low
DHEA and DHEA sulfate might predict coronary
artery disease in men.
90
These androgens can interfere
with the atherogenic process by several mechanisms.
They influence enzymes such as glucoso-6-phosphate
dehydrogenase, which can modify the lipid spectrum.
Furthermore, they can inhibit human platelet aggre-
gation, enhance brinolysis, slow down cell prolifer-
ation, and reduce plasma levels of plasminogen activator
inhibitor type 1 and tissue plasminogen activator
antigen. We suggest that all these DHEA (sulfate)
actions are dependent on sex hormone metabolic path-
ways. However, there are still insufcient data to advise
routine DHEA supplementation in elderly men.
91
ANDROGEN ADVERSE EFFECTS IN
OLDER MEN
As mentioned earlier, ART is contraindicated in men
with prostate or breast cancer; prostate cancer should
be excluded in all men over the age of 40 prior to
initiating ART, with a digital rectal examination and
determination of prostate-specic antigen. Many of the
potential risks of male HRT are increased in older men
and can be predicted by the baseline medical history,
examination, or laboratory testing.
Fluid overload from sodium and fluid retention may
occur during the rst few months of ART but is usually
minimal and transient. Caution should be used with
ART in chronically ill or frail older man due to the
risk that fluid overload may cause an exacerbation of
hypertension or congestive cardiac failure. ART may
exacerbate sleep apnea and sleep apnea may con-
tribute to low serum testosterone levels.
3638
As the
prevalence of sleep apnea is higher in older men,
patients should be specically questioned regarding
the presence of symptoms of sleep apnea before and
during ART.
Breast tenderness and gynecomastia may develop in
a small number of older men on ART. Both are more
common adverse effects of ART in older men than
younger men, due to the effects on breast tissue of the
increase in extraglandular estrogen formation, which
increases as men age.A signicant increase in red blood
cell mass and hemoglobin levels often occurs with ART
in older men and exceeds those changes seen in young
hypogonadal men receiving ART.
92
The development
of polycythemia in men on ART usually responds to a
reduction in the testosterone replacement dose but
may occasionally require cessation of therapy.
69,93
This
effect on red cell mass is less with the more uniform
and physiological plasma testosterone levels achieved
with ART using implants or transdermal patchs.
BPH and prostate cancer are common diseases in
older men. Both are promoted by androgens and
androgen deprivation therapy has been used for the
treatment of both of these diseases. ART should be
used cautiously in older men with symptoms of BPH
as it may precipitate urinary obstruction.
Prostate cancer is now the most commonly diagnosed
cancer in men, is second only to lung cancer as the
leading cause of cancer death in men and, as such, is a
major public health issue in all western countries. The
lifetime probability of prostate cancer is 1 in 6, and 1
in 3 men over the age of 50 years will die from prostate
cancer. The American Cancer Society estimated that in
1998 about 184 500 new cases of prostate cancer would
be diagnosed and 39 200 men will die of this disease
in the USA. In most countries, the age-standardized
incidence of prostate cancer increased dramatically
in the early 1990s coincident with increased public
awareness and the introduction of early detection and
screening programs based on regular digital rectal
examination and measurement of prostate-specic
antigen levels.
Whilst there is little doubt that androgens promote
the growth of diagnosed prostate cancer, the increased
risk of ART promoting the development of clinically
signicant prostate disease from preexisting, but sub-
clinical, disease is speculative. The incidence of prostate
cancer, prostate size, serum levels of prostate-specic
antigen, TRUS-guided prostatic needle biopsies, and
urodynamic parameters such as urine flow rates or
urinary bladder residual volumes in men aged 4089
years receiving ART exhibit either no change or minimal
change but remain within the normal range.
94
How-
ever, caution must be exercised as there are no long-
term safety data and the current data are insufcient
to rule out ART denitely as a causal risk of prostate
cancer.
The older man should be screened for conditions
that increase the potential risks of androgen therapy
Androgen Adverse Effects in Older Men 101
prior to initiating treatment. Prostate cancer should be
excluded in all men over the age of 40 prior to initiating
ART, with a digital rectal examination and deter-
mination of prostate-specic antigen. In men with an
elevated prostate-specic antigen level, further investi-
gation with TRUS and biopsy of the prostate should be
performed prior to initiation of ART.
Although larger longitudinal studies of male HRT
are lacking, the currently published studies indicate
that male HRT may improve mineral density, increase
muscle mass and strength, and, in some men, improve
libido and mood. There are no data, however; it can
only be speculated that ART is associated with a
reduced long-term fracture risk, improved mobility
and function, and improved overall quality of life.
Short- and intermediate-term adverse effects are well
characterized, relatively predictable, and manageable,
but long-term adverse effects on the prostate and
cardiovascular system are unclear. Despite the assertions
of special-interest groups, the media, and the pharma-
ceutical industry that male HRT reverses aging, the
duty of care of the treating physician is to offer older
men only evidence-based medical treatment and coun-
seling that the risk/benet ratio for the male HRT has
yet to be determined.
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References 105
MALE ERECTILE DYSFUNCTION
Introduction
A recent milestone in medicine allowed for a break-
through in the eld of erectile dysfunction (ED).
This event was the March 1998 Food and Drug
Administrations (FDAs) approval of the rst ever oral
agent used to treat ED. Unfortunately, prior to this
time, many ED complaints were attributed to psycho-
logical conditions and accurately diagnosed by either
urologists or primary care providers. Dr. Francois Eid
puts the impact of sildenal into perspective:
It is useful to remember that in 1997; prior to FDA
approval, only 1.7 million men were evaluated and
treated for ED. Urologists evaluated most of those
patients. Of that 1.7 million, 39% were prescribed
yohimbine, which is as efcacious as placebo.
Another 30% were prescribed the Medicated
Urethral System for Erection (MUSE), an alprostadil
suppository therefore, less than 30% of the 1.7
million men were given effective treatment in the
form of penile prosthesis, intracorporal injection
therapy, or an external vacuum device.
1
The World Health Organization (WHO) has under-
scored the impact of ED as a worldwide public health
issue. An international consensus meeting asserted
fundamental individual rights to sexual health that
include: (1) a capacity to enjoy and control sexual and
reproductive behavior in accordance with a personal
social ethic; (2) freedom from fear, shame, guilt, false
beliefs, and other factors that inhibit sexual response
and impair sexual relationships; and (3) freedom from
organic disorders, diseases, and deciencies that inter-
fere with sexual and reproductive functioning.
2
The
current WHO guidelines on ED offer a stepwise
protocol for recognizing, assessing, and treating ED
and for categorizing treatments as rst-line (oral
agents), second-line (intracavernous injection therapy
and intraurethral therapy), and third-line (surgical
prosthesis).Vacuum constriction devices can be used at
any point throughout the treatment process. In addition,
hormonal therapy and penile revascularization have
been proven successful for a small number of patients
with specic etiologies. Sex therapy can be used alone
in specic cases or in combination with other treat-
ments.
3
This chapter reviews current information on
phosphodiesterase type 5 (PDE5) inhibitors and their
role in the treatment of male and female sexual
dysfunction.
Epidemiology of ED
A literature review completed in 1999 demonstrated
a 52% prevalence of ED in non-institutionalized men
between 40 and 70 years of age in the Boston,
Massachusetts area.
4
Identied risk factors for ED
include atherosclerosis, diabetes mellitus, chronic renal
failure, liver failure, multiple sclerosis (MS),Alzheimers
disease, chronic obstructive lung disease, and endocrine
disorders. As expected, advancing age was also a pre-
dominant risk factor, with the prevalence nearly
doubling from 39% of 40-year-olds to 67% of men in
their 70s.
4
A cross-national study of over 2400 men in
Malaysia, Italy, Brazil, and Japan also reinforced the
astounding prevalence of ED. In the Japanese cohort,
71% of the 700 men reported some degree of dys-
function. Again, a higher prevalence was seen with
increasing age.
5
Physiology of erection
Erectile function is the result of a complex interaction
of hemodynamic, neurologic, neuropeptide, electro-
physiologic, and pathophysiologic factors. The primary
hemodynamic events of penile tumescence/detu-
escence are regulated by corporal smooth-muscle relax-
ation/contraction, respectively.Tumescence (erection) is
mediated by: (1) the parasympathetic nervous systems
release of acetylcholine, and (2) the non-adrenergic,
non-cholinergic cavernous nerve release of nitric oxide
(NO) with subsequent activation of cyclic guanosine
monophospate (cGMP). This NO/cGMP mechanism
appears to play a major role in modulating erectile
function. So much so, that organic or psychogenic
factors causing pathway alterations can impair the
relaxation of smooth muscle or even increase its
contraction, thereby causing ED.
4
A pivotal event in tumescence is the active clearance
of calcium from the corpora smooth muscle. This
Oral Type 5 Phosphodiesterase Therapy for
Male and Female Sexual Dysfunction
J. C. Trussell, Aristotelis G. Anastasiadis, Harin Padma-Nathan, and Ridwan Shabsigh
CHAPTER 7
smooth muscle is in a tonic state of contraction that,
upon relaxation (removal of intracellular calcium),
allows for sinusoidal enlargement, helicine artery
dilation, and eventually, emissary vein compression.
Smooth-muscle contraction relies on the interaction
between thin and thick muscle laments. This inter-
action (which results in force generation) can only occur
after the phosphorylation of a 20 kDa light chain of
myosin by a Ca
2+
/calmodulin-dependent myosin light-
chain kinase.Without the presence of calcium, thin and
thick muscle laments are held apart, allowing for
relaxation. In the normal corpora this smooth-muscle
relaxation results in tumescence.
In an effort to promote tumescence, the removal of
intracellular calcium requires energy. The corpora have
two different energy generators used to pump calcium
to the extracellular space via calcium channels, or to
sequester calcium in the cells endoplasmic reticulum
storage spaces. These two energy sources are: (1) cyclic
adenosine monophosphate (cAMP), mediated by
prostaglandin E
1
, and (2) cGMP, mediated by NO. By
inhibiting degradation, the effect of these two energy
sources can be potentiated. This is accomplished by
blocking phosphodiesterase (PDE), which acts to con-
vert active cAMP/cGMP into inactive 5AMP/5GMP
respectively. Along this line, sildenal blocks PDE type
5 (PDE5), which specically inhibits cGMP break-
down, while papaverine blocks PDE24, acting more
specically within the cAMP pathway.
Sildenal can only potentiate cGMP activity after
cGMP is manufactured. This is why sexual stimulation
is necessary to enable sildenal to be effective. Sexual
stimulation is what triggers the non-adrenergic, non-
cholinergic release of NO, thereby initiating a rise in
cGMP levels. This rise is then additionally potentiated
by sildenal.
Pharmacology of sildenal
Sildenal is an orally active, potent, and selective
inhibitor of cGMP-specic PDE5.
6
Although four PDE
isoenzymes have been identied in penile tissues
(PDE2, 3, 4, and 5) the predominant isoform is PDE5.
Since the discovery of sildenal, ve additional human
PDE families have been discovered (PDE711).
7
Fortunately, sildenal has a 1010 000-fold greater
selectivity for this particular isoform (PDE5). It also
has a 4000-fold greater selectivity for PDE5 than
PDE-3 the isoform involved in the control of cardiac
contractility.
6
Moreover, PDE5 is not expressed in
isolated cardiac myocytes, and as a result, sildenal
has no known direct effects on the myocardium. Its
potential effects on coronary circulation, specically
vasodilation, may be benecial in minimizing angina,
or even a myocardial infarction.
After oral administration, sildenal is rapidly
absorbed with an absolute bioavailability of 40%. The
time to peak plasma concentration (t
max
) while fasting
is 30120 min with a median time of 60 min.
6,8
On
the other hand, after a high-fat meal, not only is the
time to peak plasma concentration prolonged (by an
additional 60 min), but the peak plasma concentration
is reduced by 29%. The terminal half-life of sildenal
is 35 h.
6,8
Clinically, responses to the medication may
be observed for upwards of two to three half-lives
(812 h).
Sildenal is metabolized by hepatic microsomal
cytochrome P450 isoenzymes 3A4 (major route) and
2C9 (minor route).
6,8
Potent P450 3A4 inhibitors, such
as cimetidine, erythromycin, and ketaconazole, may
retard metabolism. Because of this, drug levels may be
two to eight times higher in these patients. Interestingly,
even with higher serum drug concentrations, side-effect
proles were no different from that of the general
study population. Patients receiving ritonavir, a
protease inhibitor sharing two metabolic pathways
with sildenal, should not be given sildenal at doses
greater than 25 mg or at a frequency of greater than
48 h. Since an active metabolite of sildenal is excreted
in the feces (80%) and urine (13%),
8
downward dose
adjustments (starting with 25 mg) are recommended
for patients who are over 65 years of age, have hepatic
impairment, or have severe renal insufciency.
Dosage
The recommended dose of sildenal ranges from 25 to
100 mg. Due to increased plasma concentrations and
efcacy (and possible side-effects), a 25 mg starting
dose is recommended for patients over 65 years of age,
those with liver failure, or severe renal insufciency,
and for individuals who are concomitantly taking
drugs that inhibit cytochrome P450 isoenzyme 3A4
(see above). Otherwise, the initial starting dose should
be 50 mg taken orally 1 h before sexual activity. Note,
however, that some patients have reported the onset of
activity as early as 1119 min.
6,8
Following this initial
dose, adjustments may be made upward (maximum
of 100 mg), or downward based on efcacy and
tolerability.
In the American flexible-dose study, 75% of patients
ultimately chose the 100 mg dose, 23% the 50 mg
dose, and 2% the 25 mg dose.
9
Similar results were
reported in a worldwide flexible-dose study where
60% chose 100 mg, 30% chose 50 mg, and 10% chose
the 25 mg dose.
8
Contraindications
Sildenal was initially developed and tested as a
vasodilator to be used in cardiac patients. Since small
108 Oral Type 5 Phosphodiesterase Therapy for Male and Female Sexual Dysfunction
amounts of PDE5 are also found on vascular endo-
thelium, an expected event resulting from PDE5
inhibition is the potentiation of the hypotensive (vaso-
dilatory) effects of nitrates. Because of this, sildenal is
contraindicated in patients taking organic nitrates or
other NO donors (such as nitroprusside). Be cautious
of patients taking nitrates on an intermittent basis, or
even recreationally (amyl nitrate, poppers).
10
This, of
course, includes all routes for nitrate administration:
sublingual, transnasal, transdermal, and orally. In
addition, although no case has been reported to date,
the second contraindication is a known hypersensitivity
to tablet components. Cardiovascular events, such as
myocardial ischemia/infarction, are more related to the
physical exertion of sexual activity rather than a direct
effect of sildenal. Patient stratication and recommen-
dations will be discussed later in this chapter.
Precautions
An update on product labeling by the US FDA has
cautioned against the use of sildenal in patient popu-
lations that have generally been excluded in clinical
trials. This includes patients who have sustained a
myocardial infarction, stroke, or life-threatening
arrhythmia within the past 6 months; patients with
resting hypotension (<90/50 mmHg) or hypertension
(>170/110 mmHg); patients with cardiac failure or
coronary artery disease causing unstable angina (see
later in chapter); and patients with retinitis pigmentosa.
8
Excluding the last group, these precautions also apply
to the use of any of the other vasoactive drugs used to
treat ED.
Safety of sildenal
Flexible-dose studies
The most common adverse events in sildenal clinical
trials have included vasodilatory effects such as head-
aches, flushing, and nasal congestion from hyperemic
nasal mucosa. In addition, dyspepsia has been observed.
A dog model has demonstrated that PDE5 may have
a role in maintaining gastroesophageal sphincter
integrity. Therefore, blocking PDE5 can allow for
reflux, and thereby, result in dyspepsia. A recent review
by Morales of more than 3700 patients in 18 of 21
clinical trials examined adverse experiences from
sildenal in a total exposure of 1631 man-years.
11
The
most common adverse events in 2% or more of the
placebo-controlled studies are listed in Table 7.1.
12
A total of 574 adverse events occurred in the 734
sildenal-treated patients, with most events reported
as transient in nature and described as mild (62%) or
moderate (31%).
13
Overall discontinuation rates due
to adverse events were comparable in the sildenal
(2.5%) and placebo (2.3%) treatment groups. Head-
aches (1.1%), flushing (0.4%), and nausea (0.4%) were
the most common causes leading to discontinuation.
The nausea side-effect presumably arises from
dyspepsia, which results from a relaxing effect on the
gastroesophageal sphincter. Lastly, only 1 of the 2722
patients treated with (up to) 100 mg of sildenal
discontinued treatment due to abnormal vision.
11
It is interesting to note that respiratory tract
infection, back pain, and a flu-like syndrome were
noted in 2% or more of the patients, but occurred in
equal frequency with active drug and placebo groups.
In early sildenal studies, back pain occurred in nearly
10% of patients with daily and thrice-daily dosing.
8
This effect has also been observed with other PDE5
inhibitors and is apparently not associated with the
vasculitis picture, or abnormal serum chemistries such
as creatinine kinase.
Fixed-dose studies
The American xed-dose, randomized, placebo-
controlled study provides further insight into the dose
relationship of adverse events.
14
Headaches, flushing,
dyspepsia, nasal congestion, abnormal vision, and
dizziness were not only found to be the most common
adverse-events, but were also found to be dose-
related.
11,15
Once again, headache was the most
common adverse event leading to treatment discon-
tinuation (0.6% of those in the 100 mg group). Discon-
tinuation rates due to adverse events were similar
between the 25 and 50 mg groups (0.6 and 0.4%
respectively), while they were slightly higher with the
100 mg dose (1.2%).The placebo-related adverse event
discontinuation rate was comparable at 1.0%.
12,15
Male Erectile Dysfunction 109
TABLE 7.1 Sildenal adverse event experience
in worldwide flexible-dose studies
11
Percentage of patients
Adverse event Sildenal Placebo
(n = 734) (n = 725)
Headache 16 4
Flushing 10 1
Dyspepsia 7 2
Nasal congestion 4 2
Abnormal vision 3 0
Diarrhea 3 1
Dizziness 2 1
Urinary tract infections 3 2
Long-term, open-label studies
Adverse events experienced by the 2199 patients in
10 separate long-term studies were headache (10%),
flushing (9%), dyspepsia (6%), and respiratory tract
infection (6%). Abnormal vision was reported by 2%
of the patients. In a 1-year analysis, adverse event and
lack of efcacy accounted for 2% and 4% of with-
drawals, respectively.
Headache continues to be the number-one reason
for discontinuation.
16
Although no reports of priapism,
prolonged erections, or penile brosis occurred during
the worldwide clinical trials,
8,11
after FDA approval,
there were at least 25 cases of prolonged erections (>4,
<6 h) or priapism. Notably, many of these cases were
related to combinations of sildenal with other phar-
macologic therapies for ED (either injection or intra-
urethral). The safety and efcacy of such combinations
have yet to be established.
Finally, the impact of adverse events may wane with
prolonged usage. A review of 17 studies comparing
adverse events (a biweekly evaluation over 4 months)
suggested that adverse events might be transient and
eventually decrease in frequency to levels indistin-
guishable from those experienced by placebo-controlled
arms. After 2 months of treatment, differences in
adverse events between sildenal users and placebo
were no longer statistically signicant.
17
Efcacy
Unless otherwise noted, the following efcacy statistics
are based on the sildenal New Drug Application to
the FDA. These data were based on 4526 patients: 576
in phase I studies, 3003 in phase IIIII studies, 769 in
long-term extension studies (with 550+ patients treated
for longer than 1 year), and 178 in Japanese studies.
The mean patient age was 55 years, ranging from 18 to
87. Patients were diagnosed with an organic etiology
51.8% of the time; 18% were psychogenic, and the
remaining 25.7% were considered mixed. As can be
expected with ED, comorbid conditions are common:
24% had hypertension, 16% had diabetes mellitus,
14% had cardiovascular disease, 14% had hyper-
lipidemia, 6% were individuals with spinal cord injury
(SCI), 5% had depression, and 4% had a radical
prostatectomy.
1415,16,18
Sildenal clinical trials employed four different tools
to measure efcacy (some of which have been sub-
sequently modied for efcient clinical use). These
include: (1) the International Index of Erectile Function
(IIEF): a 15-item questionnaire addressing relevant
domains of sexual function. In general these questions
address erectile function, orgasm, desire, satisfaction
with intercourse, and overall sexual satisfaction. This
questionnaire has been validated in 20 different
languages and is both sensitive and specic for detect-
ing treatment-related changes;
19
(2) a Global Efcacy
Question (GEQ). This requires a simple yes or no
response to: Did the treatment improve your
erections?;
9,20
and (3) a log of erectile activity
whereby the patient would record information on the
date and dose taken, the presence of sexual stimu-
lation, and whether successful sexual intercourse took
place. In addition, the 24-week, xed-dose, American
trial included a four-point scale to measure penile
rigidity,
9,20
where, for example, grade three was an
erection hard enough for penetration but not com-
pletely hard, in comparison to grade four a fully
rigid erection.
15
The last survey was optional and
assessed the partners perception of the patients ability
to achieve, and then maintain, an erection.
20
International Index of Erectile Function
IIEF survey results were compiled from 3000+ patients
from 21 American and European randomized, double-
blinded, placebo-controlled, phase III trials lasting up
to 6 months. To reflect the National Institutes of Health
denition of ED,
16
primary endpoints for measuring
efcacy were based on the results of only two items on
this IIEF questionnaire: item 3, the ability to achieve
an erection, and item 4, the ability to maintain an
erection.
19
In all 21 studies, sildenal produced a
signicantly improved erection when compared to
placebo. Regarding survey results, signicant improve-
ments were reported for both items 3 (attain erection)
and 4 (maintain erection), where increases of 100%
and 130% were recorded respectively.
9,20
In flexible-
dose studies, 69% (94/134) of patients taking sildenal
reported erections sufcient for vaginal penetration on
most to all occasions, compared with 23% (32/138)
taking placebo.
20
In addition, 62% (85/132) of
sildenal users were able to maintain their erections
after penetration on most to all occasions, in com-
parison with 15% (21/138) of the placebo group.
Overall, 59% (81/137) treated with sildenal reported
that they were able to achieve and maintain their
erections on most to all occasions compared to 15%
(21/138) of placebo-treated patients.
20
On subset
analysis, these results were consistent regardless of
age, race, baseline severity, or etiology of dysfunction.
Furthermore, sildenal was found to be effective for
those patients with each of the following ED risk
factors: coronary artery disease, hypertension, periph-
eral vascular disease, diabetes mellitus, coronary artery
bypass grafting, radical prostatectomy, transurethral
resection of the prostate (TURP), and SCI. This held
true even for patients currently being medicated for
those conditions. In addition, effective treatment was
also seen in depressed patients, as well as those taking
antidepressants and antipsychotic medication.
8
In addition to items 3 and 4, the remaining questions
on the IIEF questionnaire were also evaluated, and,
as expected, secondary improvements were seen in
the sildenal group regarding intercourse, orgasm, and
overall sexual satisfaction. The domain of desire,
however, was not increased by sildenal, implying that
it lacks aphrodisiac qualities.
Global Efcacy Question and diary data
General population
Overall erectile improvement with sildenal, as
evaluated by the GEQ, was 74% (101/136) compared
to 16% (23/118) in the placebo group (P < 0.0001).
20
Once again, improved erections were seen in all patient
groups regardless of etiology, with the most success
(80% of patients) seen in the psychogenic group. In
addition, improvements were noted in nearly 70% of
men with organic and 75% of mixed ED.
8,14,20
Sildenal
dose escalation also resulted in more patients with
improved erections. Compared to 24% of patients
taking placebo, 63%, 74%, and 82% of patients taking
25, 50, and 100 mg of sildenal respectively reported
improvement in erections (n = 1797).
8
A similar dose
response was extracted from the patients diary, part
of which used a four-point grading scale for penile
rigidity. On this scale grade 3 represented an erection
hard enough for penetration, but not fully hard and
grade 4 was considered a fully rigid erection.
Seventy-ve percent of patients receiving 25 mg, 80%
receiving 50 mg, and 85% of patients receiving 100 mg
of sildenal demonstrated a grade 3 or 4 erection in
comparison to 50% of patients receiving placebo.
15
In these two groups of treated patients, 80% of those
responding at grade 3 and 94% of those reaching
grade 4 also reported successful sexual intercourse.
15
Patients with diabetes
An initial pilot study of 21 diabetic patients (types 1
and 2) with a mean age of 50 years and a 3-year median
duration of ED examined the efcacy of sildenal in
doses of up to 50 mg.
21
ED improvement (measured
by diary, questionnaire, and RigiScan) was noted in
48% and 52% of the men receiving 25 and 50 mg of
sildenal, respectively, compared to 10% of patients
receiving placebo. More recently, a large study of 268
diabetic men (mean age of 57 years, mean diabetes
duration of 12 years, 21% with type I and 79% with
type 2) with a 12-year mean duration of ED was
randomized for 12 weeks of treatment.
13
This flexible-
dose study started at 50 mg with dose adjustments (up
and down) based on efcacy and adverse events. At
the end of the 12-week study, improved erections were
noted in 56% of sildenal patients compared with
22% receiving placebo (P < 0.001). Likewise, sexual
intercourse success rates were 48% versus 12%.
13
Patients with spinal cord injury
The efcacy of sildenal in the population of spinal
cord-injured individuals has also been examined in
several studies, including a single-dose, double-blinded,
two-way crossover study using RigiScan evaluation in
27 patients.
22,23
In that study 65% of sildenal patients,
compared with 8% of placebo patients, had penile
base rigidity greater than 60%. No patient discontinued
sildenal due to adverse events. A larger randomized,
double-blind, placebo-controlled, crossover, flexible-
dose study of 178 patients employed the IIEF and
partners questionnaire.
24
Fifteen percent (27/178) of
these patients had no prestudy erectile function. Erectile
function improved in 83% of patients taking sildenal,
versus 12% of those taking placebo. The sexual inter-
course success rate was greater than 70% on sildenal,
and 0% for those taking placebo (n = 45).
24
Patients with multiple sclerosis
A double-blind, placebo-controlled, flexible-dose study
of sildenal in men with MS and ED demonstrated
improved erections in nearly 90% of the sildenal
group, in contrast to a 24% response in the placebo
group.
25
Patients after radical prostatectomy
Unlike the traditional radical prostatectomy, the
nerve-sparing approach has signicantly improved
postoperative erectile function. None the less, when
objectively evaluated, up to 80% of men sustain some
degree of ED following nerve-sparing surgery. In a sub-
group analysis of men in American trials having had
prostatectomies (n = 42), 42.5% of those receiving
sildenal demonstrated improved erections compared
to 14.6% of patients receiving placebo.
8,26
The resulting
intercourse success rate was nearly 30%, compared
to 5% taking placebo. Since this study lumped all
prostatectomy patients together (both nerve-spared
and non-nerve-spared), a more accurate response rate
can be provided based on a patients specic operative
outcome. Doing this, Zippi and colleagues
27
have
demonstrated an improvement of erections in 71.7%
(38/50), 50% (6/12), and 15.4% (4/26) of men follow-
ing a bilateral nerve-sparing, unilateral nerve-sparing,
and non-nerve-sparing procedure, respectively. To
validate further the importance of sparing nerves to
improve postoperative erectile function, closer scrutiny
of the IIEF (questions 34) responses were similarly
poor for the non-nerve-sparing and unilateral nerve-
sparing, in contrast to the excellent responses seen in
bilateral nerve-spared patients.
27
In an attempt to preserve healthy corporal tissue,
more recent studies have suggested expanding the
indication of sildenal (and other non-surgical inter-
ventions) to include the immediate postop period.
Male Erectile Dysfunction 111
Considering sildenal acts to promulgate the effects
of NO, then conceptually it should work best when
cavernous nerves are intact, to allow for its release and
subsequent tumescence. In contrast, if neither caver-
nous nerve could be spared during a prostatectomy,
sildenal would have no effect on the severed nerve
bundles. In this case, injectable vasoactive agents might
work best. Reducing cavernosal brosis has been
attempted with both sildenal and PGE injections. A
study from Connecticut looked at corpora cavernosal
biopsies during and 6 months following a bilateral
nerve-sparing radical prostatectomy in 40 potent
patients. Every other night sildenal (50 or 100 mg)
was started just after Foley removal. This early sildenal
treatment resulted in preservation of corporal smooth
muscle while lessening the development of corporal
brosis. In fact, those patients taking the higher
100 mg dose seemed to develop much less brosis, and
may have even developed more corporal smooth
muscle!
28
For patients recovering after non-nerve-
sparing radical prostatectomies, consider early intra-
cavernous injections as soon as the rst postoperative
month. Waiting longer may result in cavernous veno-
occlusive dysfunction, which is the most likely expla-
nation for subsequent non-response to PGE in this
patient population.
29
These studies do not demonstrate
a return of potency, but maintenance of proerectile
corporal ultrastructure should be an integral part in
the preservation of postradical erectile function.
Patients after radiation therapy for
prostate cancer
In contrast to the sudden onset of ED in men following
radical prostatectomy, the onset of ED in those receiving
external beam radiation is more insidious. The extent
of impaired sexual function following radiation was
the most important predictor of response to sildenal.
Ninety percent of men who had partial erections
following radiotherapy also had signicant responses
to sildenal compared with only 52% of men who had
flaccid erections (P = 0.02).
30
Another study noted
an increased response to sildenal over time (40%
responded the rst week, while 77% responded at the
sixth week), warning that the drug should not be
discontinued prematurely for this group of patients
because of presumed ineffectiveness.
31
Lastly, sildenal
is also useful in treating patients with ED occurring
after prostate brachytherapy.
32
Patients with transurethral resection of
the prostate
In a subpopulation analysis (after TURP), 60% of those
who had ED after their resection saw an improvement
with sildenal, compared to 33.9% of men receiving
placebo (n = 171).
26
Patients with depression
Beyond direct effects on sexual function, ED also leads
to depressive symptoms, low self-esteem, and other
signs of psychological distress.
3336
A recent landmark
study of 152 men with untreated minor depression
(according to DSM-IV) and concomitant ED were
treated with sildenal.
37
Of the patients receiving
sildenal, 73% were considered responders, in contrast
to 14% of patients receiving placebo.The study showed
that, regardless of the treatment received (placebo or
sildenal), patients who reported a positive treatment
also claimed a signicant improvement in depression
parameters! In those patients the depression was most
likely a secondary factor to ED, but an important fact
is that the study clearly demonstrated that sildenal
treatment resulted in improvements in both sexual and
non-sexual aspects of life quality.
Patients with increased age
ED represents an important quality-of-life issue for
many aging men. Studies seem to conflict regarding
the efcacy of sildenal. For instance, a study in 1998
compared IIEF responses in men younger or older
than 65 years of age. No difference in erectile function
between the two age groups was demonstrated.
18
In
contrast, a more recent study (2002) from Japan did
nd a statistically signicant difference between the
under- and over-65-year-old groups (89.1% versus
65.75% efcacy, respectively). It is noteworthy, how-
ever, that this second study used a modied IIEF
questionnaire (the IIEF-5, which asked only ve
questions), and used only 25 and 50 mg doses of
sildenal.
38
The fact that 100 mg doses of sildenal
were not used may be signicant in light of evidence
that, as men age, the resting tone of cavernosal smooth
muscle is reset to a higher level. This higher level of
smooth-muscle tone may require a greater degree of
relaxation to permit tumescence.
39
Although the older
patients (from Japan) showed a higher prevalence of
diabetes mellitus, hypertension, and benign prostatic
hyperplasia, only the diagnosis of diabetes appeared
to decrease the efcacy of sildenal (P = 0.019).
38
Age-related changes in sexual function did not appear
to be directly related to either testicular testosterone
production or serum testosterone concentration in
most older men. Whether or not testosterone declines
with age seems controversial. Some studies demon-
strate an age-related decrease in testosterone produc-
tion related to decreased testis sensitivity to luteinizing
hormone,
4042
while others have reported no effect of
age on total testosterone concentrations.
38,43
The Japan
study did demonstrate a signicant decrease in mean
serum luteinizing hormone and follicle-stimulating
hormone concentrations in the group of men over 65
years of age.
38
Patients with premature ejaculation
Studies are just starting to look at sildenal in treating
premature ejaculation. In two studies sildenal was
added to selective serotonin uptake inhibitor (SSRI)
therapy, with signicant improvements in ejaculatory
delay.
44,45
At this time, the mechanism of action is
unclear. It is important to remember that increased
adverse events may be seen when combining sildenal
and SSRIs.
45
Partner data
In most studies, partner input was optional. However,
whenever data were present, partner ratings of the
patients ability to achieve and maintain an erection
during sexual activity were signicantly higher for
the sildenal groups compared to those taking
placebo.
8,20,46
Long-term efcacy
In long-term follow-up studies of 1, 2, and 3 years,
more than 95% of patients continued to demonstrate
not only improved erections, but also an improved
ability to engage in sexual activity.
11
More specically,
a 3-year review of efcacy after radical prostatectomy
(using the modied, ve-item IIEF questionnaire)
demonstrated that 71% (29/41) still responded to
sildenal. There was no statistical signicance between
the 1- and 3-year postop questionnaire results, regard-
less of the specic surgical category (bilateral, unilateral,
or non-nerve-sparing). Thirty-one percent (9/29) of
patients responding to sildenal did eventually require
the 100 mg dosage; on the other hand, 50% of those
who dropped out of the study (6/12) did so because
of an eventual return to natural erections. Overall,
85% of the patients were sexually satised, and 95%
were able to achieve and maintain erections during
more than 65% of their attempts.
47
Salvage of sildenal non-responders
Sildenal is an effective rst-line treatment for ED,
with 65% of initial prescriptions written by primary
care providers. Not infrequently, patients are referred
to a urologist because of sildenal failure or non-
response. Studies have shown that careful patient
reeducation with supplemental written information
and possible video instruction can turn many such
patients into responders. Many of the individuals
reporting initial failure had tried the drug only one
time, had only used 25 or 50 mg doses, and had lacked
concomitant sexual stimulation.
48,49
It is important
for patient education to include: (1) reminders that
absorption is best on an empty stomach (at least a low-
fat diet); (2) information that tobacco cessation will
improve responses; and (3) advice to avoid the
sedative effects of alcohol. In a prospective study of
622 patients referred to a urologist, 38% (98/622)
reverted to responders after higher doses (100 mg)
and reeducation.
48
A separate study reported a 54%
(41/76) salvage rate. Those with diabetes, active
smokers, and hypertensive men taking multiple agents
were most unlikely to respond to salvage efforts.
49
It
will be interesting to see if future studies include doses
of sildenal greater than 100 mg. In phase I clinical
studies of healthy male volunteers, doses of up to
800 mg were not associated with adverse events which
were different from those occurring with doses ranging
from 25 to 100 mg.
8
FEMALE SEXUAL DYSFUNCTION
Disclosure
Sildenal is currently not FDA-approved for the treat-
ment of female sexual dysfunction (FSD).
Introduction
In contrast to the plethora of information and wide-
spread interest in the research and treatment of male
sexual dysfunction, much less attention has been given
to similar female difculties. This eld of study is
relatively new, with a limited number of tools and
protocols available to help in understanding the
complex psychological and physiological interactions
that comprise normal female sexual function. In fact,
it was not until 1999 that an international consensus
panel developed a classication of FSD (Table 7.2),
which, for the rst time, included possible organic
causes. This is in contrast to classications from the
WHO International Classication of Diseases-10
(ICD-10) and Diagnostic and Statistical Manual
of Mental Disorder (DSM-IV) that rely more on
psychiatric disorder nomenclature.
50,51
Female Sexual Dysfunction 113
TABLE 7.2 Classication of female sexual
dysfunction according to the 1999 Consensus
Classication System
50
I. Sexual desire disorders:
Hypoactive sexual desire disorder
Sexual aversion disorder
II. Sexual arousal disorder
III. Orgasmic disorder
IV. Sexual pain disorders:
A. Dyspareunia
B. Vaginismus
Other sexual pain disorders
Unfortunately, medical interventions are extremely
limited.Aside from hormone replacement therapy, there
are no FDA-approved medical treatments for FSD.
52
On the other hand, several studies have demonstrated
successful treatment using sildenal (see below).
Epidemiology
FSD is a multidimensional problem that is age-related,
progressive, and highly prevalent, affecting 3050% of
American women.
53
Based on epidemiological data
from the National Health and Social Life Survey which
included 1749 women under the age of 60 years, 43%
had complaints of sexual dysfunction, 33% of women
lacked sexual interest, and nearly 25% did not
experience orgasm.
54
In addition, nearly 20% of the
women reported either lubrication difculties, and/or
nding sex not pleasurable.
50,54
Pathophysiology and oral
pharmacotherapy
Characterizing the female sexual response has evolved
several times, with the rst description by Masters and
Johnson in 1966. These researchers described four
successive phases: excitement, plateau, orgasm, and
resolution.
55
Later, Kaplan introduced desire as part
of a three-phase model: desire, arousal, and orgasm. In
this model, desire comes rst and acts to incite the
overall response cycle.
56
More recently, others have
suggested that sexual function should be viewed as a
circuit, with four main domains: libido, arousal, orgasm,
and satisfaction. Each of these can overlap and act as
negative- or positive-feedback interactions on the other
three domains.
53,57
This sexual function cycle, or circuit, is dependent
on normal anatomy and physiology. Disruptions in
one or more of the following areas may lead to FSD:
vasculogenic, neurogenic, hormonal, musculogenic,
pain conditions, and psychogenic.
The same neurogenic disorders that cause ED in men
can also cause sexual dysfunction in women. Although
women with incomplete SCI do retain the capacity for
psychogenic arousal and vaginal lubrication,
58
they do
have signicantly more difculty achieving orgasm.
In a placebo-controlled, double-blind, crossover study
of 19 premenopausal SCI patients receiving 50 mg
sildenal, a signicant increase in subjective arousal
was seen. Consistent with previous ndings in men, the
best results were observed after conditions of optimal
stimulation. The authors of this research state: further
large-scale studies of sildenals effects in women with
neurogenic sexual dysfunction are strongly indicated.
58
In women, despite the presence or absence of organic
disease, emotional and relational issues signicantly
affect sexual arousal. Sexual response is either
enhanced by self-esteem, positive body image, and a
good partner relationship, or inhibited by mood dis-
orders and depression (as well as the medications used
to treat them). In particular, one of the most commonly
used medications to treat uncomplicated depression
is SSRIs. Women receiving these medications often
complain of decreased desire, decreased arousal, and
decreased genital sensation, as well as difculty
achieving orgasm. This response can be explained, in
part, by the SSRIs peripheral mechanism of action
(at the level of NO synthase). NO synthesis is tightly
regulated by the activity of NO synthase. Nerve ter-
minal excitement, either from central input (fantasy)
or peripheral stimulation (foreplay), will cause the
events necessary for NO release.As shown in Figure 5.3,
the action of NO synthase is inhibited by SSRIs.
5557
Because of NO inhibition and the subsequent effect on
cGMP production, it is best to consider treating these
patients with sildenal in attempt to enhance whatever
cGMP effects may be present. Several studies have,
in fact, documented postsildenal improvements in
SSRI-induced sexual dysfunction in women.
59
Specic
SSRIs implicated in FSD include: fluoxetine, sertraline,
paroxetine, and fluvoxamine.
59
Safety
Keeping in mind that sildenal is not currently FDA-
approved for FSD, several studies have not only
reported efcacy, but also include an adverse event
prole very similar to that seen with the male
population,
53,59,60
except for one caveat. In a study of
33 women using 50 mg sildenal, 21% (7/33) reported
clitoral discomfort and hypersensitivity, causing
three of these patients to drop out of the study.
60
CARDIOVASCULAR EFFECTS OF
SILDENAFIL
ED is not uncommon among men who have cardio-
vascular disease. In fact, it may be among the rst signs
of small-vessel disease of the penis. Somehow, these
vessels appear to be more sensitive to atherosclerotic
occlusion than blood vessels in the heart or other areas
of the body. Because of this, physicians must consider
ED as a predictive factor for ischemic heart disease,
61
and consider the emergence of ED, in a previously
asymptomatic male, as a marker for occult coronary
artery disease.
11
As anticipated, extensive coronary
artery disease reflects worse ED. Patients whose
ischemic heart disease involves more than one vessel
often have greater trouble achieving erections than
those patients with single-vessel disease.
62
In addition
to the effects of cardiovascular disease, certain
medications used to treat heart disease (including
beta-blockers and thiazide diuretics) have been
associated with the development of ED.
62
The possibility of PDE5-inhibitors affecting the
heart has been studied extensively. To date, there is no
evidence that sildenal directly affects myocytes, or
that PDE5-inhibitors have any direct effect on either
the myocardium or the cardiac conduction system.
Recent studies have veried that sildenal is not
inotropic and does not alter cardiac output.
63,64
In men
with stable coronary artery disease, as assessed by
exercise echocardiography, sildenal had no effect on
symptoms, exercise duration, or the presence or extent
of exercise-induced ischemia.
65
In contrast, the effect
of sildenal on coronary circulation is potentially
benecial as it provides small increases in coronary
blood flow. Unfortunately, this small increase in
coronary blood flow is not globally protective.
The American Heart Association and American
College of Cardiology consensus document clearly
addressed the issue of sildenal use in male patients
with cardiovascular disease and ED, but failed to
address management of cardiac risk associated with
sexual activity.This issue was more specically addressed
at a Consensus Conference on Sexual Activity and
Cardiac Risk at Princeton University.
71
In general, it
was reported that patients can be placed into one of
three major categories (Table 7.3) at the time of initial
assessment, based on their cardiovascular status: low-
risk, high-risk, or intermediate/indeterminate-risk.
Those in the low-risk category have no specic cardiac
risk associated with the treatment of ED and sexual
activity. These patients may be treated for ED without
the need for additional cardiovascular evaluation. On
the other hand, the high-risk category includes patients
with cardiovascular disease, which requires specialized
cardiac consultation, evaluation, and priority cardio-
vascular management. Sexual activity and the manage-
ment of sexual dysfunction in such patients should be
deferred until the patients cardiac condition has been
evaluated, treated, and fully stabilized. Patients with
an intermediate or indeterminate level of risk should
not resume sexual activity, or undergo treatment of
sexual dysfunction, until a cardiac evaluation aimed at
facilitating the restratication of these patients into the
high- or low-risk category has been performed.
Similar agents in development
The success of sildenal has resulted in an explosive
growth in the eld of sexual pharmacology. Not only
are new agents being developed that act at different
locations (either centrally or peripherally), but also
additional PDE5-inhibitors are being developed in
attempts to improve efcacy and PDE-isoform speci-
city. The pharmacokinetic properties of the different
PDE5-inhibitors are shown in Table 7.4.
IC351 (tadalal, Cialis)
IC351 (tadalal, trade name Cialis, Lilly ICOS,
Indianapolis, IN) is a new compound of the PDE5-
inhibitor class, which has proven in in vitro trials to
have a higher selectivity to the PDE5 enzyme than
sildenal.
72
Compared to sildenal, IC351 has a longer
half-life of 17.5 h.
72
Clinical human experiences with
IC351 are reviewed in Porst.
72
They include a double-
blind, placebo-controlled, single-crossover RigiScan
Cardiovascular Effects of Sildenafil 115
TABLE 7.3 Cardiovascular risk groups
according to the Princeton guidelines
71
Low-risk
Asymptomatic, fewer than three risk factors for
coronary artery disease (excluding gender)
Controlled hypertension
Mild, stable angina (prior cardiovascular
assessment)
Post successful coronary revascularization
Uncomplicated past myocardial infarction
(>68 weeks)
Mild valvular disease
Congestive heart failure (New York Heart
Association (NYHA) class I)
Intermediate- or indeterminate-risk
Three or more risk factors for coronary artery
disease (excluding gender)
Moderate stable angina
Recent myocardial infarction (>2, <6 weeks) or
cerebrovascular accident
Left ventricular dysfunction/congestive heart failure
(NYHA class II)
Arrhythmia of unknown cause
High-risk
Unstable or refractory angina
Uncontrolled hypertension
Congestive heart failure (NYHA class III, IV) and
cardiomyopathies
Recent myocardial infarction (<2 weeks),
cerebrovascular accident
High-risk arrhythmias
Hypertrophic obstructive cardiomyopathy or
idiopathic hypertrophic subaortic stenosis and
other cardiomyopathies
Moderate/severe valvular disease
study in 44 men with mild to moderate ED after visual
sexual stimulation,
73
two large dose-ranging studies
in the USA and Canada,
74,75
and a Spanish 12-week,
randomized, double-blind, parallel study taken as
needed in 216 diabetic patients.
76
The various trials
demonstrated the effectiveness of IC351 in a broad-
spectrum population of ED patients, including dia-
betics. Major differences compared to sildenal are a
higher PDE5 selectivity, especially in terms of PDE6,
resulting in the avoidance of visual disturbances, and
the longer half-life time, leading to a longer window of
opportunity.
72
The trials also showed a favorable
adverse effect prole with less headaches, flushing, and
dyspepsia than reported in the rst large sildenal
trial.
72
An update on IC351 trials was recently
presented at the 2002 annual meeting of the American
Urological Association (AUA): a double-blind, placebo-
controlled study of 348 men taking 20 mg tadalal
demonstrated efcacy for at least a 36-h time period.
At 24 h postdose, 57.3% of intercourse attempts by
tadalal-treated men were successful versus 31.3% of
placebo-controlled attempts (P < 0.001). The effect was
maintained at 36 h, with 60.4% of intercourse attempts
successful, versus 29.9% of attempts on placebo
(P < 0.001).
77
Tadalal, however, may have an effect
for 6080 h and is in the blood stream for up to 100 h
in men over 60 years of age.This is also associated with
a potential for a longer period of nitrate interaction.
Tadalal was well tolerated: most adverse events
reported were only mild to moderate in intensity. Once
again, dyspepsia and headache were the most common
(>5%) treatment-emergent adverse events of this
study.
77
Little is known about tadalals direct cardiac
effect. This is important since it is an inhibitor of
PDE11, a cardiac PDE. Tadalal dosing (from 2.5 to
20 mg) was evaluated in ve randomized, double-blind,
placebo-controlled phase III trials enrolling 1112 men.
Compared with placebo, tadalal signicantly improved
all primary and secondary endpoints (IIEF, GAQ,
diaries), with 81% of tadalal-treated patients report-
ing improved erections, and the mean percentage of
successful intercourse attempts improved to 75%.
Adverse events were similar to the study above, except
that an additional 45% of men reported back pain.
78
Since some outlying subsets of patients experienced
hypotension, tadalal should not be used in combi-
nation with nitrates.
79
Vardenal
Vardenal (Bayer Corp., West Haven, CT) is another
new PDE5-inhibitor that has high potency in vitro (50%
inhibitory concentration, IC
50
, 0.1 nmol/l) and selec-
tivity for PDE5 compared with other isoenzymes.
80,81
It has been shown to be active for inducing penile
erection in a conscious rabbit model when given
orally.
82
Pharmacokinetic data in humans were
obtained in two randomized, double-blind, placebo-
controlled threefold crossover studies with a single
oral dose of 10, 20, or 40 mg of vardenal in men with
mild to moderate ED.
83,84
RigiScan data showed a
signicant difference in rigidity at the base of the penis
between placebo and vardenal at all doses, but there
was no signicant difference between 20 and 40 mg of
vardenal.The duration of rigidity greater than 60% at
the base and the tip of the penis increased from 25 min
to more than 60 min with 40 mg of vardenal. Again,
there was no signicant difference between the 20 and
40 mg doses. At-home oral administration of vardenal
was carried out in Europe, the USA, and South Africa
in randomized, double-blind, placebo-controlled studies
of 601 men with ED (reviewed in Pryor
80
). Efcacy
was assessed using the IIEF, the FuglMeyer quality
of life questionnaire as well as a global assessment
question (GAQ: Has the treatment improved your
erections?). Compared to placebo, vardenal showed
signicant improvement in the questionnaires as well
as in the GAQ.
82
Vardenal was well tolerated, with
headache (818%), vasodilation (613%), rhinitis
(18%), and dyspepsia (26%) listed as the most
common adverse events.
85
In addition, two pivotal
double-blind phase III trials were conducted in North
America (n = 749) and Europe (n = 636) and were able
to verify that vardenal signicantly improved erectile
function in patients with hypertension, hyperlipidemia,
or diabetes. Following FDA approval, vardenal had a
TABLE 7.4 Pharmacokinetic parameters of
selective PDE5-inhibitors
81
Parameter Sildenal Tadalal Vardenal
In vitro IC
50
3.5 6.7 0.1
(nmol/l)
C
max
(ng/ml) 560 378 209
T
max
(h) 0.70.8 2.0 0.70.8
t
1
2
(h) 3.7 17.5 3.9
AUC 1685 8066 74.5
(ng h/ml)
Metabolism Hepatic Hepatic Hepatic
Protein 96 94
binding (%)
Bioavailability 40 Unknown 15
(%)
In vitro IC
50
, concentration of the drug that inhibits a given
response (PDE5) by 50%; C
max
, maximum total plasma
concentration; T
max
, time to C
max
; t
1/2
, half-life; AUC, area
under the plasma concentrationtime curve.
contraindication in men receiving either nitrates or
any -blocker.
CONCLUSION
Sildenal has revolutionized the treatment of ED. Not
only is it an effective oral agent treating 70% of men
with a wide range of ED risk factors, but it also comes
with a limited adverse event prole (headache, flushing,
dyspepsia). A word of caution, however, is necessary
for those patients taking nitrates (a sildenal contra-
indication) and for those patients with exercise limi-
tations who should receive cardiac clearance before
assuming the physical strain of sexual activity.
Recently, the use of sildenal has expanded into the
eld of FSD, particularly for sexual arousal disorder.
With newer, more selective PDE5 agents on the horizon,
ED treatment options will continue to expand, and
have longer efcacy and fewer adverse events.
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INTRODUCTION
The modern era of pharmacotherapy for the treatment
of erectile dysfunction (ED) was ushered into clinical
practice by intracavernous vasoactive drugs. Prior to
the dramatic demonstrations and reports by Brindley
1
and Virag
2
in the early 1980s that direct injection of
vasoactive agents could induce penile rigidity, the only
effective means of restoring erectile function was either
surgical or by external appliances. The numbers of
men willing to undergo these forms of treatment and
their attendant costs limited treatment to a small
minority of those affected. The availability of a rever-
sible therapy, able to simulate a natural erection with a
rapid onset of action and detumescence, represented
an important medical advance. This landmark finding,
that direct local injection into the corpora cavernosa,
intracavernosal injection (ICI), could create a useful
erection, was the spark that ignited research into the
physiology of erection worldwide.
3,4
Over the past two decades, medical research into the
underlying etiology of ED has flourished. We currently
have an expanded understanding of the role of the
nitric oxide (NO)-cyclic guanosine monophoshate
(cGMP) second messenger pathway essential for
normal erectile function.
5
These advances have led to
investigators evaluating a number of potential intra-
cavernous agents in clinical trials using human volun-
teers and animal models. These include NO donors,
6
potassium channel openers,
7
vasoactive polypeptide
8
and, most recently, guanylate cyclase activators.
9
Although a large number of vasoactive compounds
have been tested, the most clinically important agents
remain prostaglandin E
1
(PGE-1), phentolamine, and
papaverine. These vasoactive agents have been reported
alone and in combination at various doses and
concentrations.
10
Local pharmacological therapies for the treatment of
male ED are logical, effective, inexpensive, and widely
available. The fact that oral therapies have largely
usurped these treatments in usage points to their
greatest weakness the need for local delivery via
needle or intraurethral application. Based on recent
North American data it is clear that the generally good
efcacy and safety of oral and sublingual pharmaco-
therapy have relegated injection therapy to a second-
line therapy.
11,12
Currently greater than 90% of new
treatment prescriptions are being written for sildenal.
In most current management algorithms a minimal
investigation is suggested with a trial of oral medi-
cation. If successful, no further diagnostic maneuvers
are recommended and ongoing use of oral agents is
suggested. If oral agents do not succeed, an attempt
with second-line therapies such as injection therapy,
intraurethral therapy, and vacuum devices are offered.
This approach is both time- and cost-effective and
allows the vast majority of men to achieve an effective
result. The Canadian Urology Association acting
through its guidelines committee has recently published
its management algorithm for ED
13
(Fig. 8.1).
In spite of the clear dominance of oral rst-line
therapy, the potential advantages of local vasoactive
treatment for ED are easily apparent. It reduces the
chance of systemic complications, is nerve-independent,
has a faster onset of action and smaller chance for drug
interaction, and is able to achieve high local concen-
trations even in situations of severe vascular insuf-
ciency (Box 8.1). An extensive clinical experience with
their use currently exists. These agents preceded oral/
sublingual ED therapy development and remain an
important treatment option for men who cannot take
or tolerate rst-line treatments.
The future of this category of agents is bright. Use
of novel agents delivered directly into the penile
circulation has been reported recently and includes
MUSE and Intracavernosal Therapies
Gerald B. Brock
CHAPTER 8
Box 8.1 Ideal candidates for local therapy
Unsuccessful at rst-line oral therapy
Nitrate use or potential for nitrate use
Neural injury from pelvic surgery, radiation, or
trauma
Desires rapid onset of erection following therapy
Diabetic or severe vasculopaths (usually after
failed rst-line therapy)
Wishes greater rigidity than achievable with oral
agents
guanylate cyclase activators, potassium-channel
openers, as well as standard vasoactive agents such
as PGE-1, where their impact on cavernous smooth
muscle and vascular function have been evaluated.
Their role in disease modication, especially in the
postradical prostatectomy patient who frequently
undergoes a period of neuropraxia postoperatively,
may prove essential to optimize erectile function.
14
The
potential of local injections to upregulate NO synthase
activity via a high-flow effect is currently under study.
15
The potential for gene therapy, delivered by direct
injection into the penile circulation, makes the role of
ICI in the future seem bright.
16
In this chapter a comprehensive review of local
treatments for ED is presented. This should not be
considered a historical review, as it is the belief of the
author that local therapy remains an important
treatment option for many men with erectile problems
unresponsive to less invasive approaches.
ESSENTIAL ANATOMY
The human penis has many design features that are
important for normal function and which the clinician
should be aware of, for optimal use of ICI therapy. In
contrast to the dog, where the two corporal bodies are
completely separated, in man they communicate freely
via an incomplete middle septum (Fig. 8.2). This fact
is essential for use with intracavernosal vasoactive
agents. Injection into a single side produces a rapid
bilateral increase in cavernous blood flow that creates
equalized pressure in both corpora, even in the face
of asymmetrical cavernous artery flow or unilateral
injury. The cavernous arteries are located asymmetri-
cally within the corpora, just lateral to the midline
septum, in a position that is unlikely to be injured by
the needle puncture. The surrounding tunica albuginea
is often a difcult anatomical structure to penetrate for
patients but can serve as an important landmark,
allowing them to recognize the proper depth of needle
advancement prior to drug delivery.
17,18
Deep to the tunica albuginea lie the cavernosal
smooth muscles, arranged in a series of potential spaces
or sinusoids lined by endothelium and separated by
trabeculae. Injection of the agent should be directly
into these open spaces, not into the muscle itself. A
misplaced needle can be easily recognized as a higher-
pressure injection or one that causes discomfort to the
patient.We routinely recommend that, if the drug does
not easily enter into the penis with minimal pressure,
the needle should be rotated; this usually dislodges the
beveled end from the trabeculae. The ideal injection
site is located at the lateral aspect of the shaft, away
from the dorsal nerve, artery, and vein.
122 MUSE and Intracavernosal Therapies
Figure 8.1 A cross sectional view of the human penis
depicting the extent of smooth muscle trabeculae located
below the fiberous tunica albuginea incomplete mid-line
section.
Figure 8.2 A longitudinal view of the penis with sites of
injection labelled.
*
*
*
*
*
*
The genius of ICI lies in its simplicity. Potentially, any
agent which induces an adequate degree of smooth-
muscle relaxation within the penis will be effective at
creating an erection. Neural stimulation of erection,
believed to be predominantly a non-adrenergic, non-
cholinergic phenomenon, plays no role in the efcacy
of injection therapy. Direct smooth-muscle relaxation
via altering the ion channels (Ca
2+
, K
+
) or through
accumulation of second-messenger molecules (decreasing
degradation or by direct activation) can produce an
erection. The neural-independent nature of ICI
allows for early use among postprostatectomy patients
as well as in the spinal cord-injured and diabetic
populations.
1921
The usual sequence of events when using intra-
cavernous agents is injection, sexual stimulation, and
erectile rigidity within 210 min mediated by a
dramatic increase in cavernous artery blood flow and
consequent compression of the subtunical venous out-
flow. Coincident with ejaculation and the attendant
increase in sympathetic tone, vasoconstriction occurs
with loss of penile rigidity. Use of penile constriction
bands or elastics, which were commonly recommended
early in the clinical experience with ICI, are now
largely of historical interest and believed to be of little
value.
22,23
THE AGENTS
Over the past two decades an extensive medical liter-
ature has developed around the use of intracavernous
vasoactive agents. A Medline search of intracavernous
penile injections, self-injection therapy for impotence,
ED and impotence reveals in excess of 1000 scientic
publications dealing with this topic in animal models
and human subjects in a variety of languages. Agents
which may provide enhanced efcacy and safety that
are currently undergoing clinical evaluations for
regulatory review will be presented in this chapter,
along with the limited number of agents approved for
intracavernous use.
Prostaglandin E
1
Independently, at the same impotence meeting in 1986,
both Adaikan
24
and Ishii
25,26
described the potential
for PGE-1 as an effective vasoactive agent for intra-
cavernosal use. It has gained widespread use and accept-
ance for ICI and intraurethral delivery worldwide.
Over the past 15 years a large number of clinical trials
and basic science evaluations with PGE-1 have been
undertaken and it represents the best studied of all the
drugs in current use.
PGE-1 is a prostanoid that has a variable impact on
vasulature throughout the systemic circulation. Within
the penis it upregulates the production of cyclic
adenosine monophosphate (cAMP) and leads to a
robust and rapid vasodilatation through alteration of
Ca
2+
ion channels. Additionally it is believed to have
an antiadrenergic effect, further enhancing its pro-
erectile function. It is a highly potent agent, requiring
only microgram amounts to induce this therapeutic
effect. Its small molecular size and ability to penetrate
the urethral mucosal layer made it the logical choice
for intraurethral delivery.
27,28
Injected PGE-1 acting on cAMP induces vaso-
dilatation mediated via gap junctions within the penis.
It is metabolized by a large rst-pass effect (90%) and,
to a smaller extent, by the liver and kidneys as well as
by local metabolism within the penis. Priapism, the
most devastating of the common adverse effects of ICI
therapy, is relatively low with PGE-1. Compilations
of recent reports describe rates of priapism between
1 and 3%. In our own experience these events are
frequently the result of rapid progression of dose by
the patient, missed initial injection, and a second
attempt or use among the young and/or neurogenic
patient. Priapism can be largely avoided through use of
a gradual and progressive dose escalation regime.
28
Our current protocol for use of PGE-1 is a starting
dose of 510 g in the vasculogenic male. In cases
where a normal vasculature is suspected or neurogenic-
based ED exists, a lower initial dose is recommended
2.5 g. After the rst injection associated with sexual
self-stimulation in the clinic, a higher or lower dose is
recommended based on response and duration of
action, with our goal of complete rigidity persisting for
1545 min. All men are informed of the technique
to optimize and increase their dose based on their
response at home. We generally recommend dose
increases of 2.55 g per attempt with a 24-h minimum
window between injections. Included in their initial
information is an explanation of priapism and how
likely they are to experience penile brosis or scarring.
All men are informed if brosis is detected on physical
examination at the start of treatment.
A vast literature exists describing efcacy and safety
of alprostadil across a wide spectrum of disease
processes and ages. Over the past 15 years since its
initial description for intracavernosal use, it has
become the dominant vasoactive agent. A wide range
The Agents 123
Box 8.2 Absolute and relative contraindications
for use
Previous priapism with vasoactive drug use
Severe penile brosis
Visual acuity which limits needle delivery
Monoamine oxidase inhibitors (would limit use of
phenylephrine for potential priapism)
of reported efcacy rates exists; however a reasonable
composite of these studies places PGE-1 intercourse
rates at 7075% among cohorts of men with mixed
etiologies, including diabetics, vasculopaths, and
situational ED. Most investigators report median doses
of 1215 g with common adverse events being
limited to bruising (common), priapism, and brosis at
13% (Boxes 8.2, 8.3 and 8.4).
2931
Recently some reports have described a potentially
important nding of increased incidence of spon-
taneous erections, disease modication, and improved
cavernous artery blood flow in men following long-
term use of PGE-1.
32
Although there exists animal
evidence reporting upregulation of the constitutive
form of nitric oxide synthase that supports these
clinical trials, much controversy continues, as there are
conflicting reports, which have failed to demonstrate
signicant objective evidence of improved nocturnal
erections. This exciting area probably requires further
studies to dene which patient populations are most
likely to experience genuine erectile enhancement
from vasoactive drug use. At present, we inform men
that ICI therapy results in a signicant minority of
men reporting improved spontaneous sexual function,
but few of these men reach the point of not needing
medication.
33,34
Among the largest groups of men considering ICI
and PGE-1 therapy are those who have failed rst-line
oral agents. Several recent reports have explored the
efcacy in this population specically. Shabsigh and
colleagues reported data from a large multicenter trial
using alprostadil alfadex among men who had failed
sildenal. Prior to entry into the study these men were
retried on sildenal at 100 mg and failed as assessed
by the International Index of Erectile Function (IIEF)
questionnaire. In 67 men, improvements in their ability
to achieve (Q3 of the IIEF) and maintain an erection
(Q4 of the IIEF) were observed in 89.6% and 85.1%
of men respectively. The investigators demonstrated a
signicant response rate among these sildenal non-
responders, indicating that progression to second-line
therapy is appropriate.
35
Discontinuation of treatment with intravenous
agents is high. Many long-term reports describe a drop-
out rate of 50%. Recently, Lehmann and coworkers
looked at a cohort of 86 men and found those most
likely to stop treatment are generally less motivated;
less satised with the treatment, and did not like the
drug-induced erection. Interestingly, side-effects such
as penile pain, brosis, and priapism were not a major
determining factor in choosing not to continue.
36
Wespes performed a novel histological review of his
penile biopsy specimens obtained from a small group
of men who had undergone between 150 and 250
PGE-1 injections in the 3-year period prior to
obtaining the sample. Among these men there was no
evidence of smooth-muscle alteration or excessive
brosis
37
(Box 8.5).
Intracavernous PGE-1 is frequently used as a
diagnostic test to assess vascular flow in men with ED.
A complete erection following injection indicates a
reasonable response to the vasoactive agent but
provides no information about the neural axis. A non-
response appears from work recently published by
Elhanbly and colleagues to indicate incompetent veno-
occlusive function and/or severe arterial insufciency.
38
Papaverine
Merck discovered papaverine in 1848: it is a
benzylquinoloine synthesized from tyrosine. Initially
Box 8.5 Common steps to correct inadequate
therapeutic response
Review injection technique
Reassess dose and increase until a reasonable
therapeutic response is achieved
Evaluate timing of injection in relation to sexual
stimulation
Change to more potent agent, if at maximum
recommended dose
If pain is a limiting factor, use combination therapy
Involve partner and reassure
Box 8.3 Strategies to optimize intracavernous
therapy
Inject agent directly into the proximal corpora
Apply gentle local pressure for 2 min to injection
site
Sexual stimulation following injection
Comfortable, unstressful environment
If unsuccessful, repeat attempt at slightly higher
dose in 23 days time; increase dose until
recommended maximum achieved
Box 8.4 Common causes for inadequate
response to intracavernosal injection
Inadequate dose
Injection into wrong location (trabeculae,
subcutaneous)
Leakage of agent prior to injection
Inadequate sexual stimulation
Premature ejaculation
Stress
reported by Virag in 1982, this agent was in common
use in the early to mid-1980s until the description of
PGE-1. It acts via a non-specic phosphodiesterase
action inducing increased levels of second messengers.
Delivered as an intracavernous agent, doses between
5 and 160 mg have been reported. It is a convenient
vasoactive agent that is inexpensive, stable at room
temperature, and effective. A compilation of reports
yields a general efcacy of 60%. It has a high rate of
priapism (16%), elevated rate of penile brosis
compared to other agents (5.7%) in a study of 1056
cases, and has never been approved for this medical
indication, which limits its use as monotherapy. It is
metabolized in the liver and in its papaverine hydro-
chloride formulation is acidic, commonly producing
pain at injection
39,40
(Table 8.1).
Phentolamine
Phentolamine is primarily an alpha-adrenergic antag-
onist. Early animal studies have shown it is a highly
effective agent at blocking the epinephrine (adrenaline)
pressor response. It also has a smaller reported
sympatholytic effect. It produces a generalized direct
vasodilatation of muscle walled vessels independent of
size in all vascular regions.Although phentolamine has
been widely used as a component of the triple mix
(phentolamine, PGE-1, papaverine), its use, as mono-
therapy for ED, has been disappointing. Stief et al.
have reported an inadequate therapeutic response in
14 of 15 consecutive men injected with phentolamine
who had responded to a trimix preparation.
41,42
Papaverine, phenoxybenzamine, and phentolamine
were all reported to have proerectile effects well
before the rise of PGE-1 as the predominant vaso-
active agent. They continue to be used largely in com-
bination preparations as bimix or trimix compounded
drugs. The advantage of the bimix (papaverine and
phentolamine) as opposed to the trimix (papaverine,
PGE-1, and phentolamine) is its stability without
refrigeration. Although not approved in most western
countries by the local regulatory drug boards, these
drug combinations are widely available. Results of
multiple studies demonstrate a good efcacy and safety
record (Table 8.1).
YC-1 is a soluble guanylate cyclase (sGC) activator,
which has been shown in recent publications to
increase intracavernous pressure in rabbit and rat
penile preparations. Delivered by the intracavernous
route, it produced erections comparable to those seen
with direct cavernous nerve electrostimulation, working
via an NO-independent pathway. Activation of sGC
induces an increased concentration of cGMP with con-
sequent smooth-muscle relaxation. Clinical trials
remain in the future but this agent may provide a novel
means of inducing erection among those men refractory
to other therapies.
4345
Recently, use of combination therapy involving
PGE-1 acting on the cAMP second-messenger system
with NO spontaneously releasing compounds such as
sodium nitroprusside have been reported. This syner-
gistic impact may salvage some men who may other-
wise remain unresponsive.The potential for hypotension
with sodium nitroprusside remains to be determined in
further work.
46
MUSE
Using a novel approach to deliver high local
concentrations of vasoactive drug (PGE-1), MUSE is a
medicated urethral system for erection. This non-
needle system has been widely approved and in use
in most developed countries for the past 5 years. A
1.4 36 mm white pellet of PGE-1 is delivered into
The Agents 125
TABLE 8.1 Comparison of drug characteristics based on published reports.
Drug Dose Efcacy Priapism Fibrosis Increased Drop-out Satisfaction
(%) >6 hours (%) liver enzymes rate (%) rate (%)
(%) (%)
Papaverine 30110 mg 61 6.87.1 5.7 1.6 4.6 Not stated
Prostaglandin 540 g 72.6 0.250.36 0.8 0 37 9095
E
1
Pain 11.5
MUSE 2501000 g 3050 0 <1 0 Not stated 6771
Pain 30
Papaverine/ 15 mg/ 68.5 6 12.4 5.4 45 Not stated
phentolamine 1.25 mg60 mg/
2 mg
Adapted from Chapter 9 International consensus on ED Virag/Porst tables.
the urethra by a single-use disposable plastic appli-
cator placed into the distal urethra, which has been
moistened by a recent urination. Following placement
of the pellet, the patient is instructed to elevate the
penis to prevent the PGE-1 from falling out, and
massage of the glans and urethra for 25 min is
suggested. The composition of the pellet allows for a
rapid dissolution and delivery of the vasoactive agent
into the local penile circulation. Transfer from the
corpus spongiosum to the corpora cavernosa occurs
via retrograde venous flow.
47
Onset of a penile response occurs as early as 7 min
postdose with maximal engorgement recorded in some
reports by 2224 min. This is a time course similar to,
but slightly slower than, ICI. Duration of the effect of
drug is a dose-dependent phenomenon with the longest
duration noted at 1000 g, being 72 min from onset to
return to a non-erect state. In addition to the corpora
cavernosa becoming erect, the use of MUSE promotes
engorgement of the glans penis. This glans fullness is
frequently a noted complaint among the post penile
implant patient who wishes to have a fuller penis.
Studies have documented a potential role for this
combination therapy
48
(Box 8.6).
Early reports described a response rate of 65%,
which in subsequent clinical reports has been lowered
to roughly 30% of men with ED of mixed (organic and
situational) etiology. Problems of penile pain (32%),
urethral pain (12%), testicular pain (5%), and minor
urethral bleeding (5%) coupled with insufcient
erectile rigidity have limited its use. Compared to ICI,
MUSE has a lower incidence of priapism (<0.1%) and
cavernosal brosis (<1%).
Recent reports suggest that a 500 g starting dose
provides the greatest likelihood of success. Titration
upward or downward after the initial few attempts is
suggested. Rare hypotensive responses appear to be
dose-independent; however penile pain was reported
more commonly among the higher doses used (500
and 100 g).
49
MUSE remains an effective option for
treatment of neurogenic cases of ED, particularly
where some impairment of manual dexterity exists.
Unfortunately, it has proven to be less effective in men
with severe vascular disease and diabetes.
4952
THE FUTURE
Intracavernous delivery of vasoactive drugs remains an
essential part of the management of male ED. In the
near term, it likely will remain an important means of
salvaging those men who fail to respond to oral agents
or cannot take them out of concern for drug inter-
actions. In the future, however, use of direct injection
into the penile circulation to delivery gene therapy
and modify the ion channels may become a more
important reason to continue using this technique.
Ongoing investigations into the potential benet from
early ICI therapy to men following radical pelvic
surgery and the potential impact on cavernous artery
flow remain controversial but interesting areas of
study. This technique has been proven, through the
test of time, to be an effective and safe means of
restoring erectile function among patients who suffer
from a variety of comorbid conditions. New thera-
peutic agents able to provide greater efcacy, improved
patient tolerability, and rapid onset may make this
delivery approach more appealing in the years to come
(Box 8.7).
REFERENCES
1. Brindley G. Cavernosal alpha-blockage: a new technique
for investigating and treating erectile impotence. Br J
Psychiatry 1983; 143:332337.
2. Virag G, Intracavernous injection of papaverine for
erectile failure. Lancet 1982; ii:938.
3. Andersson KE, Wagner G. Physiology of penile erection.
Physiol Rev 1995; 75:191.
Box 8.7 The future direction of local therapy
Administration of highly potent specic
vasoactive agents
Delivery of long-term pharmacological agents
altering smooth-muscle tone
Application of vascular endothelial growth factors
directly into the penile circulation
Neural enhancement agents
Delivery of gene-based erectile dysfunction
approaches:
Alteration of ion channels
Upregulation of guanylate cyclase
Increased synthesis of nitric oxide
Box 8.6 Strategies to optimize intraurethral
therapy
Urinate prior to placement of pellet
Advance device into proximal urethra gently
Deliver vasoactive agent
Check device to see that pellet has dislodged
Massage penis for 25 min in standing position
with penis slightly elevated
Sexual stimulation with partner
If unsuccessful at initial 500 g dose, increase
to 1000 g
4. Burnett AL. Nitric oxide in the penis: physiology and
pathology. J Urol 1997; 157:320.
5. Lue TF, Dahiya R. Molecular biology of erectile function
and dysfunction. Mol Urol 1997; 1:55.
6. Saenz De Tejada I, Cuevas P, Cuevas B et al. Nitrosylated-
adrenergic receptor antagonists as a potential drugs for the
treatment of erectile dysfunction (ED). AUA Abstract 1998.
7. Vick RN, Benevides M, Patel M et al. The efcacy, safety
and tolerability of intracavernous PNU-83757 for the treat-
ment of erectile dysfunction. J Urol 2002; 167:26182623.
8. Sazova O, Kadioglu A, Gurkan L et al. Intracavernous
administration of SIN-1 + VIP in an in vivo rabbit model for
erectile function. Int J Impot Res 2002; 14:44492.
9. Mizusawa H, Hedlund P, Brioni JD et al. Nitric oxide
independent activation of guanylate cyclase by YC-1 causes
erectile responses in the rat. J Urol 2002; 167:22762281.
10. Linet OI, Ogrinc FG. Efcacy and safety of intracavernosal
alprostadil in men with erectile dysfunction. The alprostadil
study group. N Engl J Med 1996; 334:873877.
11. Virag R, Becher E, Carrier S et al. Local pharmacological
treatment modalities. In: Erectile dysfunction; the rst inter-
national consensus consultation on erectile dysfunction.
1999: 305354.
12. IMS prescription tracking data 2001.
13. The Canadian Urology Association Guidelines Committee
Report on Management of Erectile Dysfunction. Can J Urol
2002; (in press).
14. Montorsi F, Guazzoni G, Strambi LF et al. Recovery of
spontaneous erectile function after nerve-sparing radical
retropubic prostatectomy with and without early intra-
cavernous injections of alprostadil: results of a prospective,
randomized trial. J Urol 1997; 158:14081410.
15. Escrig A, Marin R, Mas M. Repeated PGE-1 treatment
enhances nitric oxide and erection responses to nerve
stimulation in the rat penis by upregulating constutive NOS
isoforms. J Urol 1999; 162:22052210.
16. Christ GJ, Rehman J, Day N et al. Intracorporal injection
of hSlo cDNA in rats produces physiologic relevant alteration
in penile function. Am J Physiol 1998; 275:H600.
17. deGroat WC, Steers WD. Neuroanatomy and neuro-
physiology of penile erection. In: Tanagho EA, Lue TF,
McClure RD, eds. Contemporary management of impotence
and infertility. Baltimore: Williams & Wilkins; 1988:327.
18. Hsu GL, Brock GB, Martinez-Pineiro L et al. The three
dimensional structure of the human tunica albuginea:
anatomical and ultrastructural levels. Int J. Impot Res 1992;
4:117129.
19. Ismail M, Abbott L, Hirsch IH. Experience with intra-
cavernous PGE-1 in the treatment of erectile dysfunction: dose
considerations and efcacy. Int J Impot Res 1997; 1:3942.
20. Richter S, Vardi Y, Ringel A et al. Intracavernous
injections: still the gold standard for treatment of erectile dys-
function in elderly men. Int J Impot Res 2001; 13:172175.
21. Heaton JP, Lording D, Liu SN et al. Intracavernosal
alprostadil is effective for the treatment of erectile dysfunction
in diabetic men. Int J Impot Res 2001; 13:317321.
22. Brock GB, Breza J, Lue TF: High-flow arterial priapism:
a spectrum of disease. J Urol 1993; 150:968-971.
23. Ledda A. Erectile dysfunction: intracavernous treatment.
Curr Med Res Opin 2000; 16:S59S62.
24. Adaikan PG, Kottegoda SR, Ratnam SS. A possible role
for PGE-1 in human erection. In: Abstract book of the second
world meeting on impotence. Prague, Czechosolakia: 1986.
25. Ishii N, Watanabe H, Irisawa C et al. Therapeutic trial
with PGE-1 for organic impotence. In: Abstract book of the
second world meeting on impotence. Prague, Czechosolakia:
1986.
26. Ishii N, Watanabe H, Irisawa C et al. Intracavernous
injection of prostaglandin E-1 for the treatment of erectile
dysfunction. J Urol 1989; 141:323325.
27. Choi HK, Adimoelja A, Kim SC et al. A doseresponse
study of alprostadil sterile powder (S.Po) (Caverject) for the
treatment of erectile dysfunction in Korean and Indonesian
men. Int J Impot Res 1997; 1: 4751.
28. Cawello W, Schweer H, Dietrich B et al. Pharmacokinetics
of prostaglandin E-1 and its main metabolites after intra-
cavernous injection and short term infusion of prostaglandin
E-1 in patients with erectile dysfunction. J Urol 1997;
158:14031407.
29. Kunelius P, Lukkarinen O. Intracavernous self-injection
of prostaglandin E-1 in the treatment of erectile dysfunction.
Int J Impot Res 1999; 11:2124.
30. Porst H, Buvat J, Meuleman E et al. Intracavernous
alprostadil alfadex an effective and well tolerated treatment
for erectile dysfunction. Results of a long-term European
study. Int J Impot Res 1998; 10:225231.
31. Hauck EW, Altinkilic BM, Schroder-Printzen I et al.
Prostaglandin E1 long term self-injection programme for
treatment of erectile dysfunction a follow up of at least
5 years. Andrologia 1999; 31:S99S103.
32. Maniam P, Seftel AD, Corty EW et al. Nocturnal penile
tumescence activity unchanged after long-term intracavernous
injection therapy. J Urol 2001; 165:830832.
33. Wespes E, Sattar AA, Noel JC et al. Does prostaglandin
E-1 therapy modify the intracavernous musculature? J Urol
2000; 163:464466.
34. Brock G, Linet OI. Return of spontaneous erection
during long-term intracavernosal alprostadil (Caverject)
treatment. Urology 2001; 57:536541.
35. Shabsigh R, Padma-Nathan H, Gittleman M et al. Intra-
cavernous alprostadil alfadex (Edex/Viridal) is effective and
safe in patients with erectile dysfunction after failing sildenal.
Urology 2000; 55:477480.
36. Lehmann K, Casella R, Blochlinger A and et al. Reasons
for discontinuing intracavernous injection therapy with
prostaglandin E-1 (alprostadil). Urology 1999; 53:397400.
References 127
37. Wespes E. Smooth muscle pathology and erectile dys-
function. Int J Impot Res 2002; 14:S17S21.
38. Elhanbly S, Schoor R, Elmogy M et al.What nonresponse
to intracavernous injection really indicates: a determination
by quantitative analysis. J Urol 2002; 167:192196.
39. Earle CM, Keogh EJ, Wisniewski ZS et al. Prostaglandin
E-1 therapy for impotence, comparison with papaverine. J Urol
1990; 143:5759.
40. Sahin M, Basar MM, Bozdogan O et al. Short-term histo-
pathologic effects of different intracavernous agents on corpus
cavernosum and antibrotic activity of intracavernosal
verapamil: an experimental study. Urology 2001; 58:487492.
41. Stief CG, Wetterauer U. Erectile responses to intra-
cavernous papaverine and phentolamine administration in
patients with neuropathic pain. Anesth Analg 1993;
76:10081011.
42. Brock GB. Oral phentolamine (Vasomax). Drugs Today
2000; 36:121124.
43. Brioni JD, Nakane M , Hsieh GC et al. Activators of
soluble guanylate cyclase for the treatment of male erectile
44. Nakane M, Hsieh G, Miller LN et al.Activation of soluble
guanylate cyclase causes relaxation of corpus cavernosum
tissue: synergism of nitric oxide and YC-1. Int J Impot Res
2002; 14:121127.
45. Stone JR, Marletta MA. Synergistic activation of soluble
guanylate cyclase by YC-1 and carbon monoxide: implications
for the cleavage of the ironhistidine bond during activation
of nitric oxide. Chem Biol 1998; 5:255261.
46. Martinez-Pinerio L, Cortes R , Cuervo E et al.
Prospective comparative study with intracavernous sodium
nitroprusside and prostaglandin E-1 in patients with erectile
dysfunction. Eur Urol 1998; 4:350354.
47. Hellstrom WJ, Bennett AH, Gesundheit N et al. A double
blind placebo controlled evaluation of the erectile response to
transurethral alprostadil. Urology 1996; 48:851856.
48. Padma-Nathan H, Hellstrom WJ, Kaiser FE et al.
Treatment of men with erectile dysfunction with transurethral
alprostadil. Medicated urethral system for erection (MUSE)
study group. N Engl J Med 1997; 336:17.
49. Ekman P, Sjogren L, Englund G et al. Optimizing the
therapeutic approach of transurethral alprostadil. Br J Urol
2000; 86:6874.
50. Werthman P, Rajfer J. MUSE therapy: preliminary clinical
observations. Urology 1997; 50:809811.
51. Williams G, Abbou CC, Amar ET et al. The effect of
transurethral alprostadil on the quality of life of men with
erectile dysfunction, and their partners. MUSE Study Group.
Br J Urol 1998; 82:847854.
52. Fulgham PF, Cochran JS, Denman JL et al. Disappointing
initial results with transurethral aplrostadil for erectile
dysfunction in a urology practice setting. J Urol 1998;
160:20412046.
VACUUM DEVICES
Epidemiology (history)
In 1974, Geddings D. Osbon Sr., a businessman from
Augusta, Georgia, formed a company to market the rst
commercial vacuum constriction therapy for erections.
He was later awarded a US patent for this device,
which he had originally intended for his personal
use.
1,2
This invention, as well as those of a few other
inventors, was based on John Kings report in 1874 of
applying negative pressure for obtaining an erection as
well as the more detailed description by Otto Lederer,
for which the US patent ofce had issued a patent in
1917.
36
Despite the positive inroads, acceptance of the
vacuum erection device (VED) was far from universal
in its initial days. The company that was originally
started by Osbon (the Youth Equivalent Company)
had to challenge the US Postal Service in court when
it classied the companys literature on erectile dys-
function (ED) as pornography and ordered the company
to cease and desist. After overcoming this initial
hurdle, the company was again ordered to close its
doors after the Food and Drug Administration (FDA)
classied the VED as a medical device rather than a
marital aid. In 1982, the FDA granted permission for
marketing the device after it was ruled that all federal
guidelines had been satised.The rst scientic presen-
tations of the vacuum device were made by Drs Roy
Witherington and Perry Nadig, who later published on
the subject and made inroads in the acceptance of this
mechanical device in the medical community.
79
The
American Urological Association Clinical Guidelines
Panel on the treatment of organic ED listed the VEDs
as a major treatment alternative in 1996.
10
Mechanism of action and indications
The devices offered in the USA are manufactured by a
variety of companies and may be manual or battery-
operated (Fig. 9.1).The main components are the pump,
cylinder, and constriction rings to decrease venous
outflow. Many of the currently marketed devices fea-
ture a safety mechanism whereby pressures in excess
of 300350 mmHg may not be achieved. The device is
assembled by rst placing the constriction rings on to
the proximal end of the apparatus and subsequently
connecting the pump to the distal cylinder. After
lubricating the proximal open end for a better seal
around the base of the penis, negative pressure is
obtained by manual or automatic (battery) activation
of the pump and simultaneous application of pressure
on the cylinder toward the pubic area.
It has been shown that the increase in penile volume
during application of the VED is caused not only by
arterial inflow but also by venous backflow.
11
The
preplaced constriction rings on the proximal aspect of
the device are glided on to the penis once an adequate
negative pressure (and hence penile rigidity) has been
reached. Application of the constriction ring causes a
relative ischemia in the penis 30 min after application
of the constriction ring, although no study has demon-
strated related specic adverse long-term effects.
11
Indications for the use of VEDs are broad and
include all categories of ED. VEDs may be combined
with other modalities for the treatment of ED, such as
intracavernous pharmacotherapy.
12
Other investigators
have reported variable degrees of success in cases of
venoocclusive dysfunction.
13
Signicant success has also been reported in more
difcult patient populations, including those with veno-
occlusive disorders and explanted penile prostheses.
In 1989, Moul and McLeod
14
described VED use in
patients who had undergone prosthesis explantation
and concluded that VEDs may be a useful therapy for
ED in the challenging explant population despite a
history of corporeal infection and presumed brosis.
Others have reported successful use of the VED in
spinal cord injury patients, with 41% of the men still
satised with the device at 6-month follow-up.
15
Lue
and El-Sakka
16
recently reported on chronic inter-
mittent stretching with a VED after circumferential
tunical incision and circular venous grafting in 4
patients with penile shortening from severe Peyronies
disease. Although the study evaluated only a very
small cohort, all patients were satised and reported
improved psychological well-being as well as relation-
ships with partners.
In a study of the safety and efcacy of the VED in
patients with corporal venoocclusive disease (CVOD),
Vacuum Devices and Penile Implants
Hossein Sadeghi-Nejad and Allen D. Seftel
CHAPTER 9
the authors found no relationship between the severity
of disease and the rating of erection or satisfaction
with the device and recommended an initial trial of
VED regardless of the degree of CVOD. They reported
success rates similar to intracavernosal injection (ICI)
therapy.
17
In another study, satisfactory results were obtained
in 69% of patients with venous leakage based on a
questionnaire evaluation.
13
These encouraging results,
however, must be weighed against those showing lack
of efcacy in more severe cases of ED. A study of the
use, efcacy, and acceptance of the VED among 60
impotent men not satised with ICI therapy revealed
that more than 80% of those studied abandoned the
VED due to lack of efcacy. The authors concluded
that, in a group of men who have failed intracavernous
injection therapy, VED is not likely to be highly efca-
cious or widely accepted.
18
Economics
Tan
19
examined the economic cost of ED for a hypo-
thetical managed-care model based on 1998 US dollars
and concluded that, from a purely economic stand-
point, sildenal and the VED should be considered as
rst-line management strategies whereas ICI therapy,
transurethral alprostadil suppository, and penile
prosthesis implant should be reserved for second- or
third-line therapy. Overall, VED was found to be the
least costly alternative and, since at the time of publi-
cation in 2000 VED was the only treatment covered
under Medicare part B, with a 20% co-payment, Tan
concluded that VED may be the most affordable choice
to consider for seniors who live on a xed monthly
income.
Complications
The VED is usually well tolerated and free of major
complications when used correctly. Minor side-effects
are common, but most studies have not found these
to be a major deterrent. Contraindications to the use
of vacuum therapy are few and primarily include
patients with unexplained intermittent priapism and
bleeding disorders. Side-effects such as occasional
numbness, pain, penile bruising, or petechiae have a
low incidence.
1
Penile necrosis has been documented in at least one
case report with frequent and prolonged use of the
device in spinal cord injury patients.
20
It is therefore
recommended that device use be restricted to once
per day and constriction band application limited to a
maximum of 30 min.
Other unusual complications include severe urethral
bleeding in a diabetic patient, development of a penile
130 Vacuum Devices and Penile Implants
Figure 9.1ac Manual and battery-operated vacuum
erection devices with constriction bands. (Courtesy of
Endo Care.)
A
B
C
cystic mass that was seen only with VED use, but not
during the flaccid state (later found to be scrotal tunica
vaginalis!), and dorsal penile plaque formation after
4 years of VED use.
21
Patient satisfaction, future outcomes
and the effects of oral therapies
Dutta and Eid
22
evaluated the satisfaction rate,
attrition rate, and follow-up treatment of well-trained
patients with organic ED using an external VED. The
overall drop-out rate was 65% and was lowest among
patients with moderate ED (55%). One hundred per
cent of those with mild dysfunction discontinued use,
and a large number (70%) of patients with complete
dysfunction also discontinued use. Of the patients who
discontinued, the majority stopped treatment early
(median 1 month, mean 4 months) and 63% sought no
further treatment. Only 35% of patients were satised
with the device and continued long-term use (mean
37 months).
22
Cookson and Nadig
23
report the long-
term drop-out rate for VED to be 30% while Turner
et al.
24
report a 19% discontinuation rate for the rst
6 months of treatment.
A study of 61 impotent men who participated in a
clinical trial indicated that, among 32 patients with
arteriogenic impotence, 28 (88%) had satisfactory
results and had an improvement in their capacity for
spontaneous erections with the device.
25
Soderhal
et al.
26
compared the Osbon ErecAid system to ICI
therapy in relation to satisfaction, effectiveness, and
side-effects. Of the 44 patients who completed the
study, the ability to attain orgasm and the overall
satisfaction of the patient and partner with the sexual
experience were signicantly better when using
injections. In this report, those with a shorter duration
of impotence (<12 months) and those impotent
secondary to radical prostatectomy strongly favored
injection therapy.
Chen et al.
27
evaluated the preference of patients
with ED who had been effectively treated with a VED
and then switched to sildenal. Of the 36 participants
in whom the efcacy of sildenal was similar to that of
a VED, 12 (33.3%) decided to resume use of a VED
while 24 (66.6%) preferred to continue sildenal.There
were no statistically signicant differences between
the groups regarding patient age or the etiology and
duration of ED. The adverse side-effects of sildenal
were the main reasons for preferring a VED. Fewer
ejaculatory difculties, efcacy, comfort, and ease of
use were the main reasons for choosing sildenal. This
investigation revealed that a substantial number of
patients who respond to both oral pharmacotherapies
and the VED may choose the latter as their preferred
treatment modality.
PENILE IMPLANTS
Historical perspective
Following attempts at penile implant surgery using rib
cartilage and bone in the 1930s by Nicolai Bogoras,
Goodwin and Scott as well as Loeffler and Sayegh
described the use of acrylic implants for the treatment
of impotence.
2830
Similar to Pearmans Silastic rod,
proposed in 1967,
31
these devices were not implanted
intracavernosally and were not well received due to a
high erosion rate, lymphatic edema, glans irritability,
and glans slippage over the prosthesis. The use of
silicone rubber as a material for implantation was rst
suggested by Lash in 1968
32
in the plastic surgery
literature and later proposed as a device for penile
prosthesis surgery. A major improvement was reported
by Beheri in 1966
33
when he published his series of
700 intracavernosal polyethylene prostheses placed
through a midline dorsal penile incision followed by
tunical incision and corporal dilation. Morales et al.
34
described a relatively similar technique and prosthesis
in 1973. However, because of the rigidity of the device
and its rm, narrow proximal end, penile pain as
well as crural or midshaft (septal) perforations were
reported.
The next milestone in penile prosthesis surgery
was the description in 1973 by Scott et al. of intra-
cavernosal, inflatable silicone cylinders.
35
Two years
later, Small published a paper on the implantation
of the SmallCarrion prosthesis in 31 patients and
reported favorable results in 28.
30
The author described
a much easier surgical implantation technique through
a perineal surgical approach with a pair of sponge-
lled silicone prostheses and later reported a more
extensive follow-up on 160 cases.
36
Although less
extensive surgery and lower chances of mechanical
failure due to absence of hydraulic and mechanical
components were cited as advantages, it was conceded
that the Scott prosthesis, which was based on the
mechanisms of an implantable fluid transfer system
developed by Kothari et al.,
37
had excellent potential
and more closely approximated the natural physiologic
state. The permanent erectile state problem was
overcome by Finney
38
and Subrini and Couvelaire,
39
who independently introduced the concept of a hinged
device and soft silicone in the middle of the implant.
In 1986, Dr. Robert Krane reported on the
Omniphase, which was composed of a pair of silicone
rods that were able to move back and forth due to the
spring-like properties of its central cable.
40
Although
the Omniphase and its successor, the Duraphase, were
popular and combined the desirable properties of easy
concealment, rigidity for intercourse, and a straight-
forward surgical technique, they were handicapped
by relatively frequent cable failure and the need for
replacement.
41
Penile Implants 131
The improved American Medical Systems (AMS)
model in 1983 incorporated a three-layer design that
included a woven fabric layer between two silicone
layers. Although this change improved the aneurysmal
dilation problems, it limited the ability for girth
expansion.
42
Yet another change for the AMS device in
1987 came in the form of substituting polypropylene
for the fabric and the launch of the CX (controlled
expansion) device which allowed cylinder expansion.
The Mentor three-piece inflatable prosthesis is made
of Bioflex, a polyurethane material that has the advan-
tage of resisting aneurysmal dilation. First introduced
in 1983, the Bioflex material used in the Mentor
device offered signicantly higher durability than the
existing silicone cylinders. None the less, the early
versions suffered a high number of mechanical failures
in the silicone tubing.
43
Additional reinforcement of
the silicone tubing resulted in a 93% 5-year survival
from revision for mechanical reasons in the enhanced
Mentor Alpha-1 prosthesis, as reported by Wilson et al.
in 1999.
44
Unitary hydraulic devices consist of a non-disten-
sible inner chamber, which becomes rigid when lled.
These devices were ingenious in their design concept
and combined the cosmetic advantages of inflatable
multicomponent devices with the implantation ease of
semirigid implants. Unfortunately, both the Surgitek
(Flexi-flate) and AMS (Hydroflex/Dynaflex) devices
had unacceptable mechanical malfunction or patient
dissatisfaction rates and were discontinued.
45
Indications
Penile prostheses are indicated for the treatment of
organic ED due to a variety of causes. Most surgeons
recommend a trial of less invasive modalities, including
oral pharmacotherapy or ICI, before moving on to
prosthesis surgery. Despite many surgeons fear of
increased complications in radiated patients, it has
been shown that penile prosthesis surgery can be safely
and effectively performed after radiation therapy for
prostate cancer with minimal intraoperative and post-
operative adverse events.
46
Similarly, there is a denite
role for penile prostheses in the management of ED
that is refractory to conservative measures following
radical retropubic prostatectomy and some investi-
gators have advocated immediate sexual rehabilitation
by simultaneous placement of a penile prosthesis in
patients undergoing radical prostatectomy with no
apparent increase in morbidity.
47
Experienced implant
surgeons have reported successful prosthesis place-
ment in severely brotic corpora by utilizing a variety
of techniques and cavernotomes.
4851
Penile modeling over an inflatable implant was rst
described by Wilson and Delk in 1994
52
and has since
been accepted as an effective therapeutic option for
patient with simultaneous Peyronies disease and
ED.
53,54
Levine and Dimitriou
55
developed an algorithm
for surgical management and placement of penile
prostheses in this group of patients. They attempted
manual molding initially, followed by tunica incision
for insufcient straightening. For tunical defects greater
than 2 cm, polytetrafluoroethylene (PTFE) patch
grafting was performed to prevent prosthesis cylinder
herniation and recurrent deformity from cicatrix con-
traction. Full erectile capacity with a straight phallus
was achieved in all patients.
Prosthesis types
Semirigid/rod prostheses
These prostheses are manufactured by the AMS
(Malleable 650), Mentor (Acu-Form and Malleable)
and Timm Medical Technologies (Dura II) and are
constructed of two solid prostheses that are indepen-
dently placed in each corpus cavernosum. They are
ideal for patients in whom the cosmetic advantages of
the inflatable devices are not as important as the ease
of use and the lower chances of mechanical failure in
semirigid implants. Spinal cord-injured patients who
may not accept or respond to ICI therapy or those who
require external condom drainage for incontinence are
also candidates for these prostheses.
56
Another group
well served by the semirigid devices (or a two-piece
rather than a three-piece inflatable device) is pelvic
organ transplant recipients in whom traditional con-
servative therapy for ED has failed. Three-piece
prostheses should be avoided in this group because of
a signicantly higher incidence or reservoir compli-
cations in the retroperitoneal space in these patients.
57
The semirigid devices are typically made of pure
silicone rubber (e.g., the Mentor and the AMS devices)
which may be wrapped around a central coiled wire or
have a core construction of articulating segments with
metallic cables running through them (e.g., the Dura II
device). The PTFE-coated rings are interlocked and
connected by a spring-loaded cable which can lock the
rings in a straight column when activated and unlock
for a relaxed flaccid state.
The Dura II is a third-generation derivative of the
Omniphase (Dacomed, Minneapolis, MN, USA) pros-
thesis discussed in the historical review. Further
improvements achieved in the latest-generation Dura
II included substitution of the more durable high-
molecular-weight polyethylene for polysulfone and
strengthening of the cable strands (Fig. 9.2).
The current device is offered in 10 and 12 mm widths
and a 13 cm length which can be individually tailored
with distal tips of varying sizes. (image) Because of its
superb flexibility and ease of operation, the device is
particularly well suited to those with poor manual
dexterity. Conversely, it is a relatively poor choice for
those with a large-diameter penis or a very short penis,
since the smallest device is 15 cm long.
41
The Acuform and Malleable are manufactured by the
Mentor Corporation (Santa Barbara, CA: Fig. 9.3). The
former device has an outer helical wire surrounding a
silver wire core in the distal end and has greater
flexibility than the Malleable. The company offers a
lifetime warranty for mechanical failure.These implants
are available in three diameters (9, 11, 13 mm) with
standard, 0.5 cm and 1.0 cm tail caps and may be
trimmed using a standard #10 scalpel blade to 30
various sizes (the caps are tted on to the trimmed
ends).
The AMS 600 was introduced in 1983 and had a
twisted stainless-steel wire surrounded by solid
silicone. Despite excellent durability, the device had
signicant springback and was redesigned as the AMS
650 (Fig. 9.4). The improved prosthesis featured ner
strands in a spiral conguration in a polyester covering
and further encased in a solid silicone body.
41
This
prosthesis has been marketed since 1996 and is avail-
able in 13 or 11 mm girths and 12, 16, or 20 cm lengths
that are further adjustable with rear tip extenders.
Semirigid prostheses may be placed through an
infrapubic or penoscrotal incision, as described below,
with the caveat that the corporotomy incisions are
slightly larger than those used for the inflatable
cylinders. Excessive bending of the device during place-
ment through a small corporotomy may damage the
cylinders and cause poor rigidity.
58
Alternatively, the
semirigid devices may be placed through a limited sub-
coronal incision.
59
Corporal and urethral complications
encountered intraoperatively are similar to those
described in more detail in the inflatable prostheses
section, below. Other reported complications include
infection, prolonged pain, mechanical failure, and
erosion. Erosion is more frequently encountered in
spinal cord injury patients compared to the general
population (11% versus 1%).
60
Erosion of a malleable
penile prosthesis into bladder has been reported in a
patient with spinal cord injury and recurrent urinary
tract infections.
61
Penile Implants 133
Figure 9.2 Dura II semirigid penile prosthesis.
(Courtesy of Dacomed.)
Figure 9.3 Acuform semirigid penile prosthesis.
(Courtesy of Mentor.)
Figure 9.4 AMS 650 semirigid prosthesis.
(Courtesy of AMS.)
Inflatable prostheses
Unitary self-contained cylinders
The Hydroflex prosthesis was introduced in 1985
(AMS) and later succeeded by the Dynaflex. These
prostheses combined the easy implantability of the rod
prostheses with the cosmetic advantages of inflatable
devices.
62,63
Despite the elegant simplicity of design,
inferior mechanical reliability and patient satisfaction
compared to the multicomponent devices resulted in a
gradual phasing-out of the unitary devices. Wilson and
Delk have stated that the combination of semirigidity
and ability to partially inflate acted as a tissue
expander by compressing corporal tissue.
42
Over
time, this resulted in an inadequate size for a complete
rigid erection.
Two- and three-piece multicomponent
prostheses
In the USA, the multicomponent inflatable devices
are made by AMS and Mentor. Currently marketed
devices in this category by AMS are the AMS 700 CX
and CXM (smaller components than the CX; useful for
implantation in brotic corpora), the AMS 700 Ultrex
and Ultrex Plus, and the Ambicor, which is a two-piece
device with a combination scrotal pump/reservoir.
The Ambicor is currently the only marketed two-piece
inflatable prosthesis in the USA. Although its small
scrotal pump is unable to produce girth expansion,
activating the pump transfers fluid from the proximal
to the distal portion of the cylinders to obtain adequate
rigidity (Fig. 9.5).
The AMS and Mentor three-piece prostheses share a
similar general structural design: an intraabdominal
fluid reservoir to be placed in the perivesical space, a
pair of cylinders for intracavernosal implantation, a
scrotal pump for fluid transfer between the reservoir
and the cylinders, and silicone tubing for connecting
these components.
The Ultrex was introduced in 1990 and was designed
to provide combined girth and length expansion.
64
There was a higher incidence of cylinder failure with
the Ultrex as compared with the same companys CX
device and the 5-year survival from mechanical revision
was reported to be as low as 66%.
65
However, a recent
report indicates that cylinder modication in 1993
appeared to have signicantly decreased the propensity
of cylinder failure of the premodication device.
66
Additional reported problems included buckling and
accelerated wear of the Ultrex cylinders due to limi-
tations of length expansion after the natural process of
capsule formation around the cylinders.
42
Montorsi et
al. have also corroborated these ndings and reported
that in the long-term evaluation of cylinders, the CX
appears to be more mechanically reliable than the
Ultrex.
67
The AMS 700CXM with medium controlled expan-
sion cylinders was introduced in 1990 to provide an
inflatable prosthesis with controlled expansion in girth
and tness for Asian men.
68
The CX and CXM have
recently been marketed with an antibiotic coating
(inhibizone: Fig. 9.6). Long-term data regarding infec-
tion rates with the new antibiotic-coated device are
not available at the time of this writing.
Figure 9.5 Ambicor inflatable penile prosthesis.
(Courtesy of AMS.)
Figure 9.6 Antibiotic-coated inflatable AMS prosthesis.
(Courtesy of AMS.)
Mentor limits its inflatable products to the Mentor
Alpha-1 and the narrow-base version of the same
prosthesis, which is particularly well-suited for difcult
repeat implantations or postradiation surgery in brotic
corpora. Both of the Mentor three-piece prostheses are
now available with the recently introduced lock-out
valve, a mechanical enhancement of the scrotal pump
designed to inhibit undesired spontaneous auto-
inflation of the cylinders (Fig. 9.7).
Perioperative care
Adherence to strict infection control protocol, including
antibiotic prophylaxis, intraoperative shaving, careful
coverage of ostomy sites with an Ioband adhesive
layer, minimization of operating room trafc during
the procedure, 10-min antibacterial scrubbing of the
operative site with iodophore prior to the iodophore
paint skin preparation, double-gloving of all involved
personnel, and an antibacterial shower the night or
morning before surgery will reduce the incidence of
infectious complications. The presence of urinary tract
infection or any other infection at the time of surgery
is cause for rescheduling the procedure. Antibiotic pro-
phylaxis should be administered 12 h prior to surgery.
Agents effective against the most common organisms,
Staphylococcus epidermidis and Escherichia coli,
must be chosen and may include an aminoglycoside
and vancomycin or a rst-generation cephalosporin.
Fluoroquinolones have also been shown to be equally
effective against these organisms and may be
administered orally.
69
The decision to perform the procedure in an
outpatient or inpatient setting is governed by surgeon
and patient preference as well as the inescapable
realities of managed-care and insurance guidelines in
some areas. Garber has reported on successful penile
prosthesis placement on an outpatient basis with no
apparent increase in morbidity except for a 4% urinary
retention rate that was effectively managed by over-
night catheterization.
70
When the patient is kept over-
night, the Foley catheter may be left indwelling until
the following morning. Oral antibiotics (cephalosporins
or fluoroquinolones) are continued for 710 days and
the patient is instructed to refrain from heavy lifting or
using the device for 46 weeks. It is also important to
Penile Implants 135
Figure 9.7a Hydrophilic-coated Mentor Alpha-1 inflatable
penile prosthesis with lock-out valve. (Courtesy of Mentor.)
b Detail of the lock-out valve mechanism for prevention of
autoinflation. (Courtesy of Mentor.)
c Detail of the pump and release bar mechanism for the
Mentor Alpha-1 inflatable penile prosthesis. (Courtesy of
Mentor.)
A
B
C
keep the reservoir full and the cylinders deflated most
of the time during the initial 8-week period until
capsule formation around the reservoir is complete. If
the capsule forms around a deflated reservoir, auto-
inflation or difculty deflating the cylinders may be
experienced. Instructional brochures and videos on
inflation/deflation techniques are an important
educational aid for the implant recipient and may be
viewed during the healing period.
Surgical aproaches
Both inflatable and semirigid devices may be implanted
through an infrapubic or penoscrotal incision. The
choice of incision is based on surgeon preference and
the individual patients special needs and body habitus.
Comparison of infection rates shows no statistically
signicant difference between the two incisions.
71
In the infrapubic approach popularized by Furlow,
the cylinders are placed through an incision in the space
between the pubic bone and the penis. Dissection to
the level of the tunica albuginea and reservoir place-
ment in the perivesical space are relatively simple in
non-obese patients and require minimal dissection
with excellent exposure. Following midline separation
of the rectus muscles, the reservoir is placed in a
subrectus pouch under direct vision. When dissecting
on to the surface of the shiny white tunica albuginea
covering the corpora, it is critical to identify and
preserve the dorsal nerves, which are typically found
23 mm lateral to the deep dorsal vein. Absorbable
stay sutures (2-0) are placed on to the tunica and a
corporotomy is performed with a #15 scalpel blade.
It is important to avoid cautery use to minimize the
chances of nerve injury. After gentle introduction of
Metzenbaum scissors into the corpora for determi-
nation of the corporal course prior to dilation, Brooks
or Hagar dilators may be used (up to size 14) to expand
the intracavernosal space both proximally and distally.
Proximal and distal measurements are made using the
Furlow passer or the Dilamezinsert to the level of the
preplaced stay sutures. The cylinders are pulled into
their proper corporal position using the Furlow passer.
The corpora are then closed with the preplaced 2-0
sutures. Pump placement in the dependent scrotum is
performed through the same incision. After connecting
the tubing with the provided tools and connectors,
the prosthesis is once again inflated at the end of the
case to insure proper mechanical function as well as
symmetry, rigidity, and absence of leakage.
Proximal exposure (often critical in repeat implan-
tations or brotic corpora) is also limited when using
the infrapubic approach. In the authors opinion, the
added disadvantage of possible irreversible dorsal
nerve injury makes this incision less desirable than the
penoscrotal incision except in cases where blind
reservoir placement (as in the penoscrotal approach) is
truly complicated or risky (as in a patient with an
orthotopic intestinal bladder).
The penoscrotal incision allows for superb corporal
exposure throughout the corporal length and may be
vertical, longitudinal, or transverse. A transverse
incision is preferred when optimal proximal corporal
exposure (as in brotic cases) is desired. It may also be
used for combined articial urethral sphincter and
inflatable penile prosthesis placement when refractory
incontinence and ED coexist (as in a postradical
prostatectomy patient).
In the vertical midline approach, after Foley
catheterization, a 2.55 cm incision is made in the
midline raphe through the skin and the dartos layer.
Popularized by Wilson, this incision is then pulled up
on to the penis and secured in position by skin hooks
that are symmetrically attached to a Scott retractor.
After skin hook placement for exposure and dis-
section through the tissue layers on to the unmis-
takable shiny white surface of the tunica albuginea,
2-0 absorbable stay sutures (CT2 needle; detachable)
are placed into the tunica in a medial and lateral
position along the long axis of the right or left corpus
approximately 1 cm lateral to the urethra. The tunica
albuginea is then incised with a #15 scalpel blade and
further stay sutures are placed on each side of the
incision proximally.The extended incision will allow for
less tubing travel alongside the cylinders and provide
additional length for optimal pump positioning in the
dependent scrotum. Careful insertion of Metzenbaum
scissors (laterally pointed, to avoid urethral injury) will
determine the plane of distal intracorporal dilation,
which is subsequently accomplished to size 14 with
Brooks dilators. Proximal dilation to the level of the
crus is similarly performed, although proximal
Metzenbaum scissor insertion is usually unnecessary.
Experienced surgeons may use the Rossello or
Mooreville cavernotomes in brotic corpora to dilate
up to size 11 or 12. Others may use a Dilamezinsert
which is distally placed and subsequently dilated with
a prepackaged disposable dilator. Caution must be used
when using this device in brotic cases as the blind
distal dilation may cause tunical tear rather than
dilation. After proximal and distal dilation, cylinder
sizing is accomplished with sizers (Furlow passer or
the Dilamezinsert may be used) by measuring corporal
length from the proximal and distal stay sutures. The
exact same procedure is done on the contralateral
tunica and corpus.
Cylinders and rear-tip extenders (if necessary) are
then selected and positioned in the corpora using the
Furlow passer and needle, as described in the infra-
pubic section, above. They are then inflated to check
for symmetry, rigidity, absence of leakage, or kinking.
Again, it is important to provide manual support in the
area of corporotomy to prevent temporary buckling
if this maneuver is performed before corporotomy
closure. Pump positioning in the dependent scrotum is
much easier than in the infrapubic approach, but the
same principles and the creation of a dartos pouch
apply. A Babcock clamp may be used to secure the
pump in position until the end of the procedure and
the time of closure, at which time one or two sutures
may be placed just supercial to the pump to anchor it
in place and prevent pump migration.
After corporotomy closure, the Scott retractor is
removed and attention is focused on perivesical reser-
voir placement. This task is best accomplished using
small Deaver retractors (infant Deavers) to allow
cephalad retraction of the incision to the external
inguinal ring. Gentle blunt dissection medial to the
spermatic cord and over the pubic tubercle will lead to
the identication of the tranversalis fascia. Blunt dis-
section is often all that is necessary in rst implant
cases. It is advisable to empty the bladder by applying
suprapubic pressure before entering the perivesical
space. This is even more important in patients who
have had previous pelvic surgery, since it is unlikely
that blunt dissection will allow passage through the
brotic layers. In these cases, sharp dissection with
Metzenbaum scissors or a Kelly clamp is performed to
incise the fascia.The area is subsequently enlarged with
the surgeons index nger and the reservoir balloon is
positioned. It was previously recommended that all
reservoirs be lled and allowed to equilibrate. The new
Mentor lock-out valve device will prevent sponta-
neous reservoir deflation under normal intraabdominal
pressures and equilibration is therefore not necessary.
The practice is still recommended when using the
AMS prostheses. It is important to ensure proper sub-
fascial reservoir placement to minimize the chances of
intrascrotal or inguinal reservoir migration, a rare com-
plication that is almost exclusive to the penoscrotal
approach.
72
The tubing between the cylinders, reser-
voir, and pump is then trimmed, cleaned, and connected
as previously described using the manufacturers
connector tools.
Important technical considerations include lateral,
rather than medial, angulation of the scissors during
the initial passage in the corpus, gradual dilation up to
size 14 for virgin cases and size 1112 for brotic cases,
and gentle proximal pressure to avoid tunical tear.
Skin closure is performed in layers using 3-0 running
synthetic absorbable suture for the dartos layer and
interrupted 3-0 or 4-0 absorbable sutures for the skin.
Complications
Mechanical malfunction
Wilson et al. reported the results of a prospective study
of 1381 Mentor Alpha-1 penile prostheses implanted
to treat impotence, and compared the mechanical
reliability of the original and enhanced penile pros-
thesis. The 5-year survival rate increased from 75.3%
for the original to 92.6% for the enhanced model. The
failure rate of the enhanced model implants was about
0.8% per year during the rst 3.5 years and increased
to approximately 3.1% per year thereafter.
44
In
another publication, the same group reported that in
Peyronies disease cases in whom modeling was used
to straighten the penis after implantation, mechanical
survival of the Mentor Alpha-1 was superior to that
of the AMS 700CX and concluded that modeling
may predispose the AMS 700CX to earlier mechanical
failure.
52
A long-term multicenter study of the AMS 700CX
three-piece inflatable penile prosthesis reported that
mean device mechanical reliability plus or minus
standard deviation was 92.1% 3.3% after 3 years and
86.2% 4.6% after 5 years. Postoperative infection
and device malfunction developed in 3.2% and 17.5%
of the cases, respectively. Of the 207 men interviewed
by a neutral observer, 86% still had an AMS 700CX
penile prosthesis implanted, including 87.1% with
erection suitable for coitus.
73
In 1998, Dubocq and Dhabuwalas group compared
ve different types of devices and reviewed mechanical
complication rates in 83 patients with two-piece
and 283 patients with three-piece inflatable penile
prostheses for a mean time of 66 months. All device-
related complications were secondary to fluid leakage.
They noted a trend toward all three-piece prostheses
being more mechanically reliable than the two-piece;
the Mentor Alpha-1 device had a higher cumulative
proportional survival (0.957) than all other devices.
74
Goldstein et al. conducted a multiinstitutional retro-
spective study to assess safety and efcacy outcome
pertaining to the Mentor Alpha-1.With a mean follow-
up of 22.2 months, there were no morbidities of any
type in approximately 90% of implant recipients.
Fluid leak and autoinflation were reported in 2.5%.
No cylinder aneurysms were reported and only 2.5%
required revision surgery for approximately 2 years
from the original implant date. Cumulative survival of
the prosthesis at 36 months was 85 7% until device
malfunction and 75 7% until surgical intervention
(revision or explantation).
75
Corporal cross-over
Both distal and proximal corporal cross-over may
be encountered during corporal dilation or cylinder
placement, although the latter is more unusual. Neither
occurrence is catastrophic and may be easily recog-
nized and corrected during the procedure. The initial
correct lateral angulation of the Metzenbaum scissors
during distal tunneling and gradual corporal dilation
Penile Implants 137
using laterally directed Brooks dilators will help avoid
cross-over. The best means of testing either proximal
or distal cross-over is side-by-side placement of the
Brooks dilators in each corpus to check for symmetry
and proper positioning. If a cross-over is detected, the
dilator may simply be redirected with the contralateral
dilator left in place to prevent repeat cross-over.
Corporal and urethral perforation
This complication may be encountered both distally
and proximally and is more likely to occur during
dilation of brotic corpora. Careful use of specialized
cavernotomes such as the Rossello or Mooreville will
prevent uncontrolled tearing of the brotic corpus and
tunica and avoid the need for extensive corporal
excision, but these instruments have sharp edges and
may cause signicant injury if used by inexperienced
implanters.
48,49
A proximal crural perforation is
suspected when there is asymmetry of proximally
positioned dilators (i.e., when placed side-by side) or a
signicant length differential.
A variety of techniques have been described for
addressing this problem intraoperatively and include
direct repair of the perforation, placement of a wind-
sock patch of Gore-Tex or Dacron on the proximal
end of the cylinder, anchoring of cylinder tubing to the
tunica, and placement of an absorbable polyglycolic
acid patch in the defect (the plug and patch
technique).
76,77
Continued dissection to the level of
the rear-tip extenders and anchoring the extender to
the tunica are safe and widely adopted. This technique
is employed after rerouting the proximal dilation in
the affected corpus toward the proper crural tip against
the tuberosity. Attachment of the rear tip to the tunica
will prevent cylinder migration back into the per-
foration until healing is complete.
Management of distal corporal perforation and
urethral perforation is more likely to involve termi-
nation of the procedure and return at a later date,
particularly if distal perforation occurs during dilation
of the rst side. If corporal dilation has been success-
fully accomplished on one side and it is the second
side that is perforated, a single cylinder may be placed
on the non-perforated side. The tubing from the other
cylinder is removed and plugged with a standard
metallic plug provided by the manufacturers. A single
functioning cylinder may provide adequate rigidity for
penetration and the patient may elect not to undergo
a second procedure for contralateral cylinder place-
ment. Similarly, if urethral perforation occurs after one
side has been successfully dilated, the cylinder from the
perforated side is removed and the tubing is plugged.
The urethral tear may be directly repaired or, if small,
allowed to heal over a urethral catheter. Alternatively,
a perineal urethrostomy or a suprapubic urethrostomy
may be performed for urinary diversion. Because of
the potential for device infection, many surgeons will
recommend abandoning the case if there is any indi-
cation of urethral injury. However, this decision must
be balanced against the difculty of repeat surgery in
brotic corpora at a later date, especially in view of
ndings that implicate increased operative time to a
higher incidence of infections.
78
Infection
Infection is a devastating and dreaded complication of
penile prosthesis surgery which occurs in approximately
23% of rst-time implants in most series, but the
reported range is widely variable. Most infections
appear within the rst 3 months after surgery and the
vast majority will manifest within the rst year after
implantation, although delayed infections beyond
1 year have been reported.
79,80
Predisposing factors include inadequate perioperative
prophylaxis and lax sterile protocol, prolonged
hospitalization, prolonged operative time, and repeat
implantations. Carson reports that the combination of
any other procedure (e.g., hernia repair, circumcision)
with penile prosthesis surgery is associated with a
signicant increase in infections in his series.
81
The severity of infections may range from simple
supercial infections that can be managed by conser-
vative measures and wound care to the extreme of
penile gangrene which may be life-threatening. The
latter complication is fortunately rare and may be due
to Gram-negative organisms with or without anaerobic
superinfection. It may be initiated by factors including
local infection, pressure dressing, presence of a urethral
catheter, edema, and ischemia of the corpus caver-
nosum and appears to be more common in insulin-
dependent diabetics.
8285
Most infections are caused by Gram-positive
organisms that colonize normal skin, but 20% have
been attributed to Gram-negative bacteria in some
reports.
79
The latter are typically early infections that
manifest within the rst 30 days after surgery. The
causes of infection are controversial, but there is
universal agreement that weakened host defense
mechanisms and the presence of a synchronous infec-
tion at another site in the body will increase the risk.
Late infections may be due to hematogenous spread or
reemergence of bacteria previously embedded in the
biolm.
81
Jarow
78
reported an infection rate of 1.8% in men
without previous penile surgery compared to 21.7%
for procedures requiring reconstruction of the corpora.
The infection rate after revision of a penile prosthesis
was 13.3%, which was signicantly greater than that
following primary uncomplicated implantation, but
not different from that for patients requiring recon-
struction. This and other studies have not provided an
explanation for the increased incidence of infection in
patients undergoing revision who have an operative
time similar to rst-time implants.
Lynch et al.
86
reported a higher incidence of
infection in those receiving an inflatable device and
also reported a 22% incidence of infection in diabetic
patients compared to 6.7% in non-diabetics. Neither
of these ndings has been corroborated by other
investigators.
79,87
Although Bishop et al.
88
reported on
the direct relation between the degree of metabolic
control in diabetics as measured by glycosylated
hemoglobin and the risk of prosthesis infection, others
have found no meaningful difference in the median or
mean level of glycosylated hemoglobin A1C in infected
and non-infected patients regardless of diabetes.
89
The latter study also found no correlation between
elevation of fasting sugar or insulin dependence and an
increased risk of infection in diabetics undergoing
prosthesis implantation.
An interesting study by Licht et al.
90
evaluated the
presence of bacteria on implants undergoing mechanical
revision and isolated low colony counts of Staphy-
lococcus epidermidis in 40% of uninfected penile
prostheses. The authors concluded that low colony
counts of this organism are unlikely to cause an overt
clinical infection and that the role of S. epidermidis in
infections is likely to be overestimated. This reasoning
is further supported by documentation of ample
vancomycin, gentamicin, and aztreonam levels in the
corporal tissue of patients receiving antibiotic prophy-
laxis 12 h prior to device implantation.
91
Preventive measures are critical in the management
of prosthesis infections and have been addressed in the
section on perioperative care. The patient is instructed
to report any signs or symptoms of infection, which
may include a purulent exudate, a pattern of increasing
pain instead of gradual improvement, worsening
erythema and induration, and high-grade fever. Pain is
not unusual for as long as 46 weeks after surgery.
However, the normal course involves a gradual
improvement rather than deterioration. Increasing
pain, especially in the presence of chills, fever, or
leukocytosis, is an indication of possible infection.
Other clinical signs include erosion of device com-
ponents and fluctuance in the scrotum or along the
penile shaft. Most authorities recommend removal of
the entire device in severely infected cases with overt
purulence.
Some authors have advocated an early salvage and
rescue procedure for mild to moderate infections.
92,93
The technique has gained increasing popularity among
urologists for infections diagnosed in the earlier stages.
Successful salvage and return to function have been
reported in more than 80% of cases.
9395
However,
Carson
81
has warned that the procedure is not indicated
in insulin-dependent diabetics, immunocompromised
patients, or those with copious purulent drainage. The
salvage procedure involves complete removal of all
prosthesis components, copious irrigation of all affected
chambers through a rubber catheter placed in each
area with 5 liters of vancomycingentamicin solution,
and possible use of the water-pik or a similar high-
pressure irrigation device, as reported by Brant et al.
93
Erosion
Prosthesis erosion is often a telltale sign of device
infection, but device extrusion beneath the penile skin
may occur as an isolated phenomenon. Erosion is more
common in semirigid prostheses and in those with
distressed tissue and vascular supply, as may be seen
in brittle diabetics or redo implants. Erosion has
lso been described as a complication of urethral
catheterization.
Erosion presented as a late complication several
months after implantation in 80% of patients with
indwelling urethral catheters or who were using inter-
mittent clean catheterization and who had received a
penile prosthesis. The incidence of this complication
may be greatly reduced by using inflatable rather than
semirigid prostheses and by construction of a perineal
or suprapubic cystostomy.
96
Mulcahy has described a
distal corporoplasty for lateral extrusion of penile
prosthesis cylinders whereby the cylinder may be
repositioned in a more medial and secure position
under the glans penis by creating a new cavity for the
cylinder behind the back wall of the brotic sheath
that contains it.
97,98
Other complications
Reservoir herniation is an unusual complication of
three-piece inflatable prosthesis surgery through the
penoscrotal approach (Fig. 9.8). It occurs in approxi-
mately 0.7% of cases and may be caused by vigorous
postoperative coughing or failure of proper initial
reservoir placement under the transversalis fascia by
Figure 9.8 Three-piece inflatable prosthesis reservoir
herniation clinical presentation. (Courtesy of
Dr. Steven Wilson.)
Penile Implants 139
less experienced implanters. It may also be caused by
reservoir protrusion through an unrecognized existing
hernia or a large tranversalis defect created intra-
operatively.
72
The latter scenario is intuitively less
likely with decreased spontaneous autoinflation of the
cylinders in the immediate postoperative period (as
with Mentors lock-out valve mechanism). When
recognized in the immediate postoperative period, the
herniated intrascrotal reservoir may be repositioned
through the original penoscrotal incision. Alternatively,
a small inguinal incision may be used to place the reser-
voir in the perivesical space and close the defect from
above (Fig. 9.9). In the absence of clinical symptoms, a
few surgeons have reported leaving the reservoir in its
herniated intrascrotal position without adverse effects.
Glans bowing (supersonic transport
deformity)
Supersonic transport deformity is aptly named, after
the angulated tip of these aircraft. The problem may
be secondary to small prosthesis sizing or incomplete
distal dilation of the corpora. If the problem is recog-
nized intraoperatively and adequate distal dilation
has been achieved, a larger rear-tip extender may be
placed to lengthen the cylinder and see if the defect is
corrected. If the problem is noted in the immediate
postoperative period, it is wise to wait a few weeks and
allow for complete healing and scar formation, which
may result in glans xation and resolution of the
supersonic transport deformity.
81
Refractory cases may
be surgically corrected by placement of two 3/0 PDS
or permanent Prolene sutures on the underside of the
glans on each side through a circumcoronal incision.
By tying these sutures to the tunica albuginea near the
cylinder tip and away from the neurovascular bundle,
the glans is effectively secured against the cylinder
tip.
99,100
FUTURE OUTCOMES (THE EFFECTS
OF ORAL THERAPIES)
Although many implant surgeons feared a gradual
dwindling of penile prosthesis surgery with the intro-
duction of effective oral pharmacotherapeutic agents
such as sildenal, the signicant increase in the
number of men who present for the treament of ED
has further secured a role for surgical intervention.
Some investigators have postulated that the number
of penile prosthesis surgeries may actually increase in
the coming years.
101
Comparison of trends in penile
prosthesis procedures at a tertiary medical center
before and after the introduction of sildenal revealed
no signicant change in the number of penile implant
procedures done annually, although both the com-
plexity of procedures and severity of illness
increased.
102
These ndings will surely encourage
the implant surgeons, as well as the companies and
engineers, who are in pursuit of further renements
and improvements in the design of future prostheses
and the art of penile prosthesis surgery.
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INTRODUCTION
Prostate cancer is the most frequently diagnosed solid
tumor in US men with 80% of newly diagnosed cases
occurring in men older than 65 years. In 2000, it caused
an estimated 180 400 new cases and 31 900 deaths.
1
The patient faced with the diagnosis of prostate cancer
is often focused on the eradication of his disease.
Quality-of-life issues that follow the disease process
or therapies for prostate cancer may not be initially of
concern to the individual devastated by the news of
cancer. However, improvements in cancer detection
rates and longer life expectancy in the industrialized
nations have translated into signicant long-term
survivorship. Along with great strides in the direction
of cancer control for localized disease, signicant rene-
ments in surgical technique and radiation delivery have
decreased the incidence of adverse events following
therapy. The physician counseling his patient on appro-
priate treatment modalities for prostate cancer must
also understand patient expectations relating to the
aforementioned quality-of-life issues.Thus, the issue of
quality of life posttherapy for prostate cancer is of
paramount importance.This chapter will explore issues
related to sexuality and erectile dysfunction (ED) in
the context of prostate cancer.
EPIDEMIOLOGY
The average age at diagnosis of prostate cancer is 69.2
years for white men and 67.3 years for black men.
2
It follows that, in the vast majority of patients, the
impact of prostate cancer diagnosis and treatment on
erectile function must be considered in an age group
that is already at high risk for ED. Equally important is
the knowledge that, although men younger than 55
constitute only 3% of diagnosed prostate cancer cases,
there has been a striking increase of prostate cancer
detection in this population.
3,4
Quality-of-life issues
will likely assume an even greater importance in this
latter group, who will carry the burden of their diag-
nosis for a much longer period.
The National Health and Social Life Survey
(NHSLS) reported an ED prevalence rate of 18% for
men aged 5059 years in the general population.
5
The Massachusetts Male Aging Study indicated that
the probability of complete ED increased from 5.1%
to 15% between the ages of 40 and 70 years and the
probability of moderate ED increased from 17% to
34%.
6
In a prospective evaluation of patient-reported
symptoms in prostate cancer, ED, dened as having
either no erections or erections usually inadequate for
sexual intercourse, was reported by 32% of presurgical
and 45% of preradiation therapy patients.
7
The better
pretreatment erectile function in the surgical group is
likely a function of the younger age and better overall
health status of the surgical candidates. This disparity
reflects an ongoing issue in the eld of ED as it relates
to prostate cancer. The large difference in the pretreat-
ment ED rates is reflective of the inconsistencies seen
in the follow-up data in these men. Reports on the
prevalence of ED in the posttherapy prostate cancer
patients are widely variable and range from to 20 to
90%.
717
Siegel et al. evaluated pre- and posttreatment ED in
patients with localized prostate cancer who were
managed with irradiation, prostatectomy, or watchful
waiting.
13
Validated questionnaires were not used.
Sixty-nine percent of the overall cohort had pretreat-
ment erections that were sufcient for intercourse and,
as in the Talcott study, the pretherapy potency was
signicantly higher in those who later underwent
radical prostatectomy (RP) as compared to those who
received irradiation. Patients selecting watchful wait-
ing had the lowest risk of ED and 38% of this group
reported adequate erections at last follow-up (mean
follow-up 53 months). No signicant difference was
noted in posttreatment erectile function between
patients treated with RP or external beam radiation
(XRT: 10% versus 15%) and the two groups were
similar in patient age, clinical stage, and pathological
grade. The authors further note that, due to the differ-
ing times of onset of ED after XRT as compared to
RP (delayed onset versus early onset), studies with
shorter follow-up may erroneously document higher
ED rates in the prostatectomy group. The decline in
potency in the watchful waiting group was 17%, which
is similar to an age-matched population without pros-
tate cancer.
18
The incidence of ED after RP has been the subject of
many investigations in the past 1015 years. There is
Prostate Cancer and Erectile Dysfunction
CHAPTER 10
considerable variability between the reported series
from experienced urological surgeons and centers of
urological excellence compared to other epidemio-
logical surveys. For example, a study by Walsh et al.
11
to determine patient-reported rates of potency after
RP performed by an experienced surgeon found that,
by 18 months, 86% of patients were potent and 84%
considered sexual bother as none or small. Potency
was dened as the ability to have unassisted intercourse
with or without the use of sildenal, and improved
gradually over the course of the study. The authors
further commented that, although one-third of patients
at 18 months were using sildenal intermittently, only
two patients were not able to have intercourse without
its use. A similar center of excellence report from
Washington University by Catalona et al. indicated
that recovery of erections occurred in 68% of pre-
operatively potent men treated with bilateral (543 of
798) and 47% treated with unilateral (28 of 60) nerve-
sparing surgery. Recovery of erections was more likely
with bilateral than with unilateral nerve-sparing surgery
in patients less than 70 years old (71 versus 48%)
compared with patients aged 70 years old or older (48
versus 40%).
15
Similarly, in a study of factors predicting recovery of
erections after RP, Rabbani et al.
19
reported that age,
quality of preoperative erectile function, and extent of
neurovascular bundle (NVB) preservation, but not
pathological stage, were predictive of potency recovery
after radical retropubic prostatectomy (RRP). A total
of 149 of the 314 evaluated patients recovered potency
and 75% of this cohort had recovered satisfactory
erections by 11.8 months postoperatively. Median time
to potency was 3.9 months (before sildenal) with
bilateral nerve-sparing, 4.1 months with unilateral or
bilateral nerve damage, and 9.7 months with uni-
lateral nerve resection. Compared to the younger men,
those 6065 years old were only 56% and those older
than 65 years were 47% as likely to recover potency.
Patients with partial erections were only 47% as likely
to recover potency as men with full erections pre-
operatively. The authors determined the probability of
return of spontaneous erections at 24 and 36 months
for any given combination of predictive variables
from the coefcients of the Cox regression model for
variables having statistical signicance. With a median
follow-up of 25.4 months, the difference in potency
rates was statistically signicant for unilateral versus
bilateral nerve-sparing and there was a fourfold
reduction in recovery of potency rates with unilateral
versus bilateral nerve-sparing. In addition, these and
other authors have reported that pathological stage is
not an independent predictive parameter for erection
recovery.
15,19
In contrast to the above studies at urological centers
of excellence, Stanford et al.
12
found lower potency
rates in their report on the prostate cancer outcomes.
At 18 months or more following RP, 59.9% of the
1291 evaluated patients were impotent after RP.
Among men who were potent before surgery, the
proportion of men reporting impotence at 18 or more
months after surgery varied according to whether the
procedure was nerve-sparing (65.6% of non-nerve-
sparing, 58.6% of unilateral, and 56.0% of bilateral
nerve-sparing). At 18 or more months after surgery,
41.9% reported that their sexual performance was a
moderate-to-large problem. In another prospective
study, inadequate erections, present in one-third of men
prior to treatment, were nearly universal at 3 months
after surgery (96%), although some improvement,
primarily in men under 65 years of age, was evident at
12 months.
7
A study of ED in men with prostate cancer
before and after RP reported potency (unassisted inter-
course with vaginal penetration) in 2 of 187 (1.1%)
undergoing surgery without nerve-sparing, and 27 of
203 (13.3%) undergoing unilateral and 22 of 69 (31.9%)
undergoing bilateral nerve-sparing prostatectomy.
Less than half of the patients who were sexually active
postoperatively were satised with the erections or
achieved intercourse at least once a month.
20
Fowler et al. evaluated Medicare patients 24 years
after RP and reported that about 60% of patients
reported having no full or partial erections since their
surgery, and only 11% had any erections sufcient
for intercourse during the month prior to the survey.
9
Interestingly, the same authors reported on the quality-
of-life measures in this same population 2 years later
and noted that, similar to a cohort of patients with
benign prostatic hyperplasia who had undergone trans-
urethral resection of the prostate, postsurgical patients
scored comparatively high on the quality-of-life mea-
sures such as feeling positive about the results (81%),
and that most would choose surgical treatment again
(89%).
10
Despite the conflicting data, most experts agree that
Walsh and Donkers introduction of the nerve-sparing
technique in 1982 has had a signicant impact on
reducing postoperative ED.
21
The observed differences
between the different series may be attributed to
patient selection and the volume of cases, inconsistent
denitions of ED, various reporting methodologies
(i.e., patient-reported versus physician-reported), the
multifactorial etiology of postoperative ED, comor-
bidities, and the experience of the operating surgeon
in preserving the NVB.
9,11,22
Table 10.1 lists a
number of studies reporting on the prevalence of ED
following RP.
The incidence of ED following XRT and brachy-
therapy has been reported by a number of investigators.
Litwin et al. measured the effect of treatment choice
(pelvic irradiation (XRT) versus RP with or without
nerve-sparing) on sexual function and sexual bother
146 Prostate Cancer and Erectile Dysfunction
during the rst 2 years after treatment.
23
Patients
undergoing XRT or RP with or without nerve-sparing
all showed comparable rates of improvement in sexual
function during the rst year after treatment for early-
stage prostate cancer. However, in the second year
after treatment, patients treated with XRT began to
show declining sexual function; patients treated with
RP did not. Sexual function was measured by the
UCLA Prostate Cancer Index on a scale of 0100 with
higher scores representing better outcomes. Whereas
at 0 months after treatment, the RP with nerve-sparing
group had a score of 15 1.5 compared to 28 2.5 in
the XRT group, the same scoring system documented
24 1.8 (RP) versus 37 2.9 (XRT) at 12 months
and 28 2.6 (RP) versus 30 4.0 (XRT) at 24 months,
indicating the declining sexual function scores in the
XRT group with the passage of time. Otherwise stated
and similarly shown in Talcotts study, they found that
although short-term sexual function differs between
the two groups with an apparent advantage in the
XRT group, long-term function becomes increasingly
similar due to gradually worsening function in the XRT
group.
7
Zelefsky et al.
24
evaluated the incidence and
predictors of late toxicity in patients with localized
prostate carcinoma treated with high-dose three-
dimensional conformal radiotherapy (3D-CRT) and
found that 39% of patients who were potent before
treatment became impotent after 3D-CRT. The 5-year
actuarial risk of potency loss was 60% and the median
time to the development of impotence was 19 months.
Patients with pretherapy potency who received
75.6 Gy had a 68% actuarial likelihood of impotence
compared to 52% in those who received 70.2 Gy.
In addition to higher doses, the use of androgen depri-
vation therapy increased the likelihood of permanent
impotence (69% ED compared to 56% in those not
receiving neoadjuvant hormonal therapy (HT)). Stock
et al.
25
assessed erectile function after prostate brachy-
therapy and analyzed those factors affecting potency
preservation. In 313 patients who were potent before
therapy, the actuarial freedom from any decrease in
erectile function score was 64% and 30% at 3 and
6 years, respectively. The two factors found to have a
signicant negative effect on potency were high implant
dose and a lower pretreatment erectile function score.
Similar ndings were reported by Turner et al.,
26
who
showed that, while 62% of men (90 of 146) who were
potent before XRT preserved their potency 12 months
after XRT, this gure was 41% at 24 months.
Fulmer et al.
27
performed a comparative prospective
study on the effects of RP and hormone plus XRT on
ED. Initially RP patients experienced worse sexual
function scores; however, scores for RP patients
changed over time and approached the levels seen in
HT plus XRT cohort at 18 months. All of these studies
are in agreement with Litwin and colleagues report on
the worsening of erectile function with the passage of
time after XRT.
23
In a study by Sanchez-Ortiz et al.,
28
potency was
maintained in 49% of men (40/81) who were potent
prior to brachytherapy. ED rates were signicantly lower
in younger patients (48%) versus older patients (55%).
There was no difference in posttreatment potency
between men who received neoadjuvant HT and those
who did not. Two years following brachytherapy, 25%
of patients complained of complete (20/81) or partial
(26%, 21/81) ED, for an overall rate of 51% (41/81).
Short-term neoadjuvant HT (36 months) did not
increase the likelihood of posttreatment ED.
The effects of HT in combination with radiation
were also investigated by Chen et al.,
29
who evaluated
the effect of 3D-CRT with or without HT on sexual
function (SF) in prostate cancer patients whose SF was
known before all treatment. Before 3D-CRT, 87 (60%)
of 144 men were totally potent as compared to only
47 (47%) of 101 at 1-year follow-up. Of the 60 men
totally potent at baseline and followed for at least
1 year, 35 (58%) remained totally potent. Patients
who had 3D-CRT alone were more likely to be totally
potent at 1 year than those receiving 3D-CRT with
HT. Of those receiving 3D-CRT, 71% were potent pre-
therapy and 56% of this group retained potency 1 year
after therapy. For those receiving HT + CRT, 44%
were potent prior to therapy and 31% retained their
potency at 1-year follow-up.
29
However, those receiving
CRT alone (i.e., no HT) were also more likely to be
Epidemiology 147
TABLE 10.1 Prevalence of erectile dysfunction
after radical prostatectomy.
Author Year n Erectile
dysfunction (%)
Quinlan et al.
80
1991 503 32.0
Fowler et al.
9
1993 739 79.0
Geary et al.
20
1995 459 44.4
Catalona et al.
15
1999
Total 858 33.5
Bilateral nerve-
sparing 798 32.0
Unilateral nerve-
sparing 60 53.0
Stanford et al.
12
2000 1291 59.0
Walsh et al.
11
2000 70 14.0
Kao et al.
14
2000 887 89.0
Siegel et al.
13
2001 419 90.0
potent at baseline (compared to 71% in the non-HT
group, only 44% of patients receiving HT + 3D-CRT
were potent before administration of any therapy). The
authors concluded that, while the use of HT was a
signicant predictor of ED before therapy, it did not
appear to increase the risk of sexual dysfunction after
treatment. Although the study did not provide answers
regarding the length of time after which HT will
adversely affect sexual function, the authors stated
that the degree of decrement in sexual function after
CRT +HT did not appear to differ signicantly from
that in those receiving CRT alone. Table 10.2 lists a
number of studies with variable follow-up reporting on
the prevalence of ED after XRT and brachytherapy.
PATHOPHYSIOLOGY
The etiology of ED following RP and irradiation for the
treatment of prostate cancer is multifactorial. Branches
of the prostatovesicular artery and vein run together
with the cavernosal nerve branches as the NVB. The
relationship of the prostate and urethra to the caver-
nous nerve entering the perineum deep to the prostatic
venous plexus on each side is shown in Figure 10.1.
Following the pioneering work in 1982 of Walsh and
Donker,
21
who described the precise delineation of
anatomic relationship of the NVB to the bladder neck
and prostate, surgeons performing RP developed
nerve-sparing techniques in hopes of preserving sexual
function.
30
Anatomic variability in the course of caver-
nous nerves and difculties with reliable intraoperative
identication of the nerves led to the development
of CaverMap (Uromed, Boston, MA), a device that
stimulates the cavernosal nerves and measures minute
variations in penile girth. A multicenter evaluation of
the device by experienced surgeons demonstrated an
87.8% sensitivity and 54% specicity in locating the
NVB.
31
However, widespread use of this device has not
occurred due to poor specicity.
Despite signicant improvements in sexual function
and quality of life following nerve-sparing RP compared
to non-nerve-sparing RP, it became clear that a signi-
cant number of patients whose nerves were spared
developed ED after surgery. A vasculogenic etiology in
this group of patients was suggested by Bahnson and
Catalona, who demonstrated absent response to intra-
cavernosal papaverine injection.
32
Although the poor
causal relation between vasculogenic pathology and
absence of erectile response to erectogenic agents has
been demonstrated in other investigations, this work
prompted further investigations in search of a vascular
etiology for post-RP ED. In 1989, the anatomy of
penile neurovascular supply was described by Breza
et al.,
33
who found a 70% prevalence of an accessory
pudendal artery coursing over the anterolateral surface
of the prostate in a study of 10 cadavers. The high
prevalence reported was not supported by previous
reports indicating a range of 621%,
34,35
but the report
highlighted the variable origin of the artery from the
obturator (50%) or vesical arteries (47%). Polascik
and Walsh later reported their own ndings relating to
the influence of the accessory pudendal artery on
the recovery of sexual function.
36
They identied the
artery in 4% of 835 men and concluded that, because
potency rates are similar in men with or without
preservation of accessory arteries, routine preservation
may not be productive and accessory arteries that may
be identied for preservation occur infrequently.
Another possible source of vasculogenic compromise
during RP are the arteries identied beneath the
anterior capsule of the prostate under the dorsal vein.
Preservation of these arteries is difcult and potentially
complicated by massive blood loss due to their close
communication with the dorsal venous complex.
The multifactorial nature of the post-RP ED is further
demonstrated by wide variability in response to intra-
TABLE 10.2 Erectile dysfunction (ED) after radiation therapy (XRT).
Author Year n XRT versus brachytherapy ED (%)
Talcott et al.
7
1998 135 XRT 61.0
a
Merrick et al.
81
2001 34 Brachytherapy 35.0
b
Stock et al.
25
c
Talcott et al.
82
d
Siegel et al.
13
2001 319 XRT 85.0
a
Erections inadequate for sex at 12-month follow-up.
b
13-month median follow-up.
c
59% actuarial preservation of potency at 6-year follow-up.
d
Erections not rm enough for penetration without manual assistance.
cavernosal injections in different reported series. For
example, whereas Aboseif et al.
37
note vascular com-
promise (reduction in both the diameter and velocity
of blood flow within cavernosal arteries) and poor
response to injections in 40% of their patients (mean
age 65), Polascik and Walsh report that most of their
patients (mean age 57) have a positive response to
intracavernosal injection therapy.
36
These differences
are likely due to the younger age of patients and
different selection criteria in the latter report.
Aboseif et al.
37
used duplex ultrasonography to
evaluate possible vascular mechanisms responsible
for postoperative ED and documented signicantly
decreased cavernosal artery diameter and peak systolic
velocities in 40% of post-RP patients who had had a
poor response to intracavernosal injections. The role of
corporovenoocclusive dysfunction was not evaluated
in this study. After elucidation of a possible vascular
contribution to post-RP sexual dysfunction, a number
of researchers focused their attention on further
denition of the exact vasculogenic pathophysiology
and evaluation of relative contributions from arterio-
genic versus venogenic factors. DeLuca et al. reported
11% prevalence (5 patients) of postsurgical veno-
occlusive dysfunction (VOD) with impotence following
radical cystectomy and a 5% prevalence (2 patients) of
impotence following RP in a retrospective study.
38
Kim
et al. documented increased cavernosal artery end-
diastolic flow velocity and decreased resistive index on
spared and non-spared sides after RP.
39
Although these
ndings did not reach statistical signicance, involve-
ment of both VOD and arterial insufciency was
suggested as a possible cause for post-RP ED.
Two years later, Mulhall and Graydon
40
presented
pre- and postoperative cavernosometric data on post-
RP patients with ED that corroborated previous nd-
Pathophysiology 149
Figure 10.1A (schematic) and B (dissection) The relationship of the cavernosal nerve and the cavernosal vessels to the
corpora cavernosa and the urethra. (Reproduced with permission from Hinman F Jr. Atlas of Urosurgical Anatomy.
Philadelphia: WB Saunders; 1993:445.)
Dorsal artery
Dorsal nerve
Circumflex vein
Retrocoronal
plexus
Deep dorsal vein
Tunica albuginea
Circumflex artery
Lateral vein
Cavernous
vein
Cavernous artery
Carvernous
nerve
Bulbourethral
artery
Crural
vein
Periprostic
plexus
Internal
pudendal
vein
Penile artery
Prostate Endopelvic
fascia
Levator ani
muscle
Membranous
urethra
Aberrant r.
cavernous artery
R. crus
Dorsal artery
Deep dorsal vein
(ligated)
Dorsal nerve
Communication
between
cavernous and
dorsal nerve
Cavernous
nerve
ings suggestive of a vascular mechanism. The authors
found the mechanism to be predominantly arterial in
nature, but reported that some men have a mixed
pattern, with both arterial and venous components.
They further speculated that postoperative arterial
insufciency may be the result of intraoperative injury
to the accessory pudendal artery, but did not have an
explanation for the postoperative VOD.
In order to evaluate molecular changes pertaining to
erection post-RP, Podlasek et al.
41
performed bilateral
cavernous nerve resections in a rat model and
investigated changes in nitric oxide synthase (NOS)
isoform expression and distribution. A profound
decrease in smooth-muscle and endothelium NOS-I
protein was observed in the corpora. Their work high-
lighted the importance of maintaining at least partial
innervation of the penis after surgical intervention and
further demonstrated that endothelial and smooth-
muscle changes resulting from loss of innervation
may account for the ED observed in prostatectomy
patients.
Goldstein et al.
42
evaluated the erectile function in
23 patients (mean age 65 years) who received radia-
tion therapy for prostate cancer and concluded that
vasculogenic impotence is the most consistent organic
erectile abnormality in irradiated patients. All 15
patients in the study who experienced post-XRT ED
had vascular abnormalities. In two, arteriography
revealed bilateral occlusive disease in the distal internal
pudendal and penile arteries overlying the pelvic
radiation eld. The authors also found a history of
cigarette smoking as a signicant risk factor in those
who developed ED after XRT.
Cavernosal artery insufciency has been implicated
in other studies involving irradiated patients. Zelefsky
and Eid
43
performed duplex sonography to determine
the etiology of ED after treatment for prostate cancer.
In those who underwent 3D-CRT, 24 (63%) had
arteriogenic dysfunction, 12 (32%) had cavernosal
VOD, one (2.5%) was classied as mixed, and one
(2.5%) as having neurogenic dysfunction.
Mulhall et al. undertook a study to evaluate the
magnitude of the radiation to the corporal bodies
when 3-D conformal delivery techniques are used.
44
Although these techniques have lessened the radiation
delivery to periprostatic tissues, the exact degree of
proximal corporal body exposure to radiation had not
been investigated prior to this study. Based on an
outline of the proximal corpora on axial computed
tomography, the authors used computer modeling to
calculate the dose delivered to this area. It was found
that the mean radiation delivered to the most proximal
2 cm of the corporeal bodies was 31 12.8 Gy (43%
of the total dose delivered to the target areas in
prostate and seminal vesicles). The data illustrated the
high doses delivered to the proximal corpora despite
improved techniques in 3D-CRT.
44
The mechanism of ED following brachytherapy (Fig.
10.2) has not been dened and is likely multifactorial.
Merrick et al.
45
evaluated the potential relationship
between radiation dose to the NVB and the develop-
ment of ED following prostate brachytherapy. They
found no relationship between radiation dose to the
NVB and the development of postbrachytherapy ED
(median follow-up 37 months), but speculated that
such a difference may become evident with additional
follow-up.The only difference in demographics between
those who developed ED and those who did not was
that the latter were, on average, 4 years younger. Their
ndings refuted earlier reports by DiBiase et al.,
46
who
had reported that higher doses of radiation therapy
after brachytherapy were predictive of ED and that
those with ED had received NVB doses that were
signicantly higher than the prescription dose. The
proximity of the NVBs to the peripheral zone, an area
that requires the full prescription dose, restricts the
ability of radiation oncologists to reduce the dose to
those structures.
47
Stock et al.
25
assessed erectile func-
tion after prostate brachytherapy and analyzed those
factors affecting potency preservation. The authors
provided a 6-year follow-up and found pretreatment
ED as the factor with the most signicant effect on
posttreatment potency. The other factor found to have
a signicant negative effect on potency in univariate
and multivariate analyses was high implant dose. If
the D90 (dose delivered to 90% of the gland on a
dosevolume histogram from the 1-month computed
tomography-based dosimetric analysis) was greater
than 160 Gy for I-125 and greater than 100 Gy for
Pd-103, then dose had a signicant negative impact on
preservation of potency (58% preservation for those in
the high-dose versus 64% in the low-dose group).
Potters et al. assessed potency after brachytherapy
and accounted for such confounding variables as the
Figure 10.2 Radioactive seeds used in prostate
brachytherapy. 2002, Bruce Fritz. Reproduced by kind
permission of Bruce Fritz.
use of XRT, neoadjuvant androgen ablation, and patient
age.
47
This investigation is the largest prospective study
to date on ultrasound-guided transperineal brachy-
therapy and reported a 5-year actuarial potency rate of
76% for those treated with monotherapy. Addition of
XRT decreased potency rates by 20%. Potency was
further reduced to 52% when neoadjuvant androgen
ablation was added. With a median age of 69, only
41% of the patients in this study were potent pretreat-
ment and age was a signicant factor for predicting
posttherapy potency.
47
In 1992, Migliari et al. evaluated sleep-related
erections in 5 patients with stage T3N0M0 prostate
cancer treated solely with 50 mg once daily of the non-
steroidal antiandrogen, Casodex.
48
Mean follow-up
was 6 months. No signicant modications in regard to
number of nocturnal penile tumescence (NPT) episodes,
maximum penile circumference, and total rigidity time
were found before and after therapy. Only one patient
reported a decrease in sexual drive and libido. The
authors concluded that pure antiandrogen therapy did
not seem to interfere signicantly with the erectile
capability of men with prostate cancer. The study is
weakened by a small number of patients and con-
lusions that are based on a self-reported non-validated
questionnaire and NPT testing. In contrast to pure
antiandrogens that exert their effects by competitive
inhibition of androgen binding to the cytosolic
androgen receptor, administration of a luteinizing
hormone-releasing hormone agonist and reduction of
serum testosterone concentrations to a castrate level
have been shown to exert a signicant inhibitory effect
on sexual desire, sexual interest, and sexual intercourse,
with signicant changes in frequency, magnitude,
duration, and rigidity of nocturnal erections observed
in all patients.
49
Cryoablation of the prostate has been shown to have
a signicant adverse impact on the quality of erection
after treatment.
50
However, there is a paucity of data on
the exact mechanisms responsible for the dysfunction.
Aboseif et al.
51
prospectively examined erectile func-
tion before and 6 months after therapy in 15 sexually
active men who underwent cryoablation by using high-
resolution ultrasonography and color pulsed-Doppler
spectral analysis. At 6-months follow-up, ED persisted
in nine, with minimal or no response to the intra-
cavernosal prostaglandin E
1
injections. The authors
documented a signicant decrease in the peak velocity
of blood flow within cavernosal arteries and a signi-
cant increase in the time to achieve peak arterial flow.
It was concluded that vascular factors play a signicant
role in the etiology of postcryotherapy ED.
FOLLOW-UP AND TREATMENT
Both the diagnosis of prostate cancer and the variety
of existing treatments can have a devastating negative
impact on the psychological state of the patient.
Although ED can exacerbate the negative outlook for
the affected patient, there are very few, if any, patients
who cannot be treated by one of the available
modalities. It has been reported that, despite highly
successful treatment modalities for ED following RP,
fewer than 50% of patients seek therapy.
52
For patients
with ED who have had RP, Baniel et al. advocate a
progressive local treatment protocol whereby a four-
phase treatment regimen is instituted: phase I vacuum
erection device (VED); phase II sildenal; phase III
intracorporal injection; and phase IV intracorporal
injection plus the VED.
53
With a 1-year follow-up, this
progressive treatment method gave a positive response
in 94% of patients. The authors found intracorporal
injection to be the most effective method. In this study,
the positive response rate to sildenal (30% in phase
II) was lower than that reported by Zippe et al., who
reported a 72% success rate with sildenal in those
who had undergone bilateral nerve-sparing RP and
50% in those after unilateral nerve-sparing RP.
54
The
lower success rate in the former study is likely due to
a higher percentage of patients with non-nerve-sparing
RP. Indeed, introduction of sildenal (Viagra: Pzer,
New York, NY) in early 1998 revolutionized the
management strategies for patients with ED. Sildenal
citrate, an inhibitor of the enzyme phosphodiesterase
type 5, augments cavernosal smooth-muscle relaxation
through a cascade of events that involves increased
concentrations of cyclic guanosine monophosphate
and decreased intracellular calcium concentrations.
The whole mechanism, however, is dependent on the
presence of nitric oxide released by cavernous nerve
endings. Therefore, it is only intuitive that poor
sildenal efcacy would be expected under conditions
where the cavernosal nerves have been compromised.
Zagaja et al.
55
surveyed 170 men who had undergone
RP, but had not recovered natural erections sufcient
for intercourse, and had subsequently received
sildenal (50100 mg). The overall response rate was
29% in the 120 men who began taking the sildenal at
least 12 months after surgery; 80% of those younger
than 55 years of age in whom both nerves had been
preserved had a successful response. In contrast,
regardless of age, none of the patients in whom both
nerves had been excised reported a successful
response. Similarly, Feng et al.
56
reported that 71% of
bilateral nerve-sparing and 80% of unilateral nerve-
sparing groups had a positive response to sildenal,
compared to 6% of patients who had undergone a
non-nerve-sparing operation.
Montorsi et al. reported on intracavernous injections
of alprostadil administered in the early postoperative
phase after RP to facilitate corporal oxygenation and
limit the development of hypoxia-induced tissue
Follow-up and Treatment 151
damage.
57
The authors instituted this treatment
strategy 1 month after the surgical procedure (three
times a week for 3 months). Their prospective study
has shown that early postoperative administration of
alprostadil injections signicantly increases the recovery
rate of spontaneous erections after nerve-sparing RP.
The authors were able to demonstrate that at the end
of the 3-month course of empiric alprostadil injec-
tions, 67% (8 of 12) recovered spontaneous erections
sufcient for satisfactory sexual intercourse, as com-
pared with only 20% in the group that did not receive
postoperative alprostadil injections. Based on the results
of nocturnal testing and color Doppler sonographic
studies, failure of recovery of spontaneous erections in
the non-alprostadil group was attributed to cavernous
VOD (53%), arterial insufciency (13%), and nerve
injury (13%).
57
Of note, the authors documented a
17% incidence of complications ranging from priapism
to cavernous hematoma in the alprostadil group and
cautioned about the need for exhaustive documentation
of these possibilities in the consent form. Although the
study is limited by a lack of pretreatment evaluation
of erectile function, it is signicant in demonstrating
the positive impact of early postoperative cavernous
oxygenation induced by alprostadil injections.
The use of VEDs after RRP has been reported by a
number of authors. Baniel et al. evaluated response to
various modalities offered for the treatment of post-
RRP ED in 85 patients.
53
In this stepped-care model,
patients were allowed to progress to the next level of
care if they failed earlier more conservative measures.
Interestingly, a large percentage of the patients (92%)
responded to therapy with the VED. However, only
14% agreed to continue with this treatment regimen
at home. Zippe et al. have reported encouraging pre-
liminary results with early institution of daily VED
therapy soon after RRP.
58
The compliance rate was
found to be high (80%) in this early therapy group,
the complications were low, and 80% of patients
reported having sexual activity by using VED at a
frequency of twice per week.
Most experts agree that recovery of nerve function
beyond 2 years following RRP is unlikely and failure of
conservative means is an indication for more aggressive
measures. Patients who fail oral pharmacotherapy or
cavernosal injection therapy after RP may be candi-
dates for semirigid or inflatable penile prosthesis place-
ment. The use of penile prostheses in this group is
associated with low morbidity and patient satisfaction
rates around 85%.
59
Patients with a history of penile
prosthesis insertion after RP comprised 17% of a
group evaluated by Levine et al.
60
Overall patient and
partner satisfaction was 96.4% and 91.2%, respectively.
Of the respondents, 92.9% of patients and 90.1% of
partners would recommend the device to others. Of
the 85 men (65%) and 46 partners who completed the
modied Erectile Dysfunction Inventory of Treatment
Satisfaction survey, 90.6% and 82.6%, respectively,
were satised or very satised overall with the penile
prosthesis.
60
Most experienced implant surgeons place
the reservoirs for inflatable three-piece prostheses in
the retropubic space after RP. In these cases, the fascia
may be incised sharply using the Mezenbaum scissors
to enter the paravesical retropubic space. However,
some surgeons are reluctant to do this procedure blindly
and choose to make a second incision. The develop-
ment of the lock-out valve system incorporated in the
newer Mentor alpha-1 devices decreases the chance of
autoinflation and is especially helpful in cases where
an ectopic (i.e., non-retropubic) reservoir location is
chosen.
61
Although immediate sexual rehabilitation
with a prosthesis placed at the same time as the RP has
been suggested by some authors,
62
most experts do
not advocate this strategy since many patients will
regain sexual function with less invasive measures.
Nerve grafting has been advocated as a viable
alternative in men who are not candidates for nerve-
sparing during RP. Kim et al.
63
reported the results of
using an interposition sural nerve graft at the time of
RRP in an extended series of men with at least 1 year
of follow-up. Of the 23 men, 26% had spontaneous,
medically unassisted erections sufcient for sexual
intercourse with vaginal penetration and an additional
26% described 40% to 60% spontaneous erections
(fullness, no rigidity, not able to penetrate). Forty-three
percent had intercourse with sildenal and the greatest
return of function was observed at 18 months after
surgery. Despite the enthusiasm of the authors for this
technique, others have expressed reservations due to
technical difculties in precise identication of caver-
nous nerve endings and the distinct possibility that
patients who require resection of both NVBs (hence
the proposed candidate group for sural nerve grafting)
may not be curable with RP and are better served with
other treatment modalities.
64
Zelefsky et al. investigated the efcacy of sildenal
for patients with ED after radiotherapy for localized
prostate cancer.With a median follow-up of 19 months,
signicant improvement in the rmness of the erection
after sildenal was reported in 74%. Patients with
poor erectile function prior to radiation were less
likely (52%) to respond to oral pharmacotherapy with
sildenal whereas 90% of those with partial erections
had a signicant response to the medication.
65
A
prospective study by Weber et al.
66
documented 77%
with improved erectile function (sildenal 100 mg)
while Valicenti et al.
67
reported restoration of pre-XRT
sexual function in 21 of 23 patients who used sildenal
100 mg after radiation therapy. The latter study
evaluated 24 men with median age of 68 years (range
5177) who had 3D-CRT for localized prostate cancer
(median prescribed dose 70.2 Gy) and started taking
sildenal for relief of sexual dysfunction at a median
time of 1 year after completing 3D-CRT. Sexual func-
tion was assessed with the OLeary Brief Sexual Func-
tion Inventory before XRT, before sildenal therapy
(50 or 100 mg), and after completion of sildenal
therapy with a minimum of 2 months follow-up. Of
the 20 patients who were potent prior to any treat-
ments, 13 (65%) remained potent after XRT, with only
11% being fully potent. Potency was achieved in 91%
of the cohort after sildenal, with 30% reported as
being fully potent.
67
Incrocci et al. evaluated the efcacy of sildenal
citrate (Viagra) in patients with ED after 3D-CRT for
prostate cancer. Overall, 50% of the patients responded
to sildenal.
68
The authors cited lack of pretherapy
erectile function data as a potential weakness in their
study. They found a positive signicant correlation
between baseline scores after therapy and scores after
sildenal. However, no statistically signicant cor-
relation in efcacy of sildenal with age, concomitant
medication, or time after RT was noted. The authors
additionally commented that the higher dose of 100 mg
appeared to be needed for treatment of post-RT ED,
since 90% of their patients were on this dose.
68
Merrick et al. evaluated the efcacy of sildenal
citrate (Viagra) in patients with ED either before or
after prostate brachytherapy by an open-label, non-
randomized study. Fifty (80.6%) of 62 patients
responded favorably to sildenal.
69
Potters et al.
reported the largest prospective study to date on
potency after ultrasound-guided transperineal brachy-
therapy with a median follow-up of 34 months and
a median age of 68 years. In this study sildenal
improved erectile function in 83% treated with either
brachytherapy or brachytherapy + XRT. However, the
response rate was only 46% for those treated with
neoadjuvant androgen ablation and brachytherapy.
47
These ndings are illustrated in Table 10.3.
Penile prosthesis surgery is a viable option with
excellent patient satisfaction rates in post-XRT patients
who are not candidates for (or do not respond to) more
conservative measures. Outcome analysis of penile
implant surgery in 43 men following XRT for prostate
cancer has shown no evidence of infection or device
erosion with a 40-month mean follow-up.
70
The
authors reported that three of the patients were at
increased risk of infection due to reoperation for
device malfunction or previously failed operations at
other institutions. However, none of the redo
operations resulted in infections and the reoperation
was not due to previous irradiation in any of the cases.
They further concluded that penile prosthesis surgery
has no increased risk of infection or erosion and that
it is a safe and efcacious treatment modality for this
subpopulation.
FUTURE OUTCOMES
A number of studies have evaluated the psychological
and physiological impact of therapies for prostate
cancer on sexuality parameters other than erectile
function. While there is near unanimous agreement on
the psychological impact of the cancer diagnosis and
treatment on the quality of erections, the effects on
sexual desire and orgasm are more controversial.
Schover reported normal sexual desire and orgasm
after surgery despite disruption of the genital vaso-
congestion accompanying sexual arousal.
71
In contrast,
Koeman and colleagues evaluation of post-RP patients
indicated that half the patients reported diminished
sexual desire (libido) and arousal after the operation
and reported the same to occur in their partners.
72
During their dry orgasm postoperatively, none of
the patients experienced the exquisite sensation of
inevitability, the so-called point of no return. Among
those who did experience orgasm, 50% complained
that their orgasmic sensation was weakened. Four
patients reported normal pleasure and sensation com-
pared to that experienced preoperatively. The authors
also reported involuntary loss of urine in 9 of 14
patients at orgasm and this was sufcient reason to
avoid any sexual contact with their partner in 5 of
these patients.
Helgason et al.
73
performed a similar study in
patients treated with RT and found that sexual desire
diminished among 77% after treatment. Furthermore,
of those retaining orgasm after treatment, 47% reported
decreased orgasmic pleasure and 91% reduced ejacu-
lation volume. Of all men, 50% reported that quality
Future Outcomes 153
TABLE 10.3 Patients who developed impotence
after permanent brachytherapy treated with
sildenal.
Treatment n Successful
outcome to
sildenal
All patients 84 52 (62%)
All non-NAAD patients
Brachytherapy as monotherapy 15 12 (80%)
EBT and brachytherapy 21 18 (86%)
All NAAD patients
Brachytherapy as monotherapy 25 11 (44%)
EBT and brachytherapy 23 11 (48%)
Adapted from Potters et al.
47
NAAD, neoadjuvant androgen deprivation; EBT, external
beam radiation.
of life had decreased much or very much due to a
decline in the erectile capacity following XRT. The
authors concluded that XRT for prostate cancer is
associated with a reduction in sexual desire, erectile
capacity, and orgasmic functions and that this reduces
quality of life in the majority of patients.
In recent years, health-related quality-of-life (HRQOL)
outcomes have assumed a more important role as an
adjunct to survival in the assessment of the success
of therapies for prostate cancer. HRQOL discussions
related to the adverse effects of prostate cancer therapy
typically focus on incontinence and ED. Sexual func-
tion and sexual bother are two distinct, but related,
domains in HRQOL that have a signicant impact on
treatment decisions in early-stage prostate cancer. In
the context of HRQOL issues, sexual function
includes the broad domains of desire, the quality of
erections, and the ability to be physically intimate,
whereas sexual bother is dened as the degree of
interference or annoyance due to altered sexual
function.
23
Perez et al. compared self-reports of global quality
of life, sexuality, urinary continence, and physical
capabilities in 86 nerve-sparing patients, 89 standard-
prostatectomy patients, 74 prostatectomy patients who
used erectile aids, and a comparison group of 45
patients awaiting RP.
74
They showed that the best
outcomes in sexuality were reported by patients who
used erectile aids. Non-nerve-sparing prostatectomy
patients who did not use erectile aids scored worse in
most areas of sexuality than nerve-sparing patients
who did not use erectile aids. Interestingly, although
most patients reported problems in sexual and urinary
function, global quality of life did not appear to be
compromised following surgery.
Mazur and Merz assessed whether patients report
willingness to trade-off urologic adverse outcomes
urinary incontinence and total impotence for a
better chance of 5-year survival in the clinical setting
of prostate cancer.
75
Ninety-four percent of patients
were willing to choose worse short-term and better
long-term survival. The results suggested than many
patients were more concerned with long-term survival
in the clinical setting of prostate cancer than with
short-term treatment risks and that patients are more
willing to accept an impotence outcome (83%) than a
urinary incontinence outcome (62%), irrespective of
the patients reported frequency of sexual activity.
Other studies have shown that the general domain
of HRQOL which measures a patients own perception
of his well-being remains unchanged after surgery and
that, given the option, most patients would chose to
have surgery again.
8,10,22
Similarly, Kao et al.
14
report
on morbidity in men who underwent RP, mainly in the
late 1980s and early 1990s, performed by different
surgeons in the US military health care system. The
authors demonstrate that, despite negative effects on
the self-reported quality of life, most patients would
choose the same therapy again. Table 10.4 provides
descriptive statistics of multicenter patient self-reported
questionnaires on RP with illustration of patient satis-
faction measures and willingness to undergo repeat
surgery.
In a study by Braslis et al., 81% of those who saw
sexuality as a major issue and were unable to achieve
erections postoperatively stated that they would prob-
ably or denitely have their surgery again and felt that
the perceived survival benet of surgery outweighs the
loss of sexual function.
16
However, this choice must
not mask the frustration that is surely experienced at
the loss of sexual function. Additionally, the majority
TABLE 10.4 Descriptive statistics of multicenter
patient self-reported questionnaires on radical
prostatectomy.
Number of patients
(%)
Age at surgery (years)
70 or younger 853 (84.2)
Older than 70 160 (15.7)
Married 633 (62.5)
Not married 370 (36.5)
Unknown 10 (1.0)
Before 1990 145 (14.3)
After 1990 868 (85.7)
Impotence
Yes 780 (77.0)
No 94 (9.3)
Unknown 139 (13.7)
Sexual function satisfaction
Very satised 98 (9.7)
Somewhat satised 190 (18.8)
Somewhat unsatised 219 (21.6)
Very unsatised 362 (35.7)
Unknown 144 (14.2)
Quality of life
Better 149 (14.7)
Same 446 (44.0)
Worse 373 (36.8)
Unknown 45 (4.4)
Willing to be treated again
Yes 785 (77.5)
No 168 (16.6)
Unknown 60 (5.9)
Adapted from Kao et al.
14
of patients surveyed after surgery indicated that the
risk of impotence had been understated in preoperative
counseling.
16
Comparison of the nerve-sparing and non-nerve-
sparing techniques demonstrated that scores for sexual
function, sexual bother, physical function, and physical
limitation domains were signicantly better in the
nerve-sparing group.
76
Fowler et al. evaluated the
effects of urinary incontinence and sexual dysfunction
on the quality of life in a large group of Medicare
patients and reported that, overall, incontinence
appeared to have a more signicant impact on the
quality of life than sexual dysfunction.
10
Knowledge of the pretreatment sexual dysfunction
is critical in the ability to counsel patients properly on
individualized ideal therapies for prostate cancer. A
study of patient attitudes regarding treatment-related
ED at the time of diagnosis of cancer showed that
33.9% of patients reported either partial or complete
lack of erections and 31.1% were not sexually active
or active less than once per month. Although 55.4%
would be affected or very affected by lack of erections,
73.6% chose denitive treatment despite a 50%
chance of ED. Finally, 47.4% found such treatment-
induced ED to be an important or very important
problem.
77
Madalinska et al. performed a study within the
framework of a screening trial to compare the HRQOL
outcomes of RP and XRT. Patients referred for primary
radiotherapy were signicantly older than prostatec-
tomy patients. Analyses revealed poorer levels of
generic HRQOL after radiotherapy, although prostatec-
tomy patients reported signicantly higher posttreat-
ment incidences of ED.
78
However, evaluation of long-
term sexual function outcomes has shown similar rates
regardless of whether radiation or surgery is chosen as
treatment.
7,23
Additionally, Talcott et al.
7
demonstrated
that treatment choice signicantly affects sexual
function, but not sexual bother, suggesting that these
two are separate but independent psychometric con-
structs.Whereas sexual function is intimately related to
the ability to obtain and maintain erections satisfactory
for intercourse, sexual bother is related to a mans
resignation to loss of potency, availability of a sexual
partner, and the relative value of sexual function.
23
Their ndings also corroborated those by Perez et al.,
who had shown an overall quality of life after treat-
ment that was uniformly good.
74
Finally, Derby et al. have shown that physical
activity status is associated with ED, with the highest
risk among men who remain sedentary and the lowest
among those who remained active or initiated physical
activity.
79
They advocate early adoption of healthy
lifestyles as the best approach to reducing the burden
of ED on the health and well-being of older men, a
recommendation that is equally applicable to those
undergoing therapy for prostate cancer.
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Immediate sexual rehabilitation by simultaneous placement
of penile prosthesis in patients undergoing radical
prostatectomy: initial results in 50 patients. Urology 1997; 50
(3):395399.
63. Kim ED, Nath R, Slawin KM et al. Bilateral nerve grafting
during radical retropubic prostatectomy: extended follow-up.
Urology 2001; 58 (6):983987.
64. Walsh PC. Nerve grafts are rarely necessary and are
unlikely to improve sexual function in men undergoing
anatomic radical prostatectomy. Urology 2001; 57
(6):10201024.
65. Zelefsky MJ, McKee AB, Lee H et al. Efcacy of oral
sildenal in patients with erectile dysfunction after
radiotherapy for carcinoma of the prostate. Urology 1999; 53
(4):775778.
66. Weber DC, Bieri S, Kurtz JM et al. Prospective pilot
study of sildenal for treatment of postradiotherapy erectile
dysfunction in patients with prostate cancer. J Clin Oncol
1999; 17 (11):34443449.
67. Valicenti RK, Choi E, Chen C et al. Sildenal citrate
effectively reverses sexual dysfunction induced by three-
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68. Incrocci L, Koper PC, Hop WC et al. Sildenal citrate
(Viagra) and erectile dysfunction following external beam
radiotherapy for prostate cancer: a randomized, double-blind,
placebo-controlled, cross-over study. Int J Radiat Oncol Biol
Phys 2001; 51 (5):11901195.
69. Merrick GS, Butler WM, Lief JH et al. Is brachytherapy
comparable with radical prostatectomy and external-beam
radiation for clinically localized prostate cancer? Tech Urol
2001; 7 (1):1219.
70. Dubocq FM, Bianco FJ Jr, Maralani SJ et al. Outcome
analysis of penile implant surgery after external beam
radiation for prostate cancer. J Urol 1997; 158 (5):17871790.
71. Schover LR. Sexuality and fertility in urologic cancer
patients. Cancer 1987; 60 (suppl 3):553558.
72. Koeman M, van Driel MF, Schultz WC et al. Orgasm after
radical prostatectomy. Br J Urol 1996; 77 (6):861864.
73. Helgason AR, Fredrikson M, Adolfsson J et al. Decreased
sexual capacity after external radiation therapy for prostate
cancer impairs quality of life. Int J Radiat Oncol Biol Phys
1995; 32 (1):3339.
74. Perez MA, Meyerowitz BE, Lieskovsky G et al. Quality
of life and sexuality following radical prostatectomy in
patients with prostate cancer who use or do not use erectile
aids. Urology 1997; 50 (5):740746.
75. Mazur DJ, Merz JF. Older patients willingness to trade
off urologic adverse outcomes for a better chance at ve-year
survival in the clinical setting of prostate cancer. J Am Geriatr
Soc 1995; 43 (9):979984.
76. Gralnek D, Wessells H, Cui H et al. Differences in sexual
function and quality of life after nerve-sparing and nonnerve-
sparing radical retropubic prostatectomy. J Urol 2000; 163
(4):11661169; discussion 11691170.
References 157
77. Karakiewicz PI, Aprikian AG, Bazinet M et al. Patient
attitudes regarding treatment-related erectile dysfunction at
time of early detection of prostate cancer. Urology 1997; 50
(5):704709.
78. Madalinska JB, Essink-Bot ML, de Koning HJ et al.
Health-related quality-of-life effects of radical prostatectomy
and primary radiotherapy for screen-detected or clinically
diagnosed localized prostate cancer. J Clin Oncol 2001; 19
(6):16191628.
79. Derby CA, Mohr BA, Goldstein I et al. Modiable risk
factors and erectile dysfunction: can lifestyle changes modify
risk? Urology 2000; 56 (2):302306.
80. Quinlan DM, Epstein JI, Carter BS et al. Sexual function
following radical prostatectomy: influence of preservation of
neurovascular bundles. J Urol 1991; 145 (5):9981002.
81. Merrick GS, Wallner K, Butler WM et al. Short-term
sexual function after prostate brachytherapy. Int J Cancer
2001; 96 (5):313319.
82. Talcott JA, Clark JA, Stark PC et al. Long-term treatment
related complications of brachytherapy for early prostate
cancer: a survey of patients previously treated. J Urol 2001;
166 (2):494499.
INTRODUCTION
Erectile dysfunction (ED) is increasingly being con-
strued as an organic condition with vascular patho-
physiologic foundations. With the recent elucidation
of the molecular physiology of penile erection and
advanced diagnostic techniques, ED is now understood
to result from organic causes in up to 80% of cases,
1
with vascular causes accounting for the majority.
Conceptually, ED, like myocardial infarction (MI) and
stroke, may be viewed as a distinct end-organ con-
sequence of a shared vascular pathology.
Dened as the inability to achieve and maintain
penile rigidity sufcient for sexual intercourse, ED is
often a neurovascular disorder. In the healthy male,
relaxation of smooth-muscle cells (SMC) within the
penile vasculature and corpus cavernosum, along with
engorgement of corporal sinusoids, causes penile blood
pressure to approach or exceed mean arterial pressure
(MAP) (Fig. 11.1). A venoocclusive mechanism is
instrumental in the maintenance of penile erection.
This involves venous outflow obstruction as a result of
stretching of the tunica albuginea with compression of
the subtunical venous plexus. SMC relaxation within
Cardiovascular Safety of Sexual Activity and
Phosphodiesterase Type 5 Inhibition
Robert A. Kloner
CHAPTER 11
Figure 11.1 Anatomy and mechanisms of penile erection. (Adapted with permission from Lue TF. Erectile dysfunction.
N Engl J Med 2000; 342:18021813. Copyright 2000 Massachusetts Medical Society. All rights reserved.)
Prostate Deep
dorsal
vein
Dorsal
artery
Dorsal nerve
(somatic)
Circumflex
artery
Circumflex
vein
Cavernous
nerve
(autonomic)
Dorsal
artery
Dorsal nerve
(somatic)
Sinusoidal
spaces
Helicine
arteries
Trabecular
smooth
muscle
Subtunical
venular plexus
Deep
dorsal vein
Tunica
albuginea
Corpora
cavernosa
Cavernous
artery
Erect
Cavernous
artery
Flaccid
the penile vasculature and trabecular erectile tissue is
pivotal in generating a normal physiologic erection.
Either arterial pathology or a suboptimal venoocclusive
mechanism (e.g., venous leak) underlies vasculogenic
ED.
24
Nitric oxide (NO), previously termed endothelium-
derived relaxing factor, is the central mediator of
penile erection. A complex signal-transduction cascade
involving NO results in SMC relaxation with increased
penile blood flow and tissue expansion.
Produced from L-arginine by NO synthase (NOS),
NO is released at cavernous non-adrenergic, non-
cholinergic nerve terminals as a result of sexual arousal
and increased parasympathetic (cholinergic) input;
NO is also released from endothelial cells within the
vasculature of the corpora cavernosa. NO then binds to
and activates soluble guanylate cyclase (sGC) in SMC,
and the synthesis of cyclic guanosine monophosphate
(cGMP) is upregulated. Membrane hyperpolarization
with closure of gated transmembrane calcium (Ca
2+
)
channels via phosphorylation results in a reduced influx
of Ca
2+
across the cell membrane. In addition, Ca
2+
is
sequestered by cellular organelles (e.g., sarcoplasmic
reticulum) through an energy-dependent process, and
the decline in intracellular Ca
2+
is associated with
reduced formation of actomyosin complexes and
diminished smooth-muscle tone. SMC relaxation with
vasodilation of arteries and arterioles occurs; these
structures ll with blood, penile tissue expansion
occurs, and these processes result in penile erection
(Fig. 11.2).
3,5
The NOsGCcGMP signal-transduction cascade has
been recognized as a potential pharmacotherapeutic
target in ED.
6
Phosphodiesterase type 5 (PDE5)
degrades (inactivates) intracellular cGMP, and this
enzymatic hydrolysis terminates its smooth-muscle-
relaxing effects. Conversely, inhibition of this process
by selective PDE5 inhibitors prevents the breakdown
of cGMP, resulting in higher concentrations of this
substance with subsequent improved vasodilation and
enhanced erections.
SHARED RISK FACTORS BETWEEN
CARDIOVASCULAR DISEASE AND
ERECTILE DYSFUNCTION
Epidemiologic, physiologic, and clinical links exist
between coronary artery disease (CAD) and ED. With
advancing median ages in industrialized societies,
including the USA, the prevalences of both conditions
are projected to increase.
7,8
Risk factors for CAD,
including hypertension, dyslipidemia, diabetes, smoking,
obesity, and lack of physical activity, also either
directly or indirectly elevate the risk of developing
ED.
912
Hypertension
Abundant evidence lends credence to the close associ-
ation between hypertension and ED. In an early study
of 302 patients, ED was present in 6.9% of normo-
tensive men, 17.1% of men with untreated hyper-
tension, and 24.6% of men with treated hypertension
(P < 0.001).
13
The Massachusetts Male Aging Study
(MMAS), a random-sample observational study of
men aged 4070 years, showed that ED was more
160 Cardiovascular Safety of Sexual Activity and Phosphodiesterase Type 5 Inhibition
Hyperpolarization
Relaxation
+
+
-
-
NO
GC
PLC PL
3
Endothelium
Nerves
Na
+
/K
+
-ATPase
Ca
2+
K
+
PKA
PLB cGMP PKG
Ca
2+
-channels
Ca
2+
-ATPase
IP
3
-receptor
K
+
-channels
[Ca
2+
]
Ca
2+
Figure 11.2 Schematic
representation of the
mechanisms involved in penile
smooth-muscle relaxation by the
cyclic guanosine monophosphate
(cGMP) pathway. GC, guanylate
cyclase; IP
3
, inositol triphosphate;
PKA, protein kinase A; PKG,
protein kinase G; PLB,
phospholipase B; PLC,
phospholipase C; NO, nitric
oxide. - indicates inhibitory effect;
+ indicates stimulating effect.
(Adapted with permission from
Senz de Tejada I. Molecular
mechanisms for the regulation of
penile smooth muscle
contractility. Int J Impot Res 2000;
12 (suppl 4):S34S38. Copyright
2000 Nature Publishing
Group.)
prevalent in men with hypertension than the age-
matched general population.
11
The age-adjusted
probability of complete ED was 15% in patients with
treated hypertension compared with 9.6% in the
entire sample.
11
Further, in a hypertension clinic outpatient study
that used the International Index of Erectile Function,
68.3% of men with hypertension exhibited some
degree of ED, and ED was more severe in patients with
hypertension than in the general population.
9
Finally,
a 4-month study of 101 patients from a Danish out-
patient hypertension clinic revealed that 27% of men
with hypertension experienced ED compared with 4%
of men in the general regional population (P < 0.001).
14
Of note from this study, the cause of ED in 89% of
patients with hypertension was arterial dysfunction,
14
which was assessed using Doppler ultrasonography of
the penile arteries with or without papaverine (60 mg)
injection. In addition, the prevalence of ED was related
to the degree of secondary organ manifestation.
Advanced hypertension according to World Health
Organization classications (P = 0.01), intermittent
claudication (P = 0.001), and ischemic heart disease
(P = 0.005) were the most reliable determinants of ED.
Pathophysiologic connections between ED and
hypertension implicate endothelial dysfunction as a
shared mechanism. Endothelial dysfunction implies
that the blood vessels are incapable of normal vaso-
dilation through a defect in the NOcGMP pathway.
Indeed, the term ED may stand for endothelial dys-
function almost as readily as erectile dysfunction.
The diminished vascular compliance, increased vascular
thickness, and endothelial dysfunction associated with
hypertension can lead to increased vascular tissue
resistance within the corpus cavernosum, inadequate
penile blood flow, and, hence, ED.
Recent in vivo and in vitro studies performed in
spontaneously hypertensive rats demonstrated that
hypertension markedly compromised erectile function.
15
Endothelial dysfunction was responsible for impaired
SMC relaxation in both the aortas and corpora caver-
nosa of these organisms. An imbalance of endogenous
vasoactive substances, including relative declines in
NO bioavailability and the cyclic nucleotide signal-
transduction cascade in general, occurs in both the
systemic circulation and penile vascular beds in the
setting of hypertension. The NO-decient state is a
potential unifying theme in patients with ED secondary
to cardiovascular disease or diabetes, among other
conditions.
16
Certain drugs prescribed to treat hypertension,
including certain thiazide diuretics, are also considered
to be risk factors for the development of ED.
11
However, the wide variety of antihypertensive agents
(with different mechanisms of action) that have been
reported to induce ED suggests that hypertension per se
contributes more signicantly to the development of
ED than administration of individual antihypertensive
drugs in particular.
14,17
All antihypertensive drugs do not exert equal effects
on erectile function. In a cross-over study of 160 men
aged 4049 years with newly diagnosed hypertension
and no history of ED, sexual activity signicantly
declined with administration of the -blocker carvedilol
but not the angiotensin-receptor blocker (ARB)
valsartan over 16 weeks.
18
In addition, a study of men
and women at 110160% of their ideal body weight
who took chlorthalidone showed that adherence to a
weight-loss diet signicantly improved well-being and
measures of distress, including sexual problems.
19
Atherosclerosis
Atherosclerosis is the most common cause of vasculo-
genic ED,
1
partly because atheromata, which constitute
a form of endothelial insult, can reduce penile perfusion.
In an in vivo study, 93% of animals with experimen-
tally induced stenosis (luminal occlusion >50%) of the
iliohypogastric arteries exhibited ED, although other
contributing factors, such as hypertension-induced
alterations of broelastic properties of the corpus
cavernosum, could not be ruled out.
20
Even in the
absence of stenotic lesions, hypercholesterolemia was
associated with an increased probability of ED.
Balloon de-endothelialization of the common and
internal iliac arteries and hypercholesterolemia induced
by a high-cholesterol diet of 1.6% cholesterol and 4%
triglyceride over 8 weeks resulted in impaired erectile
function in 16 (76%) of 21 animals.
20
Advancing age, which is also a risk factor for athero-
sclerosis, correlates with reduced NOSNOsGC
cGMP signaling.
2,21,22
Downregulation of this signal-
transduction mechanism in the setting of vascular
disease with aging renders PDE5 inhibition a highly
rational pharmacotherapeutic approach.
6
Dyslipidemia
High levels of total cholesterol and low levels of high-
density lipoprotein (HDL) cholesterol are risk factors
for ED as well as CAD. In the MMAS,
11
the probability
of ED was inversely correlated with HDL-cholesterol
levels. In men aged 4055 years, the age-adjusted
probability of moderate ED increased from 6.7% to
25% as HDL cholesterol decreased from 90 to
30 mg/dl. In men aged 5670 years, the probability of
complete ED increased from close to 0 to 16% as HDL
cholesterol decreased from 90 to 30 mg/dl (Fig. 11.3).
Further epidemiologic evidence supports the associ-
ation between dyslipidemia and ED. In a longitudinal
study, 3250 men aged 2583 (mean 51) years were
followed for 648 (mean 22) months after rst
Shared Risk Factors between Cardiovascular Disease and Erectile Dysfunction 161
presentation with dyslipidemia, at which time they did
not have ED.
10
In these men, every 1 mmol/l increase
in total cholesterol was associated with a 1.32 times
increase in the risk of incident ED, whereas every
1 mmol/l increase in HDL cholesterol was associated
with a 0.38 times decrease in the risk of ED. Men with
HDL cholesterol levels of greater than 1.55 mmol/l
(60 mg/dl) had 0.30 times the risk of ED compared
with men with HDL cholesterol levels of less than
0.78 mmol/l (30 mg/dl). Men with total cholesterol
levels greater than 6.21 mmol/l (240 mg/dl) had 1.83
times the risk of ED compared with men who had
total cholesterol values of less than 4.65 mmol/l
(180 mg/dl).
10
Diabetes
Approximately 3550% of men with diabetes mellitus
suffer from ED,
23,24
and ED is often the rst sign of
diabetes. The age-adjusted probability of complete ED
is 28% in men with treated diabetes versus 9.6% in
the general population;
11
the prevalence of ED in
3034-year-old men with diabetes has been estimated
at 15% and in men aged 60 years at 55%. The onset of
ED tends to occur earlier in patients with diabetes
than in the general population.
11
In a cohort study using self-report that evaluated
365 patients under age 30 years at diagnosis of type 1
diabetes, had diabetes for 10 years or longer, and took
Probability
None Minimal Moderate Complete
Degree of impotence
0.0 A 0.5 1.0
Excessive alcohol: No
Yes
Age 4055 HDL-C (mg/dl): 30
60
90
Age 5670 HDL-C (mg/dl): 30
60
90
DHT (ng/ml): 0.01
0.1
1
Cortisol (g/dl): 5
25
75
DHEAS (g/ml): 0.5
1
5
10
Age-adjusted Probability
Degree of impotence
0.0 B 0.5 1.0
Hypoglycemic agents: No
Yes
Vasodilators: No
Yes
Cardiac drugs: 30
Yes (non-smoker)
Yes (smoker)
Antihypertensives: No
Yes (non-smoker)
Yes (smoker)
Figure 11.3 Association of
excessive alcohol consumption,
high-density lipoprotein
cholesterol (HDL-C), serum
hormone levels and medication
use with probability of erectile
dysfunction, imputed by
discriminant analyses in 1290
respondents to sexual activity
questionnaires. Probabilities for
HDL-C are stratied by age.
Other probabilities are age-
adjusted by regression. DHEAS,
dehydroepiandrosterone sulfate;
DHT, dihydrotestosterone.
Feldman HA, Goldstein I,
Hatzichristou DG et al. Impotence
and its medical and psychosocial
correlates: results of the
Massachusetts Male Aging Study.
J Urol 1994; 151(1):5461.)
insulin,
25
the prevalence of ED increased sharply with
advancing age. A more than 40-fold increase in ED
prevalence was evident in men from ages 21 to 30
years (1.1%) to those aged 43 years or older (47.1%;
P <0.0001). Moreover, 10 (83%) of 12 diabetes patients
aged 65 years or older experienced ED.
25
The prevalence of ED also increased dramatically
with increasing duration of diabetes: men with diabetes
for more than 35 years were 7.2 times as likely to
report ED as men with a duration of 1014 years
(P < 0.0001; Fig. 11.4). Other factors signicantly
associated with an increased likelihood of ED in men
with diabetes included higher body mass index and
systolic blood pressure (SBP), treated hypertension
(including diuretic treatment), and smoking.
25
A multi-
center study involving 1460 patients with diabetes
also demonstrated signicant associations among ED,
diabetes, and depression.
26
Putative pathophysiologic mechanisms linking
diabetes and ED include impaired neurogenic and
endothelium-mediated smooth-muscle relaxation; NO
deciency secondary to the formation of advanced
glycation end-products, which form protein cross-links
that scavenge NO; autonomic insufciency; and gonadal
dysfunction.
1,27
Mechanisms that may underlie the
association between hyperglycemia and vasculopathy
are presented in Figure 11.5.
Smoking
Both clinical and epidemiologic evidence suggests that
cigarette smoking exerts deleterious effects on erectile
function and is an independent risk factor for the
development of vasculogenic ED. These adverse effects
may be synergistically amplied in the presence of other
risk factors, such as hypertension and CAD.
11,12,28,29
A comprehensive review of the literature found that
smoking increased the likelihood of moderate to com-
plete ED twofold.
12
Smoking also increased the age-
adjusted probability of complete ED in patients taking
cardiac drugs (from 14% to 41%), antihypertensive
agents (from 7.5% to 21%), or vasodilators (from 21%
to 52%).
11
In a follow-up to the MMAS that analyzed
513 men aged 4070 years, baseline cigarette smoking,
passive cigarette smoke exposure, and cigar smoking
were associated with odds ratios of approximately
2.0 for developing ED over a 10-year period (P < 0.05
versus general population for all variables).
30
The pathophysiologic mechanisms responsible for
the damaging effects of smoking on erectile function
may also be related to endothelial dysfunction.
12
In
animal models, inhalation of cigarette smoke caused
failure of the venoocclusive mechanism and a decline
in arterial blood flow;
28
smoking also exerts well-
documented adverse effects on the vascular
endothelium in general.
12
Adding to any existing NO
deciency, free radicals and aromatic compounds from
cigarette smoke decrease endothelial NOS (eNOS)
activity and elicit superoxide-mediated NO degra-
dation, which tends to increase penile smooth-muscle
tone and promote flaccidity (Fig. 11.6).
12
Other puta-
tive mechanisms for the chronic adverse effects of
nicotine on erectile function include hypercoagulability,
increased platelet aggregation, release of free fatty
acids and catecholamines, and direct toxic effects of
nicotine and carbon monoxide on the vascular
endothelium.
28
Duration (years)
P
r
e
v
a
l
e
n
c
e

o
f

e
r
e
c
t
i
l
e

d
y
s
f
u
n
c
t
i
o
n

(
%
)
0
>1015 >1520 >2025 >2530 >3035 >3540 >40
100
25
50
75
Figure 11.4 Duration of diabetes
and prevalence of erectile
dysfunction. (Adapted with
permission from Klein R, Klein
BE, Lee KE et al. Prevalence of
self-reported erectile dysfunction
in people with long-term IDDM.
Diabetes Care 1996; 19:135141.
Copyright 1996 American
Diabetes Association.)
Hyperglycemia
Glucose
auto-oxidation
Oxidative stress
O
2
/NO
Polyol
pathway
Protein
glycation
Oxidative
factors
Antioxidant
defense
Heparan
sulfate
NCV
Endoneural
blood flow
LDL
oxidation
Vasculopathy Retinopathy Neuropathy Nephropathy
NO-dependent
vasodilation
Ca
2+
VSMC
proliferation
Hemorrheologic
alterations
Coagulation
activation
Hypoxia
Figure 11.5 Possible links

between hyperglycemia-induced
oxidative stress and diabetic
complications. NO, nitric oxide;
VSMC, vascular smooth-muscle
cell; LDL, low-density lipoprotein;
NCV, nerve conduction velocity.
Giugliano D, Ceriello A,
Paolisso G. Oxidative stress and
diabetic vascular complications.
Diabetes Care 1996;
19(8):257267. Copyright 1996
The American Diabetes
Association. Reprinted with
permission from The American
Diabetes Association.)
Figure 11.6 Mechanism of smoking-induced altered smooth-muscle relaxation. Free radicals and aromatic compounds
decrease endothelial synthesis of NO by affecting endothelial nitric oxide synthase (eNOS), causing impaired endothelium-
dependent relaxation of arteries. This may result from reduction in activity of eNOS that is attributable to inadequate
supply of coenzyme BH
4
. Smoke also causes contraction of smooth muscle by superoxide anion-mediated degradation
of NO. Akt, serine threonine kinase; CaM, calcium calmodulin; ACh-R, acetylcholine receptor; VEGF, vascular endothelial
growth factor; VEGF-R, vascular endothelial growth factor receptor; IP
3
, inositol triphosphate; eNOS, endothelial nitric
oxide synthase; BH
4
, tetrahydrobiopterin; NO, nitric oxide. (Adapted with permission from McVary KT, Carrier S,
Wessells H. Smoking and erectile dysfunction: evidence based analysis. J Urol 2001; 166(5):16241632.)
VEGF
Shear Akt
Acetylcholine
IP
3
Ca
2+
Ca
2+
eNOS
L-Arginine
NO
BH
4
CaM
CaM
Superoxide anion degradation
Free radicals
Aromatic compounds
Reduced
supply
Cigarette smoke extract
Nicotine
ACh-R
VEGF-R
Multiple risk factors
The presence of more than one risk factor sharply
augments the probability of developing ED. Using
duplex ultrasonography, the effects of smoking,
diabetes, and hypertension on vasculogenic ED were
evaluated in 132 patients.
28
The incidence of vascular
impairment was higher in patients with one risk factor
than no risk factors, and the proportion of vascular
penile abnormalities rose signicantly as a function of
the number of risk factors (Fig. 11.7).
In an evaluation
31
of arterial risk factors (smoking,
diabetes, lipid abnormalities, hypertension) in 440 men
(mean age, 46.8 years) with ED, the frequency of
organic ED increased from 49% in men with no risk
factors to 100% in men with three or four risk factors.
The barometer of dysfunction in this trial was the
penile blood-pressure index (PBPI), which is expressed
as the ratio of lowest systolic pressure in one of four
main penile arteries to systolic pressure in the arm. In
the overall population and in men with arterial ED
specically, the PBPI declined as an inverse function of
the number of arterial risk factors present. Whenever
two or more arterial risk factors were evident, PBPI
was signicantly reduced (Fig. 11.8).
Arterial
impotence
n = 318
Total
series
n = 448
Non-organic
impotence
n = 44
Organic
non-arterial
impotence
n = 36
P
e
n
i
l
e

b
l
o
o
d

p
r
e
s
s
u
r
e

i
n
d
e
x
0.3
1.1
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0
1
2
3,4
1
2
3,4
Figure 11.8 Penile blood-
pressure index and arterial risk
factors. The numbers 1, 2, 3, 4
refer to the number of risk
factors. (Reprinted with
permission from Virag R, Bouilly
P, Frydman D. Is impotence an
arterial disorder? A study of
arterial risk factors in 440
impotent men. Lancet 1985;
1:181184. Copyright 1985
Elsevier Science.)
Figure 11.7 Effects of smoking,
diabetes, and/or hypertension on
vascular evaluation. (Reprinted
from Shabsigh R, Fishman IJ,
Schum C et al. Cigarette smoking
and other vascular risk factors in
vasculogenic impotence. Urology
1991; 38:227231. Copyright
1991 Elsevier Science.)
%

o
f

p
a
t
i
e
n
t
s

w
i
t
h

a
b
n
o
r
m
a
l

v
a
s
c
u
l
a
r

f
i
n
d
i
n
g
s
0
No risk factors
67
P < 0.05
1 risk factor
75
2 risk factors
90
3 risk factors
100
120
10
20
30
40
50
60
70
80
90
100
110
ERECTILE DYSFUNCTION AS A
MARKER FOR CONCOMITANT
CONDITIONS
ED may be a risk marker for occult CAD,
32,33
depression,
3436
cardiovascular complications,
36
and
diabetes.
37
For instance, in an angiographic trial
involving 40 men (mean age 56.6 years) with ischemic
heart disease, the severity of ED correlated with the
extent of CAD.
38
Patients with single-vessel CAD
had more frequent (P < 0.04) and rmer (P < 0.001)
erections and fewer difculties achieving erection
(P < 0.007) than their counterparts with multivessel
disease.
Major depressive disorder, cardiovascular disease,
and ED have been characterized as a mutually
reinforcing triad, in part because the affective disorder
can diminish a patients interest in and compliance
with treatment.
34
Depression is not only a risk factor
for ED but is also a signicant predictor of coronary
events
39
and mortality after MI.
40
As with coronary prevention through diet and exer-
cise as well as pharmacotherapy, lifestyle modication
may serve as a rst, baseline initiative for preventing
ED and concomitant conditions. As is also the case
with coronary events and all-cause mortality, the
likelihood of developing ED within a 10-year interval
may be reduced through increased physical activity in
sedentary men, even if undertaken at middle age.
41
Finally, as with the emerging CAD prevention model,
management of global risk factors should be considered
to reduce the risk of developing ED in patients with
cardiovascular disease.
42
These factors include dia-
betes, hypertension, obesity, and dyslipidemia.
Irrespective of its etiology, even if deemed strictly
organic, ED warrants some degree of counseling of
the patient and/or spouse or sexual partner. Nowhere
is this need more acute than in the middle-aged, post-
MI man with a diminished ego who is concerned about
resuming sexual activity after a hiatus. Fortunately, with
the aid of a workup for cardiovascular risk strati-
cation, the clinician should be able to reassure many
patients and counsel them to resume sexual activity.
The following sections will characterize the hemo-
dynamic and metabolic costs of sexual activities and
review consensus guidelines for risk stratication.
METABOLIC AND HEMODYNAMIC
COSTS TO THE HEART AND
CARDIOVASCULAR RISK OF SEXUAL
ACTIVITY
Although sexual intercourse may pose cardiovascular
risks to certain individuals, a number of epidemiologic
studies suggest that continuing sexual activity into the
elder years may actually enhance longevity.
4345
With
proper individual assessment and risk stratication,
many CAD patients can be advised to continue with or
resume sexual activity without fear of adverse cardio-
vascular events.
Hemodynamic and metabolic
parameters during sexual activity
Studies show that oxygen (O
2
) requirements and heart
rate (HR) during sexual activity are generally moderate
and consistent with values observed during daily
activities.
46,47
In an outpatient cardiac-rehabilitation
setting, no signicant differences in HR were recorded
with 24-h ambulatory electrocardiographic (ECG)
monitoring during sexual activity (mean 118
21 beats/min) compared with daily activities (mean
113 18 beats/min).
46
In fact, HR was higher during
moderate exercise than sexual activity (Fig. 11.9).
Patients without ischemia actually had signicantly
Figure 11.9 Mean peak heart
rate (standard deviation)
during sexual intercourse
compared with exercise test and
daily activities. In 11% of patients,
peak heart rate during
intercourse was 150180
beats/min. (Data from Drory Y,
Shapira I, Fisman EZ et al.
Myocardial ischemia during
sexual activity in patients with
coronary artery disease. Am J
Cardiol 1995; 75:835837.)
H
e
a
r
t

r
a
t
e

(
b
e
a
t
s
/
m
i
n
)
0
Intercourse Exercise Daily activities
113
(18)
118
(21)
138
(19)
200
NS
P< 0.001 P< 0.001
50
100
150
(P < 0.001) lower mean peak HR values during inter-
course (117 21 beats/min) than during exercise (150
13 beats/min).
46
Further, in a study that measured hemodynamic
parameters during stair-climbing and sexual activity
in healthy individuals and patients with CAD, HR
responses to both activities proved to be similar in
the two groups.
48
For the healthy individuals, mean
maximal HR values during sexual activity and stair-
climbing were 123 8 and 122 5 beats/min, respec-
tively. Maximal HR for the men with CAD during
sexual activity and stair-climbing were 115 7 and
118 6 beats/min, respectively; men with CAD had
lower HR values than healthy men during both
activities, as well as higher SBP during stair-climbing
than during sexual activity. SBP during stair-climbing
reached a maximum of 164 mmHg in men with CAD
versus 146 mmHg in healthy men but was similar in
both groups during sexual activity (Fig. 11.10). The
preponderance of the literature involving either
healthy volunteers or CAD patients suggests that the
mean peak HR during sexual activity is approximately
105130 beats/min, and peak SBP ranges from about
150 to 180 mmHg.
4650
An early study involving 10 healthy men (mean
age 29.3 years) and their sexual partners determined
that peak HR, blood pressure (BP), and rate pressure
product (RPP: HR SBP) were not signicantly dif-
ferent in men irrespective of their position vis--vis
their female partners (i.e., man-on-top versus woman-
on-top).
51
In a later study
49
involving 10 healthy married
couples aged 2543 (mean 33) years who performed
four different sexual activities man-on-top coitus
(husband prone), woman-on-top coitus (husband
supine), non-coital stimulation of husband by wife,
and self-stimulation by the husband values for HR,
RPP, and oxygen uptake (VO
2
) peaked during orgasm,
then rapidly approached baseline levels during the
resolution phase.
49
For man-on-top coitus, the average
HR, RPP, and VO
2
values peaked during orgasm at 127
23 beats/min, 21 200 6100 beats/min mmHg
(68% 20% of maximum), and 3.3 METs (metabolic
equivalents of O
2
consumption; 22% of maximum),
respectively. (Table 11.1 shows METs required for
selected physical activities for comparison.
52
)
Man-on-top coitus was associated with marked inter-
individual disparities in energy expenditures, however.
For example, VO
2max
during man-on-top orgasm ranged
from 2.0 to 5.4 METs.
49
In light of the considerable
variation in the workloads of sexual activity in different
individuals (Figs 11.11 and 11.12), energy require-
ments of sexual activities should not be oversimplied
by generalizations such as equal to climbing two
flights of stairs, and the importance of individual
workup cannot be overestimated.
52
Cardiovascular risks of sexual activity
Sexual intercourse incurs a nite, albeit minuscule
and transient, increase in the risk of ischemia, MI,
arrhythmia, or death. However, whereas the relative
risk of these events may rise transiently, the absolute
risk of these events is quite low.
5255
First, forensic and other studies showed that coital
death was more likely in men who engaged in
Metabolic and Hemodynamic Costs to the Heart and Cardiovascular Risk of Sexual Activity 167
TABLE 11.1 Energy requirements (METs) of
selected physical activities.
METs
Walking 2 mph, level 2
Walking 3 mph, level 3
Sexual activity, preorgasm 23
Sexual activity, during orgasm 34
Cycling 10 mph, level 67
Walking 4.2 mph, incline 13
METs, metabolic equivalents of oxygen consumption;
mph, miles per hour.
Adapted with permission from DeBusk RF. Evaluating the
cardiovascular tolerance for sex. Am J Cardiol 2000;
86:51F56F. Copyright 2000 Excerpta Medica.
Figure 11.10 Mean systolic blood pressure during stair-
climbing test and sexual activity. W, walking level; T, top of
stairs; I, intromission; O, orgasm; R1, rest sit (sex), rest
supine (stairs); R2, rest supine (sex), rest sit (stairs);
CAD, coronary artery disease. (Adapted from Bohlen JG,
Held JP, Sanderson MO, Patterson RP. Heart rate, rate-
pressure product, and oxygen uptake during four sexual
activities. Arch Intern Med 1984; 144:174548.) Copyright
1984 America Medical Association.
R1 R2 Rest WT 0 I
Sexual activity (CAD)
Stair-climbing (CAD)
Sexual activity (normals)
Stair-climbing (normals)
S
y
s
t
o
l
i
c

b
l
o
o
d

p
r
e
s
s
u
r
e

(
m
m
H
g
)
0
0 5 10 15 20 25
170
100
110
120
130
140
150
160
extramarital sexual activity, often with an unfamiliar
or younger partner and/or outside the home.
56,57
Second, in the Determinants of Myocardial Infarction
Onset Study
54
of 1774 US inpatients with MI, 858
(48.4%) of whom were sexually active during the year
before MI, 9% reported sexual activity within 24 h
before MI and 3% within 2 h before MI symptom
onset. Although the relative risk of MI during the 2 h
following sexual intercourse increased more than two-
fold among all patients, this risk was no higher among
men with a history of angina as compared with their
counterparts without prior CAD.
The foregoing study also suggested that coronary
events after sexual activity were more likely among
physically inactive men. Sedentary men, who exercised
to a minimum level of 6 METs once weekly or less,
had a relative MI risk of 3.0. However, patients who
were physically active and exercised three times a
week or more had a lower relative risk, equal to 1.2.
Although the relative risk of experiencing MI
attributed to sexual activity increases during sex and
within approximately 2 h afterward, the absolute risk
remains minuscule, on the order of 2 chances/million/h
for a 50-year-old man without an MI history and
20 chances/million/h for a 50-year-old man with
an MI history (as calculated in the Determinants of
Myocardial Infarction Onset Study,
54
based on data
from the Framingham Heart Study
58,59
). The absolute
MI risk is also reduced among men who can exercise
to more than 7 METs without symptoms on an exercise
stress test,
52,54
emphasizing the benet of regular exer-
cise in minimizing cardiovascular risk. In addition, an
early study evaluating the effects of exercise demon-
strated that the increase in VO
2max
resulting from
aerobic training was also associated with a decline in
peak HR during coitus.
50
Similar ndings regarding the low absolute risk of
MI in CAD patients, and the benets of regular physical
exercise in further reducing this risk, were reported
in the Stockholm Heart Epidemiology Programme.
60
In 699 MI individuals aged 4560 years, sedentary
patients had a higher relative risk (4.4) of MI during
sexual activity than those who were physically active
(0.7).
Possible mechanisms by which sexual activity might
trigger MI include rupture of vulnerable athero-
sclerotic plaque; coronary artery vasoconstriction in
the presence of endothelial dysfunction; and increased
myocardial O
2
demand in response to physical and
emotional stressors, which can potentially heighten
sympathetic activity. However, it is important not to
ascribe all MIs that occur after coitus to sexual activity
per se. The actual impact of sexual activity on CAD
morbidity, as measured by the risk of MI that is
directly attributed to sexual activity (0.9%) is, in fact,
lower than the risk of MI directly ascribed to physical
exertion (4.4%).
54,61
With regard to arrhythmia, either the appearance
or exacerbation of simple ectopic activity was the
prevailing pattern observed in 88 male outpatients
with stable CAD (mean age 52 years) who exhibited
rhythm disturbances during exercise testing (89%),
whereas such exacerbations occurred in a minority of
men with arrhythmia during sex (22%; P < 0.001).
Overall, sex-related rhythm disturbances were typical
of those seen with daily activities, and there were
no cases of life-threatening arrhythmias during sexual
activity.
55
Figure 11.11 Workload of sexual activity in healthy men
aged 33 years. HR, heart rate; METs, metabolic equivalents
of O
2
consumption. (Adapted with permission from
DeBusk RF. Evaluating the cardiovascular tolerance for
sex. Am J Cardiol 2000; 86:51F56F. Copyright 2000
Excerpta Medica.)
Figure 11.12 Workload of sexual activity in men aged 53
years with silent ischemia. HR, heart rate; METs, metabolic
equivalents of O
2
consumption. (Adapted with permission
from DeBusk RF. Evaluating the cardiovascular tolerance
for sex. Am J Cardiol 2000; 86:51F56F. Copyright 2000
Excerpta Medica.)
Heart rate (beats/min)
Peak treadmill HR
Peak coital HR
Functional reserve
T
r
e
a
d
m
i
l
l

c
a
p
a
c
i
t
y

(
M
E
T
s
)
0
60 75 90 105 120 135 150 165 180
16
4
8
12
14
Heart rate (beats/min)
Peak treadmill HR
Peak coital HR
Functional reserve
T
r
e
a
d
m
i
l
l

c
a
p
a
c
i
t
y

(
M
E
T
s
)
0
60 75 90 105 120 135 150 165 180
16
4
8
12
14
RISK STRATIFICATION AND
MANAGEMENT OF SEXUAL ACTIVITY IN
CARDIOVASCULAR PATIENTS
To address the issue of managing sexual dysfunction in
patients with cardiovascular disease, an international
consensus panel was convened, and this panel issued
the Princeton guidelines for risk stratication in sexually
active patients with cardiovascular disorders.
62
At the
initial clinical assessment, patients may be categorized
according to three graded classications: low, inter-
mediate, or high cardiac risk (Table 11.2). The majority
of patients are considered low-risk, including men with
controlled hypertension; mild, stable angina; successful
coronary revascularization; a history of uncomplicated
MI; mild valvular disease; no ischemic symptoms; or
fewer than three risk factors. These men may be safely
encouraged to resume sexual activity and receive treat-
ment for ED.
Intermediate-risk patients may have moderate angina;
recent MI (>2- but <6-week history); left ventricular
(LV) dysfunction or New York Heart Association
(NYHA) class II congestive heart failure (CHF); non-
sustained low-risk arrhythmias; or three or more risk
factors. These men require additional cardiac evalu-
ations such as exercise tolerance testing, after which
they can usually be restratied as either low- or high-
risk. High-risk patients have unstable or refractory
angina; uncontrolled hypertension; NYHA class III
or IV CHF; very recent (<2-week) MI history; high-
risk arrhythmias; obstructive cardiomyopathies; or
moderate-to-severe valvular disease. Such patients
should be stabilized, and their cardiac conditions
treated, before being advised to resume sexual activity
or receive treatment for ED (Fig. 11.13).
In summary, sexual activity, which is in general
considered to be a weak precipitant of coronary events,
imposes a moderate metabolic stress on the heart.
Although the relative risk of MI during, or within 2 h
after sexual intercourse may be slightly increased,
the absolute risk of MI induced by sexual activity is
very low.
TABLE 11.2 Graded cardiovascular risk assessment and management recommendations of the
Princeton Consensus Panel.
Grade of risk Categories of cardiovascular disease Management recommendations
Low-risk Asymptomatic, <3 major risk factors for CAD, Primary-care management
excluding gender Consider all rst-line therapies
Controlled hypertension Reassess at regular (612-month)
Mild, stable angina intervals
Post-successful coronary revascularization
Uncomplicated past MI (>68 weeks)
Mild valvular disease
LVD/CHF (NYHA class I)
Intermediate-risk 3 major risk factors for CAD, excluding gender Specialized cardiovascular testing
Moderate, stable angina (e.g., ETT, Echo)
Recent MI (>2, <6 wk) Restratication into high- or low-risk
LVD/CHF NYHA class II based on results of cardiovascular
Non-cardiac sequelae of atherosclerotic disease assessment
(e.g., peripheral vascular disease, CVA)
High-risk Unstable or refractory angina Priority referral for specialized
Uncontrolled hypertension cardiovascular management
LVD/CHF (NYHA class III or IV) Defer treatment for sexual
Recent MI (<2 weeks), CVA dysfunction until cardiac condition
High-risk arrhythmias stabilized, based on specialist
Hypertrophic obstructive and other recommendations
cardiomyopathies
Moderate/severe valvular disease
CAD, coronary artery disease; MI, myocardial infarction; LVD, left ventricular dysfunction; CHF, congestive heart failure;
NYHA, New York Heart Association; ETT, exercise tolerance test; Echo, echocardiogram; CVA, cerebrovascular accident.
Adapted with permission from DeBusk RF, Drory Y, Goldstein I et al. (2000) Management of sexual dysfunction in patients with
cardiovascular disease: recommendations of the Princeton Consensus Panel, Am J Cardiol 2000; 86:17581. Copyright
2000 Excerpta Medica.
Risk Stratication and Management of Sexual Activity in Cardiovascular Patients 169
In addition, men who engage in regular exercise can
further decrease the cardiovascular risks of sexual
activity.
50,54,60
Although the energy requirements of
sexual activity are generally not dissimilar to those of
moderate exercise, wide potential interindividual
variation in the hemodynamic effects of sexual activity
warrants an individualized workup in each case. By
adhering to the Princeton guidelines,
62
clinicians can
appropriately risk-stratify and soundly reassure cardio-
vascular patients about resuming sexual activity.
CARDIOVASCULAR SAFETY OF
PHOSPHODIESTERASE TYPE 5
INHIBITORS
Because PDE5 exists in the systemic vasculature as
well as the penile vasculature and corpus cavernosum,
sildenal citrate was actually rst investigated as an
antianginal agent with potential cardiac-unloading
properties. In healthy volunteers, sildenal exerts
modest systemic hypotensive effects (approximately
10/7 mmHg
63
) that are similar to those of organic
nitrates. Apart from a potentially synergistic effect
when administered with nitrates, NO donors (an abso-
lute contraindication to sildenal use) or -blockers,
PDE5 inhibitors exert minimal hemodynamic effects
in healthy persons and most patients with stable CAD.
In fact, emerging evidence suggests that sildenal
may actually confer salutary hemodynamic effects in
certain patients.
However, given the lack of denitive data, as well as
sildenals potential vasodilator effects and theoretical
potential to increase sympathetic drive, as suggested
in one study
64
(although in most clinical studies, it
does not increase HR), this drug should be prescribed
with caution to patients with a recent (6-month) MI
history, unstable angina, stroke, recent life-threatening
arrhythmia, or severe CHF or low-volume states.
65
The aforementioned Princeton guidelines should be
followed when evaluating sexually active patients with
cardiovascular diseases who are candidates for PDE5
inhibitors or other ED therapies.
62
OVERVIEW OF
PHOSPHODIESTERASES
Widely distributed, protean enzymes with enormous
functional diversity and potentially relevant cardio-
vascular effects (e.g., through effects on platelet
aggregation and inducible expression by proliferating
vascular SMC
66
), PDEs represent potentially viable
pharmacotherapeutic targets for a number of disorders.
Whereas PDE5 is expressed preferentially in the corpus
cavernosum, it is also distributed in smaller amounts
throughout the systemic vasculature (but not cardiac
myocytes
67
). Sildenal has an approximately 4000-fold
afnity for PDE5 compared with PDE3, which is
involved in regulating cardiac contractility.
68
Other
investigational PDE5 inhibitors (e.g., tadalal,
vardenal) also exhibit high selectivity for PDE5 over
PDE16, by 10 to more than 1000 times.
Figure 11.13 Simple algorithm:
sexual activity and cardiac risk.
Tx, therapy. (Reprinted from
DeBusk RF, Drory Y, Goldstein I
et al. Management of sexual
dysfunction in patients with
cardiovascular disease:
recommendations of the
Princeton Consensus Panel,
Am J Cardiol 2000; 86:17581.
Copyright 2000 Excerpta
Medica.)
Sexual
inquiry
Clinical
evaluation
Indeterminate
risk
High
risk
Cardiovascular
assessment and
restratification
Low
risk
Initiate or
resume sexual
activity
or
Tx for sexual
dysfunction
Sexual activity
deferred until
stabilization of
cardiac
condition
In brief, oral sildenal therapy is safe and well
tolerated in a broad spectrum of patients with mild-to-
severe ED of diverse origins. Such treatment is highly
acceptable to many patients and their partners, because
it is typically painless, reversible, convenient, and con-
sistent with a natural sexual encounter. In a 12-week,
double-blind, placebo-controlled study
69
involving
514 men (mean age 56 years) with ED, including 32%
with organic etiologies (e.g., cardiovascular disease)
but neither a recent (6 month) history of stroke/MI
nor concomitant nitrate therapy, 24%, 67%, 78%, and
86% of men receiving placebo or oral sildenal 25, 50,
or 100 mg, respectively, reported that the previous
4 weeks of treatment improved erections (P < 0.0001
for overall treatment effect).
The PDE5 inhibitor tadalal, which has a prolonged
plasma residence and can be taken without restrictions
on food intake, may reduce the need for planning sexual
activity around dosing. In integrated analyses of ve
randomized, double-blind, placebo-controlled studies
(of minimum 12 weeks duration) involving 1112 men
(mean age 59 years) with ED ascribed to multiple
etiologies (with similar cardiovascular exclusions to
the sildenal study by Montorsi et al.
69
), 35%, 67%,
and 81% of men randomized to placebo or oral
tadalal, taken as-needed at maximum daily doses of
10 or 20 mg, respectively, reported that treatment
improved erections (P < 0.001 for each comparison
versus placebo).
70
Finally, in a 12-week, double-blind, placebo-controlled
trial involving as-needed oral vardenal therapy in
601 men with ED of mixed etiologies, 30%, 76%,
and 80% of men randomized to placebo or vardenal
10 mg or 20 mg, respectively reported that therapy
enhanced erections (P < 0.001 for each comparison
versus placebo).
71
Side-effects with PDE5 inhibitors
include headache, flushing, and dyspepsia, as well as
back pain, rhinitis (nasal congestion), nausea, and visual
disturbances (e.g., color-tinged vision) in a minority of
patients.
HEMODYNAMIC EFFECTS OF
INHIBITORS
In most patients, including men with CAD who are not
taking nitrates, administration of PDE5 inhibitors does
not result in deleterious hemodynamic effects. Overall,
the incidences of MI in a pooled analysis of 30 double-
blind, placebo-controlled studies and 23 open-label
trials with sildenal were 1.11/100 person-years for
placebo and 0.80/100 person-years for sildenal; cor-
responding data for incidences of death were 0.74/100
person-years (placebo) and 0.42/100 person-years
(sildenal).
72
Healthy men
In healthy subjects not taking nitrates, other anti-
anginal medications, or -blockers, sildenal elicits
marginal, transient hemodynamic effects that are
similar to those of a mixed vasodilator (e.g., nitrate)
(Fig. 11.14). After intravenous administration of
sildenal (20, 40, 80 mg) to healthy men, signicant
decreases were observed in supine SBP and diastolic
blood pressure (DBP) at peak plasma levels of the
drug: 7.0/6.9 mmHg and 9.2/6.7 mmHg for
sildenal 40 and 80 mg, respectively.
73
These reductions
were transient, with BP returning to normal after 5 h,
and not dose-related.
Intravenous sildenal also elicited modest non-
dose-related declines in systemic vascular resistance
(maximum 16%) and exerted no signicant effect
on HR compared with placebo for up to 12 h after
infusion. Brachial artery infusion of sildenal at up
to 300 g/min resulted in modest vasodilation of
resistance arteries, with an increase in venous com-
pliance and forearm volume (2326%) following pre-
constriction with norepinephrine (noradrenaline).
73
Similarly, therapeutic or supratherapeutic single oral
doses of sildenal (100, 150, 200 mg) produced no
signicant changes in cardiac index over 12 h versus
placebo (Fig. 11.14). The overall hemodynamic effects
of sildenal were similar to, but less pronounced than,
those of nitrates.
Coronary artery disease
In 14 patients with CAD who were not taking nitrates
and were candidates for percutaneous revascularization
to correct severe (>70% luminal) stenosis of at least
one coronary artery, oral sildenal 100 mg exerted
no signicant effect on pulmonary capillary wedge
pressure, right atrial pressure, HR, or cardiac output
(CO).
74
Small, but statistically signicant, decreases
from baseline in aortic BP, SBP, DBP, and MAP of
approximately 56% (P = 0.01); 89% declines from
baseline in systolic and mean pulmonary arterial
pressure (PAP) (P = 0.03); and an approximate 8%
decline in RPP (P = 0.02) were observed with sildenal.
The PDE5 inhibitor did not signicantly affect
coronary flow velocity or coronary artery diameter. In
addition, sildenal induced signicant increases in
coronary blood flow reserve (1213%) with intra-
coronary adenosine challenge in the stenosed and
reference arteries of 11 CAD patients (Fig. 11.15).
A randomized, double-blind, placebo-controlled
cross-over trial conducted at the Mayo Clinic supported
the fundamental cardiovascular safety of sildenal
during physical activity in men with ED and stable or
suspected CAD and a resting ejection fraction of
56%.
75
Among the 105 men (mean age 66 years), who
Hemodynamic Effects of Phosphodiesterase Type 5 Inhibitors 171
discontinued nitrates at least 72 h before supine bicycle
exercise tests and received sildenal (50 or 100 mg) or
placebo 1 h before such testing, sildenal reduced SBP
by 7 mmHg (5%) from baseline (P < 0.001), a decline
that was also signicantly more marked compared
with placebo.
However, sildenal exerted no signicant effects on
resting DBP (2 mmHg), resting HR, or any of the exer-
cise parameters, including exercise-limiting symptoms
(dyspnea, angina), exercise duration, exercise-induced
ischemia, wall-motion score index, or exercise-induced
increments in HR or BP (versus placebo).
75
Further-
more, in another study, sildenal 100 mg signicantly
prolonged the time to limiting angina and overall
exercise duration compared with placebo in men with
chronic stable angina.
76
Blood pressure was similar in
both the active-treatment and placebo-control groups
after exercise; RPP was lower postdrug in the sildenal
group at rest, during exercise, and throughout the
recovery period.
Figure 11.14 Hemodynamic
changes ( standard deviation)
after oral sildenal administration
in healthy men.
(A) Supine systolic blood
pressure changes from baseline;
(B) mean supine cardiac index.
(Adapted from Jackson G,
Benjamin N, Jackson N et al.
Effects of sildenal citrate on
human hemodynamics. Am J
Cardiol 1999; 83:13C20C.
Copyright 1999 Excerpta
Medica.)
Time postdose (h)
M
e
a
n

c
a
r
d
i
a
c

i
n
d
e
x

(
l
/
m
i
n

p
e
r

m
2
)
0
B
Baseline
6
1
2
3
4
5
1 3 6 9 12
Time postdose (h)
M
e
a
n

c
h
a
n
g
e

f
r
o
m

b
a
s
e
l
i
n
e

i
n
s
u
p
i
n
e

s
y
s
t
o
l
i
c

b
l
o
o
d

p
r
e
s
s
u
r
e

(
m
m
H
g
)
-20
A
15
Placebo
Sildenafil, 100 mg
Sildenafil, 150 mg
Sildenafil, 200 mg
-15
-10
-5
0
5
10
1 3 6 9 12
Further, in an open-label pilot study
73
involving
eight men with stable ischemic heart disease (mean
time since diagnosis of angina 1.7 years), administration
of sildenal 40 mg intravenously for 60 min led to
decrements from baseline in PAP of 27% at rest and
19% during exercise, with corresponding decreases in
CO of 7% and 11%. As shown in Table 11.3, hemo-
dynamic responses to exercise were not impaired after
sildenal administration.
73
Finally, incidences of head-
ache, flushing, and dyspepsia were similar in sildenal
patients with or without CAD at baseline (Table 11.4).
77
In summary, sildenal even at supratherapeutic doses
was well tolerated in cardiovascular patients who
were not taking nitrates.
63,73
Data from a canine model of coronary artery
stenosis lend further credence to the cardiovascular
safety of sildenal in the presence of ischemia.
78
In
a model of hibernating myocardium and unstable
angina, sildenal exerted no adverse effect on regional
myocardial blood flow and did not exacerbate myo-
cardial ischemia or compromise coronary perfusion
(during stable hypoperfusion). On the other hand, in a
setting of recurrent thrombosis, sildenal-treated dogs
proved refractory to the expected antiplatelet (anti-
aggregatory) effects of adenosine A
2
receptor stimu-
lation, with no improvement in coronary patency
compared with placebo. The clinical signicance of this
nding is unknown at this time.
TABLE 11.3 Effects of sildenal on hemodynamic parameters
a
at rest and during exercise in patients
with stable ischemic heart disease.
At rest After 4-min exercise test
Parameter Baseline Sildenal 40 mg IV Baseline Sildenal 40 mg IV
(n = 7) (n = 8) (n = 8) (n = 8)
PAOP (mmHg) 8.1 5.1 6.5 4.3 36.0 13.7 27.8 15.3
PAP (mmHg) 16.7 4.0 12.1 3.9 39.4 12.9 31.7 13.2
RAP (mmHg) 5.7 3.7 4.1 3.7 NR NR
Systolic SAP (mmHg) 150 12 141 16 200 37 188 30
Diastolic SAP (mmHg) 74 8 66 10 85 10 80 9
Cardiac output (l/min) 5.6 0.9 5.2 1.1 11.5 2.4 10.2 3.5
Heart rate (beats/min) 67 11 67 12 102 12 99 20
IV, intravenously; PAOP, pulmonary arterial occluded pressure; PAP, pulmonary arterial pressure; RAP, right atrial pressure;
NR = not recorded; SAP, systemic arterial pressure.
a
Values represent mean standard deviation.
Reprinted with permission from Jackson G, Benjamin N, Jackson N et al. Effects of sildenal citrate on human
hemodynamics. Am J Cardiol 1999; 83:13C20C. Copyright 1999 Excerpta Medica.
Figure 11.15 Individual and mean ( standard deviation)
values for coronary flow reserve dened as the ratio of
hyperemic average peak velocity (after intracoronary
adenosine) to the average peak velocity before adenosine
in 25 coronary arteries before (baseline) and after sildenal
administration. Filled circles, severely diseased arteries;
open circles, reference vessels. (Adapted with permission
from Herrmann HC, Chang G, Klugherz BD, Mahoney PD.
Hemodynamic effects of sildenal in men with severe
coronary artery disease. N Engl J Med 2000;
342:16221626. Copyright 2000 Massachusetts Medical
Society. All rights reserved.)
C
o
r
o
n
a
r
y

f
l
o
w

r
e
s
e
r
v
e
0
At baseline
P = 0.003
After sildenafil
4
1
2
3
Hemodynamic Effects of Phosphodiesterase Type 5 Inhibitors 173
Hypertension
Analyses of sildenal administration in men with
hypertension also support the PDE5 inhibitors cardio-
vascular safety. In 10 double-blind, placebo-controlled,
randomized studies involving 3414 men with ED,
1218 (36%) of whom were taking sildenal 5200 mg
together with antihypertensive drugs, the mean inci-
dence of treatment-related adverse cardiovascular
events (hypotension, dizziness, syncope) was 34%,
which was similar to the incidence in men taking
sildenal without antihypertensive agents (38%).
79
In addition, syncope and hypotension were seen
infrequently (if at all) in patients taking sildenal and
antihypertensive agents, and the overall number of
antihypertensive agents taken (from among ve
classes) had no effect on the adverse-event prole of
sildenal (Table 11.5).
In a post-hoc subanalysis of ve prospective,
randomized, double-blind, placebo-controlled studies,
among 667 (40%) of 1685 patients receiving sildenal
or placebo in addition to antihypertensive agents,
differences between the effects on SBP, DBP, and
HR were similar in the sildenalplacebo group versus
the sildenalantihypertensive subpopulation.
80
For
instance, a decrease in SBP/DBP of 3.6/1.9 mmHg
was observed in the sildenalantihypertensive arm
compared with a decrease of 2.2/2.0 mmHg in the
sildenalplacebo arm. The change in HR was
0.6 beat/min for sildenal plus antihypertensives
as compared with +0.4 beat/min for sildenal alone.
Oral sildenal 100 mg exhibited no synergistic inter-
action but likely a small, additive interaction when
administered with the dihydropyridine calcium
antagonist amlodipine (5 or 10 mg) in patients with
hypertension in a double-blind, two-way cross-over
study.
81
Mean maximal changes from baseline in stand-
ing SBP/DBP and HR for sildenalamlodipine were
19.8/11.1 mmHg and +3.7 beats/min, respectively,
versus 9.9/3.5 mmHg and 3.8 beats/min, respec-
tively, for placeboamlodipine. Declines in BP were
not dissimilar to those seen when sildenal was
administered alone to healthy men or when a second
antihypertensive agent was administered with
amlodipine.
The investigational PDE5 inhibitor tadalal has also
shown either no effect on, or minor, non-synergistic
augmentation of, the BP-lowering effects of diverse
antihypertensive agents when concurrently administered
in controlled phase I interaction studies,
82
including
angiotensin-converting enzyme (ACE) inhibitors,
ARBs, -blockers, and thiazide diuretics. In addition,
tadalal did not increase either the frequency or
severity of cardiovascular adverse events in patients
TABLE 11.4 Adverse events in patients with or without ischemic heart disease who received placebo or
sildenal in 11 studies.
No of Patients (%)
Placebo Sildenal
Adverse event
a
With IHD Without IHD With IHD Without IHD
(n = 120) (n = 1212) (n = 237) (n = 2103)
Headache 2 (2) 67 (6) 60 (25) 434 (21)
Flushing 0 18 (2) 33 (14) 306 (15)
Dyspepsia 2 (2) 21 (2) 28 (12) 204 (10)
Abnormal vision
b
2 (2) 4 (<1) 20 (8) 153 (7)
Respiratory tract infection 5 (4) 65 (5) 19 (8) 158 (8)
Rhinitis 0 23 (2) 12 (5) 118 (6)
All cardiovascular (excluding flushing) 10 (8) 43 (4) 13 (5) 66 (3)
Myocardial infarction 3 (3) 0 8 (3) 1 (<1)
IHD, ischemic heart disease.
a
Adverse events of all causes occurring in 5% of patients in any treatment group.
b
Predominantly changes in color, hue, or brightness perception.
Reprinted with permission from Conti CR, Pepine CJ, Sweeney M. Efcacy and safety of sildenal citrate in the treatment of
erectile dysfunction in patients with ischemic heart disease. Am J Cardiol 1999; 83:29C34C. Copyright 1999 Excerpta
Medica.
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Phosphodiesterase Type 5 Inhibitornitrate Interactions 175
randomized to concomitant treatment with the PDE5
inhibitor together with these antihypertensive agents.
Arrhythmia
There is no convincing evidence from randomized,
double-blind, placebo-controlled clinical trials moni-
toring cardiovascular adverse events that therapy with
sildenal, tadalal, or vardenal is arrhythmogenic.
71,8386
INHIBITORNITRATE INTERACTIONS
Both clinical and in vivo evidence demonstrates that
sildenal can potentiate the hypotensive effects of
nitrates and NO donors. Sildenal causes a slight
decrease in systemic arterial pressure (8.0 mmHg
systolic and 5.5 mmHg diastolic) in most men, but
synergistic, profound decreases in systemic arterial
pressure have been reported in patients taking
sildenal with nitrates or NO donors.
87
In a double-blind, placebo-controlled cross-over
study that evaluated the effects of oral sildenal 50 mg
on BP in men with a history of stable angina taking the
NO donor isosorbide mononitrate (ISMN) or glyceryl
trinitrate (GTN) for stable angina,
88
sildenalISMN
reduced standing mean maximum SBP/DBP from
baseline by 52/29 mmHg versus a 25/15 mmHg
decline for placeboISMN (P < 0.001). Corresponding
decreases were 36/21 mmHg for sildenalGTN
versus 26/11 mmHg for placeboGTN (P < 0.01).
In an animal model, sildenal caused vasodilation in
normal coronary arteries, but the combined effect of
sildenal and isosorbide dinitrate resulted in large
and protracted declines in mean SBP (46.2%) and
coronary blood flow in coronary arteries with critical
stenoses.
89
Cases of MI in patients taking sildenal and nitrates
have been reported.
90,91
Such reports and other
evidence prompted the publication of a joint con-
sensus statement by the American Heart Association
and the American College of Cardiology
65
(Table 11.6)
as well as a statement in the manufacturers labeling
92
that sildenal is clearly contraindicated in patients
taking short- or long-acting nitrates.
It is important to note, however, that, in a sub-
sequent prescription event monitoring study involving
5601 patients ranging in age from 18 to 90 (mean 57.4)
years, there was no evidence of a higher incidence of
fatal MI or ischemic heart disease among men taking
sildenal as compared with the general population.
93
Other postmarketing studies have also suggested that
the incidences of MI and death among patients in
sildenal clinical trials were within the expected ranges
for age.
83
In fact, the incidence of serious cardiovascular
adverse events was comparable for patients who
TABLE 11.6 Summary of clinical recommendations.
Administration of sildenal clearly contraindicated Concurrent nitrate therapy
Nitroglycerin
Isosorbide mononitrate
Isosorbide dinitrate
Pentaerythritol tetranitrate
Erythrityl tetranitrate
Isosorbide dinitrate/phenobarbital
Illicit drugs containing organic nitrates
Cardiovascular effects of sildenal may be Active coronary ischemia (not taking nitrates)
hazardous; prescribe based on individual CHF and borderline low blood pressure and
assessment borderline low volume status
Complicated, multidrug antihypertension regimen
Concurrent drugs that may prolong half-life of sildenal
Antibiotic/antifungal
Cardiovascular
HMG-CoA reductase inhibitors
Central nervous system
Other
CHF, congestive heart failure; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A.
Adapted with permission from Cheitlin MD, Hutter AM Jr, Brindis RG et al. ACC/AHA expert consensus document. Use of
sildenal (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association.
J Am Coll Cardiol 1999; 33:273282. Copyright 1999 American College of Cardiology and American Heart Association Inc.
Permission granted for one-time use. Further reproduction is not permitted without permission of the ACC/AHA.
received sildenal in placebo-controlled trials (or
open-label studies) and those who received placebo
94
(Table 11.7).
According to preliminary evidence, the combination
of the investigational PDE5 inhibitor tadalal with
nitroglycerin led to higher frequencies of BP
outliers;
95
in a subset of patients, tadalal augmented
the BP-lowering effects of nitrates. In clinical studies,
the incidence of MI in tadalal-treated patients was
0.39/100 person-years as compared with 1.1/100
person-years in placebo-treated patients.
86
Partly because of the prospect of life-threatening
PDE5 inhibitornitrate interactions, the importance of
taking a thorough medical history and performing
both a focused physical examination and selected
laboratory tests (e.g., lipids, glucose) before prescribing
PDE5 inhibitor (or any other) therapy for ED cannot
be overstated.
96
Such a workup can also help identify
possible underlying cardiovascular diseases or diabetes
associated with ED, while use of the Princeton guide-
lines for risk stratication can help to reassure both the
patient and clinician about the advisability of resuming
sexual activity.
62
Emergent presentation with angina related to
sexual exertion should prompt suspicion concerning
coadministration of sildenal and nitrates. In addition,
the health-care provider should remember to address,
and urge caution concerning, occult nitrate use,
including recreational nitrates such as amyl nitrate
(poppers) and nitrate sprays. Patient counseling
should also cover the matter of recommended bed-
room preparations, such as warming the room and
bedsheets to a comfortable temperature and banishing
any previously prescribed nitrates so that the patient is
not tempted to use them in the event of angina during
sexual activity after taking sildenal.
POTENTIAL FUTURE INDICATIONS
FOR PHOSPHODIESTERASE TYPE 5
INHIBITORS IN CARDIOVASCULAR
DISEASE
Preliminary evidence suggests that PDEs, enormously
heterogeneous enzymes with wide organ-tissue distri-
butions that mediate diverse physiologic functions,
are possible pharmacotherapeutic targets for clinical
indications apart from ED. Numerous PDE isozymes
belonging to seven families based on genetic and
functional characteristics have been identied in
mammals,
97
and elucidation of their physiologic roles
may culminate in the development of other therapeutic
uses for PDE inhibitors.
Potentially relevant to the management of cardio-
vascular diseases, PDEs are widely distributed through-
out the systemic vasculature. For instance, PDE1C
may represent an inducible PDE in atherosclerosis
because it is expressed by proliferating, but not
quiescent, vascular SMC.
66
Selective inhibitors of PDE3
may play roles as antithrombotic or cardiac inotropic
agents.
98
Experimental data also suggest a putative
role for PDE5 inhibitors in enhancing BP regulation
through effects on vascular architecture, endothelial
function, and large-artery compliance, among other
mechanisms.
21,22,99,100
In addition, lung tissue is richly endowed with
PDE5,
98
and preliminary clinical evidence suggests
that PDE5 inhibitors may be useful in the treatment of
pulmonary hypertension, which is suboptimally treated
TABLE 11.7 Incidence of serious cardiovascular events/myocardial infarction in patients receiving
sildenal or placebo in phase II and III studies.
Incidence (95% CI)
a
Sildenal Placebo
Phase II/III placebo-controlled studies
Serious cardiovascular events
b
4.1 (2.75.5) 5.7 (3.38.2)
Myocardial infarction 1.7 (0.82.6) 1.4 (0.22.6)
Phase II/III open-label extension studies
Serious cardiovascular events
b
3.5 (2.34.7)
Myocardial infarction 1.0 (0.31.6)
a
Incidence expressed as rate per 100 person-years of treatment. CI, condence interval.
b
Serious cardiovascular events include myocardial infarction, angina, and coronary artery disease.
(Reprinted with permission from Morales A, Gingell C, Collins M et al. Clinical safety of oral sildenal citrate (Viagra) in the
treatment of erectile dysfunction. Int J Impot Res 1998; 10:6973. Copyright 1998 Nature Publishing Group.)
Potential Future Indications for Phosphodiesterase Type 5 Inhibitors in Cardiovascular Disease 177
at present and has a generally dismal prognosis. In
a randomized controlled trial, sildenal attenuated
hypoxia-induced rises in PAP without signicant effects
on systemic BP in humans.
101
Further, a case report described a 21-year-old man
with pulmonary hypertension who was successfully
treated with sildenal at a dose of up to 100 mg ve
times a day.
102
After 3 months of such treatment, PAP
declined from 120 mmHg at presentation to 90 mmHg.
In addition, a small clinical trial demonstrated that
coadministration of sildenal with the prostacyclin
analog iloprost lowered mean PAP signicantly more
than iloprost alone: by 13.8 1.4 compared with 9.4
1.3 mmHg (P < 0.009).
103
Another therapeutic area in which PDE5 inhibitors
have potential value is CHF, the pathophysiology of
which may involve impaired endothelium-dependent,
NO-mediated vasodilation through downregulation of
the NOSNOsGCcyclic nucleotide signaling path-
way. In 48 patients with NYHA class II or III CHF,
single oral doses of sildenal 25 or 50 mg signicantly
elevated brachial-artery flow-mediated vasodilation
versus placebo.
104
CONCLUSIONS
Given the recent elucidation of the molecular mech-
anisms underlying physiologic erection and ED, which
involves the same NOSNOsGCcyclic-nucleotide
signal-transduction mechanism that influences both
systemic and penile vascular smooth-muscle relaxation,
it is not surprising that this condition has patho-
physiologic, clinical, and epidemiologic links with
cardiovascular disease. A largely vasculogenic disorder
in many patients, ED shares risk factors with CAD and
stroke, including hypertension, dyslipidemia, diabetes,
and smoking. Emerging evidence suggests that endo-
thelial dysfunction may underlie both ED and cardio-
vascular diseases.
Abundant ndings from studies concerning the
physiologic costs to the heart of sexual activities,
which are not dissimilar to those of daily activities,
support the essential safety of sex in men who do not
have serious cardiovascular conditions, such as very
recent MI or class III or IV CHF. Coitus is, in general,
a quite weak precipitant of coronary events.
Although the relative risks of coronary events and/or
death are transiently elevated after coitus, the absolute
risk during or shortly after any sexual encounter is
low. In addition, this exceedingly low absolute risk may
be further reduced through lifestyle changes, including
aerobic exercise appropriate to the patients overall
cardiac status. The Princeton guidelines are useful
when counseling cardiovascular patients who wish to
engage in, or resume, sexual activity and/or receive
treatment for ED.
On the other hand, concomitant administration of
sildenal and nitrates or NO donors is contraindicated
because sildenal can potentiate the hypotensive
effects of these agents. With adequate, individualized
diagnostic workup, including a medical history, focused
physical examination, and selected laboratory tests,
the vast majority of ED patients, including those with
stable CAD not managed with nitrates, are suitable
candidates for sildenal treatment of ED.
Large clinical trials involving sildenal, as well as the
PDE5 inhibitor tadalal, have demonstrated that these
agents do not signicantly elevate the incidence of MI
or other adverse cardiovascular events (e.g., syncope,
dizziness) as compared with placebo controls or men
on a number of agents with hypotensive effects (aside
from nitrates). Indeed, preliminary evidence suggests
that sildenal might have therapeutic utility in the
management of other cardiovascular conditions,
including pulmonary hypertension, systolic hyper-
tension, and CHF.
ACKNOWLEDGMENTS
Editorial assistance was provided by Stephen W.
Gutkin, Rete Biomedical Communications Corp.,
Ridgewood, New Jersey, USA.
ADDENDUM
Since this chapter was written it is recommended that
sildenal >25 mg not be given within 4 h of -blocker
administration, as some patients exhibit orthostatic
hypotension. The PDE5 inhibitor vardenal is contra-
indicated with -blocker use, and the PDE5 inhibitor
tadalal is contraindicated with -blockers other than
tamsulosin 0.4 mg.
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References 181
INTRODUCTION
Erectile dysfunction (ED), a condition dened by the
inability to attain or maintain penile erection sufcient
for intercourse, is a common and undertreated disorder.
1
It is estimated that the worldwide prevalence for 2025
will be 322 million affected men.
2
Major risk factors
for ED include advancing age, the presence of chronic
illness such as heart disease, hypertension, diabetes
mellitus or depression, smoking, stress, alcohol and
drug abuse, and sedentary lifestyle.
3
The main causes
of ED are organic (vascular, neurogenic, hormonal,
anatomical/structural, drug-induced), psychogenic, or
mixed, the mixed form being the most common.
4
Causes can be acquired or congenital; psychogenic
causes can be either generalized or situational. Aging
constitutes an independent risk factor for ED.
5
According to a stepped-care approach, therapeutic
options for the ED patient range from lifestyle changes
and counseling to surgical procedures.
6
Due to recent
progress in pharmacotherapy, the therapeutic spectrum
has been signicantly broadened after the introduction
of safe and effective treatment with phosphodiesterase
type 5 (PDE5) inhibitors. However, despite the overall
success and efcacy of existing therapies, side-effects,
complications, and contraindications can limit their use.
The on-demand nature of medical treatments prior
to sexual activity is another limiting factor. In addition,
the fact that treatments are not successful in a signi-
cant subset of patients with moderate to severe ED
implies the need for further therapeutic improvement.
The development of future therapeutic options
should therefore, ideally, result in a treatment which
restores physiologic erectile function, while having
no adverse effects or contraindications, even in patients
with severe ED.
Gene therapy as a therapeutic approach has
traditionally been regarded as a treatment for life-
threatening disease, like cancer or hereditary diseases.
Although ED, being a non-life-threatening condition,
is a relatively novel area of gene therapy research, rst
reports documenting proof of concept have been
published in the late 1990s.
7,8
The purpose of this
review is to provide an overview about the most recent
gene therapy strategies in ED (Fig. 12.1).
BASIC CONCEPTS OF GENE
THERAPY
The concept of gene therapy, or the insertion of genetic
material into cells to force the expression of a specic
protein, has been of interest to scientists for over
30 years.This concept, which was previously considered
to bection-based, was brought to the attention of
the scientic community by Friedmann and Roblin in
1972, who convincingly debated the potential merit of
replacing mutated genes with corrected sequences.
9
Continuous technical advancements have brought
this eld to the cusp of being an effective treatment
paradigm for many different diseases. Even in the light
of limited clinical success thus far, the concept of gene
therapy as an approach to treat disease has led to the
innovation of powerful new technologies concerning
the manipulation of DNA. These approaches include a
variety of different methods of DNA transfer, including
both non-viral and viral-based protocols. With such
an explosion of new technology, it is not difcult to
imagine that the time when gene therapy is commonly
used for a broad spectrum of diseases and other
medical conditions may not be far off.
Effective gene therapy involves delivering genes into
the nucleus in a manner in which they are effectively
expressed. Several barriers, both extracellular and intra-
cellular, have been identied that must be overcome
for the successful delivery of the gene of interest.
10
Extracellular barriers include opsonins, phagocytes,
extracellular matrices, and degradative enzymes.
Opsonins and phagocytes can inactivate a gene and/or
its system, resulting in degradation. Large DNA carrier
systems can be inhibited from making into the cell due
to the physical barrier posed by the extracellular
matrix. Furthermore, naked DNA is rapidly digested
by DNases that are present in the extracellular fluid.
Once a gene and its delivery system successfully pass
the plasma membrane and enter the cell, a new series
Gene Therapy for Erectile Dysfunction
Aristotelis G. Anastasiadis, Debra L. Bemis, J. C. Trussell, Brian C. Stisser, and
Ridwan Shabsigh
CHAPTER 12
of threats are encountered. These include cytosomal
nucleases and endosomal entrapment.
11
Additionally, the gene must be able to enter the
nucleus and become transcribed and translated. Of
course, this is not the nal step. The new protein(s)
must be transported to the appropriate cellular location
and be able to perform the intended function(s). Even
if the gene delivery system can successfully get past all
of these barriers, it must do so without eliciting an
immunogenic response and be able to be produced in
large quantities. As stated previously, although many
technological advances have been made, a flawless
system for gene delivery has yet to be discovered.
Viral gene transfer
The use of viruses as gene delivery systems has been
a favorite approach for many investigators due to the
specialized properties that viruses have developed
for cell binding, entry, and genomic integration.
Technologies based on viral gene transfer include the
use of the adenoviral, adeno-associated, retroviral
(including lentiviral), and herpes simplex type 1 viral
vectors. None of these have yet proven to be perfect.
For the purpose of this chapter, we will focus on
adenoviral vector systems, since most work with gene
therapy for ED treatment has utilized this technology.
Adenoviruses are non-enveloped viruses made up of
double-stranded DNA within an icosahedral protein
capsid.
12
The protein capsid is comprised of the hexon,
the penton base, and ber monomers. An abundance
of research has focused on adenoviral vectors for gene
therapy due to their many favorable characteristics.
These include the ability to transfer genes into both
dividing and quiescent cells, the relative ease in
producing adenoviral vectors in high titers, the non-
oncogenic properties of adenovirus, and the inability
of this viral DNA to be integrated into the host
genome.
12
The rst-generation adenoviral vectors were
engineered to retain all the essential genes except E1A
and E1B, which are required to activate most other
viral genes. In second-generation adenoviral vectors,
the DNA-binding protein and viral DNA polymerase
encoded by E2 or the E4 gene, which also has
oncogenic potential, were eliminated. The third and
most current generation of adenoviral vectors are
completely gutted and the genes are replaced with
those of helper viruses. Several varieties of these
vectors are under study by many groups.
13,14
As with all gene delivery systems created thus far,
adenoviral vectors also have disadvantages associated
with them. Of primary concern is the toxicity of
adenoviral vectors.A signicant barrier for the effective
use of adenovirus-mediated gene therapy is the
sequestration of adenovirus by the liver. Research has
demonstrated that levels as high as 90% of adenoviral
DNA are eliminated by the liver within 24 h of dosing
prior to expression of the transgene.
15
Therefore, a
high dose of adenovirus is required in order to achieve
effective concentrations of adenovirus for many tissues,
which results in an unfavorable therapeutic index. This
was the case in 1999 when an 18-year-old patient being
treated at the University of Pennsylvania tragically
died from an immunogenic reaction following a high
dose of recombinant adenovirus carrying the ornithine
transcarbamylase (OTC) gene administered via the
hepatic artery. One of the main goals of the newer-
generation vectors was therefore to eliminate any
potential for toxicity. However, conflicting reports on
184 Gene Therapy for Erectile Dysfunction
Figure 12.1 Gene therapy
strategies for erectile dysfunction.
Viral gene transfer
Nitric oxide synthase (NOS)
Calcitonin gene-related peptide (CGRP)
Brain-derived neurotrophic factor (BDNF)
Naked DNA/protein transfer
Vascular endothelial growth
factor (VEGF)
Calcium-sensitive K-channels
Nucleus
Cell-based gene transfer
Microvessel endothelial cells (MVEC)
the immunogenicity of the third-generation gutted
vectors exist in the literature, and their safety for use
in humans has yet to be fully dened.
16
At this time,
these newer vectors are also difcult to produce in
both high-titer batches and batches that are free of
contamination by the live helper virus.
16
In order for
adenoviral gene delivery to be a suitable strategy for
prolonged gene therapy regimens involving repetitive
infections, vectors that successfully avoid triggering
an immune response in the host will have to be
developed.
In general, adenoviral vectors have a relatively low
efciency of gene delivery. Adenoviral gene delivery
depends on the initial interaction of the vector (Ad2
and Ad5 of subgroup C, the commonly used vectors
for gene therapy) with the target cell via the coxsackie-
virus and adenovirus receptor (CAR).
17
Once bound
to the CAR, the vector enters the cell via receptor-
mediated endocytosis. However, gene delivery systems
relying on target cell CAR expression have been
shown to lack specicity due to the native tropism of
adenovirus, and to be relatively ineffective in tissues
with low CAR expression, including smooth muscle.
18
The CAR-based adenoviral systems generated to date
are not optimized for gene therapy protocols in the
treatment of ED. CAR-independent adenoviral vectors
that are able to deliver genes more specically and
efciently to target cells are currently being developed.
12
These strategies consider altering the virion to inhibit
CAR binding and target vector binding to other cellular
receptors. Such modications of the adenoviral gene
delivery system could lead to clinical uses in many
areas of medicine, including urology.
Non-viral gene transfer
Due to the potential risks associated with viral vectors,
many researchers have focused on the development of
effective, non-viral-based delivery systems.
19
Methods
of non-viral gene delivery are engineered to take
advantage of normal uptake mechanisms of cell and
the intracellular transport of macromolecules to the
nucleus.
20
These technologies include naked DNA,
liposomal, protein/peptide, and chemical and physical
gene transfer systems. For the purpose of this chapter,
we will focus on naked DNA gene transfer, since this
technology has been considered for use in the treat-
ment of ED. Plasmid DNA generally does not invoke
an immune response, and therefore is thought to have
less potential for toxicity than viral vectors. Also,
plasmid DNA does not inappropriately integrate into
the host DNA, which is a signicant risk associated
with viral vectors that can lead to damage of healthy
cells and tissues.
21
Plasmid DNA can also be con-
structed with relative ease and produced in large
amounts. However, naked DNA is only able to enter a
limited number of cell types, such as skin, thyroid
gland, liver cells, and myocardial cells.
2225
Since both
DNA and cellular membranes have net negative
charges, DNA is repelled from most membranes.
26
Plasmid DNA also has a very low efciency rate, typi-
cally less than 1% of the target cells, and expression of
the desired protein is characterized as transient.
27
However, enhanced protein expression can be
obtained by combining other technologies with naked
DNA. One such technology is the use of a vector such
as a liposome. Liposomes are aqueous lled spheres
formed by a lipid membrane that help to stabilize the
DNA and enhance cellular entry by fusing with the
membrane. While in vitro expression levels have been
shown to be elevated with the use of liposomes, the
same has yet to be repeated in vivo, demonstrating
that many technical barriers still exist which need
to be overcome.
28,29
Another means of enhancing the
entry of naked DNA into the cell is by physical means,
such as a gene gun (Intraject, Weston Medical,
Cambridge). These instruments utilize a pressurized
stream of helium to force gold particles with DNA
coated on to them into the cytoplasm. The use of a
stream of liquid, instead of helium, under pressure has
also been tried for injecting genetic material into a
cell.
22
Although the optimal delivery system has yet to
be developed, novel chemical and physical methods
of enhancing exogenous gene transfer into a cell are
constantly being reported.
The disadvantages of gene therapy that have been
discussed, including low transfection efciency, short
periods of gene expression, and immunogenic responses,
might not pose such a large problem for the develop-
ment of an effective gene therapy regimen used in the
treatment of ED. Since corporal cavernosal smooth-
muscle cells are interconnected by gap junctions which
allow the exchange of ions and second messengers
between cells, a neuronal signal elicited by gene
delivery to one cell could be transduced to neighboring
cells.
30,31
Therefore, methods that are characterized by
relatively low transfection efciency, such as naked
DNA and liposomal transfer, may have success for this
disease. Additionally, due to the low turnover rate
of the vascular smooth-muscle cells in the penis, a
transfected gene will potentially have a longer
expression time than in a tissue with a high turnover
rate.
27
Lastly, a large-scale immunogenic response is
less likely when gene therapy is applied to the penis.
The external location of the penis from the body core
would enable the blood flow to be temporarily
restricted while the therapy is administered, thereby
decreasing the amount of the vector system that could
enter into systemic circulation.
27,32
The use of gene
therapy for the treatment of ED is under review in
a variety of ongoing clinical studies that will be
described next.
Basic Concepts of Gene Therapy 185
GENE THERAPY FOR ERECTILE
DYSFUNCTION
Up to this time point, no studies have been conducted
in humans. All reported studies have been conducted
in the rat model. Recent gene therapy strategies
include gene therapy with nitric oxide synthase (NOS),
calcitonin gene-related peptide (CGRP), brain-derived
neurotrophic factor (BDNF), vascular endothelial
growth factor (VEGF), K channels, and cell-based gene
therapy.
33
Gene therapy with nitric oxide synthase
The main neurotransmitter mediating penile erection
is nitric oxide (NO), which is released from the endo-
thelium of the corpora cavernosa during non-adrenergic,
non-cholinergic neurotransmission.
34
Within the muscle
cell, NO activates a soluble guanylyl cyclase, which
raises the intracellular concentration of cyclic guanosine
monophosphate (cGMP). cGMP in turn activates a
specic protein kinase, which phosphorylates certain
proteins and ion channels, resulting in the opening
of potassium channels and hyperpolarization of the
muscle cell membrane, sequestration of intracellular
calcium by the endoplasmic reticulum, and blocking of
calcium influx by calcium-channel inhibition. The con-
sequence is a drop in cytosolic calcium concentration
and relaxation of the smooth muscle, resulting in
dilation of arterial vessels and increased blood flow
into the sinuses of the corpora cavernosa.
34
The strategy used so far has been to target the
enzyme responsible for NO synthesis, NOS, which
synthesizes NO from L-arginine and molecular
oxygen. Three isoforms have been targeted: neuronal
NOS (nNOS), endothelial NOS (eNOS), and inducible
NOS (iNOS).
7,3538
Gene therapy with nNOS
In the most recent of the NOS studies, Magee et al.
investigated whether the neuronal NOS variant
responsible for erection, penile nNOS (PnNOS) would
ameliorate ED in aged rats, and whether the com-
bination of electroporation with a helper-dependent
adenovirus (AdV) would improve gene transfer.
38
PnNOS and -galactosidase cDNAs were cloned in
plasmid and gutless AdV vectors, and injected into
the penis of adult (-gal) or aged (PnNOS) rats, with
or without electroporation. Penile erection was
measured at different times after PnNOS cDNA
injection, by electrical stimulation of the cavernosal
nerve. The expression of -galactosidase or PnNOS
was detected in penile tissue by either histochemistry
and luminometry or Western blot, and the effects
of AdV-CMV-PnNOS on mRNA expression were
examined by DNA microarray.
The authors found that electroporation increased
pCMV--gal uptake, and its expression was detectable
at 56 days. In the aged rats treated with pCMV-PnNOS
and electroporation, the maximal intracavernosal:
mean arterial pressure ratios were elevated for 11 and
18 days when compared with those in controls.
Electroporation intensied penile uptake of as few as
10
6
viral particles (vp) of AdV-CMV--gal, and with
10
7
vp -galactosidase was still detectable at 60 days.
Electroporated AdV-CMV-PnNOS (10
7
vp) was effective
at 18 days in stimulating the erection of aged rats,
without inducing the expression of cytotoxic genes. In
summary, intracavernosal gene therapy with PnNOS
cDNA corrected the aging-related ED for at least
18 days when given by electroporation in a helper-
dependent AdV at low viral loads.
Gene therapy with eNOS
The group at Tulane University School of Medicine
reported their experience with gene transfer of eNOS.
In their rst report in 1999, they administered a
recombinant adenovirus containing the eNOS gene
(AdCMVeNOS) into the corpora cavernosa of aged
rats. Adenoviral expression of the -galactosidase
reporter gene was observed in cavernosal tissue 1 day
after administration of AdCMV-gal 1 day after
administration of AdCMVeNOS, transgene expression
was conrmed by immunoblot staining of eNOS
protein, and cGMP levels were increased. The increase
in cavernosal pressure in response to cavernosal
nerve stimulation was enhanced in animals transfected
with eNOS, and erectile responses to acetylcholine
and zaprinast were enhanced at a time when the
erectile response to the NO donor sodium 1-(N,N-
diethylamino)diazen-1-ium-1,2-diolate was not altered.
35
In their second report, published in 2000, the
authors wanted to determine if adenoviral-mediated
gene transfer of eNOS could reverse age-related ED in
rats. Two groups of animals were transfected with
adenoviruses: (1) aged rats (60 weeks) with AdRSV-
gal; and (2) aged rats (60 weeks) with AdRSVeNOS.
Five days after transfection, these study animals under-
went cavernosal nerve stimulation (CNS) to assess
erectile function and their responses were compared
with young (20 weeks) control rats. Cross-sections of
the rat penises transfected with AdRSVeNOS were
examined after trichrome staining. Adenoviral trans-
duction efciency of -galactosidase reporter gene was
measured by a galacto-light chemiluminescent reporter
gene assay in cavernosal tissues of rats administered
with AdRSV-gal. The transgene expression of eNOS
was examined by reverse transcriptase-polymerase
chain reaction (RT-PCR) in rats transfected with
AdRSV-gal and AdRSVeNOS. eNOS and iNOS
protein levels were measured by Western blot analysis,
and cGMP levels were assessed in cavernosal tissue by
enzyme immunoassay.
Adenoviral expression of the -galactosidase
reporter gene was observed in cavernosal tissue for up
to 30 days, with peak expression registered at 5 days
after intracavernosal administration of AdRSV-gal.
Cross-sections of the rat penises transfected with the
AdRSVeNOS revealed no pathological changes. Five
days after administration of AdRSVeNOS, eNOS protein,
mRNA and cGMP levels in the corpora cavernosa were
signicantly increased (P < 0.05), while iNOS protein
levels remained unchanged (P > 0.05).
In conclusion, enhanced expression of eNOS
employing an adenoviral vector signicantly increased
the erectile response to cavernosal nerve stimulation
in the aged rat, similar to the response observed in
younger rats. The authors therefore suggested that in
vivo adenoviral gene transfer of eNOS can physio-
logically improve erectile function in the aged rat.
36
Gene therapy with iNOS
Experiences with gene therapy using the inducible NOS
isoform, iNOS, were rst reported from University of
California at Los Angeles (UCLA) in 1997, and later
from the University of Pittsburgh in 2001.
The group from UCLA investigated whether the
stimulation of penile NOS expression by local induc-
tion or gene therapy could mitigate ED in the aged rat.
A mix of iNOS inducers was continuously delivered to
the penises of 5- (adult), 20- (old), and 30- (very
old) month-old rats for 36 days, and the erectile
response to electrical eld stimulation of the caver-
nosal nerve was measured.The ED observed in old and
very old rats as compared to adult animals could be
ameliorated by treatment with iNOS inducers. Penile
iNOS was detectable in the penis of these rats by
Western blot, NADPH diaphorase, and NOS activity
assays. Inducible NOS was inducible in vitro in both
rat and human corpora cavernosal tissue and in rat
penile smooth-muscle cells (RPSMC), as shown by
Western blot. However, NO synthesis in cavernosal
tissue upon iNOS protein induction remained low,
indicating that the increased NOS levels were under
physiological control. The authors also reported the
improvement of aging-associated ED after injection of
cDNA of the coding regions of penile iNOS from the
rat into the penis. The iNOS construct was detected in
cavernosal tissue by PCR, and its expression by RT-
PCR and Western blots.
7
Similarly, the group from Pittsburgh injected the
inducible form of the enzyme NOS (iNOS) into
the corpus cavernosum of adult rats using a solution
of plasmid, adenovirus, or adenovirus-transduced
myoblast cells. They also injected plasmid, adeno-
virus, and adenomyoblast encoding the expression of
the -galactosidase reporter gene. Expression of
-galactosidase throughout the corpora cavernosa
after injection of each of the three solutions could be
observed. Staining was greatest for adenomyoblast,
followed by adenovirus and then plasmid. The basal
intracavernous pressure (ICP) of iNOS-treated animals
(adenovirus and adenovirus-transduced myoblast)
increased to 55 23 cm/H
2
O versus 5 6 cm/H
2
O in
control animals (P = 0.001). Stimulation of the caver-
nous nerve resulted in a twofold increase in ICP
(adenovirus and adenomyoblast) from the basal level
of the iNOS-treated animals. In the present report,
myoblast-mediated gene therapy was more successful
in delivering iNOS into the corpus cavernosum than
were the direct adenovirus or plasmid transfection
methods.
37
A major limitation of the NO approach is the limited
duration of gene expression and its concomitant
functional effect. As mentioned earlier, the longest
detected time point at which an ICP response was
detected was 18 days. At 30 and 60 days postinjection
there was no effect of gene transfer.
38
The explanation
for the relatively short duration of efcacy is undeter-
mined, but may be related to either the presence of the
viral vector or tight cellular regulation of the gene
product.
33
While no adverse immunologic, histologic,
or circulatory effects were observed, the potential
long-term side-effects of NO overexpression are not
known, and the possibility of priapism could be a con-
cern in this approach.
33
Gene therapy with calcitonin gene-
related peptide
CGRP is considered to play an important role in
modulating erectile capacity by virtue of its ability to
produce a receptor-mediated increase in intracellular
cyclic adenosine monophosphate (cAMP) levels, and a
cellular hyperpolarization via increased K-channel
activity.
33,39
Using an adenoviral-mediated delivery system,
Bivalacqua et al.
39
examined whether gene transfer of
prepro-CGRP (AdRSVCGRP) could enhance erectile
responses in aged rats. They found a signicant
decrease in CGRP concentrations and in cAMP and
cGMP levels in aged rat cavernosal tissue compared to
younger rats. Aged rats also had signicantly lower
erectile function as determined by cavernosal nerve
stimulation compared to younger rats. Five days after
transfection with AdRSVCGRP, these aged rats had an
approximately threefold increase in cavernosal CGRP
levels compared to animals transfected with adeno-
viruses encoding nuclear-targeted -galactosidase
(AdRSV-gal). The AdRSVCGRP-transfected animals
also demonstrated an increase in CGRP mRNA and
immunohistochemical localization of CGRP in the
smooth muscle of the corpora cavernosa. In addition,
Gene Therapy for Erectile Dysfunction 187
cAMP levels in the corpora cavernosa were signicantly
increased, whereas cGMP levels remained unchanged.
Adenoviral transduction efciency of -galactosidase
reporter gene was measured by chemiluminescence
and was observed in cavernosal tissue 5 days after
transfection with AdRSV-gal 5 days after adminis-
tration of AdRSVCGRP; a signicant increase was
observed in the erectile response to cavernosal nerve
stimulation in the aged rat, similar to the response
observed in younger rats.
Gene therapy with brain-derived
neurotrophic factor
Neuropathy is a signicant factor in many patients with
ED. Bakircioglou et al. from University of California at
San Francisco (UCSF) examined the ability of gene
therapy with BDNF to restore erectile function in a rat
model of neurogenic ED.
40
Rats underwent bilateral
cavernous nerve freezing and intracavernous injection
of adeno-associated virus-LacZ or adeno-associated
virus-BDNF. Erectile function was assessed by caver-
nous nerve electrostimulation at 4 and 8 weeks, and
samples of penile tissue and the major pelvic ganglia
were evaluated histologically. In the BDNF group mean
maximal ICP standard deviation was signicantly
higher than in the LacZ group at 4 and 8 weeks. In
addition, in the BDNF group, reduced NADPH
diaphorase staining and neuronal NOS immuno-
staining revealed signicantly more positive nerve
bers in the dorsal nerves and cavernous tissue than in
the LacZ group at each time point and the percentage
of neuronal NOS-positive neurons in the major pelvic
ganglia was also signicantly greater. Moreover, in the
LacZ group most neurons showed a light staining
pattern with irregular contours and numerous vacuoles
in the cytoplasm.
The authors therefore suggested that intracavernous
injection of adeno-associated virus-BDNF may prevent
the degeneration of neuronal NOS containing neurons
in the major pelvic ganglia and facilitate the regen-
eration of neuronal NOS containing nerve bers in
penile tissue, thus enhancing the recovery of erectile
function after bilateral cavernous nerve injury.
40
Gene therapy with vascular endothelial
growth factor
A study by Burchardt et al. has documented the
presence of a number of VEGF isoforms in the corpora
cavernosa of humans and rats.
41
More recently, Lee
et al.
42
from UCSF tested the effects of intracavernous
injection of VEGF regarding restoration of erectile
function in a rat model of traumatic arteriogenic ED
via bilateral ligation of the internal iliac arteries.
Signicant recovery of erectile function was noted in
VEGF-treated rats, and hypertrophy and hyperplasia
of the endothelial cells, especially those lining the
small capillaries, could be observed morphologically.
Gene-based approaches using angiogenic factors
may be useful in the treatment of ED. The potential
pleiotropic actions of the cytokines on multiple cell
types, however, may be clinically problematic.
33
Gene therapy with K channels
K channels provide an important mechanism for the
regulation of the cell tone of smooth-muscle cells in
the corpus cavernosum, and represent a converge point
for mediating the effects of a wide array of endogenous
substances, like neurotransmitters, neuromodulators,
and hormones.
33
They therefore seem an attractive
therapeutic target for both traditional small-molecule
pharmacology and gene-based approaches.
43
The group around Christ at Albert Einstein College
of Medicine have focused their gene transfer efforts
on the human large-conductance, calcium-sensitive K
channel (K
Ca
, maxi-K, hSlo).
8,44
The tight link between
K channels, transmembrane calcium flux, and corporal
smooth-muscle tone has been the rationale for this
approach.
43,45
Already in the late 1990s Christ et al. demonstrated
that naked hSlo DNA can be incorporated into corporal
smooth muscle via microinjection and, furthermore,
that expression is sustained for 24 months in corporal
smooth-muscle cells in vivo.After expression, hSlo was
capable of measurably altering nerve-stimulated penile
erection.
8
In a most recent report, the authors evaluated the
contribution of the maxi-K channel subtype to the
generation of contractile responses in isolated human
corporeal tissue strips by performing pharmacological
studies of phenylephrine contracted isolated corporeal
tissue strips in the presence and absence of two maxi-
K channel blockers and a maxi-K opener (NS1619).
Preincubation with NS1619 produced a signicant,
approximately 20% decrease in the peak steady-state
contractile response and an approximate 38% increase
in the half-time of the phenylephrine-induced con-
tractile response. Adding NS1619 to phenylephrine-
precontracted smooth-muscle strips resulted in a
3050% reduction in steady-state contractile tension.
These in vitro studies conrmed and extended previous
observations indicating the importance of the maxi-K
channel for regulating human corporeal smooth-muscle
tone. Specically, overexpression of hSlo in corporal
smooth-muscle cells is hypothesized to increase their
responsiveness to a diminished supply of endogenous
smooth-muscle relaxants, resulting in a restoration of
sufcient smooth-muscle relaxation for normal penile
erection.
33
This therapeutic approach has the following advan-
tages: rst, the gene product, the maxi-K channel,
exhibits little or no activity in smooth muscles during
flaccidity, but is activated during tumescence by
endogenous erectile pathways. Therefore, priapism, a
potential side-effect, was not observed during pre-
clinical studies. Second, no morphologic effects
(inflammatory or immune response) were observed
on corporal tissue histology or architecture. Finally,
another advantage is the longevity of expression. As
was mentioned earlier, physiologic effects of a single
intracorporal injection of hSlo/pcDNA (naked DNA)
can last up to 4 months, and more recent data from
Christ et al. extend that time frame to up to
6 months.
8,33
Cell-based gene therapy
Another approach to ED treatment is the reimplant-
ation of genetically modied cells into the corpus
cavernosum in order to restore physiologic charac-
teristics.As a rst step toward a cell-based gene therapy
for ED,Wessells et al. transplanted fluorescently labeled
autologous microvessel endothelial cells (MVEC),
which were isolated from the epididymal fat pad, into
the rat corpus cavernosum. Two to 15 days after trans-
plantation the penises were removed, cryosectioned,
and examined under epifluorescent and phase contrast
microscopy. In seven consecutive animals transplanted
fluorescent cells were identied in the corpora caver-
nosa. Bilateral distribution was noted in each animal.
Transplanted endothelial cells were shown to adhere
and persist in the corporal sinusoids.
46
The next step of
this approach could be to alter the genetic charac-
teristics of these cells before their reimplantation. The
long-term viability of autologously transplanted cells
in the corpus cavernosum as well as the duration of
an exogenously transfected gene in these cells is not
known.
FUTURE PERSPECTIVES
Preclinical data using the rat model have demonstrated
the feasibility of various gene transfer approaches for
the treatment of ED. Although medical therapy has
evolved signicantly in the eld, gene therapy would
offer the advantages of potentially offering a cure
of ED by restoring physiological erectile function
and, therefore, eliminate the need for on-demand
medication before sexual activity.
The main issue in gene therapy after a fatal episode
of a young volunteer in a clinical trial in 1999 remains
the demonstration of safety and efcacy, especially
when dealing with non-life-threatening disorders. In
that regard, it is exciting to note that the group from
Albert Einstein College of Medicine in New York
(Drs. Melman and Christ) has recently made a
successful presentation to the NIH Recombinant DNA
Advisory Committee of a Human Gene Transfer
Protocol entitled Pilot Study of the Use of the Human
hSlo/maxi-K Gene to Treat Erectile Dysfunction.
33
Hopefully, proof of concept for the utility of gene
transfer in ED treatment will be forthcoming in the
near future, opening the door to a treatment of a wide
range of other human smooth-muscle disorders.
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EPIDEMIOLOGY
The condition known today as Peyronies disease (PD)
was rst reported in the literature by Fallopius in 1561.
However, it was named after the famous French surgeon
Franois de la Peyronie, who reported on a small
clinical series of men with penile curvature in 1743.
1
PD is a localized disorder of the penis characterized
by changes in the collagen composition of the tunica
albuginea. The result is a brotic plaque, containing an
excess of collagen, which causes pain during erection,
penile shortening, and curvature.
2,3
In addition, erectile
dysfunction (ED) occurs in 2040% of men with PD.
PD is recognized to affect quality of life, with 77% of
men with PD exhibiting signicant psychological
disturbances.
2,4
PD is usually seen in males between the ages of 40
and 70. While previous estimates of PD were an
incidence of 0.392%, a recent cross-sectional study
from Germany noted the prevalence of PD as 3.2%.
2,5
Moreover, in a multicenter, population-based epidemi-
ological study, the prevalence of PD was noted to
increase with age, with 7.1% in men aged between
50 and 69 years having PD by self-report.
6
In fact, the
actual prevalence of PD may be even higher, but
patient embarrassment and insufcient reporting by
physicians have likely underestimated its occurrence.
Recently, a number of clinicians have noted that the
cohort of patients with PD seems to have increased
with the advent of oral sildenal (Viagra, Pzer, New
York, NY), because more men are either becoming
manifest and/or less reluctant to seek evaluation for
sexual problems.
2
In most studies, PD is usually rst
recognized in men in their 50s; however, in one recent
study, the prevalence of PD in men under 40 was
reported as 8.2%.
7
PATHOPHYSIOLOGY
Proposed theories for causation of PD include vitamin
E deciency, various medications such as propranolol
and methotrexate, and increased levels of serotonin.
In addition, some investigators suggest that because of
the PD association with Dupuytrens contracture and
human leukocyte antigen (HLA)-B7 antigens, there
may be a genetic predisposition for PD. Systemic
disorders, such as Pagets disease, diabetes, and gout,
have been associated with PD. Additionally, trauma
and urethral instrumentation are correlated with its
occurrence.
2,813
Recently, heavy smoking has been
found to be a risk factor for PD development.
6
Another
retrospective review of 307 PD patients suggested
that risk factors such as hyperlipidemia, diabetes, and
hypertension have a signicant impact on the severity
of PD.
14
Currently, most authorities believe that PD results
from repetitive minor trauma to the tunica albuginea
of the penis. The inflammatory process incites a low-
level autoimmune response.
2
Devine et al.
15
have
hypothesized that minor penile trauma commonly
occurs during coitus, causing a delamination injury of
the tunica albuginea, especially at the dorsal aspect of
the penis. This process incites further inflammation,
induration, and brin deposition between the layers of
the tunica albuginea, leading to a proliferation of local
broblasts and leukocytes.
15
Histopathological studies of PD reveal an inflam-
matory process, characterized by chronic lymphocytic
and plasmacytic inltration of the tunica albuginea
and surrounding erectile tissues at the site of injury.
This, in theory, is followed by excessive generation of
free radicals known as reactive oxygen species, and
inflammatory cytokines (chemokines).
16
The balance
between extracellular matrix and scar tissue formation
exceeds the normal degradation of collagen and extra-
cellular matrix due to abnormal broblast activity.
Thus, PD exhibits wound-healing abnormalities, similar
to keloid formation, hypertrophic scars, and Dupuytrens
contractures.
16,17
A number of investigations have examined the
collagen content changes in the tunica albuginea of
patients with PD. Both type-1 and -3 collagen
expression is commonly witnessed in scar tissue, while
type-3 collagen is more frequently found in Peyronies
plaques. In addition, type-3 collagen in the tunica
albuginea is more common in patients who suffer from
venooclusive dysfunction or who have PD, a nding
that is not observed in the tunica albuginea of normal
men.
18
Moreover, elastic ber content in the tunica is
signicantly decreased in PD patients and in men with
Peyronies Disease
Mustafa F. Usta and Wayne J. G. Hellstrom
CHAPTER 13
ED compared to PD patients without ED. PD patients
typically exhibit increased levels of antitropoelastin
and anti--elastin, reflecting elevated elastin synthesis
and destruction. This observation gives further support
for an autoimmune process affecting the elastin frame-
work in the pathogenesis of PD.
19
INVESTIGATIONS
The origin of the initial inflammatory process, which
leads to brosis, calcication, and plaque formation in
the penis of men with PD, is unknown. It is generally
believed that microvascular trauma during sexual
intercourse initiates the inflammatory process.
2,13,17
Collagen biosynthesis in adult tissues is regulated by
several endogenous and exogenous factors. Biologically
active peptides such as interleukin-1, tumor necrosis
factor, epidermal growth factor, and transforming
growth factor- (TGF-) have been implicated in
normal collagen biosynthesis and pathologic brosis.
TGF-, a cytokine that is vital to tissue repair, especially
during tissue injury and inflammatory responses, can
cause brosis and plaque formation.
16
El-Sakka et al.
20
demonstrated an upregulation of TGF- in the tunica
albuginea of PD patients when compared to controls.
In a rat model, El-Sakka et al. explored the role of
TGF- and surgical trauma in induction of a Peyronies-
like condition.
21
Their studies demonstrate histo-
logical and ultrastructural alterations in the rat penis
similar to PD in humans. Histological changes include
chronic inflammatory inltration, focal and diffuse
elastosis, thickening, disorganization, and clumping of
the tunica albuginea. Bivalacqua et al, further charac-
terized nuclear factor kappa B (NF-B), a transcription
factor that regulates expression of several genes, in
this TGF--induced PD rat model. NF-B was present
at the early stages (rst 3 weeks) after either TGF-
injection or mechanical injury to the rat penis.
22
In
addition, inducible nitric oxide synthase (iNOS) was
induced in this model. Nitric oxide (NO) induces
reactive oxygen species (ROS) and nitrotyrosine, as
noted by others to be present in human Peyronies
plaques.
23
According to this hypothesis, NF-B, TGF-,
NO, and ROS are involved and interrelated in the
pathophysiology of PD.
16
More recently, Lin et al.
24
have shown increased levels of monocyte chemo-
attractant protein-1 (MCP-1) in Peyronies plaques.
They demonstrated that MCP-1 production is related
to TGF- and therefore MCP-1 may become a novel
therapeutic target in PD.
24
Mulhall and colleagues
25
analyzed the expression of the brogenic cytokine,
basic broblast growth factor (bFGF), from broblasts
derived from Peyronies plaques. They suggested a
potential role for bFGF overexpression in tunical
brosis. In another related in-vitro study, the same
authors revealed an aberration of the p53 pathway
in broblasts derived from Peyronies plaques. They
concluded that these results explain the high cell
proliferation rates in these cells and thereby postulated
a perturbation of the p53 pathway in the pathogenesis
of PD.
Using a molecular approach to understand the patho-
physiology of PD, Magee et al. investigated the prole
of differential gene expression between PD plaques
and control tunica albuginea using DNA microarrays.
They reported that the genes involved in collagen
synthesis, myobroblast differentiation, tissue remodel-
ing, inflammation, ossication, and proteolysis are
upregulated, and the genes that inhibit these processes
are all downregulated in PD.
26
CLINICAL MANIFESTATIONS
Patients with PD may present with any combination of
penile curvature, palpable penile plaque, pain during
erection, and ED. Most patients with PD have a well-
dened plaque that is palpable on physical examination.
However, 3862% of patients are unaware of the
presence of plaque.
2,3
The penile plaque is the main
reason for penile pain and curvature, with the erect
penis angulating toward the side of the plaque (Fig.
13.1). Painful erections and a palpable penile plaque
are usually manifested as clinical hallmarks during the
acute phase of PD, which may last for 1218 months.
2,3
The chronic phase occurs when the curvature stabilizes
and pain becomes minimal. Penile plaques are gener-
ally located on the dorsal aspect of the penis, usually
producing an upward curvature during erection.
However, plaques can be identied on the ventral or
lateral sides of the penis, causing downward and/or
lateral curvatures. Other presentations include wasting,
narrowing, hourglass, and swan-neck deformities.
2,3
An almost universal complaint of men suffering with
192 Peyronies Disease
Figure 13.1 Patient with Peyronies disease. Penile
erection demonstrating typical lateral curvature.
PD is generalized shrinkage or shortening of the penis.
Recently, Perimenis et al. reported on the clinical
presentation of 134 PD patients. While all men had
a palpable scar, only 51 (38%) had noticed the indu-
ration. Penile curvature was found in 87 men (65%)
and ED due to severe penile deformity was present
in 16 patients (11.9%). Furthermore, 53 patients
(39.5%) reported painful erections and 18 (13.4%)
remembered a history of penile trauma during sexual
intercourse or manipulation. The penile plaque was
located in the dorsal midline in 77.6% of cases.
27
Another retrospective study reviewed 307 PD patients.
Penile deformity, painful erection, and palpable nodule
were the most common (85%) presenting symptoms.
The remaining 15% of men were unaware of the
penile deformity and were diagnosed during standard
evaluation for ED. Dorsal (45.6%) and ventral
(29.3%) were the most frequent types of curvature. In
addition, 54.4% of patients complained of ED and the
probability of diminished erectile capacity was 86.7%
in patients older than 60 years, when PD was present
for more than 12 months.
14
DIAGNOSIS
PD is easy to diagnose by patient history and physical
examination alone. A detailed medical and sexual
history needs to include the time and mode of onset
(sudden or gradual), the progression of the condition,
history of previous penile surgery, instrumentation,
trauma, medications, smoking, and a family history of
PD or Dupuytrens contracture, and risk factors for
ED.
2,3,28
Sexual history needs to determine the ability
of the patient to attain or maintain erection for satis-
factory sexual intercourse. Other related information of
importance includes subjective assessment of penile
shortening, induration, pain with or without erection,
frequency of intercourse, libido, and the individuals
psychological state. A home Polaroid picture taken
after achieving an erection can be added to the
chart.
3,28
On physical examination the penis is gently
stretched and carefully palpated for a plaque. The
number, size, and locations of other plaques are
recorded. The patient is also examined for Dupuytrens
contracture or plantar brotic changes. Further
embellishment includes photography or free-hand
drawing of the erect penis after an articial erection
has been induced. The physician examines the erect
penis and carefully measures the angle of penile curva-
ture. The size of the plaque can be roughly assessed
by manual study while in some situations penile ultra-
sonography can be used.
2,3,28
PD patients do not
necessarily need to have a penile vascular investi-
gation at initial visit. However, if contemplating a
surgical approach or if patients complain of ED, duplex
ultrasound is recommended. Objective evaluation of
penile vascular status is achieved by assessment of
penile arterial inflow, venous outflow, and resistance
indexes. Color Duplex ultrasound can detect collateral
arterial connections between dorsal, cavernosal, and
spongiosal arteries, and may be important prior to
considering reconstructive Peyronies surgery. Dynamic
infusion cavernosometry/cavernosography (DICC)
and nocturnal penile tumescemce (NPT) are ancillary
studies used by some clinicians to conrm the diag-
nosis of ED. Magnetic resonance imaging (MRI) gives
further anatomical detail, but rarely influences the
eventual surgical procedure.
2,3,28
DIFFERENTIAL DIAGNOSIS
During the evaluation of PD, other possible causes for
penile curvature and induration are considered in the
differential diagnosis. These include congenital penile
curvature, penile chordee, penile vein thrombosis
(Mondors disease), brosis secondary to trauma,
leukemic inltration of the penis, late syphilitic
lesions, and penile inltration with lymphogranuloma
venereum.
3
Although PD is usually a benign condition,
its differential diagnosis may include a number of
malignant processes, including epithelioid sarcoma,
angiosarcoma, carcinoma of the urethra, and metastatic
penile tumors.
29
These malignant conditions may
initially mimic PD in clinical presentation and can lead
to misdiagnosis. Any delay in diagnosis of a malignant
condition can understandably hasten a patients
demise.
30
FOLLOW-UP
Many patients with PD do not complain of any clinical
problems, and reassurance that the palpable nodule or
plaque is benign is all that is necessary. Therapy is only
indicated if there is signicant penile pain (an indi-
cation of the acute phase of PD disease) or a severe
penile curvature, which precludes sexual intercourse.
Early reports described PD as a process of gradual
spontaneous resolution. However, more recent litera-
ture does not support this viewpoint. Gelbard et al.
showed that, in a study of 97 patients, only 13% of
these patients experienced complete resolution of
penile curvature during the observation period; 47%
remained unchanged and 40% progressed.
4
Kadioglu
et al. reported similarly, in 63 patients presenting with
acute disease, that 30.2% reported progression of the
deformity, while 66.7% had stable disease after a
mean follow-up of 8 months without any treatment.
Complete spontaneous resolution of the penile curva-
ture occurred in only two cases in this study.
14
Follow-up 193
Medical treatment
Despite many treatments being available, PD has
remained a therapeutic dilemma. Historically, de la
Peyronie suggested use of Barege spa water and
mercurial ointments. In the 1830s, iodine, arsenic, and
camphor were used. More recently, energy transfer
techniques, such as radiation, ultrasound, shortwave
diathermy, laser therapy, and shock-wave lithotripsy,
have been proposed without much established scientic
benet in any treatment of PD.
31
Currently, most authorities recommend an initial
conservative approach during the acute inflammatory
phase, which can last from 6 to 18 months, and is
characterized by penile pain, curvature, and plaque.
2,3
Most pain symptoms resolve spontaneously and, for
that reason, medical management and reassurance are
the only therapies recommended.
2,3
A number of studies
have shown that patients with earlier-stage disease
are more likely to have resolution (Table 13.1).
Medical treatment options can be categorized into oral
(systemic), intralesional, and local therapies.
Oral (systemic) treatment
Oral vitamin E (tocopherol) is commonly employed in
the initial treatment of PD, mainly because it is easy to
take, inexpensive, and free of side-effects. It is usually
prescribed as an over-the-counter agent at 400 mg
twice daily. Its rationale for use is its free radical
scavenger activity, which impedes the development of
brosis. In 1948, Scardino and Scott reported a
decrease in penile curvature in 78% and a decrease in
plaque size in 91% of patients.
32
Devine and Horton
33
described an overall 60% improvement in patients
treated with vitamin E. Twenty percent had resolution
of their penile plaque, 33% reported complete penile
straightening, and 13% had pain resolution. In a
follow-up study presented at the National Institutes of
Health Conference on PD in 1993, Devine and Snow
presented their updated results on 105 patients on oral
vitamin E therapy: there was a 99% reduction in pain
and a 13% reduction in penile curvature, but 70% of
patients reported no improvement.
2
The use of oral potassium aminobenzoate (Potaba)
in the treatment of PD was rst reported in 1959 by
Zarafonetis and Horrax. It is theorized to decrease
brogenesis by decreasing serotonin levels through
increased tissue use of oxygen and increased activity
of monoamine oxidase. The dosage is 12 g/day for
3 months. In a large study of 2752 patients in Germany
treated with Potaba, there was a mean subjective
improvement in 60% of patients.
34
A more recent
retrospective report claimed complete resolution of
penile curvature in 25.8% of patients; 58% of men
noted a decrease in plaque size. Unfortunately, its high
cost and signicant incidence of gastrointestinal side-
effects often lead to low compliance.
35
Tamoxifen is a non-steroidal antiestrogen, which
facilitates the release of TFG- from human broblasts
in vitro, suggesting that it can inhibit inflammation and
decrease broblast production and/or angiogenesis.
A dose of 20 mg twice a day is recommended and the
TABLE 13.1 Treatment results of various non-surgical modalities
Therapy Patients Mean Curvature Resolution Decrease in
(n) follow-up improvement of pain plaque size
Colchicine 24 25 months 37% 78% 50%
Colchicine 60 11 months 30% 90% NR*
PABA 2653 NR 53% NR NR*
Tamoxifen 36 6 weeks 35% 80% 34%
Tamoxifen 25 1 month 46.1% 66.6% 30.7%
Vitamin E 23 9 months 18% 100% 91%
Verapamil (IL) 38 22 months 54% 97% 23%
Verapamil (IL) 140 30.4 months 60% 84% NR*
Interferon-2 (IL) 21 6 weeks 65% 90% 85%
Interferon-2 (IL) 23 22 months 4.3% 68.4% 0%
EMDA 65 13 months 75% 100% 85%
Iontophoresis 100 210 months 37% 96% 53%
NR, not reported; IL, intralesional injection treatment; EMDA, electromotive multidrug administration.
main side-effects are gastrointestinal tract upset and
alopecia. Ralph et al.
36
reported improvement in
penile pain in 80% of patients, penile straightening in
35%, and plaque resolution in 34%. A follow-up study
comparing oral tamoxifen and placebo in men with PD
claimed subjective pain resolution in 66.6%, penile
deformity improvement in 46.1%, and plaque size
decrease in 30.7%.
37
However, objective measurement
did not reveal any differences in plaque area or penile
angulation. Because of the absence of long-term
studies, limited information on its mechanism of action,
and few data on its side-effect prole, oral tamoxifen
for the treatment of PD is not widely used in North
America.
Oral therapy with colchicine is a more recent
addition to the oral agents for PD therapy. Colchicine
possesses antiinflammatory activity, decreases collagen
synthesis, and stimulates collagenase activity. Colchicine
interferes with the transcellular movement of collagen
by diminishing the activity of the enzymes responsible
for collagen processing. The recommemded dose is
0.61.2 mg daily during the rst week of treatment
followed by an increase to 1.82.4 mg daily for
3 months. One study showed a decrease in plaque size
and an improvement in penile curvature in 50% of
patients.
38
Another retrospective report of 60 men had
showed improvement in penile curvature in 30%, and
penile pain resolution in 95%.
39
A recent study in
54 PD men treated with colchicine showed diminish-
ment in painful erections in 72%, plaque size decrease
in 30%, and penile curvature improvement in 26%.
The well-known side-effects of colchicine include
gastrointestinal upset, with diarrhea in 33% of
patients.
40
Intralesional therapy
Because of their recognized antiinflammatory effects,
steroids have been used for many years as an intra-
lesional modality for treatment of PD. A 1954 report
on the steroid dexamethasone showed a decrease in
both plaque size and penile pain, but no statistical
difference was noted when comparing results with the
natural history of the disease.
41
In 1980, Williams and
Green used a long-acting glucocorticoid, triamcinolone
hexacetonide in 45 patients with PD, and reported
36% complete or marked improvement in patient
symptoms.
42
Despite the positive results in some
reports, the side-effects of tissue atrophy, brosis, and
thinning of the skin have caused steroid injection
therapy to fall out of favor as a treatment option
for PD.
In 1985, Gelbard et al.
43
used puried clostridial
collagenase injections in 31 patients with Peyronies
plaque and reported a 65% improvement in penile
curvature. However, in men with severe penile curva-
ture, the response to treatment was not found to be
statistically signicant.
Orgotein, an antiinflammatory metalloprotein, was
suggested to have a superoxide dismutase activity. In a
few European studies, a subjective benet of 8090%
was reported. However, its clinical use has since been
restricted because of signicant toxicity.
44
Calcium-channel blockers have been shown in both
in-vivo and in-vitro studies to inhibit synthesis and
secretion of extracellular matrix molecules. Intralesional
verapamil as a treatment for PD was popularized by
Levine in 1996.
45
In his rst study, intralesional
verapamil therapy reduced pain in 91% of patients,
resolved hourglass deformity in 100%, improved
penile curvature in 42%, and restored sexual function
in 58%.
45
In a controlled study, Rehman et al.
46
reported a decrease in plaque volume in 57% of
patients after verapamil plaque injection treatment.
There was no statistically signicant improvement in
curvature with treatment but there was an observable
trend of improvement in those treated by verapamil
compared to placebo groups. Teloken et al. tried
perilesional injections with saline, steroid, or verapamil
and found no advantage with verapamil, as there was
30% improvement in penile curvature in all treatment
groups.
47
A more recent uncontrolled report by Levine
et al.
48
using intralesional injection of verapamil in
140 patients with PD reported an objective decrease
in curvature, increase in rigidity distal to the plaque,
and improvement in sexual function in 62%, 80%, and
71% of patients respectively.
In 1991 Duncan et al.
49
rst demonstrated the
potential use of interferons in preventing scar for-
mation. His in-vitro studies documented that interferons
inhibit broblast proliferation, diminish collagen
production, and stimulate the activity of collagenase.
Another similar basic research investigation using an
in-vitro model of corpus cavernosal derived myo-
broblasts revealed how collagen production stimulated
by exposure to oxygen free radicals could be inhibited
by exposure to interferons.
50
The use of intralesional
interferon- was rst proposed in a preliminary study
in 10 PD patients by Benson et al.,
51
in which there
was signicant plaque softening, diminished curvature
(50%), and total pain relief (50%). Wegner et al.
52
reported their results on 25 patients who underwent
subcutaneous injection of interferon-, adjacent but
not into the Peyronies plaque. After the treatment,
they reported a 28% decrease in plaque size as well as
pain subsiding in all but one patient. In a subsequent
study, the same authors used interferon- at a higher
dose, and reported contrary results with no change in
plaque size in any patient with 82% incidence of side-
effects (flu-like condition).
Another case-control trial using intralesional inter-
feron by Judge and Wisniewski
53
showed no changes in
Follow-up 195
a control (saline) group, while the study drug patients
reported signicant resolution of pain, decreased penile
curvature, plaque softening, and decreased plaque size.
Another clinical study using intralesional interferon-
reported that nine of 10 patients (90%) had resolution
of penile pain with treatment. Sixty-ve percent of
study patients had signicant improvement in penile
curvature, and 85% had an objective decrease in
plaque size.
54
Recently, Brake et al.,
55
using interferon-
treatment in 23 patients, reported total resolution of
penile pain in all; penile curvature was reduced in only
one individual, and plaque size remained unchanged
in all patients. Surprisingly, self-reported sexual func-
tion improved in 30% of these men.
Topical treatment
Iontophoresis, the electrokinetic transport of ionic
molecules, has been used experimentally in order to
enhance the topical delivery of drugs into Peyronies
plaque for many years. In 1967, iontophoresis using
C21 esteried glucocorticoids in the treatment of 12
men with PD resulted in plaque softening in all men.
56
A later study comparing iontophoresis of lidocaine
(lignocaine), verapamil, and dexamethasone for the
treatment of PD found that pain resolved in 96% of
patients, while plaque size diminished in 53% and
penile curvature improved in 37%.
57
A recent
controlled study of iontophoresis in 40 men with PD
compared placebo with a combination of lidocaine,
orgotein, and dexamethasone. In patients who received
active treatment, the plaque resolved in 47%, decreased
signicantly in 32%, and remained unchanged in 20%.
Sixty-two percent had improved angulation, while
38% remained unchanged. Pain resolved in all patients
presenting with this symptom.
58
Transdermal application of verapamil gel to the
penile shaft has been advocated in recent years. A
double-blind randomized analysis in 50 PD men over
3 months found verapamil signicantly better than
placebo in regard to curvature correction, decreased
plaque size, and improved erectile quality.
59
A contra-
dictory study at another institution showed the total
lack of entry of verapamil into the tunica albuginea
after being applied to the penile skin the night before
plaque surgery.
60
Unfortunately, at this time no fool-
proof, reliable, efcacious, and denitive medical
therapy for PD exists. A better understanding of
wound healing and the inflammatory response will
undoubtedly open new therapeutic avenues, possibly
altering cytokine action and broblast modiers.
Surgical treatment
The surgical treatment of PD consists of either cor-
rection of the penile deformity or insertion of a penile
prosthesis in patients with concomitant ED. Surgical
therapy of penile curvature is reserved for patients
who fail conservative treatment options. Several
criteria have been established by leading authorities in
the eld as requirements before surgical intervention:
1. Severe curvature, narrowing, or indentation of
more than 1 years duration (except the presence
of calcied plaques, in which case surgery may be
undertaken earlier)
2. Disease activity (progression of deformity or sexual
dysfunction, or both) needs to be stable and
unchanged for at least 3 months
3. Presence of severe curvature, which impedes sexual
intercourse
4. Severe penile shortening
Because penile vascular abnormalities are commonly
associated with PD, a detailed evaluation of penile
vascular status and erectile function is recommended
by most authorities.
2,3,28
If the patient has some degree
of vascular insufciency, penile prosthesis implantation
is usually indicated. Because of different penile
anatomies and clinical presentations of PD, there is no
single standard procedure that can be used for all
cases. The surgical approaches can be divided into
three main categories:
2,3
1. Shortening of the convex side of the tunica
albuginea (Nesbit technique, plication procedures,
or corporoplasty)
2. Lengthening of the concave side of the tunica
albuginea (incision or excision of the plaque and
grafting procedures)
3. Penile prosthesis implantation
Shortening procedures are performed on the convex
side of the penis opposite to the penile plaque. These
procedures are generally easy to perform, but patient
selection is very important. For a patient with ample
penile length, a minimal distal curvature and adequate
erectile function, and without hourglass deformity, the
choice of a Nesbit or plication procedure is reasonable.
In 1965, Nesbit described the correction of congenital
penile curvature by excision of an ellipse of the tunica
albuginea and shortening of the normal, non-affected
side of the penis.
60
In 1979, the Nesbit procedure was
again popularized for the surgical treatment of PD.
Depending upon the degree of curvature, more than
one ellipsoid may need to be excised to correct the
deformity completely. Closure of the defect is made
with a non-absorbable, atraumatic suture, and burying
of the suture knots.
61
With the Nesbit procedure, it
should be emphasized that no attempt is made to
remove the penile plaque. Ralph et al.
62
of the UK have
operated on 359 patients over 16 years and reported a
satisfaction rate of 82% with this technique. Over
time, the surgical results of the Nesbit technique for
this condition by this group have improved. However,
despite normal erectile function, penile shortening is
still the most problematic complaint.
Rehman et al.
63
reported on a modied Nesbit
plication with partial-thickness shaving instead of
conventional excision of a wedge of the tunica
albuginea. This modied procedure was employed in
32 patients with congenital penile curvature or PD,
with satisfaction rates of 100% and 78%, respectively.
Lemberger et al.
64
proposed another modication of
the Nesbit procedure, in which, instead of removing an
ellipse of the tunica, a longitudinal incision is made in
the corpora cavernosa and closed horizontally in order
to achieve a straight penis. These authors reported
satisfaction rates between 79% and 95% with this
technique.
64
Another variation of the Nesbit procedure
is the plication technique. In this method, non-
absorbable sutures are placed on the convex side of
the tunica albuginea without excising an ellipse of
tunica albuginea in order to achieve a straight penis.
Erpenbach et al. used the plication technique and
reported a 96% satisfaction rate.
65
A retrospective
analysis on the long-term documented results of
patients who have undergone the EssedSchroder
plication procedure documented the cosmetic and
functional results as good or sufcient in 81% of
patients.
66
More recently, Gholami and Lue
67
reported
the results in 132 cases with congenital penile curva-
ture (n = 16) and PD (n = 116) corrected with the
1624-dot, minimal-tension technique using multiple
parallel plications. Postoperatively, 93% of the 132
patients reported straight erections while 7% com-
plained of slight curvature and 4% complained of
decreased erectile function. Of note, 41% of patients
complained of penile shortening, which was the most
commonly encountered complication.
67
In patients with severe and/or proximal penile curva-
ture, signicant shortening, or gross deformity of the
penis with narrowing or hourglass deformities, then
lengthening procedures are generally indicated. These
procedures are performed with plaque incision or
excision and subsequent grafting. Grafting materials
may be autogenous (such as dermis, saphenous vein,
tunica vaginalis, temporalis fascia, vascularized
preputial), autologous (processed cadaveric/bovine
pericardium), or synthetic (such as Dacron, GoreTex,
and Silastic; Figs 13.213.6). Excision of the entire
plaque and use of a dermal graft were rst popularized
by Devine and Horton in a series of 12 patients
with PD.
33
More recently, Chun and colleagues
68
have
compared the results of plaque incison/excision and
dermal or cadaveric pericardial graft techniques. They
concluded that minimal preoperative preparation and
Follow-up 197
Figure 13.2 Plaque dissection in a patient with lateral
penile curvature.
Figure 13.3 Plaque excision is made through the tunica
albuginea with a knife.
Figure 13.4 (A and B) Following the bovine pericardial graft preparation, the graft is tailored.
A B
Figure 13.5 Cadaveric pericardial graft inlay after the
excision of tunica albuginea.
Figure 13.6 After grafting, articial erection has been
performed to evaluate residual penile curvature.
decreased patient morbidity make cadaveric peri-
cardium a more suitable graft compared to dermis.
Accordingly, Hellstrom and Reddy
69
reported excel-
lent results using cadaveric pericardial grafting material
after plaque excision in 11 patients. This material is
ideal for coverage of a tunical defect. As another
alternative, Helal and colleagues
70
reported that 58%
of PD patients were satised using plaque excision and
a tunica vaginalis graft.
Some authors have suggested that excision of a
plaque may impair erectile venoocclusive function. It
is recognized that the pathologic process of PD is not
only located in the plaque itself but involves the whole
tunica albuginea. For this reason, some surgeons
recommend incision of the plaque as a better choice
than wide tunical excision. Gelbard and Hayden
71
reported 100% success with incision of the plaque and
grafting with temporalis fascia in 12 patients with
a follow-up of 2 years. Further, Ganabathi et al.
72
performed incision and GoreTex grafting, and reported
excellent results in their series. Alternatively, Teloken
et al. used a crural graft as the grafting material after
plaque incision in seven patients and reported complete
penile straightening in six patients.
73
Recently, Knoll
reported on the use of a small-intestinal submucosal
(SIS) graft for covering the incised penile plaque.
Eleven of 12 patients reported excellent results in his
study.
74
Furthermore, Egydio and colleagues
75
published
the results of incomplete circumferential incision of
the penile plaque and use of a bovine pericardial graft
in 33 patients with PD. They reported that penile
correction was achieved in 87.9% of patients. More-
over, all patients recovered their ability to have sexual
intercourse without any difculty, with a mean
increase of 2.21 cm in the size of the penis.
The use of a vein graft combined with plaque
incision has been popularized by Lue and has since
been further advocated by several investigators. The
reported success rates range between 75% and
95.5%.
76
Lue and others reported that the saphenous
vein has a number of advantages, such as increased
elasticity, ability to cover the tunical defect without
contracture, easy harvest, inexpense, and no risk of a
foreign-body reaction.
7780
More recently, Hatzichristou
and colleagues
81
have used the tunica albuginea free
graft combined with corporoplasty in 17 patients. They
reported complete penile straightening in all patients
with a mean follow-up of approximately 40 months.
When patients with PD have both penile deformity
and ED, penile prosthesis implantation with or without
excision or incision of the tunica is the standard of
care. In the past, a penile prosthesis would be placed
in any patients who had a penile deformity but without
ED. However, currently most authorities believe that,
because of the advances in the medical treatment (i.e.,
sildenal) of ED, prosthesis implantation should be
reserved as the nal treatment modality in patients
with concurrent severe ED. In most situations with
mild to moderate curvatures, the insertion of a penile
prosthesis alone is sufcient to achieve full penile
straightening. However, if a man has severe penile cur-
vature (>60), incision and grafting of the tunical defect
may be necessary during prosthesis implantation.
82
Ghanem et al.
83
treated 20 PD patients with placement
of malleable penile prostheses and reported an 80%
success in a follow-up of 1 year. Carson
84
inserted
AMS 700CX inflatable penile prostheses in 30 men
with PD and ED. He found that 93% of patients had
complete penile straightening in his study. Studies by
Montorsi et al.
85
also used the AMS 700CX penile
prosthesis for the treatment of 33 PD patients and
reported 79% and 75% patient and partner satis-
faction rates, respectively.
In 1994, Wilson and Delk
86
reintroduced the model-
ing technique in the treatment of PD with ED. In this
method, after inserting and inflating the prosthesis, the
penis is bent forcibly in the direction opposite to the
curvature and held for at least 90 s. Wilson et al.
87
reported that, despite the 4% urethral injury rate,
the long-term follow-up of this technique in 138 PD
patients showed greater than 90% patient satisfaction.
In situations in which modeling is ineffective or the
penile defect is very severe e.g., bottlenecking,
unilateral cavitation, or curvatures greater than 90
use of grafting materials, in addition to prosthesis
implantation, is warranted. Fortunately, most patients
respond extremely well to these surgical reconstruc-
tions and are among the most grateful of all urologic
patients.
FUTURE OUTCOMES
PD remains a therapeutic dilemma and represents a
challenging problem in urologic practice. It is widely
accepted that initial treatment should be conservative,
with expectant therapy and medical management.
Surgical therapy for PD is reserved for patients with
severe penile deformity that impedes sexual inter-
course and fails to improve with medical and intra-
lesional treatment options. The introduction of
experimental models of PD, the entry of a number of
double-blind placebo-controlled clinical trials, and the
use of new molecular diagnostic methods will
hopefully delineate many of the unknowns related to
this condition. In particular, innovations in other elds
of medicine involving idiopathic brosing conditions,
such as Dupuytrens contracture, keloids, and hyper-
trophic scarring, will undoubtedly illuminate our
understanding of the pathogenesis of PD. With time
and research, more targets for study and intervention
will become available.
Future Outcomes 199
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INTRODUCTION
Hypogonadism is the decrease or absence of hormonal
secretion from the gonads. In males, this condition is
called androgen deciency, and is characterized by the
decrease or absence of testosterone (T) secretion from
the testes.
T plays an essential role in normal male devel-
opment as well in as the maintenance of many male
characteristics, including muscle mass and strength,
bone density, libido, potency, and spermatogenesis.
Androgen deciency results from testicular disorders
that directly reduce T output or from hypothalamic
pituitary disorders that reduce pituitary luteinizing
hormone (LH) secretion, thus disrupting T production
by the interstitial (Leydig) cells of the testes.
Traditionally, the main indication for androgen
replacement therapy (ART) has been the management
of males with hereditary or acquired hypogonadism.
In this setting, the aim of androgen replacement is
virilization in prepuberal hypogonadal boys and resto-
ration or preservation of virilization in postpuberal
men. ART in these hypogonadal males is of proven
clinical benet.
Relative to levels seen in younger men, decreases
of serum T (total, free, and bioavailable) associated
with aging are routinely observed in otherwise healthy
older men. With advancing age, men can experience
degenerative changes and functional declines in certain
androgen targets such as bone, muscle, central nervous
system, and testes. The importance and relevance of
age-related androgen deciency are underscored by
population trend projections indicating that the
number of males over the age of 65 will grow rapidly
throughout the next several decades. Interventions
that could prevent disease in this growing population
are critical for public health and economic reasons.
For the individual, preventive treatments that reduce
age-associated disease and improve quality of life are
invaluable. Consequently, there has been growing
interest in studying the effects of ART in aging men.
NORMAL TESTOSTERONE
METABOLISM
T secretion by Leydig cells of the testes is regulated
by a negative-feedback loop involving gonadotropin-
releasing hormone (GnRH) and LH. T is normally
produced in men at a rate of about 48 mg/day
(~0.24 mol/day), occurring in a pulsatile manner.
14
The diurnal pattern has a peak level in the early
morning and a nadir in the evening. T can be converted
to dihydrotestosterone (DHT) within androgen target
cells (skin, liver, prostate, and other organs) that con-
tain the enzyme 5a-reductase.
5
T is also metabolized
to estradiol (E
2
) by the aromatase enzyme complex
in brain, fat, and the testes.
5
In typical healthy males,
the ratios of the resulting serum levels of DHT and E
2
to the total T level are approximately 1:10 and 1:200,
respectively.
In normal males, 2% of T is free (unbound) and
30% is bound to sex hormone-binding globulin
(SHBG).
2,4,6,7
The remainder is bound with lower
afnity to albumin and other serum proteins. Free and
albumin-bound portions make up the bioavailable T
fraction. These steroid-binding proteins (SHBG and
albumin) modulate androgen function. SHBG has a
higher afnity for T than for E
2
, and changes in SHBG
concentration change or amplify the hormonal milieu.
Elevated estrogens, thyroid hormone, and aging
increase serum SHBG levels and thereby decrease the
free T fraction. On the other hand, androgens, growth
hormone, and obesity depress SHBG levels and
increase the free T levels.
MECHANISMS OF ANDROGEN
ACTION
Androgens and estrogens, like other steroid hormones,
initiate their effect at the cellular level by interacting
with high-afnity receptor proteins located within
target cells. Androgen receptors are present in the
highest concentration in androgen target tissues such
Hypogonadism and Androgen Replacement
Therapy
Joel M. Kaufman and Allen D. Seftel
CHAPTER 14
as the accessory organs of male reproduction.
8
T acts
in cells directly through androgen receptor-mediated
interactions and indirectly through the metabolism of
T to either E
2
or DHT. DHT acts principally through
the androgen receptor and primarily on the prostate;
E
2
acts directly on the estrogen receptor. The role of
other T metabolites is not well dened.
CONDITIONS CHARACTERIZED BY
HYPOGONADISM
Some common causes of hypogonadism are listed
in Table 14.1. Testicular failure may have a genetic or a
developmental basis, or may be acquired. Klinefelter
syndrome, the most common cause of primary testicular
failure, occurs in 1 in 500 to 1000 male births.
Hypogonadism may occur if the hypothalamic
pituitarygonadal (HPG) axis is interrupted at any
level. Hypergonadotropic hypogonadism (primary
hypogonadism) results if the gonad does not produce
the amount of sex steroid sufcient to suppress
secretion of LH and follicle-stimulating hormone (FSH)
at normal levels. Hypogonadotropic hypogonadism
(secondary hypogonadism) may result from failure of
the hypothalamic LH-releasing hormone (LHRH)
pulse generator or from inability of the pituitary to
respond with secretion of LH and FSH. Most commonly,
204 Hypogonadism and Androgen Replacement Therapy
TABLE 14.1 Clinically dened hormone deciencies
Type Description Reference
Trauma A direct physical injury to the testes may damage the cells that 9
produce T
Orchitis Testicular inflammation can occur after a postpuberty bout of 10
mumps (higher risk of infertility than of low T), radiation treatment,
or chemotherapy. These therapies for other diseases may damage
the T-producing cells of the testes
Testicular tumors Treatment of testicular tumors may directly affect T production 11
Klinefelter syndrome Occurs in 1 in 500 to 1 in 1000 male births. T production is low to 12
low-normal; men with this syndrome may also have markedly
reduced bone density
Kallmann syndrome Usually a recessive genetic disorder associated with the 13
X chromosome; occurs in about one in every 10 000 men.
A deciency of GnRH impairs the release of LH and FSH, thus
decreasing T production; men with the syndrome lack the sense
of smell; testes do not enlarge at puberty
PraderLabhartWilli A genetic disorder characterized by muscle tone that is decreased 14
syndrome in infancy but improves with age, underdeveloped genitals
(including undescended testes in boys), and low sex hormone
levels. An obsession with food and compulsive eating, also linked
with this disorder, may begin before the age of 6
Myotonic dystrophy The most common adult form of muscular dystrophy, this genetic 15
condition only occurs in men and is carried on the Y chromosome;
because testicular failure usually occurs around the age of 3040,
men may have sons at risk for the disease
Pituitary tumors The growth of abnormal tissue in the pituitary can disrupt the 16
glands normal functioning and interfere with hormone production
HIV/AIDS Viruses or other infectious agents may directly or indirectly affect 17
the hypothalamus, pituitary, or testes and can decrease T levels;
as many as 50% of men infected with the human immunodeciency
virus (HIV) may have low T
T, testosterone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone;
AIDS, acquired immunodeciency syndrome.
hypogonadotropic hypogonadism is observed as one
aspect of multiple pituitary hormone deciencies
resulting from malformations (e.g., septooptic dysplasia
or other midline defects) or lesions of the pituitary
that are acquired postnatally.
Non-age-related clinically dened
hormone deciencies
See Table 14.1.
Age-related declines in serum
testosterone
Although wide interindividual variations exist, mean
total and free T levels decline with age, whereas DHT
and E
2
levels tend to remain relatively constant. At
75 years, mean total T level in the morning is about
two-thirds of the mean level at age 2030 years,
whereas the mean free T and bioactive T (free T plus
albumin-bound T) levels are only 40% of the mean
levels in younger males.
18
Moreover, the circadian
rhythm (higher levels in the morning than in the
evening) of serum T levels is generally lost in elderly
men.
19
Numerous cross-sectional and longitudinal studies
have conrmed the age-related decrease in serum T
concentration.
2028
The Baltimore Longitudinal Study
on Aging,
26
which found that there were invariant,
longitudinal effects of age on both T and the free T
index, is noteworthy. Based on measurements of total
T, the incidence of hypogonadal T levels increases to
about 20% in men over 60, 30% in men over 70, and
50% in men over 80 years of age (Figure 14.1).
Changes with aging in the
hypothalamicpituitarygonadal axis
The age-related decline in T is attributable to several
factors, including decreased Leydig cell mass, decreased
testicular blood perfusion with relative hypoxia, and
alterations in pituitaryhypothalamic function.
21,29
Additionally, the levels of non-specically bound free
T decrease with age as a result of age-dependent
increases in SHBG binding capacity.
3,3035
This
endocrine circuit, the HPG axis in men, is illustrated in
Figure 14.2.
Conditions Characterized by Hypogonadism 205
Age (years)
F
r
e
e

T
-
i
n
d
e
x

(
n
M
o
l
/
n
M
o
l
)
0.1
0.2
0.3
0.4
30 40
(177)
(144)
(151)
(158)
(109)
(43)
50 60 70 80 90
0.5
Age (years)
T
e
s
t
o
s
t
e
r
o
n
e

(
n
M
o
l
/
L
)
10
12
14
16
18
30 40
(177)
(144)
(151)
(158)
(109)
(43)
50 60 70 80 90
20
Figure 14.1 Longitudinal effects
of aging on date-adjusted
testosterone (T) and free T index.
Linear segment plots for total T
and free T index versus age are
shown for men with T and sex
hormone-binding globulin
(SHBG) values on at least two
visits. Each linear segment has a
slope equal to the mean of the
individual longitudinal slopes in
each decade, and is centered on
the median age, for each cohort
of men from the second to the
ninth decade. Numbers in
parentheses represent the
number of men in each cohort.
With the exception of free T index
in the ninth decade, segments
show signicant downward
progression at every age, with no
signicant change in slopes for T
or free T index over the entire age
range. (Reproduced with
permission from Harman SM,
Metter EJ, Tobin JD et al.
Longitudinal effects of aging on
serum total and free testosterone
levels in healthy men. Baltimore
Longitudinal Study of Aging.
J Clin Endocrinol Metab 2001;
86:724731.)
CLINICAL MANIFESTATIONS OF
DECLINES IN SERUM TESTOSTERONE
Effects of testosterone deciency at
androgen target organs
Sexual function
Sexual interest and activity and erectile rigidity and
duration decline in men as they age. Erectile dys-
function (ED) is seen with an age-stratied incidence
of 1.9% at 40 years and 25% or greater by age 65.
36
The reported incidence of endocrinopathy as the
etiology of ED is 135%.
37
Interestingly, the incidence
of abnormally low serum T levels even among men
with ED is generally small (6.6%). The majority of
studies show that ED has a clear association with aging,
but no consistent correlation of total T with erectile
condition had been identied.
3842
The role T levels
play in penile erection is unclear, and so far appear
to be different from the effects that T has on the
peripheral mechanism of erection in animal models.
The physiological functions required for erection
require vascular changes that alter the trabecular
structure of the corpora cavernosa. Although no direct
link has been made to muscular atrophy or penile
neurologic control, it may be that T not only affects
human behavior, but also subtly changes a number of
physiologic parameters.
43
Bone and osteoporosis
Decreased bone density occurs in about 25% of
patients with Klinefelter syndrome and probably
reflects both decreased bone formation and increased
bone resorption.
44
Even in the absence of overt hypo-
gonadism, bone mineral density (BMD) loss in males
Figure 14.2 Changes with age in the hypothalamicpituitarygonadal (HPG) axis in men. Gradual changes with age in
the regulation of the HPG axis result in a mixture of partial dysfunctions at each organic level. Primary gonadal failure
leading to partial hypergonadotropic hypogonadism (A) is intermingled with central defects of the hypothalamicpituitary
unit, usually causing only mild secondary gonadal failure or hypogonadotropic hypogonadism (B). Age-associated
changes at the testicular level are reductions in the numbers of Leydig and Sertoli cells, thickening and hernia-like
protrusions of the basal membrane of the seminiferous tubules, development of vacuolization, accumulation of lipofuscin
within the Leydig cells, and a decrease in the testosterone (T) production capacity when the testes are stimulated by
human chorionic gonadotropin; moreover, SHBG levels in serum are upregulated with age. The sum of all these changes
results in diminished levels of bioavailable T. This in turn should lead to compensatory upregulation of the
hypothalamicpituitary unit but concomitant changes at these levels (failure of the hypothalamus to generate appropriate
amplitudes of the pulsatile secretion, bursts of gonadotropin-releasing hormone (GnRH), higher sensitivity to the
suppressive effects of T, and smaller amounts of GnRH released at each pulse) seem to be responsible for age-
associated inadequate T production and availability. Moreover, despite declining opioidergic suppression of GnRH
secretion, old men fail to restore GnRH adequately and luteinizing hormone (LH) synchronous pulsatility and amplitudes
to compensate for mostly mild primary hypogonadism reflected by too low T serum levels. FSH, follicle-stimulating
hormone. (Reproduced with permission from Harman SM, Metter EJ, Tobin JD et al. Longitudinal effects of aging on
serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab
2001; 86:724731.)
Hypothalamus
Hypergonadotropic
GnRH
Pituitary
Gonadotroph
LH
+
+
-
-
+
T
FSH
Leydig cell
Inhibin
Testosterone
Testis A B
Sertoli cell
Hypothalamus
Hypergonadotropic
GnRH
Pituitary
Gonadotroph
LH
+
+
-
-
+
T
FSH
Leydig cell
Inhibin
Testosterone
Testis
Sertoli cell
is often observed after the third decade of life and
increases with age, accelerating after age 70.
45
Aromatization of T to E
2
plays an important role
in mediating T-induced increases in BMD. Serum T and
E
2
levels decline with advancing age in men, but the
contribution of these changes to age-related bone loss
remains unclear. Generally, E
2
is the major regulator
of osteoclastic activity, while both E
2
and T regulate
osteoblast activity.
46
Nevertheless, hypogonadism is
widely considered an important cause of male osteo-
porosis, occurring in up to 20% of men with vertebral
fractures and 50% with hip fractures.
47
Body composition
Approximately 2030% of skeletal muscle mass is lost
between the ages of 20 and 80. This age-related loss of
muscle mass, sometimes described as sarcopenia of old
age, is the result of a multifactorial process that can
be related to nutrition and level of physical activity,
as well as to age-associated changes in the bodys
hormonal environment.
A link between serum T levels and muscle mass
and strength has been demonstrated.
48,49
Baumgartner
et al. studied 121 male participants in the New Mexico
Elder Health Study and found that free T index,
insulin-like growth factor-1 (IGF-1) levels, and physical
activity were strong predictors of muscle mass and
strength.
48
Perry et al. studied 65 older African-
American men (aged 70102 years) in the Saint Louis
University Inner City Aging Project, and demonstrated
an age-related decline in T levels in this cohort.
49
Additionally, T levels correlated with upper- and lower-
limb strength and functional status. The mechanisms
by which T affects muscle have been reported to be
increased protein synthesis, increased intramuscular
mRNA concentrations of IGF-1, and decreased con-
centrations of the inhibitory IGF-binding protein 4.
50
The data overall indicate a stimulation of the intra-
muscular IGF-1 system during T administration.
5052
Hematopoiesis
With aging, hemoglobin and hematocrit values tend
to decline.
53
Androgens stimulate erythropoiesis by
enhancing erythropoietin production by means of
receptor-mediated transcription and by a direct effect
on bone marrow.
53
Androgen receptors are present on
cultured erythroblasts and exogenous androgens have
direct stimulatory effects on bone marrow stem
cells.
54,55
T also enhances the production of heme and
globin.
56
The stimulatory effects androgens have on erythro-
poiesis are so pronounced that, before the widespread
use of synthetic erythropoietin, androgens were
frequently used for the treatment of patients with
anemia and chronic diseases such as end-stage renal
failure.
55
It is generally understood that T, but not DHT,
stimulates erythropoiesis in a dose-dependent manner.
Clinically, T levels within the low-normal range for
men are required for maximal stimulation of
erythropoiesis.
57
Cognition and mood
Biologically plausible mechanisms derived from animal
studies suggest that endogenous sex hormones affect
cognition.
5861
Relatively few studies have investigated
the relationship between endogenous sex steroid
levels and cognition in humans; studies examining the
relationshipbetween endogenous T levels andcognition
have yielded conflicting results.
6270
Cardiovascular, brinolytic, and immune
systems
Epidemiologic data indicate that elderly men who
suffer an acute thrombotic stroke have lower circulating
levels of T thantheir healthy counterparts.
71
Moreover,
some investigators have found an inverse relationship
between serum T levels and the extent of coronary
artery disease.
72,73
The underlying mechanisms explain-
ing the detrimental effects of hypotestosteronemia on
the cardiovascular system are not clear, but may relate
to inhibition of normal brinolytic activity.
7476
Androgen receptors have been identied on various
immune cells, suggesting that these cells are directly
affected by hormones, conrming the long-appreciated
influence of these steroids on the immune system.
77
In several animal models of autoimmunity, T has
antiinflammatory properties and exerts immuno-
suppressive effects.
78
Tsung and Ajlouni
79
found that
certain types of immune effector cells were lower in
men with Klinefelter syndrome than in age-matched
controls.
ANDROGEN REPLACEMENT
THERAPY IN THE HYPOGONADAL
MALE: RISKS AND BENEFITS
Age-related clinical problems prevalent in older men
are numerous, including sexual dysfunction, muscle
weakness and wasting, changes in body composition,
osteopenia and increased prevalence of hip and
vertebral fractures, decreased hematopoiesis, and
memory loss, and their etiologies are multifactorial.
Age-related androgen deciency or insensitivity may
play a role in the pathophysiology of these disorders
and ART may help prevent or reverse them.
However, the number of well-controlled studies
investigating the potential benets of androgen
supplementation in elderly males is still small, and
the number of patients evaluated is limited to a few
hundred. Hence the experience is narrow and the
clinical results should be interpreted critically.
Androgen Replacement Therapy in the Hypogonadal Male: Risks and Benefits 207
Benecial effects
Sexual function
Although the correlation between ED and low levels
of T is weak, there is, nevertheless, evidence of patient
benet from ART in hypogonadal men. Jain et al.
80
reviewed the literature to assess the usefulness of
androgen replacement for ED. They evaluated 73
reports retrieved from a MEDLINE search from 1966
to 1998 and included 16 in their analysis. The overall
response rate to ART was 57%. In the nine studies
with responses rated by etiology, patients with primary
versus secondary testicular failure had a response rate
of 64% versus 44% (P < 0.001). Intramuscular and oral
routes of delivery were equivalent, with a response
rate of 51.3% and 53.2%, respectively. However, the
response to transdermal therapy was signicantly better
than that of intramuscular and oral treatment (80.9%
versus 51.3% and 53.2%, respectively, P < 0.001).
In addition, there was a statistically signicant differ-
ence favoring T over placebo in response rate, implying
a role for T supplementation in select groups for
the treatment of ED. In a study of 227 hypogonadal
men Wang et al. also noted improvements in sexual
function and mood that peaked after 30 days of
treatment.
81
Other evidence indicates that ART in aging hypogo-
nadal men results in increased libido and sexual
activity,
82
and that T can improve penile rigidity.
83,84
Corroborating observations were also reported in a
study by Davidson et al. that found the stimulatory
effects of T on sexual activity were rapid, reliable, and
not due to a placebo effect.
85
Bone
As the natural lifespan increases, osteoporosis is
increasingly a problem for the elder male. ART has
been reported to improve bone mass but not to prevent
fractures in young and older hypogonadal men.
8690
A number of studies have evaluated the effects of
T therapy on BMD (over 36 months) and the bio-
chemical parameters of bone turnover in older men
(over 3 months).
52,91
Some, but not all, of the studies
enrolled older men who were osteoporotic at baseline,
with one study evaluating T therapy in men undergoing
chronic treatment with glucocorticoids. T therapy
slowed the rate of bone degradation and signicantly
increased BMD, especially in the lumbar spine.
90
Signicant positive changes were observed in all
three randomized trials
88,90,91
that compared T with
placebo treatment in a total of 188 men. Using varied
assessments, including hydroxyproline excretion,
lumbar spine BMD, or femoral neck BMD, investigators
demonstrated that short-term T supplementation in
older men results in slowed bone resorption and higher
BMD.
Body composition
It appears clear that muscle mass increases with
ART, but associated increases in strength have not
been demonstrated.
48
There remains a need to dene
relevant outcomes using muscle strength, power, and
endurance parameters as aspects of T replacement.
Investigators agree that ART increases fat free mass,
muscle size, and maximal voluntary strength in young,
healthy, androgen-decient men. The long-term effects
of T supplementation on muscle strength and physical
function in older men are unknown. Several short-
term studies have examined the anabolic effects of
T replacement on body composition in older men with
low T levels. The landmark studies of Tenover
91
and
Snyder et al.
92
demonstrate that physiological T
replacement in older men with low T levels produces
modest increases in lean body mass, BMD, and grip
strength. It remains to be seen whether physiological
T replacement can induce clinically meaningful changes
in muscle function, reduce falls and fractures, or
improve quality of life in older men. Also, the effects
of T supplementation in the frail elderly (particularly
the oldest old, the population that is the most at
risk for falls, fractures, and debility) have not been
examined. Most studies of androgen effects have used
relatively low doses of T. It is conceivable that a higher
T dose may yield larger effect sizes.
A total of 211 hypogonadal men were evaluated for
body composition changes linked to T supplementation
in six randomized, placebo-controlled studies.
9196
In four of the six studies signicant changes favoring
T over placebo in lean body mass or strength were
observed.
91,92,95,96
In a study of 23 middle-aged obese
men, Marin et al.
97
found that T treatment was followed
by a decrease of both visceral fat mass and lean body
mass. Insulin resistance improved, and blood glucose,
diastolic blood pressure, and serum cholesterol
decreased with T treatment. Furthermore, a report by
Ferrando et al.
94
highlights the specic mechanisms
that may be responsible for these changes, identifying
signicant changes in IGF-1 and muscle metabolism
that favored decreased muscle breakdown in older
men treated with T.
Lipid metabolism
Evidence is emerging that supports both the associ-
ation of low T levels with potentially unfavorable
changes in triglycerides and high-density lipoprotein
(HDL) cholesterol and the hypothesis that such abnor-
malities can be corrected by restoring physiological
levels of androgens.
98
On the other hand, some concern
exists about elevations in low-density lipoprotein (LDL)
cholesterol following administration of exogenous
androgens. In three placebo-controlled studies of 188
men, ndings concerning T supplementation effects
on lipid prole varied, with one study of 13 men
98
reporting a reduction in total cholesterol, a second
study of 108 men
99
reporting no signicant changes
between placebo and treatment groups, and a third
study of 67 men
100
reporting reductions in HDL
cholesterol only. The clinical consequences of the
changes in lipids associated with ART have not been
claried.
101
Cognition and mood
Assessing the impact of ART on cognition and mood in
aging hypogonadal males is a complex challenge, and
only preliminary work has been completed. Several
small, blinded, placebo-controlled T replacement
studies in older men demonstrated that subjects
randomized to T reported an improved sense of well-
being when compared with a similar group on
placebo.
100,102105
Four studies have evaluated ART
and neurocognitive function in older men.
102105
Each
showed encouraging results with ART, but much
additional investigation is needed in this area.
Cardiovascular
Epidemiological studies have shown a generally
inverse relationship between endogenous T and the
presence or severity of coronary artery disease.
106108
In several small controlled studies of 96 men overall,
T treatment was found to decrease exercise-induced
ST segment depression, perhaps reducing the degree
of coronary artery disease in these patients.
109,110
Other
studies have found no effect of T upon the vascular
system, while HDL levels have been reduced.
100
Immune system
The association of hypogonadism with an increased
risk of autoimmune and rheumatic diseases was
investigated by Yesilova et al.
111
in a study comparing
pre- and posttreatment effects on immune system para-
meters. In this study, 29 male patients with idiopathic
hypogonadotropic hypogonadism were treated with
human gonadotropin combined with human chorionic
gonadotropin (hCG) to stimulate T production. Favor-
able changes were noted in both cell-mediated and
humoral immunity, suggesting that T levels may play
a role in modulating these aspects of the immune
system.
Testosterone regulation of prostate cells
The critical influence of androgens on cell turnover
within the prostate makes this organ particularly sensi-
tive to ART.
Androgens are the major regulators of cell prolifer-
ation and death within the normal prostate. This is
because androgens regulate the total number of
prostatic epithelial cells by chronically stimulating the
rate of cell proliferation while simultaneously inhibiting
the rate of cell death of specic subsets of androgen-
sensitive and -dependent epithelial and endothelial
cells within the prostate.
112114
Within the normal prostate, the glandular epithelial
and a subset of endothelial cells are androgen-
dependent; without sufcient levels of circulating
androgen, their rate of cell proliferation is lower than
their rate of cell death.
112114
The cells within the basal
compartment can be divided into two types: the
prostatic basal cells, which are androgen-independent,
and the amplifying cells, whose rate of cell prolifer-
ation over rate of cell death is enhanced by androgen
(i.e., these cells are androgen-sensitive but not
androgen-dependent). Thus, the prostate is hetero-
geneously composed of a limited number of androgen-
independent stem cells that give rise to a larger subset
of progeny while maintaining their own limited
numbers.
The majority of these androgen-sensitive amplifying
cells differentiate into androgen-dependent transit (i.e.,
glandular) epithelial cells. Once the normal number
of these transit cells is reached, their rate of cell
proliferation balances their rate of cell death such that
neither prostatic regression nor continuous glandular
overgrowth occurs.Thus, in the presence of physiologic
androgen, the normal prostate is at steady state,
heterogeneously composed of androgen-independent,
-sensitive, and -dependent epithelial cells. Due to the
clonally expansive nature of this hierarchical stem cell
organization, the vast majority of the epithelial com-
partment is composed of androgen-dependent glandular
cells, with lower numbers of androgen-sensitive basal
cells, and a limited number of androgen-independent
basal stem cells.
115
Adverse effects
Potential averse effects of testosterone
treatment in the prostate
As is true for all forms of medical therapy, before
initiating ART, one must understand and balance the
possible therapeutic benets against the potential
risks. No placebo-controlled trial of ART has reported
an increased incidence of prostate cancer in men on
therapy, but the total extent of assessed treatment in
these trials is merely 1500 man-years.
116
Safety con-
cerns must be carefully evaluated without large, long-
term, placebo-controlled studies to support denitive
statements about the effects of ART on prostate cancer
or symptomatic benign prostatic hypertrophy (BPH)
incidence.
Benign prostatic hypertrophy
The primary potential risks associated with ART
are focused on the prostate. Hypogonadal young men
tend to have small prostate glands that increase in size
Androgen Replacement Therapy in the Hypogonadal Male: Risks and Benefits 209
to those of age-matched controls with androgen
replacement.
117,118
Whether a similar growth of the
prostate would affect clinical symptoms of urinary
obstruction in older men undergoing ART remains a
subject of great interest. Clinical trials of ART in aging
men showed no difference between controls and
T-treated men in the need for invasive treatment;
however, study population size was relatively small
and treatment time relatively short. Evaluation of
markers of BPH has shown no signicant rise with
T treatment.
119
Other studies examining prostate size
have found that prostate size increases with age
regardless of the patients ART status.
120
Interpretation
of these generally favorable ndings must be tempered
by the understanding that these trials excluded men
with overt prostatic enlargement.
Prostatic cancer
Prostate cancer is the most prominent of the safety
concerns associated with ART. Whether T therapy in
older men places them at increased risk of developing
clinically important prostate cancer from preexisting
but subclinical disease is unknown. Only the concept
that T promotes growth of an established adeno-
carcinoma is rmly established. Since autopsy series
show that the overall frequency of latent prostate
cancer is between 20% and 40% for men aged 6080
years,
121
this is a safety concern that deserves
consideration. Although many of these undetected
cancers probably have limited invasive potential, the
addition of exogenous androgen stimulation may
theoretically lead to cancer growth and spread. In a
study that investigated whether the effectiveness of
chemotherapeutic agents would be enhanced by con-
current T therapy, Fowler and Whitmore
122
found that,
among 52 patients with metastatic adenocarcinoma
of the prostate who were treated with exogenous T,
serious morbidity or mortality, seemingly due to the
T administration, occurred in eight cases (15%), and
87% experienced unfavorable subjective and/or
objective responses.
Evidence that the prostate cancer risks from use of
ART may not be as great as postulated comes from
several sources. Using prostate-specic antigen (PSA)
as a marker for prostate cancer, all trials have shown
no change or only a modest (within normal range)
increase in PSA after T administration.
116,123,124
Further-
more, there has been no conclusive evidence, despite
numerous epidemiologic studies, that levels of
circulating T in individuals developing prostate cancer
are higher than in controls.
125,126
The current evidence suggests that ART has little
effect on the prostate in up to 3 years of treatment.
127
It is possible that treatment of longer duration could
affect the prostate. Until longer studies are initiated,
PSA levels should be carefully monitored during ART.
An increase of PSA levels by more than 0.75 ng/ml
in two consecutive evaluations would be considered
reason for treatment termination.
128
Hematopoiesis
The stimulatory effects androgens have on erythro-
poiesis are distinctly pronounced, and it should not be
surprising that the effects of ART on hematopoiesis
must be monitored.
55
Polycythemia with ART is more likely to occur in the
elderly than in the young, and it may be necessary
either to terminate therapy or to decrease the dose
of T. In a 12-month randomized controlled trial of
T replacement, 22 older hypogonadal men were
enrolled and 17 received T treatment. Three patients in
the placebo group and seven in the T group withdrew
from the study, with three of the seven withdrawing
because of an abnormal elevation in hematocrit.
95
Cardiovascular risk
Although male hypogonadism may confer some
increased risk for certain cardiovascular factors,
evidence supporting a potential for a negative impact
of ART on cardiovascular risk includes the higher
incidence of cardiovascular disease in men when
compared with women of the same age, the decrease
in HDL cholesterol levels at puberty in boys, the
increase in HDL cholesterol seen when either young
or old men are made hypogonadal, and the develop-
ment of a more atherogenic serum lipid prole in
young adult men who are taking non-aromatizable
androgens.
Sleep apnea
T has a direct effect on the neuromusculature of the
upper airway and may exacerbate or lead to develop-
ment of obstructive sleep apnea,
129
so it is important
to evaluate the effects that ART may have on sleep
apnea.
However, a recent long-term study did not nd any
difference in the respiratory distress index between
patients being treated with T patches and those
receiving a placebo.
92
APPROACH TO DIAGNOSIS
No denitive criteria have been established to identify
the appropriate candidate for supplemental androgen
therapy, and even dening the hypogonadal state in
certain settings remains controversial. Few would argue
with treatment of patients with sexual dysfunction
and low T levels caused by Klinefelter syndrome or
hypothalamicpituitary dysfunction. The uncertainty
centers on men with sexual dysfunction and low-
normal T levels. Generally, a diagnosis of hypo-
gonadism in an elderly male should be based on initial
symptom presentation and evaluation with a symptom-
based instrument, followed by a laboratory work-up of
serum T.
42,128
In a large series of men with ED screened
for hypogonadism, low serum T was correlated with
age over 50, low libido, and small testes.
42
Although there is general understanding of what
constitutes normal T levels in healthy younger indi-
viduals, there is no consensus on the serum T levels
that can be used to dene androgen deciency in
older men. Furthermore, no clinically useful biological
marker for androgen action is available. Total T levels
below 300 ng/dl
4,130132
or bioavailable T levels below
60 ng/dl
95
may warrant ART, especially if associated
with symptoms suggestive of androgen deciency.
Andropause
Andropause, the male equivalent of menopause, is
gaining recognition as a clinical problem in the aging
male. Admittedly, andropause is a normal physiologic
phase of aging, but for some men, it is accompanied by
distressing declines in sexuality, mood, and energy.
Not all physicians agree that these symptoms need
treatment with T. Indeed, lifestyle changes and other
interventions may improve many of the symptoms
associated with andropause. Nevertheless, in the face
of new clinical data, long-held negative views on the
need for and effects of ART in the aging are being
challenged. A growing number of clinicians now agree
that, for select patients, T supplementation may
provide real benet.
The clinical manifestations of male secondary hypo-
gonadism were rst described more than 50 years ago
by Werner.
133
The symptom complex is composed of
at least one of the following components:
Decreased sexual desire and erectile quality,
particularly nocturnal erections
Changes in mood, with concomitant decreases in
intellectual activity and spatial orientation ability,
and increases in fatigue, depression, and anger
Decrease in lean body mass, with associated
diminution in muscle volume and strength
Decrease in body hair and skin alterations
Decrease in BMD, resulting in osteoporosis
Increase in visceral fat.
Clinical suspicion of the existence of age-related hypo-
gonadism does not require that all of the signs or
symptoms be present.
Questionnaires
Three validated questionnaires have been developed
to aid in the identication of males with aspects of the
andropause symptom complex. These instruments
provide reasonable screening questionnaires to detect
androgen deciency. Each has been validated by
comparing questionnaire results with other aspects of
andropause, including laboratory T levels.
The three tests are:
a new Aging Males Symptoms (AMS) rating
scale
134
Androgen Deciency in Aging Males (ADAM)
135
eight-item screener, validated using Massachusetts
Male Aging Study (MMAS) participants
136
More sophisticated diagnostic and monitoring question-
naires are in development.
Serum endocrine evaluations
Choice of assay
In addition to an adequate history and physical
examination, a biochemical assessment is necessary
if hypogonadism is suspected. The most relevant
measurement of T bioavailability should be the
unbound or free fraction, but commercial assays for
free T are inconsistent and have been considered
invalid by some investigators. Methods used to measure
serum T vary substantially, and even standardized
methods such as radioimmunoassay (RIA) are variable
depending on whether serum is extracted and/or
undergoes chromatography before RIA. Measurement
of free T by equilibrium dialysis methods is technically
demanding and measures that moiety of T not bound
to either SHBG or albumin, but is not available to
most clinicians. Some investigators prefer to use the
free T index, a calculated value, usually the ratio of
T to SHBG, but, for the most part, investigators rely on
the measure of total serum T.
128,137,138
Serum testosterone range
The problem of identifying the normal cutoff level for
T beyond which therapy should be initiated remains
unresolved. Wide individual variability in the thres-
hold of serum T below which impairment of androgen-
dependent processes becomes evident makes both
diagnosis and treatment difcult.
Although the range of normal values for serum T
varies among laboratories, morning T values below
300 ng/dl suggest hypogonadism and should be con-
rmed by a second determination.
It is generally accepted that two standard deviations
below normal values for young men is conclusively
abnormal. This range of values still adheres to the
concept of a societal mean that may not be relevant for
older men; indeed, the level of serum T that denes
deciency specically in an older man has yet to be
established.
Serum hormonal status
The circadian rhythm of T levels should be considered
in measuring serum T, with blood for measurement
drawn between 6:00 a.m. and 9:00 a.m.
Approach to Diagnosis 211
One or more of the following serum laboratory
measures may be required to diagnose andropause and
other clinically dened hormone deciencies:
Total/free/bioavailable T
SHBG
LH
FSH
THERAPY AND MONITORING
Androgen supplementation therapy is indicated in
patients with clinical manifestations supported by a
biochemical diagnosis. When biochemical hormonal
measurements are borderline abnormal, patients com-
plaints should be the deciding factor. The endpoints of
therapy should be based on the initial assessment of
the symptom complex. The target improvements are
clinical; numerical biochemical changes alone are of
limited clinical relevance. Thus, it is imperative that the
index symptoms be followed over a suitable period of
time with reassessments. If there are no measurable
symptomatic improvements over an appropriate
interval, therapy should be discontinued.
The trial of ART for andropause symptoms, including
ED or low libido, should be 23 months in duration.
This length of time is usually necessary to differentiate
true benets of therapy from placebo effects. Although
the use of androgen supplementation to improve
conditions such as osteoporosis or sarcopenia (i.e., loss
of muscle mass) is not usually the primary reason a
urologist would initiate such therapy, and improve-
ment of these conditions may be an added benet to
the patient. At the end of this trial period, a reassess-
ment of sexual function and other parameters is
indicated. Objective improvements in muscle mass and
BMD may require longer duration of therapy (6 months
or longer).
Dosage
Dening the optimum replacement regimen remains a
complex issue. It is not known whether T effects are
dose-dependent and whether dose requirements for
maintaining the various androgen-dependent processes
are similar. The critical issue is whether improvement
in sexual dysfunction and increases in muscle mass and
function can be achieved with dosages that will not
adversely affect lipid proles, cardiovascular risk, and
the prostate.
A basic general principle in hormone replacement
therapy is to mimic the endogenous prole of the hor-
mone being replaced. In the case of T, the complexities
of the diurnal pulsatile and circadian rhythms make
the endogenous prole difcult to mimic. Furthermore,
different androgen-dependent processes may have
different doseresponse requirements. For instance,
sexual function may be normalized by T concentrations
in the lower end of the normal male range.
The standard should be the lowest dose that
provides a mid-normal serum T range found in healthy
young men.
Monitoring testosterone replacement
therapy
Monitoring ART is an important aspect of treatment,
since prolonged ART can be associated with com-
plications, particularly in the prostate. In men aged
more than 40 years, a digital rectal examination and
PSA determination are mandatory before treatment.
For the rst year, patients should be followed up
quarterly to assess the response to therapy (clinical
and biochemical), including hemoglobin, digital rectal
examination, and PSA. Serum T should be normalized,
based on the mid-normal range for healthy young
men. Skin irritations should be monitored when patients
use transdermal T preparations. Lipid measurements
should be followed. Patients should be queried for
sleep apnea issues. Patients who remain stable may
subsequently be evaluated annually.
128,139141
Testosterone preparations
Although a wide choice of androgen formulations
and delivery systems is available (Table 14.2), the
pharmacokinetic prole of each available agent is
different, and the patients experience will differ
depending on the drug and delivery system selected.
Several alkylated derivatives of T are available for oral
or sublingual use, including methyltestosterone and
fluoxymesterone. However, they are not recommended
for use as replacement therapy because of their
associated adverse effects.
142
T undecanoate, an oral
non-alkylated androgen formulation not approved in
the USA, has a short half-life requiring multiple daily
doses. Long-acting intramuscular T (T enanthate, and
T cypionate) can be administered at 2- or 3-week
intervals and were previously the most widely used
preparations. A major disadvantage of intramuscular
TABLE 14.2 Testosterone (T) delivery systems
Delivery system Reference
T gel 46, 81, 93, 144146
Injectable T esters 147
Transdermal T patches 148150
T pellets 151155
Oral T undecanoate capsules 156
administration of T esters is inconsistent serum T levels
over time: the high level of serum T produced for
several days after injection, and the low level resulting
at the end of the dosing interval.
143
Transdermal
administration delivers T at a controlled rate into the
systemic circulation, avoiding the high and low levels
observed with intramuscular injections. Because
scrotal skin is more permeable to T than other skin
sites, the rst available T transdermal delivery system
was a scrotal patch. Patch and gel transdermal systems
for the delivery of T across non-scrotal skin have
largely supplanted scrotal patches. The relative lack of
skin irritation coupled with high compliance make T
gel a more favorable transdermal androgen delivery
method than the T patch.
When T gel is applied to the shoulders, upper arms,
and/or abdomen, its alcohol base dissolves, leaving
a clear, non-oily T lm that is absorbed into the
skin. From the skin, the T is slowly released into the
blood stream. T gel is now the most widely used T
preparation and the subject of denitive studies
concerning T administration.
81
Contraindications
Androgen administration is absolutely contraindicated
in men suspected of having prostate or breast cancer.
In men being treated for advanced prostate cancer, the
permissive effects of androgen replacement have been
shown by Fowler and Whitemore, who documented
(see Prostatic Cancer, above, in Adverse Effects
section) the enhancement of prostate cancer growth by
supplemental T, intended to render prostate cancer
more chemosensitive and radiosensitive.
122
Another
absolute contraindication to ART is severe bladder
outlet obstruction due to an enlarged clinically benign
prostate. Precautions are required for a number of
relative contraindications (Table 14.3 and see the
Adverse Effects section, above).
128, 139141
For an entirely different group of men from those
studied by Fowler and Whitmore, that is, males who
have been clinically cured of localized, favorable
pathology prostate cancer by radical prostatectomy,
ART may be an acceptable therapeutic approach, if
they have clinical manifestations of hypogonadism
supported by endocrine evaluation. Anecdotal reports
and small series of such patients have provided
very preliminary evidence that ART can be safely
administered to this group with careful monitoring and
follow-up.
157
FUTURE DIRECTIONS
Selective androgen receptor modulators
Androgen receptors are found in a wide range of tissues,
and androgens control a broad range of physiologic
functions. Current androgen replacement treatment,
while effective in improving certain clinical conditions,
is non-selective. The discovery and development of
selective androgen receptor modulators (SARMs)
provide the opportunity to design molecules that target
androgen receptors in different tissues to elicit the
desired activity.
Other androgen receptor-mediated effects that
are considered undesirable would be diminished or
eliminated with SARM treatment.
158
For example, if
the target is bone growth in elderly men with osteo-
penia or osteoporosis, but with no overt signs of hypo-
gonadism, a more anabolic SARM with clear effects on
bone and muscle, but lesser activity on prostate or
other sex accessory tissues, would be benecial.
158
Recent studies have identied a number of xenobiotic
ligands and non-steroidal compounds derived from
known antiandrogen pharmacophores.
159,160
These
compounds represent the series of molecules being
developed that selectively regulate the androgen
receptor.
CONCLUSIONS
In the current era of evidence-based medicine, the data
on ART in the aging male are mostly circumstantial,
based on experience in the treatment of transitional
or chronic endocrine deciencies in young men due to
disease or of a genetic nature. However, recently there
has been an increasing interest in evaluating whether
ART may be benecial for a specic category of aging
men in preventing or delaying some aspects of aging.
This chapter has reviewed the current state of research
on androgen supplementation for hypogonadal men,
TABLE 14.3 Contraindications to androgen
administration
Absolute
Existing prostate cancer
Existing or prior history of breast cancer
Severe obstructive BPH
Sensitivity to T formulation ingredients
Hematocrit 55%
Relative
Hematocrit 52%
Untreated sleep apnea
Moderate obstructive BPH
Advanced congestive heart failure
BPH, benign prostatic hypertrophy; T, testosterone.
Conclusions 213
with particular reference to aging men. Whether
and to what extent cognition and mood, bone and
muscle mass, sexual function, and the cardiovascular,
brinolytic, and immune systems can be altered
benecially by T replacement remain to be claried
by improved outcome measures and larger studies.
Although there have been suggestive positive results,
it is inappropriate to draw rm conclusions without
longer and larger studies. Larger, longer-term studies
are also required to analyze possible adverse effects
of T supplementation on lipid metabolism, prostate
health, and cardiovascular disease incidence.
The critical problem of dening the clinical and
laboratory diagnostic criteria that identify the appro-
priate target population for treatment with ART is the
focus of current research. Large placebo-controlled,
clinical studies will clarify whether men with chronic
illness and low T levels or those with sexual dysfunction
and low-normal T levels should receive supplemental
androgen therapy.
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INTRODUCTION AND DEFINITION
Priapism is a relatively uncommon medical condition
that is dened as a pathological prolonged engorgement
or erection of the penis or clitoris that is unrelated to
sexual arousal. The condition is more common in men
and typically involves the paired corpora cavernosa,
although rare exceptions with involvement of the
corpus spongiosum and sparing of the cavernosal
spaces have been reported.
1
The term priapism is
derived from Priapus, a minor god of fertility, luck, and
the deity of gardens and elds in Greek mythology.
2
A
famous painting in the entrance to the House of Vettii
in Pompeii depicts Priapus with a disproportionately
large phallus, leaning against a pillar and weighing
his massive penis. Conditions related to the prolonged
engorgement of the penis were associated with Priapus
in the Greek language and were later assimilated into
Latin and modern languages.
2
Priapism is broadly
classied as low-flow (ischemic) or high-flow (arterial
and non-ischemic). Low-flow priapism and the
associated severe decrease in venous drainage from the
corpora cavernosa is a potential medical emergency
and may lead to irreversible ischemic tissue changes.
High-flow priapism is less commonly encountered and
involves unregulated inflow that is typically secondary
to some form of arterial trauma. Stuttering priapism
refers to a condition of recurrent, intermittent, painful
erections. Malignant priapism is a rare clinical entity
that is caused by metastasis of solid tumors to the
penis.
EPIDEMIOLOGY AND ETIOLOGY
The incidence of priapism in the general population
has been evaluated by Eland et al. These investigators
conducted a population-based retrospective cohort
study using a longitudinal observational database from
the patient records of a group of general practitioners
in the Netherlands. They found an overall incidence
rate of 1.5 per 100 000 person-years.The incidence rate
in men 40 years old and older was 2.9 per 100 000
person-years.
3
The authors acknowledged that not all
patients with priapism will seek medical care and the
reported data may be an underestimation of the actual
rate in the general population. The incidence of
priapism in special at-risk subpopulations is much
higher. At-risk populations include men with cocaine
drug use, advanced pelvic or hematologic malignancy,
and those on antipsychotic medications.
47
Pohl et al.
8
evaluated various etiologies for priapism in a study of
230 single case reports in the literature: idiopathic
causes comprised one-third of the cases while 21%
were attributed to alcohol abuse or medications, 12%
to perineal trauma, and 11% to sickle-cell anemia
(SCA).
Intracavernosal injection therapy with
erectogenic agents
For individuals on intracorporal injection therapy
for erectile dysfunction (ED), the incidence range or
priapism episodes is from 1% for those on prosta-
glandin E
1
, and as high as 17% for patients who
receive intracorporal injections of papaverine.
9
The
most likely cause of prolonged erection as a result of
intracavernous injection therapy is overdosage. Proper
injection technique and gradual upward titration of
the dose by the patient will help decrease this adverse
event.
Sickle-cell hemoglobinopathies
Priapism associated with sickle-cell disease is classi-
cally described as ischemic, although rare exceptions
of high-flow priapism in association with sickle-cell
disease have been reported. The pathophysiology of
high-flow priapism in patients with sickle-cell disease
is not known.
10
Fowler et al.
11
evaluated the incidence
and prevalence of priapism in sickle-cell conditions.
The authors reported frequent self-limited priapistic
episodes, mostly occurring during sleep, that last less
than 3 h. Priapism associated with SCA was unusual
before puberty and in keeping with previously reported
6% prevalence of priapism in children with SCA.
12
No correlations are observed between the average
number of priapism episodes per year and the duration
of a typical episode. A similar study from Jamaica
documented a 42% prevalence of priapism in SCA
patients.
13
Priapism was signicantly associated with
Priapism
CHAPTER 15
low hemoglobin F levels as well as high platelet counts
and over one-fourth of those who had suffered priapism
had some degree of impotence. A more recent survey
of patients with homozygous SCA (Hb SS) and sickle-
cell beta(0)-thalassemia (Hb S-beta(0)) between 5 and
20 years of age found an 89% actuarial probability of
experiencing priapism by 20 years of age. The mean
duration of an episode in this study was 125 min.
Episodes typically occurred around 4.00 a.m., and
75% of the patients surveyed had at least one episode
starting during sleep or upon awakening from sleep.
14
Medications and drugs
Drug-induced priapism has been reported with a
variety of medications, most commonly related to the
antihypertensive drugs guanethidine, prazosin, and
hydralazine as well as psychotropic medications.
15
Antipsychotics are associated with a small but denite
risk of priapism and the most commonly cited agents
are trazodone (desyrel), thioridazine, and chlor-
promazine.
16
Abber et al.
17
investigated the mechanism
of drug-induced priapism in dogs by intravenous and
intracorporal injection of the antipsychotic agent
chlorpromazine and the antidepressant trazodone. The
authors demonstrated that both drugs induced erection
in a manner similar to that of intracorporal injection of
papaverine and showed venous restriction as well as
slight increases in internal pudendal arterial flow at
the beginning of tumescence. The authors stated that
the -adrenergic antagonist properties of chlor-
promazine and trazodone probably cause priapism by
local action. Psychotropic-induced priapism is almost
always associated with low-flow pathology and is
currently believed to be caused by the
1
-adrenergic
antagonism of these medications. Chlorpromazine and
thioridazine are conventional antipsychotics with the
greatest
1
-adrenergic afnity and have been most
frequently reported to be associated with priapism.
4
The exact pathophysiology has not been elucidated,
but is likely multifactorial and may be related to the
ratio of -adrenergic blockade to anticholinergic
activity. Risperidone, olanzapine, and clozapine are
the atypical antipsychotics that have been reported to
cause priapism on rare occasions.
4
It has been reported that trazodone and cocaine may
have synergistic effects in promoting priapism and
their combination may pose an additional risk of
priapism. Clinicians should be aware of the possible
additive risk of priapism in this patient population,
since trazodone is commonly employed as a hypnotic
and is often chosen for polysubstance abusers due to
its low abuse potential.
18
Cocaine-induced priapism
has been reported in association with topical appli-
cation to enhance sexual performance, as well as intra-
nasal and intracavernous injections.
1921
Priapism has
also been reported in association with the recreational
drug Ecstasy.
22
Androgens have been implicated as an important
etiological factor, with reports of priapism in hypo-
gonadal men receiving gonadotropin-releasing hor-
mone or high-dose testosterone, testosterone-induced
priapism in adolescents with SCA, and priapism after
androstenedione intake for athletic performance
enhancement.
2326
Neurological factors
Examples of neurological etiologic factors include
priapism in patients with degenerative stenosis of the
lumbar canal, where symptoms may be fully relieved
by surgical decompression, and priapism secondary
to cauda equina syndrome (following degenerative
stenosis of the lumbar canal and lumbar arachnoiditis),
herniated disk, or blockage of the central inhibitory
influences, as seen during general or regional
anesthesia.
27,28
Systemic illnesses, total parenteral
nutrition, and miscellaneous etiologies
Noteworthy reports of systemic illnesses implicated as
etiologic factors include reports of priapism occurring
in widespread amyloidosis.
29
Other uncommon
etiologies include glucose phosphate isomerase
deciency (the third most commonly occurring
erythroenzymopathy) that can cause priapism through
increased rigidity of red blood cell membrane and
resultant increased blood viscosity; cell sludging in
the corpora and increased acidity; Fabrys disease
(glycosphingolipid lipidosis) presenting with a combi-
nation of renal insufciency and priapism; high con-
centration (i.e., 20% rather than 10%) fat emulsion
in total parenteral nutrition (TPN); and paradoxical
thromboembolic events in heparin- or warfarin-
induced priapism.
3034
Possible etiologies for increased
thromboembolic events in TPN-induced priapism
include increased blood coagulability and fat emboli as
well as direct cellular effects by high fat content.
Increased platelet function assessed by the levels of
antiheparin platelet factor IV and -thromboglobulin
has been documented in priapism following 20% fat
emulsion TPN.
33
Malignancy
The mechanism of malignant priapism has not been
denitively elucidated, but may be due to extensive
organ replacement by carcinoma, venous obstruction by
the tumor, or continual stimulus to the erectile afferent
or efferent neural pathways.
35
Tumor inltration is
most frequently from the bladder and prostate (32%
220 Priapism
and 28% respectively) followed by kidney (17%),
gastrointestinal tract (8%), and, rarely, from testis,
lung, liver, bone, and sarcomas as the primary source.
36
It has been reported that 2053% of cases of penile
metastasis from other primary tumors initially present
with priapism.
37
Trauma
Blunt perineal or genital trauma with resultant injury
to the arterial system and formation of an arterio-
lacunar stula is most often implicated as the causative
factor in non-ischemic high-flow priapism. The venous
outflow system is typically unaffected in these
conditions and the blood in the corpora remains well
oxygenated. High-flow priapism is far less common
than ischemic priapism and has been described in a
variety of conditions causing perineal trauma, including
bicycling injuries.
38
The most common etiology for
high-flow priapism in children is traumatic arterial
laceration, but cases associated with inherited meta-
bolic disorders (i.e., Fabrys disease) or hematological
diseases such as SCA have also been described.
3941
Table 15.1 is a classication of priapism by etiology,
as agreed upon by the American Foundation for
Urologic Disease (AFUD) Thought Leader Panel on
Priapism.
42
A more detailed list of etiologic factors
based on low-flow versus high-flow subtypes of
priapism is given in Table 15.2.
PATHOPHYSIOLOGY
Low-flow
Ischemic or venoocclusive priapism is a medical
emergency and the most common form of priapism.
It is characterized by a painful, rigid erection, absent
cavernosal blood flow, and severely acidotic corpora.
The spectrum of clinical symptoms and signs is
analogous to those found in other compartment
syndromes and mandates immediate decompression
to minimize the chances of long-term sequelae. The
combination of venous outflow obstruction, high-
Pathophysiology 221
TABLE 15.1 Etiology (AFUD classication)
41
Drug-induced
Hematologic
Sickle-cell disease and other
hemoglobinopathies
Thrombophilia states (protein C and other
thrombophilias, lupus)
Hyperviscosity states (hyperleukocytosis,
polycythemia)
Idiopathic
CNS-mediated
Other
AFUD, American Foundation of Urologic Disease;
CNS, central nervous system.
TABLE 15.2 Etiologic factors in priapism
Low-flow states (venoocclusive or ischemic type)
Hemoglobinopathies and sickle-cell disease
Thrombophilia states (lupus, protein C)
Warfarin/heparin-induced
Fabrys disease
Dialysis
TPN (high fat content)
Vasculitis
Hematologic malignancies
Pelvic/lower genitourinary tract (bladder and
prostate) cancer and metastatic (i.e., renal)
malignancies
Psychotropics and antidepressants
(chlorpromazine, trazodone, risperidol)
Antihypertensives (guanethidine, hydralazine,
prazosin)
Erectogenic agents (intracavernosal vasoactives;
sildenal; intraurethral PGE
1
)
Spinal cord stenosis
Amyloidosis
Glucose phosphate isomerase deciency
Alcohol
Androgens/testosterone
High-flow states (arterial or non-ischemic type)
Penile/perineal trauma
Straddle injury
Cavernosal artery injury
Arteriosinusoidal stula
Cocaine
Metastatic malignancy
Fabrys disease
Iatrogenic (following deep dorsal vein
arterialization)
TPN, total parenteral nutrition; PGE
1
, prostaglandin E
1
.
pressure chambers, and poor-to-absent inflow can lead
to trabecular interstitial edema and ultrastructural
changes in trabecular smooth-muscle cells and func-
tional transformation to broblast-like cells. In priapism
lasting more than 24 h, severe cellular damage and
widespread necrosis may occur.
43
Destruction of the
endothelial lining, formation of blood clots within the
corpora, and widespread transformation of the
smooth-muscle cells to broblast-like cells or necrosis
occurs in cases lasting beyond 48 h and eventually
results in irreversible ED.
43
Lack of these changes in
priapism lasting less than 12 h emphasizes the import-
ance of patient education and early intervention.
In an animal model, anoxia has been shown to
eliminate spontaneous and drug-induced contractile
activity, suggesting a likely explanation for the failure
of penile injection of -adrenergic agonists to reverse
prolonged ischemic priapism when the penis is in its
maximal rigid state.
44
The failure of detumescence
seen in low-flow priapism may be secondary to failed
-adrenergic neurotransmission, endothelin decit, or
inactivation of intracellular cofactors of smooth-muscle
contraction due to hypoxia and/or hypercarbia.
44
Recurrent episodes of venoocclusive priapism, occur-
ring anywhere from a few times monthly to recurrent
daily episodes, are quite disabling and often have an
idiopathic etiology. Levine et al. evaluated six patients
with recurrent venoocclusive priapism and ruled out
mechanical occlusion of corporeal venous drainage
by demonstrating elevated flows to maintain intra-
cavernosal pressures following smooth-muscle con-
traction and markedly decreased flow rates following
smooth-muscle relaxation.
45
The authors proposed
that a functional alteration of the adrenergic and/or
endothelial-mediated mechanisms that control penile
tumescence and maintain penile flaccidity may develop
secondary to the initial ischemic episode and reported
that the use of oral phenylpropanolamine reduced
the frequency and duration of the recurrences, and
markedly reduced the need for adrenergic self-
injection. Treatment of the recurrent episodes with
intracavernous self-injection of phenylephrine resulted
in successful detumescence in that series as well as the
authors experience with similar cases. The patients
must be instructed on the proper and early use of
phenylephrine self-injections.
Seftel et al. have reported on two cases of veno-
occlusive priapism refractory to conventional therapy
who later developed high-flow priapism.
46
The authors
suggested that the high-flow state observed after
treatment of venoocclusive priapism may represent a
variant of non-ischemic priapism or, alternatively,
may be the pathophysiology of recurrent idiopathic
priapism.
Neurologic control of the efferent erectile pathway
is via the pelvic nerves that are joined by the pre-
ganglionic parasympathetic nerves. The pelvic nerves
join the pelvic plexus that gives rise to the cavernous
nerve of the penis. Normally, penile stimulation will
cause reflexogenic erections that are primarily controlled
by the sacral parasympathetic nerves originating from
the S2S4 segment located at the T11L1 vertebral
levels. The afferent limb of the erection response is
mediated by the dorsal penile nerve (a branch of the
pudendal nerve) which transmits sensory impulses to
the spinal cord. The role of the sympathetic nervous
system in penile erection is not entirely clear, but its
activation is generally associated with contraction of
corpus cavernosal smooth muscle and penile detu-
mescence. The neuropathophysiology of priapism in
patients with lumbar stenosis has not been fully
elucidated, but it is postulated that it may be due to
parasympathetic efferent hyperactivity in the S2S4
cauda equina nerve roots within the narrowed thecal
sac. The parasympathetic hyperactivity may be
secondary to increased intrathecal pressure at the
stenotic level and altered circulation within the cauda
equina during walking.
47
Sickle-cell hemoglobinopathy results from the
inheritance of one or two genes coding for an
abnormal S hemoglobin and manifests in 0.15% of
black Americans in the form of sickle-cell disease
(homozygous for hemoglobin S) and in 8% as sickle-
cell trait (heterozygous for hemoglobin S). Inheritance
of a combination of a hemoglobin S gene and a second
gene coding for an abnormal hemoglobin (i.e., B
+
thalassemia or C hemoglobin) is possible and, as
in the homozygous type, may result in ischemic
complications.
11
The pathophysiology of SCA-induced
priapism is thought to result from decreased oxygen
tension and pH developing in stagnant blood within
the corporal sinusoids, which in turn leads to a cycle of
erythrocyte sickling and sludging, followed by even
more hypoxemia and acidosis.
48
Although the vast
majority of the cases are of the low-flow ischemic type,
high-flow priapism may be observed in patients with
sickle-cell hemoglobinopathy in rare instances.
10
High-flow
Non-ischemic or arterial priapism is a less common
form of priapism that presents clinically as a painless
erection that typically follows some type of penile or
perineal trauma, leading to unregulated arterial inflow
into the sinusoidal space. Unlike the venoocclusive
variant, high-flow priapism is not an emergency: the
outflow mechanism is intact and the cavernosal milieu
is not anoxic. The penis is often not maximally rigid in
these cases, but intercourse may be possible. Other
clinical observations include delayed onset of priapism
after perineal trauma and a state of constant sub-
optimal rigidity that may become more rigid with
222 Priapism
arousal.
48
Diagnosis is typically based on the afore-
mentioned clinical history and physical examination,
as well as demonstration of arterial blood on aspirated
cavernosal blood-gas studies. Spycher and Hauri have
shown that, at the level of trabecular smooth-muscle
cells, the ultrastructural changes and broblast-like
cellular transformation seen in low-flow states do not
occur with arteriogenic priapism, even when the latter
has been present for prolonged (as late as 5 months)
periods.
43
A mechanism for the pathophysiology of
high-flow priapism is described by Goldsteins group
in Boston: unlike a traditional arteriovenous stula,
the condition is described as an arterial-lacunar stula,
where the helicine arteries are bypassed and the blood
passes directly into the lacunar spaces. In turn, the
high flow in the lacunar space will create shear stress
in adjacent areas, leading to increased nitric oxide
release, activation of the cyclic guanosine mono-
phosphate pathway, and smooth-muscle relaxation/
trabecular dilatation.
49
The authors also postulate that
the delay in onset of high-flow priapism may be
secondary to a delay in the complete necrosis of the
arterial wall after the initial penile/perineal trauma.
Alternatively, the delay may be secondary to clot
formation at the site of injury followed by the normal
lytic pathways which follow in a few days.
DIAGNOSIS
Physicians caring for patients with priapism should
remember at all times the signicant anxiety and fear
experienced by most patients with this condition and
make a genuine effort to alleviate their apprehension.
A thorough history and physical examination are
prerequisites to diagnostic accuracy. The sexual and
medical history should especially focus on medications,
trauma, and predisposing comorbidities. Presence or
absence of pain is a fairly reliable predictor of low-flow
versus high-flow priapism respectively. The latter
diagnosis is further suggested by a history of penile or
perineal trauma. Absence of pain in arterial priapism
frequently results in less patient anxiety and discomfort
as compared to venoocclusive priapism. Consequently,
those with arterial priapism may present days or even
weeks after the original injury.The fundamental aim of
the initial phase of assessment is to distinguish arterial
from ischemic priapism. The AFUD panel recommen-
dations for the management of priapism are illustrated
in Figure 15.1 and follow a stepped-care model that
has been modied and rened over the years.
42,50
Physical examination of the penis is critical and will
typically reveal rm corpora cavernosa and a soft
glans, indicating sparing of the corpus spongiosum in
low-flow priapism. Findings in high flow states usually
reveal a partial to full erection and sparing of the
corpus spongiosum in most cases (as in low-flow states).
General diagnostic tests include urine toxicology
screening for psychoactive drugs and metabolites of
cocaine.
5,42
These tests are particularly helpful if the
diagnosis is unclear. The AFUD panel has additionally
suggested reticulocyte count (if indicated), urinalysis
(if indicated), complete blood count, platelets, and
differential white blood cell count, as well as urologic
consultation. Urologic management of priapism
includes: (1) history and physical (penile) examination;
and (2) assessment of corporal blood flow status
(corporal aspirate and visual inspection by color and
consistency or corporal blood-gas, including pH, PO
2
and PCO
2
, or penile duplex Doppler ultrasound).
42
Low-flow priapism is suggested by nding low oxygen,
high carbon dioxide, and low pH in the blood-gas
analysis of the aspirate. When a high-flow state is
suspected based on the bright-red appearance or
blood-gas analysis of the corporal aspirate, duplex
Doppler sonography may identify a dilated cavernosal
artery or pseudocapsule formation at the site of arterial
sinusoidal stula.These ndings will be helpful if super-
selective arterial embolization is performed.
51
Patients presenting with refractory low-flow
priapism who later convert to a high-flow state
represent a less common cohort of priapism patients.
Since the management of the low-flow and high-flow
states is radically different, sonography should be
considered if conventional corporal irrigation and
intracavernosal sympathomimetics (i.e., phenylephrine)
fail to resolve the initial venoocclusive priapism.
46
When a hemoglobinopathy is suspected, hemoglobin
electrophoresis may be performed. The AFUD panel
has also recommended testing for prostate-specic
antigen when indicated.
Treatment
The duration of the venoocclusive period in priapism
will have a signicant impact on the potential for
recovery of spontaneous erections. Conservative
measures and a trial of medical therapy should always
be attempted prior to surgical therapy. Immediate
reduction of intracorporal pressure in low-flow states
is of paramount importance. Treatment options are
further separated based on the etiology. For patients
with non-sickle-cell priapism, initial comfort measures
include local penile or systemic anesthesia in the form
of dorsal nerve block, circumferential penile block, sub-
cutaneous local penile shaft block, and oral conscious
sedation for the pediatric patient.
42
The initial diag-
nostic penile aspiration is also used as a therapeutic
measure and, except where contraindicated, should
be combined with intracavernosal instillation of a
sympathomimetic agent (i.e., phenylephrine injection
after aspiration) to induce detumescence. This combi-
nation addresses the two important goals of therapy in
Diagnosis 223
low-flow states: decreased inflow (phenylephrine) and
increased outflow/reduced pressures (aspiration).
Transient increases in systemic blood pressure are
possible and monitoring of vital signs is indicated when
using sympathomimetic agents. Because of its potent
and selective
1
-adrenergic stimulatory properties
and lack of
1
-stimulatory effect, which could cause
arrhythmias and angina in susceptible patients, phenyl-
ephrine is a preferred agent for achieving detumescence
by intracavernosal injection and has been extensively
reviewed by Lee et al.
52
These authors have also
prepared a useful chart for preparation of dilutions
of a-adrenergic agonists for intermittent injection or
irrigation. Failing this approach, the next step in the
224 Priapism
Figure 15.1 Stepped-care treatment model for the management of priapism recommended by the American Foundation
of Urologic Disease (AFUD) thought leader panel.
41
CBC, complete blood count; UA, urinalysis; PE, premature
ejaculation; ABG, arterial blood gas; US, ultrasound; HB, hemoglobin; PSA, prostate-specic antigen; DDU, duplex
Doppler ultrasonography; VS, vital signs; CA, cavernosal artery.
Priapism
Initial management
Urologic management
Non-ischemic
Complete resolution Partial resolution No resolution
Ischemic
Sickle cell
Opioid analgesia
Hydration i.c. vs p.o.
Oxygen if hypoxic
Transfusion (simple or exchange)
Penile vs systemic anesthesia
Dorsal nerve block
Circumferential nerve block
Local penile shaft block
Oral vs IV conscious sedation
Aspiration pharmacologic detumescence
With monitoring of VS
Observation
Patient education
DDU
History and PE (penile)
Assessment of corporal blood flow status
Corporal aspirate (visual inspection vs ABG)
Penile erection that persists
beyond or is unrelated to
sexual stimulation
History (medical and sexual),
physical examination
General diagnostic test: urine
toxicology; ? psychoactive drug
screening; CBC; platelets diff;
Reticulocyte count (if indicated)
UA (if indicated)
Urologic consultation
Duplex Doppler US
HB electrophoresis (if indicated)
PSA (if indicated)
Selective pudendal embolization
Clot vs foam
? Coils
Patient education (instructions)
Follow-up
Pain management
Percutaneous vs surgical shunt
Distal first
Proximal if absent CA flow by DDU
Impatient observation
Interval PE
Interval assessment of
corporal blood flow
Visual inspection vs ABG/DDU
Alphaagonist (oral vs intracavernosal)
Non-sickle cell
process is irrigation with saline pharmacologic agent,
except when contraindicated. The authors have success-
fully used a closed system for corporeal aspiration and
irrigation, as described by Futral and Witt, that has the
advantages of reduced risk of body fluid exposure and
corporeal contamination and the capacity for extended
irrigation without repeated corporeal puncture.
53
The authors agree with observations by Pautler and
Brock
51
indicating that most cases of venoocclusive
priapism treated without excessive delay (<12 h) will
respond to -agonist therapy and that failure of
resolution after 20 min of injection (0.1 ml/min of a
500 g/ml phenylephrine solution for a total infused
dose of 1 mg) call for alternative strategies for manage-
ment as these patients are unlikely to respond. The
AFUD panel highly recommended rst-line treatments
(aspiration and irrigation) for low-flow priapism of
more than 4 h duration before undertaking more inva-
sive surgical shunts and further suggested that these
therapies have not shown a benet in preserving
potency when priapism has persisted beyond 72 h.
42
Failure of resolution after conservative measures as
described will move the stepped-care process to the
surgical level. A number of different surgical shunts for
diversion of blood away from the corpus cavernosum
have been described. The consensus among authorities
is that, in general, distal corporospongiosal shunts
should be undertaken before proximal shunts; how-
ever, there is no consensus regarding the choice of
percutaneous versus open surgical shunts. The authors
prefer to start with a transglandular Winter shunt
(corporoglandular) using a gun biopsy device to create
multiple channels between the corpus spongiosum and
the corpora.
54
If this technique is not successful, a
larger communication between the corpora cavernosal
and the corpus spongiosum may be created by a
modied Al-Ghorab shunt in which the distal tunica
albuginea of the corpora cavernosa is removed through
a transglandular incision (Figs 15.2 and 15.3).
Proximal shunts have been described by a number of
authors and are recommended if these shunts fail and
absent cavernosal artery flow is assessed by Doppler
sonography.
42,55
A few authors have advocated early
use of penile prostheses in cases of refractory or
recurrent priapism associated with corporal brosis
and ED.
56
The AFUD panel recommendations for management
of priapism in patients with SCA include intravenous
hydration and parenteral narcotic analgesia while
preparing for aspiration and irrigation, supplemental
oxygen, and exchange transfusion.
42
Initial efforts
are directed at relief of pain and anxiety, as well as
hydration with hypotonic fluids at 1.5 times main-
tenance. Powars et al.
57
state that in the static, hypoxic,
and acidotic corporal environment, it is unlikely that
red cells can reach the area of involvement and
question the utility of red-cell transfusion. Further-
more, they emphasize that blood volume and viscosity
must be closely monitored in patients undergoing
exchange transfusion or rapid single-unit transfusion,
as there is an increased risk of cerebrovascular
accident, coma, and intracranial hemorrhage. Low-
flow infarctive priapism is uncommon. None the less,
adolescent patients are more likely to develop this
condition compared to younger children who are more
likely to respond to hydration, rest, analgesia, and
warmth.
57
Failing conservative measures as described,
the rest of the management algorithm for SCA patients
with low-flow priapism is very similar to that described
for non-SCA priapism. Stuttering or recurrent painful
Figure 15.2 The Al-Ghorab distal cavernoglandular shunt:
glandular incision and excised distal tunical albuginea on
each side with a wide corporoglandular communication.
(Courtesy of Dr. Ricardo Munarriz.)
Figure 15.3 The Al-Ghorab distal cavernoglandular shunt:
glandular appearance after glans closure (tunica left open
on each side). (Courtesy of Dr. Ricardo Munarriz.)
Diagnosis 225
priapism episodes in this population have been managed
successfully with instruction on sympathomimetic self-
injection and gonadotropin-releasing hormone analog
injection in refractory cases.
58,59
This experience has
been corroborated by the authors. Rutchik et al. have
reported on a single case of refractory venoocclusive
priapism (failure of response to intracavernosal
a-adrenergic injection/irrigation and recurrence after
an Al Ghorab surgical shunt) that responded to intra-
cavernosal injection of 15 mg tissue plasminogen
activator.
60
The authors resorted to this therapy due to
severe penile congestion and risk of penile necrosis
with further shunting. However, it must be emphasized
that experience with this approach is very limited.
A novel approach for treatment of priapism was
suggested by deHoll et al. who described the use of
methylene blue, a guanylate cyclase inhibitor, in 11
patients with priapism and reported immediate
detumescence in 67%.
61
A possible explanation for the
success of this therapy is blockage of cyclic guanosine
monophosphate-induced muscle relaxation following
the initial aspiration attempts. Recently, successful
treatment of recurrent idiopathic priapism with oral
baclofen has been reported in two patients.
62
The treatment options for high-flow arteriogenic
priapism mainly consist of conservative measures
aimed at preservation of sexual function. Mechanical
measures include external compression with occlusion
of arterial inflow and topical application of ice. If these
approaches fail, surgical, pharmacological, or radio-
logical approaches may be employed. Surgical and
pharmacological interventions have not had great
success in resolution of high-flow priapism and
restoration of potency.
63
Superselective transcatheter
embolization has been performed to occlude the
source of arterial inflow, with potential preservation
of potency in up to 80% of patients in one recent
report.
64
However, this treatment has been rarely
associated with perineal abscess formation.
65
When
embolization is used, serial perineal duplex studies
should be performed in follow-up to assure complete
resolution of the arterial lacunar stula and ultimate
restoration of normal cavernosal blood flow.
63
Based
on the experience at the Boston Medical Center, a
course of watchful waiting with regular follow-up
examinations should be discussed with the patient as
a reasonable (if not preferred) alternative in order to
maximize the chances of preserving potency and
avoiding non-essential intervention in high-flow
priapism.
63
When available, arterial embolization of
arteriocavernous stulas has been advocated by
Volkmer et al. as the rst line of therapy in prepubertal
boys with traumatic high-flow priapism when hemato-
logical or metabolic causes have been eliminated.
38
In areas with no access to tertiary care centers and
angiographic expertise, a trial of cavernosal aspiration
and corporal irrigation with dilute epinephrine
(adrenaline) may be tried early in the course of
priapism and has been associated with a positive
outcome (resolution of priapism and ability to achieve
normal erections with follow-up) in at least one case
report.
66
COMPLICATIONS
Early complications typically result from injection of
a-adrenergic agents and include headaches, palpitation,
hypertension, and cardiac arrhythmias. Vital signs
should be monitored during this phase of therapy.
Additional adverse events include urethral injury
and urethrocutaneous or urethrocavernosal stula
from aggressive needle decompression, bleeding, and
infection.
67
Rare cases of gangrene of the penis after
corporospongiosal shunt have been reported.
68
Com-
plications in high-flow states are usually secondary to
the angiographic embolization used in the therapeutic
stage of management. Use of angiography for diag-
nostic purposes is seldom necessary. Color duplex
Doppler ultrasound evaluation and a thorough history
and physical examination will readily delineate the
diagnosis in nearly all cases. Late complications are
usually the sequelae of ischemic damage to cavernosal
tissue and commonly manifest as corporal brosis and
ED. Early decompression of the penis in the low-flow
state is the most important preventive measure against
these adverse events.
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228 Priapism
INTRODUCTION
Primary care clinicians (PCCs), i.e., nurse practitioners,
physicians, or physicians assistants, may effectively
manage the great majority of cases of erectile dys-
function (ED) in the ofce setting, reserving cases for
referral which are refractory to traditional therapies,
require invasive procedures, or have secondary
etiologies which independently merit subspecialty
consultation. Alternatively, it is incumbent upon the
primary care provider not interested in treating this
disease entity at least to identify the specic problem
and make the appropriate referral, depending on the
presenting issue. The basic epidemiology, patho-
physiology, and management of ED have been detailed
in earlier chapters. Of course, there is nothing
different in the epidemiologic underpinnings of ED,
nor is their any variation in the pathophysiologic
derangements seen in primary care than in urology or
endocrinology. On the other hand, there are some
issues that suggest that ED management should be
tailored to the PCC somewhat differently than the
subspecialty provider. The synthesis and application of
the pertinent ED knowledge base for utilization by
PCCs will necessarily require an adaptation which
recognizes the typical current-day limitations of ofce-
based practice, as well as the training experience,
condence, and skills of a broad range of providers.
For instance, the PCC will typically be presented with
a number of other competing diagnoses at the ofce
visit during which ED is acknowledged.
For the last two decades, the general public has
become accustomed to investing energy in addressing
heart disease, colon cancer, and lung disease, but has
had little health-related impetus, save the recently
proliferating direct-to-consumer advertising, to initiate
a discussion on the topic of ED. Similarly, PCCs
resonate this stratication of priorities. Many of the
middle-aged and more mature men who suffer ED
will provide a compelling need for the treatment of
hypertension, obesity, hyperlipidemia, diabetes, chronic
obstructive pulmonary disease, and other mortal dis-
orders, and their PCCs join them in such agendas.
Our discussion of primary care perspectives on ED
will be based on a number of premises:
1. PCCs do provide, and will continue to identify, the
majority of sexual dysfunction problems and be
involved in a signicant portion of sexual dys-
function therapy in the USA.
2. More widespread inclusion of ED into the daily
treatment panel of many PCC will require a
remolding and reprioritization of practice energies.
When provided with compelling rationale(s) for
changes in behavior, clinicians will evolve in an
appropriate direction.
3. PCC anxieties that form obstacles to the identi-
cation and treatment of ED (e.g., alleged time
constraints, unfamiliarity with the topic, hesitancy
because of the sensitive nature of the topic,
gender bias issues) may retard the adoption of best-
treatment behaviors. Anticipating such obstacles,
with sensible, ready provision of solutions, is funda-
mental so that PCCs can embrace ED management.
4. The pathophysiology of erectile function, ED,
pharmacotherapies, and mechanical therapies is
complex. Simplicity of direction is essential to
streamline the knowledge base and its application
in the ambulatory setting.
There are seven pillars to a sound foundation for
shepherding the PCC into a greater role in ED manage-
ment; each will be addressed in more detail:
1. ED is an epidemiologically important public health
problem, inadequately addressed by PCCs.
2. ED, which has heretofore been dominantly
addressed as a quality of life (QoL) issue, most
often reflects a substantial burden of underlying
cardiovascular risk factors.
3. Evaluation and diagnosis of ED may be effectively
achieved within the time constraints of the typical
PCC ambulatory setting.
4. Some of the tools for restoring sexual function
appropriately address the deranged physiology
underlying ED as we understand it today. For
instance, phosphodiesterase type 5 (PDE5)
inhibitors may effectively counteract the endo-
thelial dysfunction commonly associated with ED,
Primary Care Issues in the Management of
Erectile Dysfunction
Louis Kuritzky
CHAPTER 16
by enhancing the activity of cyclic guanosine mono-
phosphate (cGMP). Since most ED patients have
endothelial dysfunction, PDE5 inhibitors, which
prevent breakdown of cGMP, effectively augment
its activity.
5. As is typical of numerous other PCC scenarios, the
choice of agent(s) to restore sexual function should
be a negotiated decision between the clinician and
the patientpartner unit, based on an informed
presentation of the available modalities and their
individual advantages and disadvantages, including
efcacy, side-effects, cost, and convenience.
6. Currently, PDE5 inhibitors are the cornerstone of
ED treatment for most patients. Their safety prole,
including cardiovascular safety, is well established.
The only absolute contraindication to adminis-
tration of all currently available PDE inhibitors is
coadministration of organic nitrates. Additionally,
for vardenal, coadministration of -blockers is a
contraindication (PDR Levitra package insert,
2003).
7. There is nothing remarkable about sexual activity,
when compared with other vigorous physical
activities, as a risk factor for adverse cardiovascular
events. Clinicians should employ the same
judgments applicable to any person for whom new
vigorous physical activity would present increased
cardiovascular risk, seeking cardiovascular risk
stratication if indicated.
PILLAR 1: ED IS AN
EPIDEMIOLOGICALLY IMPORTANT
PUBLIC HEALTH PROBLEM
PCCs are oriented towards practically prioritizing
their clinical energies by both patient presenting com-
plaints, and current standards of care for prevention
and screening. In the most recent communication from
the US Preventive Services Task Force there is no
mention of screening for ED.
1
This, despite the fact that
risk factors for ED mirror those associated with cardio-
vascular disease. As many as 30 million American
men
2
t the current denition for ED, and assuming
that currently prevailing epidemiologic demographics
continue, by the year 2025 that number may increase
by as much as an additional 10 million. Most men
who consult a health professional for ED initially seek
counsel from their PCC. Assuming that the data
reported in the 1994 Massachusetts Male Aging Study
echoes the state of sexual function in men across the
USA, the PCC can anticipate that over half of men
between the ages of 40 and 69 suffer from some
degree of ED.
3
The epidemiologic magnitude of ED,
then, is on parity with hypertension and obesity among
American men of comparable age. Unfortunately,
recent data suggest that as few as 10% of impotent
men seek or receive treatment.
4,5
Communication hurdles affect both poles of the
physicianpatient dyad. For patients, impotence is
listed as the number-one problem of the top-10 medical
conditions too embarrassing for patients to discuss
with their family physician.
6
PILLAR 2: ED IS AN IMPORTANT
HARBINGER OF CARDIOVASCULAR
DISEASE RISK FACTORS
Even if ED were merely a quality of life (QoL) issue,
most men would strongly prefer its resolution.
Certainly ED has an impact on QoL: degrees of
depression correlate with the presence and severity of
ED. Yet, since it is often hardly considered a medical
condition, men may feel little motivation to consult
their PCC about ED. In addition to age being a promi-
nent predictive factor, other vasculopathies predict a
shift to the left in the prevalence of ED; for instance,
by age 30, as many as 15% of diabetic men suffer
impotence.
7
In surveys of senior men, vasculopathy
was the single most frequent underlying cause of
impotence.
8
Vascular disease, cardiac problems, hyper-
lipidemia, and hypertension are all major risk factors
for ED.
9,10
It should not be surprising, then, that
cigarette smoking also increases the risk of ED
twofold.
11
The man presenting to a PCC with ED, or
upon identication of ED, should be considered a
vasculopath until proven otherwise. Patients who
might otherwise neglect ED, considering it trivial,
may be more forthright about their sexual function
history once cognizant of the relationship between
cardiovascular risk and ED.
PILLAR 3: ED MANAGEMENT FITS
WITHIN THE TIME CONSTRAINTS OF
THE AMBULATORY SETTING
The typical ofce visit in primary care lasts 1215 min.
Streamlining of the ED evaluation can be enhanced
either by questionnaires that evaluate sexual function,
such as the Sexual Health Inventory for Men, or by
direct inquiry from the clinician. When ED presents
as an oh-by-the-way complaint, at the exit from an
ofce visit, clinicians may provide patients with
educational tools which address sexual dysfunction,
including leaflets and videos. Industry sources that
produce injectables, oral medications, and vacuum
constriction devices for restoration of sexual function
also provide videos with helpful information about
sexual dysfunction. The clinician may wish to provide
such a video with the suggestion that it be shared with
the patients sexual partner, and discussed at the next
visit. An appropriately targeted sexual history and
230 Primary Care Issues in the Management of Erectile Dysfunction
targeted physical examination (genitals, secondary
sexual characteristics, genitorectal neurologic exam-
ination, and prostate examination) can all be
accomplished within the typical ambulatory visit. If
desired, the patient and partner can be directed to
return for a separate indepth visit to discuss the sexual
malady.
PILLAR 4: ED TOOLS MATCH
PATHOPHYSIOLOGY
The commonest cause of ED is vasculopathy, i.e.,
endothelial dysfunction with subsequent insufcient
supply of nitric oxide. Ultimately, nitric oxide results
in the generation of cGMP, which is responsible for
relaxing and dilating not only the arterial supply to the
penis, but also the sinusoids of the corpora cavernosa.
Once cGMP has performed its task of smooth-muscle
relaxation, it is degraded by PDE5. Any PDE5
inhibitor, then, will produce accumulation of cGMP,
resulting in enhanced erectile responsiveness.
The most common tools for the restoration of ED,
sildenal and vardenal, relies on the inhibition of
PDE5. PCCs employed phosphodiesterase inhibitors
before the advent of sildenal: caffeine, aminophylline,
dipyridamole, and cilostazol are a few of the PDE
inhibitors with which the PCC is likely familiar. There
are over 50 individual subfamilies of PDE, but they are
generally grouped amongst 1114 major families.
Different PDE is localized in different tissue com-
partments. PDE5, the substrate of sildenal, tadalafil,
and vardenal, is most concentrated in the genital
vasculature. Some PDE5 is also located at distant sites,
and its inhibition results in adverse effects like headache
and dyspepsia. Most side-effects of PDE5 inhibitors
are modest, respond to the same readily available
remedies as are used for such symptoms when they
present spontaneously, and are rarely the cause for
drug discontinuation. New PDE5 inhibitors all work
from a similar basic mechanism, but differences in
pharmacokinetics and PDE specicity offer different
utilization potential. For instance, the long (17.5 h)
half-life of tadalal may offer the opportunity for coital
activity as long as 36 h after drug administration.
Tadalal does not show any interruption of absorption
with food; both sildenal and vardenal have demon-
strated reduced absorption when coadministered with
a high-fat meal (Viagra and Levitra package inserts,
2003, PDR).
Vacuum constriction devices may function as a useful
tool for men who cannot afford, have contraindications
to, or simply prefer a mechanical device. Additionally,
since the erect penis with a constriction device at the
base remains turgid postejaculation, premature ejacu-
lators nd such tools useful. As with other mechanical
devices such as contraceptive diaphragms, respiratory
metered-dose inhalers, or insulin delivery systems, the
clinician must provide direct a hands-on demonstration
of how best to use a vacuum constriction device.
Manufacturers of these devices have generally been
strong supporters of providing in-ofce education for
PCC who wish to become more adept at their use.
PCCs can employ intracavernosal injection (ICI).
Urologists usually compound mixtures of vasoactive
substances for greater efcacy and tolerability. On the
other hand, injectable alprostadil is the only approved
agent for this indication. As with vacuum constriction
devices, industry support personnel have been readily
available to provide education and instruction for the
best use of this technique by PCCs. ICI can provide
relaxation of the sinusoids of the cavernosal smooth
muscle by a parallel path to the generation of
cGMP: cyclic adenosine monophosphate (cAMP) is
also a direct relaxation inducer of vascular smooth
muscle. ICI alprostadil stimulates the local production
of cAMP. The rationale for choice of alprostadil as a
Food and Drug Administration (FDA)-approved agent
is that it has a very low incidence of priapism (<1%),
prolonged erections, i.e., 46 h duration, occur in as
many as 4% of users (2002 PDR package insert:
Caverject p. 2778). Although local pain is a common-
place experience (37% of patients report this adverse
event), it is usually mild to moderate, and only 3% of
patients discontinue use because of this side-effect
(2002 PDR package insert: Caverject p. 2778). Of equal
concern as relates to transient symptoms is the brotic
change that can be associated with ICI. Although
short-term studies indicate that only a few percent of
patients develop brosis (3%), longer-term studies
indicate that the frequency increases over time. Hence,
clinicians should perform manual examination of the
penis in ICI and discontinue use if brotic changes,
angulation, or overt Peyronies disease is detected
(2002 PDR package insert: Caverject p. 2778).
PILLAR 5: ED TREATMENT AS A
NEGOTIATED DECISION
The treatment of ED is an intensely personal choice.
It is suggested that the PCC inform patients of all
available modalities before selecting a single one.
Additionally, including the patients partner in the
decision process has been demonstrated to have a
signicant impact on the ultimate choice.
12,13
Some
spouses have little interest in resuming sexuality after
a hiatus, so it is important to acquaint the patient with
the notion that he should discern his partners con-
cordance with resuming sexuality before embarking
upon a plan of sexual function restoration. Lastly, some
mature partners may have their own medical problems
that obstruct harmonious sexual function, such as
vaginal atrophy, poor lubrication, limited mobility due
Pillar 5: ED Treatment as a Negotiated Decision 231
to arthritis, or other maladies. Hence, it is wise to
incorporate the partner whenever possible in the
management process for the most smooth transition to
resumption of sexual intercourse.
PILLAR 6: PDE5 INHIBITORS AS A
CORNERSTONE OF TREATMENT
It is not uncommon for patients directly to request
Viagra from their PCC. The notoriety of sildenal has
become party conversation as well as professional
conversation. Most couples desire to have an inter-
vention which can be easily administered in a private
setting, without interrupting spontaneity and without
requiring an alteration in sexual ritual behavior. For
most couples, PDE5 inhibitors address these needs
well. Disappointingly, only a minority of individuals
for whom the PDE inhibitor sildenal is prescribed are
still using the medication 1 year later. The reasons for
drug discontinuation remain incompletely elucidated,
but include adverse effects, loss of partner, loss of
motivation by the patient, competing health problems,
and lack of adequate effect.
In the authors experience, as many as half of men
who report lack of efcacy of sildenal have used it in
a suboptimal fashion. Some are unclear that sexual
stimulation is required after drug administration.
Others dont time intercourse activity appropriately
after the medication. Some neglect to observe the
proscription of fatty food when taking sildenal, or try
to initiate erection too soon after a meal, which may
delay drug absorption. For some individuals, anxiety,
with its attendant augmentation of sympathetic tone,
overrides the positive effects of PDE5 inhibition, hence
diminishing or aborting an erection. Some individuals
do not escalate the drug dosage appropriately as
needed. The literature supports the idea that as many
as eight trial doses of sildenal may be necessary
before a patient may be truly designated as a non-
responder, yet many patients become discouraged or
discontinue if they do not respond within the rst few
doses. Some patients become distracted by adverse
symptoms that misdirect them from their originally
intended activity. Fortunately, the vast majority of
such instances can be happily resolved by careful
attention to detail in instruction, coupled with good
follow-up visits to ensure appropriate medication use
and patient satisfaction.
PDE5 inhibitors will not work for all patients, but
have enjoyed successful enhancement of sexual
responsiveness in a broad range of patient populations,
including unselected men, the elderly, diabetics, and
(less successfully) postprostatectomy patients. It is not
anticipated that the efcacy of newer PDE5 inhibitors
(e.g., tadalal, vardenal) will be remarkably different
from sildenal. Rather, new agents will demonstrate
different selectivity for the PDE5 receptor, which
should result in a more narrow adverse effect prole,
and differences in drug onset or duration (e.g., no food
effect, longer window of opportunity) which justies
their consideration for inclusion as primary choices in
the therapy of ED once they become available.
PILLAR 7: SEXUAL ACTIVITY IS
VIGOROUS PHYSICAL ACTIVITY, BUT IT
NEED NOT BE SINGLED OUT AS A
PARTICULAR RISK FOR
CARDIOVASCULAR CONSEQUENCES
The typical maximum workload of sexual intercourse
is only 35 METS of activity, the peak of which endures
for less than 30 s.
14
Accordingly, the American College
of Cardiology guidelines indicate that risk for ischemia
during coitus is low if a patient can exercise more than
56 METS without evidence of ischemia on exercise
treadmill testing.
17
Men who have engaged in regular
vigorous activity without evidence of coronary
ischemia are at very low likelihood of coitus-induced
cardiac events; indeed, if a man can comfortably climb
two flights of stairs without chest pain or dyspnea, his
cardiac reserve is likely sufcient for safe intercourse.
15
For a simple clinical decision rule, if the patient can
walk 1 mile within 15 minutes or less (the equivalent
of 4 mph, or 4 METS), he has done his own free-living
treadmill, and risk of cardiovascular misadventure
with sexuality is minimal. The decision to do cardiac
risk stratication for men embarking upon new sexual
activity is no different from that presented to the PCC
if a patient wishes to embark on any exercise program.
It has been demonstrated that exercise treadmill test-
ing provides good guidance about exercise tolerance,
enabling a condent exercise prescription. On the
other hand, there are no data to prove that exercise
treadmill testing of asymptomatic men reduces the risk
of mortality or cardiac events associated with physical
activity. Hence the choice of whether or not routinely
to encourage cardiac risk stratication by means of
treadmill testing for middle-aged and more mature
men should remain a shared decision by the PCC and
the patient.
Although treadmill testing will doubtless uncover
signicant silent coronary artery disease that is
remediable by intervention, it will also provide a
substantial number of false-positive results, with the
attendant requirement for follow-up and potentially
invasive procedures, without the benet of data indi-
cating a net favorable impact. Clinicians who may be
daunted by the fear of medicolegal consequences for
not obtaining stress testing may be more motivated to
consider stress testing routinely. An expert consensus
panel has recently suggested a risk stratication plan in
reference to coronary adverse events, which directs
232 Primary Care Issues in the Management of Erectile Dysfunction
clinicians to determine whether the patient is high-,
low-, or intermediate-risk for myocardial infarction
based on a variety of signs and symptoms. These
Princeton guidelines (so named because they were
conceived and developed in the city of Princeton, NJ,
not because they represent a document generated by
Princeton University) may simplify uncertainties about
which patients require further evaluation or referral
prior to initiating sexual intercourse.
16
ED is a primary care disorder. PCCs should maintain
a therapeutic conversation with specialists in the elds
of urology and endocrinology for the small subgroup
of ED sufferers who are non-responders to traditional
therapy, those who require or desire invasive restoration
modalities, or patients who have competing comor-
bidities which demand subspecialty consultation to
best manage ED.
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(24):18021813.
Impotence and its medical and psychological correlates:
151:5461.
4. McKinlay JB.The worldwide prevalence and epidemiology
of erectile dysfunction. Int J Impot Res 2000; 12 (suppl. 4):
S6S11.
5. American Association of Retired Persons. AARP/modern
maturity sexuality. Washington: AARP, 1999.
6. Preboth MA, Richards R, Wright S. Quantum sufficit (Just
enough). Am Fam Phys 1999; 59 (1):18.
7. Bennet A. Impotence. Philadelphia: WB Saunders; 1994:9.
8. Mulligan T, Katz PG.Why aged men become impotent.
Arch Intern Med 1989; 149 (6):13651366.
9. Martin-Morales A, Sanchez-Cruz JJ, Saenz de Tejada I et al.
Prevalence and independent risk factors for erectile dysfunc-
tion in Spain: results of the Epidemiologia de la Disfuncion
Erectil Masculina study. J Urol 2001; 166 (2):569574;
discussion 574575.
10. Braun M, Wassmer G, Klotz T et al. Epidemiology of
erectile dysfunction: results of the Cologne Male Survey.
Int J Impot Res 2000; 12 (6):305311.
11. McVary KT, Carrier S, Wessells H and Subcommittee on
Smoking and Erectile Dysfunction Socioeconomic Committee,
Sexual Medicine Society of North America. Smoking and
erectile dysfunction: evidence based analysis. J Urol 2001;
166 (5):16241632.
12. Kuritzky L, Ahmed O, Kosch S. Management of impo-
tence in primary care. Comp Ther 1998; 24 (3):137146.
13. Tiefer L, Melman A. Interview of wives: a necessary admu
ct in the evaluation of impotence. Sex Disabil 1983; 6:167.
14. Arruda-Olson AM, Mahoney DW, Nehra A. Cardiovascular
effects of sildenal during exercise in men with known or
probable coronary artery disease. JAMA 2002; 287:719725.
15. Mobley DF, Baum NH. What you need to know before
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conference on the management of erectile dysfunction: over-
view consensus statement Int J Impot Res 2000; 12 (suppl. 4):
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References 233
INTRODUCTION
Sophisticated clinicians no longer conceptualize the
etiology of erectile dysfunction (ED) in simple binary
terms, that is, labeling the mans dysfunction as either
psychogenic or organic. This outmoded model was
replaced by a contemporary biopsychosocial paradigm
that captures the complex and dynamic nature of the
multiple forces that predispose, precipitate, and main-
tain the mans/couples ED.
14
Such a biopsychosocial
model integrates the psychological and medical factors
in an additive, interactive and ever-changing fashion
and is consistent with the National Institutes of
Healths Consensus Conference recommendations.
5
This paradigm encompasses both the psychological
impact that the dysfunction has upon the man and
couples sexual equilibrium, and the fluctuating
influence of medication, lifestyle, and disease.
It might appear that writing a chapter on the treat-
ment of psychogenic ED ignores such current thinking,
especially in the age of reliable, safe and effective
phosphodiesterase type 5 (PDE5) oral agents. How-
ever, not all men desire treatment with medication
and some specically seek psychological intervention.
This chapter focuses on those men who seek sex
therapy or psychotherapy and whose ED is pre-
dominantly psychological with minimal contributions
from biology, aging, illness, or medication.
Complementing this biopsychosocial approach to
treating ED is the notion of the sexual equilibrium.
2,6
The sexual equilibrium is dened as the balance among
factors that promote sexual health and maintain
normal as well as problematic sexual functioning.
Sexual life exists in a closed system such that change
in one partner influences change in the other. In the
case of erectile problems, the ED affects both partners
in different ways, both physically and psychologically.
For example, the ED may be a reflection of a mans
fear of failure or performance anxiety. However his
partner may perceive it as a rejection of her, or his
interest in another.
The strength of the equilibrium is often under-
estimated by couples and by therapists. The need for
balance (no matter how dysfunctionally it has been
maintained) often overpowers the desire for sexual
health. Traditionally, mental health clinicians refer to
this phenomenon as resistance and it is often seen when
the man overcomes his ED only to nd that either he
or his partner have no desire for lovemaking.
THE PROTOTYPICAL COUPLE
PRESENTING WITH PSYCHOGENIC
ERECTILE DYSFUNCTION
Hal is a 54-year-old married man who has waited
3 years before seeking treatment. He rst consulted a
urologist who, after checking his testosterone (normal),
performing nocturnal penile tumescence testing
(sustained erections noted on all three nights) and
Doppler ultrasonography (normal), concluded that
Hals ED was primarily psychological. He referred Hal
for sex therapy but Hal was reluctant to follow through
with the urologists recommendation.
Over the past 3 years Hal has felt increasingly
inadequate and anxious about sexual performance
and pleasing his wife. He has become irritable and
depressed; his wife, Barbara, has resented his
unwillingness to approach her for lovemaking or alter-
natively his delay in seeking treatment for the dys-
function. Hal stopped any displays of affection such as
hand-holding, hugging, or even endearing compliments
for fear that they might be interpreted by her as an
invitation for sexual activity. He offers rationalizations
such as being too busy, too tired, or too old (e.g., Im
not a teenager anymore), goes to bed either before or
after his wife, and picks arguments to circumvent any
possibility of a sexual encounter.
Barbara has suffered doubts associated with her
husbands apparent lack of desire for her. She wonders
if she is still attractive or if Hal is having an affair.
Barbara longs for the initial romance in their relation-
ship. She began noticing his avoidance of intimacy
around 5 years ago but 2 years ago things signicantly
worsened when all physical and emotional contact
ceased. In order to lessen her pain of feeling rejected,
she colluded with his pattern of avoidance. She too has
stopped showing affection and is spending less time
alone with Hal. She has also become more irritable
and overtly resentful of Hal in front of others.
Treating Psychogenic Erectile Dysfunction
Sheryl A. Kingsberg and Stanley E. Althof
CHAPTER 17
GOALS OF TREATMENT
In order to treat psychogenic ED effectively, clinicians
must rst help patients dene success. Patients (and
clinicians also) tend to have too narrow a denition of
success, focusing solely on mechanistic outcomes, such
as the rmness of the mans erection, as opposed to
restoring the couples lovemaking.
Treatment of psychogenic ED aims to restore a
mans ability to obtain and sustain an erection to his
optimal ability given his physical health and relation-
ship circumstances. However, successful treatment of
psychogenic ED also includes helping patients gain
insight into the psychological barriers that have pre-
cluded satisfying sexual activity. Again, the clinician
can remind patients that satisfying is not limited to
physiologic ability. Instead, success includes enhanced
psychological and relational well-being. Those couples
who present with severe premorbid psychological or
relationship dysfunctions have the poorest prognosis
given that these problems serve as barriers to successful
treatment of ED.
EVALUATION AND TREATMENT
The establishment of a respectful, comfortable and
healing therapeutic relationship is the foundation of
an effective evaluation. The evaluation process is a
diagnostic tool where the clinician and patient
construct tentative formulations of the contextual
factors that contribute to the overall individual and
relational symptomatology.
Hal is a manufacturing plant supervisor. Five years
ago, shortly after Hal was promoted to supervisor, the
economy took a serious downturn and Hal was forced
to enact cutbacks, including lay-offs of friends and
long-standing coworkers. In addition, Hals own job
was at risk of being eliminated. He often worked 60-h
weeks with very little vacation. Fortunately, over the
last year, business improved considerably and Hals job
is now secure.
Hal has had some difculties with sleep over the
past few years. He has trouble falling asleep and has
occasional early-morning wakening. His appetite has
not changed signicantly. Hal has noticed some mild
difculty concentrating but attributes this to his
overwhelming schedule. He reports that when his job
was the most stressful he had lost interest in many of
the hobbies and activities he used to nd enjoyable,
such as his bowling league, golf, and reading books
on fly-shing. Recently he has resumed some of these
hobbies. He characterizes his mood as blue but
denies being depressed.
Hals most recent physical (required by work
annually) indicates that in general he is in good health.
He takes no medication, denies any history of sub-
stance abuse, and does not smoke. He has had no major
illnesses or surgeries. He has rm morning erections
and is able to have rm erections with masturbation.
When asked about his marriage, Hal became visibly
distressed. He stated that he felt like a failure and had
lost condence in his sexual ability. He had fearful
thoughts about losing his wife and revealed that he
was becoming increasingly worried about his ED. Hal
wondered if there was something wrong with his penis
and was questioning whether his penis was losing
sensitivity. Although worried about his ED, Hal
admitted that he was only presenting for treatment
due to the most recent argument with Barbara when
she questioned if she could endure the lack of a sexual
relationship much longer. He states that he was too
embarrassed to ask for help and was also afraid that he
would be told that there was nothing that could be
done to correct his ED.
Barbara admitted that she was nding it more
difcult to understand Hals resistance to getting help.
She has felt betrayed and believed that Hals lack of
arousal was due to her. She denies having any sexual
dysfunction herself, although she has become avoidant
of initiating because she has been afraid of his
rejection. She has wanted Hal to seek help but became
weary after Hals repeated denials that there was a
problem. She has become increasingly anxious that the
psychological and relational consequences may be too
difcult to overcome.
As the identifying information reveals, there are
several factors that have provided a contextual under-
standing of ED.
It is clear from the outset that Hal and Barbara have
previously enjoyed a satisfying sex life. Prior to the
current onset of symptoms they had sex approximately
once or twice per week. Hal initiated most often but it
was not a surprise if Barbara also initiated. Both felt
satised with their sexual life and were usually easily
aroused and orgasmic.
The current manifestation of symptoms appears to
be precipitated by a set of circumstances relative to
Hals employment his promotion and having to lay
off friends and long-time coworkers as well as his
concerns regarding his own job security. Additionally,
he was no longer deriving meaning or satisfaction from
his social and leisure pursuits. It is also not surprising
that Barbaras feelings reflect the couples history and
long-term concerns for the future of the relationship.
This 25-year lack of involvement with one another,
both physically and emotionally, has nally mobilized
them to seek treatment.
Hals depressive symptoms merit investigation; the
therapist should assess whether Hal suffers from any of
the following: sleep and appetite disturbance, weight
loss, fatigue, mood, suicidal ideation, hopelessness,
236 Treating Psychogenic Erectile Dysfunction
self-deprecation, pessimism, and decreased libido.
Depression and ED often coexist, although it is unclear
if the depression caused the ED, if the ED caused the
depression, or if a third factor caused both.
7
Moreover,
depressed men with ED are more likely to drop out of
ED therapy;
8
even those men with restored erections
generally have impaired sexual desire. A narrow focus
on the ED alone would be insufcient to help Hal and
Barbara become lovers again.
Addressing depressive symptoms is necessary
because they have also contributed to the diminished
quality of the couples emotional relationship over the
past 5 years. Attending to their distress provides a
mechanism for helping them calmly to discuss their
deeply held emotions that they have found too difcult
to address previously. Most patients are initially uneasy
and reluctant to discuss their sexual and emotional
life. However, facilitating discussion of difcult material
in the controlled environment of the therapists ofce
has the potential to improve their communication.
The evaluation session suggests that Hal suffers from
secondary (onset of the symptom after a period of
normal functioning) psychogenic ED. Prior to 5 years
ago he had reliable erections, a frequent, satisfying
sexual life, and felt had constructed a comfortable
sense of his sexual self in relation to Barbara. He
maintained a monogamous and committed relation-
ship to Barbara and was able to be emotionally and
sexually intimate with her. Prior to the onset of the
dysfunction Barbara was pleased in her interpersonal
and sexual relationship with Hal. There appears to be
no evidence suggestive of primary ED respective to
disturbances in gender identity, orientation, paraphilias,
or psychotic functioning.
The therapist chose to work with the couple rather
than Hal alone because she understood that both
partners were distressed and motivated to become
lovers again. Hal begins to understand that his work
stressors are precipitating factors that are interfering
with his sexual functioning. He and Barbara begin to
appreciate the deleterious impact of Hals palpable
performance anxiety. They recognize that Hals
symptom and avoidance affect both of them in
different ways and that a return to a healthy sex life is
possible only within this contextual understanding of
the problem, which includes the honest discussion of
their relationship as a key factor to the goal of enduring
intimacy.
The clinician also anticipates resistances to treat-
ment in both the individual and conjoint aspects of the
therapy, and may in fact express this to the couple at
the outset. This is a preventive tool that seeks to reveal
in an open and detailed discussion how each person
has had an individual contribution to secondary EDs
initiation and maintenance in the couple. In addition,
normalizing potential conflict relative to discussing a
couples sexual life is also important and serves to assist
in the honest exploration of often deeply held beliefs,
cultural norms, and religious taboos. Discussions of
possible resistances include:
1. the need for erectile problems to remain in the
relationship so that both partners can avoid feelings
of vulnerability and inadequacy
2. refusal to complete homework assignments. This
allows the therapist directly to address sabotage of
treatment, both conscious and unconscious
3. shameful or embarrassing secrets that have been
hidden from the partner. These include uncon-
ventional fantasies, traumatic childhood sexual
experiences, extramarital relationships, and related
concerns that have contributed to the current
problem. It should be emphasized that the impact
of these hidden secrets will compromise the
therapy. The couples treatment will not succeed if
there are certain secrets that cannot be discussed.
Conversely, sharing long-held secrets that are not
directly related to the partner and that have served
as a barrier to emotional intimacy can enhance the
potential for sexual intimacy
The anticipation and discussion of these potential
barriers to treatment can enable each partner to under-
stand how the need for such symptoms endangers the
desired treatment outcome. If treatment is successful,
this need is understood and worked through during
therapy sessions.
Successful treatment outcomes with secondary ED
involve the consistent discussion of concerns and issues
relative to a man and his partner that ultimately result
in a renewed emotional and cognitive perspective.
6
Finally, the therapist must assist the couple in over-
coming performance anxiety.While Hals work stressors
may have precipitated the ED, the symptoms are main-
tained by performance anxiety. Hal must regain the
condence that he can reliably generate rm erections
and focus on pleasure rather than his fear of failure.
There are several schools of thought regarding the
treatment of primarily psychogenic ED. A brief review
of several treatment approaches follows to illustrate
how different modes of intervention can be utilized to
treat ED effectively.
Classic psychoanalytic theory posits that internal,
unconscious conflicts left unresolved from childhood
shape and influence current psychological and physical
symptoms. This is also a view shared by contemporary
analysis which adds that past influences can also con-
tribute to relationship conflicts via a more dynamic
understanding of the role that envy, hatred, and rage
play in the formulation of a loving, safe, and committed
relationship. ED could be an end result of a series of
unsuccessful attempts at separation-individuation and
Oedipal losses. The merging of an intrapsychic and
interpersonal context supports the view that the
Evaluation and Treatment 237
individual and his environment collectively contribute
to sexual dysfunction.
9,10
A behavioral perspective holds that men with ED
share a common anxiety, that past failure to achieve
or maintain an erection will return in future sexual
relations, creating a performance anxiety. It is then
the anxiety that maintains the avoidance pattern, not
necessarily the ED itself. Barlow
11
would suggest that
it is not just the anxiety that precipitates the dys-
function but the mans distractibility as well. The man
seems unable to focus on the pleasurable sensations
and allows himself to be distracted, resulting in erectile
failure.
Behavior therapy focuses on specic tasks and
attention to resistances in the completion of those
tasks. Sensate focus exercises
12
are often utilized to
lessen performance anxiety and desensitize individuals
to increasingly sensual and sexual experiences while
decreasing anxiety and distractions.
13
Techniques such
as systematic desensitization in this case would include
teaching the man relaxation techniques and gradually
to have him engage in approximations of the sexual
behaviors that he has avoided due to his anxiety.
Cognitive therapy examines an individuals irrational
beliefs that have, in this case, interfered with a sexual
response.These beliefs generate maladaptive behaviors
and uncovering ones ineffectual scripts can lead to
an emotional and cognitive confrontation of ones mal-
adaptive coping strategies.
13
Men are often confronted
with both societal and individual values that contribute
to irrational beliefs, such as those about adequate
penis shape and size, or beliefs about the penis as a
machine that must perform perfectly, or beliefs about
the rmness of an erection as the source of a partners
satisfaction.There are numerous other beliefs that shape
the context of lovemaking which men, and women,
often ascribe. Uncovering these will greatly assist in
the development of a personal and interpersonal con-
text for success through which a renewed sexuality can
occur.
14,15
Most treatments today consist of a combination
of all of these modalities in formats of individual,
couples, and group treatments. The determination of
which or which combination of modalities to use is,
again, both an evaluation task, as well as the personal
preference of the clinician and the particular patient. It
is important to note that this integrated approach to
psychogenic dysfunction is for secondary ED. Primary
ED is often best resolved in individual, long-term
psychotherapy, focusing on unresolved gender identity
conflicts, paraphilias, and severe character pathology.
Long-term, intrapsychic, dynamic psychotherapy is often
best utilized for intervention into these dilemmas.
For Hal, several recommendations could be made.
Hal presents with a situational anxiety that could
benet from some behavioral tasks like systematic
desensitization for his lost condence over his sexual
ability and sensate focus exercises to help the couple
nd a comfortable way to resume erotic and sexual
activity with each other. Hals belief that he is losing
sensitivity in his penis appears to be a function of his
anxiety but could be explored in a cognitive format
aimed at further assessment of internalized beliefs and
norms around sexuality. A physical reexamination
would also be scheduled, as this will be discussed later.
Lastly, Hals minor depressive symptoms with sub-
sequent social and familial withdrawal may also con-
tribute to worsening of his ED. Although the situations
that triggered the symptoms have resolved, treating
the feelings they stirred up may be useful. In addition,
couples therapy would also be recommended for the
purposes of systemic intervention into the presenting
problems and the subsequent dysfunctional patterns
of communication that have influenced the current
manifestation of the ED. Most therapies for proto-
typical ED are often short-term in duration.
Some experts in the treatment of psychogenic ED
will also incorporate the use of medical treatments.
The rationale behind using a treatment for an organic
dysfunction is primarily to provide additional con-
dence to a man who has developed signicant
performance anxiety. Once the man has successfully
achieved erections with the assistance of the medical
intervention, his condence will be restored and he
will no longer need that intervention. With the intro-
duction of the PDE5 inhibitors (e.g., sildenal), this
option has become more widely used due to their
relative safety and ease of use.
Psychoeducational materials can also enhance
overall treatment success. For example, providing
pamphlets or videotapes in the ofce setting can be an
easy way to provide some initial educational infor-
mation. Providing bibliotherapy can also be very
helpful. It is well known that patients often hear and
remember very little of what occurs during an ofce
visit. The outside reading can help reinforce and
enhance the content of the information a therapist
is trying to teach. It is also a useful platform for
couples to use to begin discussions of sexuality at
home when it is often awkward or difcult to initiate
such communication.
OUTCOME STUDIES
While long-term randomized, double-blind, placebo-
controlled studies are lacking, there is a convincing
body of evidence that suggests that men with lifelong
and acquired ED achieved signicant gains both
initially and over the long term following participation
in sex therapy. Men with acquired disorders tended to
fare better than those with lifelong problems. Masters
and Johnson
12
reported initial failure rates of 41% and
26% for lifelong (primary) and acquired (secondary)
ED respectively. Their 25-year follow-up of this cohort
indicated that the men had sustained their gains.
Masters and Johnsons work
12
remains unparalleled;
no other clinical center has been able to rival the
magnitude of their success, or report on as extensive a
cohort with such an extended follow-up interval. There
are, however, other well-controlled investigations
1620
that have demonstrated the efcacy of psychological
interventions for ED. In an excellent review of the
studies of treatment for ED, Mohr and Beutler
21
wrote:
The component parts of these treatments typically
include behavioral, cognitive, systemic and inter-
personal communications interventions. Averaging
across studies, it appears that approximately two-
thirds of the men suffering from erectile failure will
be satised with their improvement at follow-up
ranging from six months to six years (p. 123).
All studies with long-term follow-up noted a tendency
for men to suffer relapses. McCarthy
15
in discussing
relapse prevention in the treatment of ED suggests that
therapists schedule periodic booster or maintenance
sessions following termination. Patients remark that
knowing that they will be seen again in 6 months keeps
them on target because they know they will have to
report on their progress. The follow-up sessions can
also be used to work out any glitches that have
interfered with their progress.
THE FUTURE
The introduction of sildenal in 1998 dramatically
altered the treatment landscape for ED. Physicians
now have a simple, efcacious, and safe intervention
that restores potency in approximately 5070% of
men with ED.
22,23
Given the efcacy of PDE5 inhibitors
one might conclude that psychotherapy for ED is an
obsolete and antiquated intervention. On the contrary,
we believe psychotherapy is now more relevant than
ever.
24
Just as the etiological models have abandoned the
binary model of psychogenic versus organic ED, we
predict that treatment models will follow suit and
move away from treating the dysfunction medically
or psychologically. Integrated or combined treatments
will evolve that offer patients the best of both
worlds.
25,26
Such treatments will move beyond a
narrow mechanized focus on genital function and help
men and/or couples become lovers again.
REFERENCES
1. Althof S, Seftel A. The evaluation and treatment of erectile
dysfunction. In: Oldham J, Riba M, eds. Annual review of
psychiatry, vol. 18. Washington, DC: American Psychiatric
Press; 1999:5587.
2. Levine S. Sexual life: a clinicians guide. New York: Plenum;
1992.
3. Schnarf D. Constructing the sexual crucible. New York:
Norton; 1990.
4. Tiefer L. Sex is not a natural act and other essays. Boulder:
Westview Press; 1995.
5. National Institutes of Health. Consensus development
conference statement on impotence. Bethesda: NIH; 1992.
6. Althof S. Erectile dysfunction: treatment of men and
couples. In: Lieblum S, Rosen R, eds. Principles and practices
of sex therapy, 3rd edn. New York: Guilford Press; 2000:
242275.
7. Seidman SN, Roose SP, Menza MA et al. Treatment of
erectile dysfunction in men with depressive symptoms:
results of a placebo-controlled trial with sildenal citrate. Am
J Psychiatry 2001; 158:16231630.
8. Shabsigh R, Klein LT, Seidman S et al. Increased incidence
of depressive symptoms in men with erectile dysfunction.
Urology 1998; 52:848852.
9. Daines B, Barnes T. Psychotherapy in the treatment of
erectile dysfunction. In: Carson C, Kirby R, Goldstein I, eds.
The textbook of erectile dysfunction. Oxford, UK: Isis Medical
Media, 1999:465484.
10. Scharff DE. The sexual relationship. London: Routledge;
1982.
11. Barlow D. Causes of sexual dysfunction: the role of
anxiety and cognitive interference. J Consult Clin Psychol
1986; 54:140148.
12. Masters W, Johnson V. Human sexual inadequacy. Boston:
Little Brown; 1970.
13. Barnes T. Integrated sex therapy: the interplay of
behavioral, cognitive and medical approaches. In: Carson C,
Kirby R, Goldstein I, eds. Textbook of erectile dysfunction.
Oxford, UK: Isis Medical Media; 1999:451463.
14. Leiblum S, Rosen R. Erectile disorders, assessment and
treatment. New York: Guilford Press; 1992.
15. McCarthy B. Relapse prevention strategies and techniques
in sex therapy. J Sex Marit Ther 1993; 19:142147.
16. DeAmicus L, Goldberg DC, LoPiccolo J et al. Clinical
Behav 1985; 14:467489.
17. Hawton K, Catalan J, Faff J. Sex therapy for erectile
dysfunction: characteristics of couples, treatment outcome,
and prognostic factors. Arch Sex Behav 1992; 21:161175.
18. Heiman JR, LoPiccolo J. Clinical outcome of sex therapy.
Arch Gen Psychiatry 1983; 40:443449.
19. Kilmann PR, Milan RJ, Boland JP et al. Group treatment
of secondary erectile dysfunction. J Sex Marit Ther 1987;
13:168182.
20. Reynolds B. Psychological treatment of erectile dys-
function in men without partners: outcome results and a new
direction. J Sex Marit Ther 1991; 2:136145.
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21. Mohr DC, Beutler LE. Erectile dysfunction: a review of
diagnostic and treatment procedures. Clin Psychol Rev 1990;
10:123150.
22. Goldstein I, Lue T, Padma-Nathan H et al. Oral sildenal
in the management of erectile dysfunction. N Engl J Med
1998; 338:13971404.
23. Padma-Nathan H, Earley I, Kloner RA et al. A four year
update on the safety of sildenal citrate (Viagra). Urology
2002; 60 (suppl. 2):6790.
24. Althof SE. When an erection alone is not enough; bio-
psychosocial obstacles to lovemaking. Int J Impot Res 2002;
1 (suppl.):S99S104.
25. Althof S. Therapeutic weaving: the integration of treat-
ment techniques. In: Levine S, Risen C, Althof S, eds. Hand-
book of clinical sexuality for mental health professionals.
Brunner-Routledge 2003:359376.
26. Rosen R. Medical and psychological interventions for
erectile dysfunction: toward a combined treatment approach.
In: Lieblum S, Rosen R, eds. Principles and practice of sex
therapy: update for 2000. New York: Guilford Press;
2000:276295.
INTRODUCTION
Erectile dysfunction (ED) is experienced at least some
of the time by most men who have reached 45 years of
age, and it is projected to affect 322 million men
worldwide by 2025. The prevalence of ED is high in
men of all ages and rises greatly in the elderly. This
chapter reviews the epidemiology of ED, with an
emphasis on older men; normal age-related changes in
the structure and function of the penis that may
contribute to the increased risk for ED with advancing
age; how the accumulation of ED risk factors with age
may contribute to the high prevalence of the disease
in older men; and established and emerging therapies
for ED. Both the normal aging process and age-related
risk factor accumulation contribute to the increased
prevalence of ED in the elderly. Remarkable progress
has been made in the treatment of ED. At present,
inhibition of phosphodiesterase 5 with oral agents
such as sildenal appears to be the initial treatment of
choice. These drugs have been shown to be safe and
effective, and sildenal has demonstrated efcacy in
patients with many of the comorbidities observed in
older men with ED. New treatments, in particular
transfection with genes for key mediators of erectile
function that are known to be downregulated in elderly
men, also hold promise. Further research into the
neural, vascular, and molecular mechanisms involved
in penile erection will lead to the development of even
safer, more effective, and more convenient therapies
for men with ED.
ED, the inability to achieve and/or maintain an erec-
tion sufcient for satisfactory sexual activity, affects as
many as 30 million men in the USA alone and 152
million men worldwide.
1
It has been suggested that, by
age 45, many men will have experienced ED at some
time,
1
and the results of one recent projection suggest
that as many as 322 million men worldwide will have
ED by 2025.
1
While ED can occur in men of all ages, it
is more common in the elderly. This chapter focuses on
ED in the aging male. It reviews the epidemiologic
relationship between ED and age, how advancing age
may impact erectile function independent of comor-
bidities, the manner in which other diseases common
in older men may influence erectile function, treat-
ments that have been shown to be effective in treating
ED, and potential new therapies for this disease.
EPIDEMIOLOGY OF ED: THE RISK IS
HIGH IN OLDER MEN
The prevalence of ED increases dramatically with age
(Fig. 18.1). According to the Massachusetts Male Aging
Study,
2
the overall probability of complete impotence
tripled from 5% in subjects 40 years old to 15% in
subjects aged 70 years.These results are consistent with
those from a number of other epidemiologic studies
that have evaluated the relationship between ED and
age. For example, Masumori et al.
3
compared age-
related prevalences of ED among 289 Japanese and
2115 American men (the latter group were from the
Olmsted County study). Results from both groups
indicated an age-related decline in erectile function,
sexual libido, and sexual satisfaction. In particular,
71% of Japanese men aged 7079 years reported
having erections only a little of the time or less when
sexually stimulated, and 80% perceived sexual drive
once or less during the past month. Marumo et al.
4
reported a similar increase in the prevalence of ED
among 2311 Japanese men between 23 and 79 years
of age.
Erectile Dysfunction in the Elderly: Epidemiology,
Etiology, and Approaches to Treatment
Allen D. Seftel
CHAPTER 18
Figure 18.1 Association between erectile dysfunction and
age. (Reprinted with permission from Feldman HA,
Goldstein I, Hatzichristou DG et al. Impotence and its
medical and psychosocial correlates: results of the
Massachusetts Male Aging Study. J Urol 1994; 1:54.)
Probability
None Minimal Moderate Complete
A
g
e

(
y
e
a
r
s
)
70
65
60
55
50
45
0.0 0.5 1.0
40
Blanker et al. carried out a similar epidemiologic
study in the Netherlands. Their results indicated at
least some degree of ED in approximately 22% of men
5054 years of age and in approximately 54% of men
7078 years old.
5
Braun et al.
6
mailed a validated
questionnaire on male ED to a sample of 8000 men
(3080 years of age) in Cologne, Germany, and
obtained 4489 replies. The overall prevalence of ED
was 19.2%, with a steep age-related increase.
These studies leave little doubt regarding the strong
relationship between advancing age and increased risk
for ED. However, they do not provide insight as to
why this relationship might exist. On one hand, the
increased risk for ED in the elderly may be a result of
systemic changes and/or alterations in the structure
and function of the aging penis that are independent of
other disease. Alternatively, the increased risk for ED
in older men may be due to the age-related accumu-
lation of comorbidities that negatively impact erectile
function.
Mulligan et al.
7
attempted to untangle this problem
by assessing erectile function in young men, men
6575 years of age, and men greater than 75 years of
age. Their analysis indicated that age alone increased
the relative risk of sexual dysfunction (relative risk, 2.2
for men 6575 years old and 7.9 for those older than
75). However, self-reported poor health, diabetes, and
bowel or urinary incontinence increased the risk for
sexual dysfunction in all age groups. These results
suggest that aging per se, and diseases that occur most
often in older men, may both play signicant roles in
the development of ED.
AGE-RELATED CHANGES IN
ERECTILE FUNCTION
The process of penile erection
While there have been substantial advances in our
understanding of neural, hemodynamic, and molecular
mechanisms involved in penile erection, this process is
still incompletely understood. The penis is innervated
by both autonomic and somatic nerves (Fig. 18.2). Sym-
pathetic and parasympathetic bers in the cavernous
nerves regulate blood flow into the corpus cavernosum
242 Erectile Dysfunction in the Elderly: Epidemiology, Etiology, and Approaches to Treatment
Figure 18.2 The anatomy and mechanism of penile erection. (Reprinted with permission from Lue TF. Erectile
dysfunction. N Engl J Med 2000; 2:1802. Copyright 2000 Massachusetts Medical Society. All rights reserved.)
Prostate Deep
dorsal
vein
Dorsal
artery
Dorsal nerve
(somatic)
Circumflex
artery
Circumflex
vein
Cavernous
nerve
(autonomic)
Dorsal
artery
Dorsal nerve
(somatic)
Sinusoidal
spaces
Helicine
arteries
Trabecular
smooth
muscle
Subtunical
venular plexus
Deep
dorsal vein
Tunica
albuginea
Corpora
cavernosa
Cavernous
artery
Erect
Flaccid
during erection and detumescence.
8
Erection begins
with transmission of impulses from parasympathetic
nerves and non-adrenergic, non-cholinergic (NANC)
nerves. This neural stimulus leads to release of nitric
oxide (NO) from the NANC nerves and possibly the
endothelial cells. NO is synthesized from NO synthase
(NOS). NO increases intracellular levels of cyclic
guanosine monophosphate (cGMP) in the cavernosal
smooth muscle, which acts to relax cavernosal tissue,
perhaps by activating protein kinase G and stimulating
phosphorylation of proteins that regulate corporal
smooth-muscle tone (Fig. 18.3).The actions of the para-
sympathetic nervous system, NO, and cGMP permit
rapid blood flow into the penis and the development
of an erection.
9
As pressure within the corporal body
increases, small emissary veins transversing the tunica
albuginea are occluded, trapping blood in the corpus
cavernosum. The erection is maintained until ejacu-
lation, which usually leads to detumescence.
9
Phosphodiesterases (PDEs), which hydrolyze both
cGMP and cyclic adenosine monophosphate (cAMP),
play a key role in the physiology of erection. Studies
using reverse transcriptase-polymerase chain reaction
(RT-PCR) have demonstrated the presence of
messenger RNA (mRNA) transcripts specic for many
of the 14 different human PDE isoenzymes in human
corpus cavernosum (Fig. 18.4). However, PDE2, 3, 4,
and 5 appear to be the dominant active isoforms in this
tissue.
10
As will be discussed in more detail below,
PDE5 is the enzyme that has been targeted for oral
treatment of men with ED. There are three isoforms
of this enzyme in human penile tissues: PDE5A1,
PDE5A2, and PDE5A3.
11
A wide range of additional neurotransmitters and
neuromodulators are expressed in penile tissues and/or
the nerves that supply them. These include vasoactive
intestinal polypeptide (VIP), calcitonin gene-related
peptide (CGRP), substance P, pituitary adenylate
Age-related Changes in Erectile Function 243
Figure 18.3 A Mechanism of contraction of the penile smooth-muscle cell. Norepinephrine (noradrenaline) release from
adrenergic nerve terminals keeps the cell contracted. (Reprinted with permission from Lue TF. Erectile dysfunction. N Engl
J Med 2000; 2:1802. Copyright 2000 Massachusetts Medical Society. All rights reserved.)
Adrenergic
Effector
(phospholipase C)
Diacyglycerol
Protein
kinase C
Ca
2+
G protein
Norepinephrine
(noroadrenaline)
Smooth-muscle
cell
Receptors
Increased
inositol
triphosphate
Endoplasmic
reticulum
Increased
Ca
2
1

2
Adenylyl
Decreased
cAMP
Endothelial
cell
Endothelins
Prostaglandin
F
2
Ca
2+
calmodulin
Myosin light-
chain kinase
Inactive
Active
Ca
2+
-calmodulin-myosin
light-chain kinase complex
Myosin light-chain
phosphorylation
Cycling of myosin
cross-bridges along actin
Smooth-muscle
contraction
Stimulation
Inhibition
cyclase-activity peptide, adenosine triphosphate (ATP),
serotonin (5-HT), dopamine, oxytocin, and histamine.
12
The roles of these molecules in the normal erectile
response remain controversial.
Changes in aging that may have
negative effects on erectile function
Many systemic changes and alterations in the structure
and function of the penis are independent of disease
and can have a negative effect on erectile function.
Systemic changes
As men age, they undergo a number of hormonal
changes (Table 18.1
13
), including a marked decrease in
the serum levels of testosterone and free testosterone.
14
Schiavi et al.
15
evaluated both sexual and erectile
function and levels of pituitary and gonadal hormones
in 77 healthy married men aged 4574 years. Aging
was negatively correlated with bioavailable testos-
terone (bT) and positively correlated with luteinizing
hormone (LH) levels. bT and the ratio of bT to LH
showed a close association with sexual behavior,
Figure 18.3 (Contd) B Mechanism of relaxation of the penile smooth-muscle cell. Nitric oxide (NO) is synthesized in the
non-adrenergic, non-cholinergic nerve terminal, as well as the endothelium, and diffuses through into the smooth cell.
NO stimulates formation of cyclic guanosine monophospate (cGMP), which produces smooth-muscle relaxation.
cAMP, cyclic adenosine monophosphate; ATP, adenosine triphosphate; PDE, phosphodiesterase; GTP, guanosine
triphosphate; eNOS, endothelial nitric oxide synthase. (Reprinted with permission from Lue TF. Erectile dysfunction.
N Engl J Med 2000; 2:1802.)
Cavernous
nerve
Adrenergic
Endothelial
cell
Cavernous
nerve
Non-adrenergic
non-cholinergic
Nitric
oxide
l-Arginine
Increased
inositol
triphosphate
Ca
2+
O
2
Acetylcholine
Prostaglandin E
1
Receptors
Smooth-muscle
cell
Forskolin
G-protein
Adenylyl
cyclase
ATP
cAMP
5' AMP
PDE
2, 3, 4
Papaverine
Ca
2+
K
+
cAMP specific
protein kinase
Endoplasmic
reticulum
Ca
2+
Decreased
Ca2+
Myosin
head detaches
from actin
cGMP
specific protein
kinase
Guanylyl
cylase
GTP
cGMP
5' GMP
PDE 5
K
+
Ca
2+
Sildenafil
papaverine
zaprinast
Smooth-
muscle
relaxation
eNOS
Stimulation
Inhibition
whereas total testosterone, estradiol, and prolactin did
not. However, the age-related effect of bT was a more
important determinant of reported sexual behavior
than was bT, independent of age. These investigators
concluded that changes in circulating hormones have
relatively little influence on erectile function in healthy
aging men.
Others have noted that a decline in serum testos-
terone occurs as part of the normal aging process and
that a small fraction (about 2%) of aging men have
subnormal serum testosterone levels. However, it is
unclear whether these decreases are associated with
the development of ED.
16
Thus, although testosterone
and free testosterone, like sexual function, decline with
age, the contribution of these hormonal changes to the
development of ED is thought to be only minor.
17
Penile structure
Signicant changes in penile structure occur with aging.
Collagen and elastic bers in the tunica albuginea are
key structures that permit increases in girth and length
of the penis during tumescence, and ultrastructural
analysis of penile biopsies has shown that the con-
centration of elastic bers decreases with age.
18
This
decrease results in a reduction in elasticity that could
contribute to ED in elderly men. Additional studies
have shown that there is a decrease of up to 35% in
the smooth-muscle content of the penis in men older
than 60 years of age. Decreases in the ratio between
corpus cavernosum smooth muscle and connective
tissue has been associated with increased likelihood of
diffuse venous leak that may contribute to ED.
19
It has
also been noted that the concentration of type III
collagen decreases and that for type I collagen increases
(Fig. 18.4) in the aging penis.
20
It has been suggested
that this change makes the corpus cavernosum less
compliant, reduces lling of vascular spaces, and also
contributes to venoocclusive dysfunction.
20
It has also
been hypothesized that changes in the collagen
content of the penis may result in chronic ischemia
that leads to loss of smooth-muscle cells.
21
Penile function
A large number of physiological and biochemical
changes in the aging penis may contribute to the
development of ED in older men. Not surprisingly,
Age-related Changes in Erectile Function 245
Figure 18.4 Collagen III (A) and collagen I (B) in the human penile corpus cavernosum tissue (400). The antibodies are
commercial and are used in a 1/30 dilution. The technique is standard immunohistochemistry.
A B
TABLE 18.1 Hormonal changes in the aging
male.
Hormone Change in the
aging male
Testosterone Decreased
(especially after
age 70)
Free testosterone Decreased
Bioavailable testosterone Decreased
Sex hormone-binding globulin Increased
Luteinizing hormone Increased
(especially after
age 70)
Follicle-stimulating hormone Increased
Dihydrotestosterone No change
Estradiol No change
Dehydroepiandrosterone Decreased
Dehydroepiandrosterone sulfate Decreased
Triiodothyronine Decreased
Insulin Decreased
Reprinted with permission from Margolese HC. The male
menopause and mood: testosterone decline and depression
in the aging male is there a link? Geriatr Psychiatry Neurol
2000; 13:93. Copyright 2000 by Sage Publications Inc.
mechanical sensitivity of the penis is decreased.
Rowland and associates
22
used psychophysical methods
to demonstrate marked increases in the threshold
for response to vibrotactile stimulation in both older
(mean age, 67.3 years) and diabetic men. Surprisingly,
the decline in penile sensory function in older men
was not matched by a corresponding reduction in the
sensitivity of the nger to vibrotactile stimulation (Fig.
18.5). It is not known whether this functional change
results from a decrease in the afferent nerve supply
to the penis or an increase in the thresholds for an
unchanged number of bers.
Animal studies have provided conflicting evidence
regarding changes in the innervation of the penis with
aging. Carrier et al.
23
reported that the number of NOS
immunoreactive bers is decreased in the penis of
aging rats, while Warburton and Santer
24
and Amenta
et al.
25
reported no signicant changes in the inner-
vation of the penis by CGRP- and VIP-containing
axons, respectively. It is important to note that these
studies provide limited insight regarding age-related
changes in the innervation density in the penis, because
results reflect density of immunostaining for products
within nerve bers that may change independently of
the number of penile sensory or sympathetic axons.
Increased understanding of the molecular pathways
involved in erectile function has prompted consider-
able research into the ways specic molecules related
to erection may change with age. Much of this attention
has focused on NO and NOS. As noted immediately
above, there is evidence that NOS-positive axons are
decreased in the penis of aged rats.
25
Garbn et al.
26
also noted that NOS activity per gram of penile tissue
was decreased by 63% in senescent (30-month-old)
rats.
Simple conclusions about age-related changes in the
amount or activity of NOS in the penis with aging are
complicated by the fact that there are three NOS
species: endothelial NOS (eNOS), inducible NOS
(iNOS), and neuronal NOS (nNOS).
27
eNOS (Fig. 18.6)
and nNOS are constitutive and activated in part by
an increased concentration of intracellular calcium and
calmodulin binding to the enzyme. iNOS is thought to
be associated primarily with macrophages and is
activated by specic cytokines as part of inflammatory
and immune responses.
28
Both eNOS and iNOS are
expressed in human cavernosal smooth-muscle cells,
and nNOS is expressed in nerve bers innervating the
penis.
29
Ferrini and associates reported that iNOS exhibits a
3.6-fold upregulation (as demonstrated by immuno-
staining) in penile smooth muscle of aged (24- to
30-month-old) rats. This rise was associated with a 3.6-
fold increase in apoptotic cells and a 2.0-fold increase
Figure 18.6 Endothelial nitric oxide synthase (eNOs) polyclonal antibody staining in the rat corpus cavernosum
(A, 200, 1:200 dilution) and the human corpus cavernosum (B, 400). The technique is standard immunohistochemistry
and the antibody commercial. Note the intense staining in the helicine artery and the smooth muscle (B).
A B
Figure 18.5 Rowland and associates
22
used
psychophysical methods to demonstrate marked increases
in the threshold for response to vibrotactile stimulation in
both older (mean age, 67.3 years) and diabetic men. This
decline in penile sensory function in older men is not
matched by a corresponding reduction in the sensitivity of
the nger to vibrotactile stimulation.
A
m
p
l
i
t
u
d
e

(
)
0
Finger Penis
5
1
2
3
4
Young
Aging
Diabetic
in collagen bers. These investigators suggested that
induction of iNOS and the resulting peroxynitrite for-
mation in the aging penis may result in both apoptosis
and proteolysis.
30
This suggestion is consistent with
the above-noted loss of smooth muscle in the aging
penis.
20
It is also reasonable to speculate that increased
iNOS expression may be associated with inflammatory
processes that could impair erectile function.
Haas et al.
31
reported that eNOS was upregulated in
the penile corporal tissue of aging rabbits. Despite this
increase, acetylcholine (ACh)-NO-mediated smooth-
muscle relaxation was markedly impaired in these
animals. These investigators showed further that caver-
nosal smooth-muscle relaxation in old, but not young,
rabbits was enhanced in the presence of the calcium
ionophore A23187. This suggests that the decreased
smooth-muscle relaxation observed in the aging penis
may be due to altered calcium flux, possibly at the
level of the calciumeNOS interaction. This speculation
is consistent with the recent suggestion that aging-
associated ion channel abnormalities may play a role
in the development of ED.
32
The age-related upregulation in eNOS activity in the
penis may be a response to reduced NO in this tissue.
Advanced glycation endproducts (AGEs) (Fig. 18.7)
accumulate in the aging penis in both corporal tissues
and the tunica albuginea.
33
AGEs form protein and
DNA adducts and cross-links. The cross-links may func-
tion as NO scavengers, reducing levels of this mediator
in corporal tissue. Studies in other tissues have shown
clearly that decreasing NO levels with a scavenger
(oxyhemoglobin) increases eNOS activity.
34
Thus, the
apparently paradoxical age-related rise in an enzyme
known to be involved in erectile function may actually
reflect lower levels of its product, NO.
One additional change in the aging penis is worthy
of mention. As already noted, CGRP appears to play a
signicant role in erectile function. Several years ago,
Wimalawansa
35
reported that levels of this peptide are
decreased in the penis of aged rats.
Some or all of the above-described changes in
structure, physiology, and molecular function may
underlie penile hemodynamic changes observed in
normal aging men. For example, Chung et al. showed
that advancing age was associated with a signicant
decrease in cavernous arterial flow velocity in response
to intracavernous injection of 10 g prostaglandin E
1
(Fig. 18.8).
36
Importantly, all of the men in this study
were free of any cardiovascular risk factors, so it is
unlikely that systemic disease was responsible for the
observed hemodynamic change.
In summary, studies to date strongly suggest that
the normal aging process produces changes in penile
anatomy and in the molecular and cellular processes
involved in erectile function. It thus seems reasonable
to suggest that aging, in the absence of disease, is
sufcient to produce ED in at least some men. This
conclusion is consistent with results reported by
Mulligan et al.,
7
who showed that age alone was a
signicant risk factor for ED. Advancing age also raises
the risk for a number of other diseases that in turn
increase the chance of ED.
COMORBIDITIES IN ED PATIENTS
ED is often associated with a number of other
conditions that are common in aging men. The most
important of these involve the cardiovascular system.
However, psychiatric disease can also increase the risk
Comorbidities in ED Patients 247
Figure 18.7 The advanced glycation endproduct, pyrraline
(1:400 dilution, 200 magnication) in the human penile
corpus cavernosum. Note the intense staining in the
smooth muscle and the media of the blood vessel.
Figure 18.8 Relationship between age and maximum
peak systolic velocity (PSV) in the cavernosal artery.
(Reprinted with permission from Chung WK, Park YY,
Kwon SW. The impact of aging on penile hemodynamics in
normal responders to pharmacological injection: a Doppler
sonographic study. J Urol 1997; 157:2129.)
Age (years)
P
S
V
m
a
x

(
c
m
/
s
)
0
20 30 40 50 60 70 80
100
20
40
60
80
P = 0.003 by simple regression test
for ED.
37
Diseases that occur with increasing frequency
in older men may interact with the normal age-related
changes in penile structure and function to increase
the risk for ED. For example, it was noted above that
levels of NO may be reduced in the aging penis, and
that this may increase the risk for ED. This suggestion
is consistent with ndings indicating that production of
NO by the vascular endothelium in other portions of
the body decreases with age.
38
Vascular NO levels are
also decreased in patients with hypertension.
39
NO
reductions associated with normal aging and those
resulting from elevated blood pressure may interact to
magnify the risk for ED signicantly.
Cardiovascular disease and ED
The prevalence of cardiovascular disease increases with
age,
40
and such disease markedly elevates the risk for
ED. Chew and associates assessed the prevalence of
ED and comorbidities in 1240 men between 18 and
91 years of age.
41
Of these, 488 men reported some
degree of ED. Hypertension, ischemic heart disease,
and peripheral vascular disease were all frequently
associated with ED in this cohort.
42
The results of the
Massachusetts Male Aging Study also showed that the
age-adjusted risk for ED was signicantly increased by
the presence of heart disease or hypertension.
42
These
ndings are supported by the results of several other
smaller-scale epidemiologic studies. Parazzini et al.
43
showed that a history of cardiopathy, hypertension,
peripheral vascular disorder, and thrombotic or hemor-
rhagic stroke all increased the risk of ED in a cohort of
2010 men. Martin-Morales et al.
44
also showed that
high blood pressure, peripheral vascular disease, and
cardiac disorders were associated with signicantly
increased risk for ED in a sample of 2476 men between
25 and 70 years of age.
The link between cardiovascular disease and ED
is strongly supported by results from a study by
Greenstein et al., who assessed the relationship
between ED severity and ischemic heart disease in 40
men who underwent coronary angiography.
45
They
found a signicant correlation between the severity of
ED and the number of obstructed coronary vessels.
Patients with one-vessel disease had more and rmer
erections with fewer difculties in achieving erection
than did men with two- or three-vessel disease. They
also noted a signicant association between hyper-
tension and ED.
Kawanishi and colleagues provided evidence that the
presence of ED is predictive of undiagnosed ischemic
heart disease.
46
They performed echocardiograms,
treadmill tests, thallium exercise scintigrams, and
coronary angiograms in 58 patients with ED. Fourteen
patients (24.1%) were diagnosed with ischemic heart
disease. Although six patients had already been diag-
nosed at the time of testing, eight were newly diagnosed
by the exercise tests.
46
While the relationship between vascular disease and
ED would seem straightforward, the reason for the
strong independent relationship between hypertension
and ED is less clear. For example, Jaffe and associates
reported that penile peak systolic velocity, resistance
index, and penile brachial index did not differ signi-
cantly between hypertensive and normotensive men
with ED.
47
However, NO production is reduced in
patients with essential hypertension,
48
and it is reason-
able to speculate that this decrease may contribute to
the increased risk for ED in patients with high blood
pressure.As noted above, NO production by the vascular
endothelium also decreases with age independent of
disease,
38
and it is possible that a hypertension-related
decrease in NO may exacerbate the normal age-
associated fall and potentially increase the risk for ED
in older men with elevated blood pressure.
Diabetes
The risk of diabetes increases with age,
49
and the
presence of diabetes signicantly raises the risk for
ED.
4144
It has also been shown that ED severity is cor-
related with the degree of impaired glycemic control.
50
Diabetes is associated with both neural and micro-
vascular disease, which may contribute to the develop-
ment of ED.
50
Diabetes also results in increased
formation of AGEs in the human tunica albuginea and
corpus cavernosum.
51
As noted above, AGE-associated
changes in DNA and proteins can result in scavenging
of NO and thus decreased erectile function. Unlike
aging, however, diabetes is associated with a marked
reduction in eNOS in the cavernosal endothelium and
smooth muscle but upregulation of iNOS.
51
As with
cardiovascular disease, molecular events that occur in
patients with diabetes may interact additively or even
synergistically with those that result from normal
aging. AGEs accumulate in the aging penis
33
as well as
in many other tissues.
52
Thus, in elderly men, diabetes
may have the potential substantially to increase
normally occurring AGE formation and perhaps
elevate the risk for ED.
Benign prostatic hyperplasia
The prevalence of benign prostatic hyperplasia (BPH)
increases with age,
53
and the presence of BPH increases
the risk for ED.
54
Namasivayam et al. noted that over
one-half of a cohort of 140 men with BPH also had
some degree of ED.
54
However, it is not clear whether
the presence of BPH increases ED risk independent
of age, or whether the increased risk of ED in men
with BPH is due to the fact that the prevalence of
both conditions is increased in the elderly. Current
evidence appears to support the latter of these two
possibilities.
55
Depression
The association between age and the risk for depression
is controversial, but there appears to be a complex
relationship between depression and advancing age,
with a peak prevalence in the years before retirement,
a low prevalence during the rst 1015 years there-
after, and another increase in those older than 75 years
of age.
56
There is a signicant age-independent cor-
relation between the presence of depression and ED.
57
Several investigators have suggested that the age-
related decrease in the production of testosterone
and perhaps other hormones (e.g., growth hormone,
thyroxine, dehydroepiandrosterone, melatonin) may
contribute to the development of both conditions.
58
THERAPIES FOR ED IN THE ELDERLY
There is a wide range of treatments for ED, and
virtually all of them can be used in older patients.These
therapies can be divided into two broad categories:
non-oral and oral.
Non-oral treatments and early oral
therapies
There are a variety of non-oral approaches to the treat-
ment of ED, including vacuum constriction devices,
penile self-injection therapy, hormone injections, and
penile prostheses.
59
While all of these approaches can
result in signicant improvements in male sexual func-
tion, none are completely satisfactory. For example,
self-injection treatments may be associated with side-
effects such as prolonged erection, priapism, and brosis
of the corpus cavernosum.
59
While intercavernosal
injection therapy consistently produces erections in up
to 87% of patients, there is a dropout rate of about
50%.
59
Finelli et al.
60
evaluated treatment preferences
and commitment to specic therapeutic choices in a
cohort of 88 elderly men (mean age, 69.5 years) with
ED. The treatment options available to these patients
included older oral medications (e.g., yohimbine,
trazodone), vacuum devices, injection therapy, penile
prostheses, counseling, and testosterone replacement
(when indicated). Patients were followed from 1 to
63 months after initial consultation (median follow-up,
9 months).The most popular initial treatment choice in
this group of older men with ED was injection therapy
(30%), followed by vacuum devices (27%) and oral
medication (20%; yohimbine in 16 patients and
trazodone and sildenal each in one patient). Of the
84 patients treated, 40% switched therapies over the
course of follow-up. The dropout rate was signicantly
higher for patients who began with oral therapy (78%)
than for those who selected intracavernosal injection
(48%) or a vacuum device (29%). Another long-term
(3-year) study of ED treatment in 69 men (mean age
60.5 years) indicated that injection therapy with prosta-
glandin E
1
was effective and generally well-tolerated,
and that it resulted in the development of spontaneous
erections in 35% of these patients.
61
These results
appear to support the view that injection therapy
was the best ED treatment for older men, at least until
the time when new, highly effective oral treatments
became available.
Newer oral therapies
A wide range of oral treatments have been used
in men with ED, including sildenal, apomorphine,
oral phentolamine, trazodone, and yohimbine.
62
New
drugs in late-phase development include several new
PDE5 inhibitors and agents with other mechanisms of
action.
63,64
As noted above, older oral drugs, such as
yohimbine and trazodone, appear to be relatively
ineffective in older men.
60
The PDE5 inhibitor sildenal (Figs 18.918.11) is by
far the best studied oral therapy for the treatment of
men with ED, and it has been shown to be effective in
elderly men, including those with comorbidities likely
to be present in this age group. Rendell et al.
65
recently
reported that sildenal signicantly improved the
ability of men 65 years of age or older to achieve and
maintain erections (Table 18.2). While the response
rate to sildenal (based on the response to a general
efcacy question) was similar in men 65 years of age
and those 5064 years old (50% versus 53%), these
response rates were lower than those for men 1849
years of age (72%).
Wagner et al.
66
analyzed data from ve double-
blind, 12-week to 6-month placebo-controlled studies
to evaluate the efcacy and tolerability of sildenal in
411 patients 65 years of age or older having ED with
a broad spectrum of etiologies. Efcacy was assessed
using a global efcacy question, questions three and
four of the International Index of Erectile Function
(IIEF),
67
and the ve sexual function domains of the
IIEF. All efcacy assessments indicated that sildenal
signicantly improved erectile function both in elderly
patients with ED of broad-spectrum etiology and in
elderly patients with ED and diabetes. The most
common adverse events in these men were mild-to-
moderate headache, flushing, and dyspepsia. The rates
of discontinuation due to adverse events were low and
comparable to the rates with placebo.
Sildenal has also been shown to be effective in men
with ED and hypertension,
68
and in men with both ED
and ischemic heart disease.
69
Conti et al.
69
reported
that 70% of patients who received sildenal had
Therapies for ED in the Elderly 249
Figure 18.9 Oral type 5 phosphodiesterase inhibitors. All drugs have a similar chemical composition to cyclic guanosine
monophosphate (cGMP). That is their mechanism of action. They are all competitive inhibitors of cGMP.
Sildenafil
cGMP
Tadalafil
N
S
O
HN
O
O
O
OH
P
O
O
H
H
N
NH
O
O
O
N
N
N
O
OH
HN
O
O
N
N
N
O
N
H
3
C
H
2
C
CH
3
CH
3
CH
3
CH
3
Vardenafil
N
S
O
HN
O
O
N
N O
N
H
3
C
CH
3
CH
3
CH
3
Figure 18.10 Mechanism of
phosphodiesterase type 5 (PDE5)
inhibition. The oral PDE5
inhibitors competitively inhibit the
PDE5 enzyme to prolong the
effects of cyclic guanosine
monophospate (cGMP) and yield
a longer-lasting erection. GTP,
guanosine triphosphate; nNOS,
neuronal nitric oxide synthase;
eNOS, endothelial nitric oxide
synthase; cAMP, cyclic adenosine
monophosphate. (Reprinted with
permission from Lue TF. Erectile
dysfunction. N Engl J Med 2000;
2:1802.)
Guanylyl
cyclase
cGMP-specific
protein kinase
cAMP-specific
protein specific
Adenylyl
cylase
GTP
cGMP
5' GMP
Ca
2+
Ca
2+
PDE5
eNOS
nNOS
eNOS
improved erections, versus 20% in the placebo group,
in patients with both ED and ischemic heart disease
who were not taking nitrates.
Sildenal is also effective in patients with depression.
In a retrospective analysis that included 134 patients
with a medical history, past or present, of depression,
76% of the patients who received sildenal reported
improved erections versus 18% for placebo.
70
Although sildenal has been shown to be efcacious
in a wide range of individuals with ED, it is not effec-
tive in all patients. Martnez-Jabaloyas et al.
71
recently
evaluated risk factors for treatment failure with
sildenal and noted that diabetes, non-nerve-sparing
radical prostatectomy, and high baseline disease
severity, as reflected by Sexual Health Inventory for
Men (SHIM) scores, were all predictors of a lower
success rate for sildenal therapy.
The new agent tadalal (IC351), a reversible inhibitor
of PDE5, is more selective for PDE5 versus PDE6 than
is sildenal.
64
An assessment of the safety and effective-
ness of tadalal in patients older than 65 years of age
versus younger patients indicated that it was safe and
effective in both groups, with improved erections in up
to 81% of men in the combined population.
72
Vardenal, another novel selective PDE5 inhibitor,
has also been shown to be safe and effective for the
treatment of ED in a 12-week, multicenter, randomized,
double-blind, placebo-controlled trial that included
601 men with mild-to-severe ED.
73
While the study was
not specically directed toward evaluating the efcacy
of vardenal in older individuals, results showed that
the 20-mg dose improved erections in 80% of patients.
Oral therapies with mechanisms of action that differ
from those of sildenal and the other PDE5 inhibitors
are in development. These include an oral agent that
opens large-conductance calcium-activated potassium
channels (maxi-K), and agents that block the actions of
the catecholaminergic input to the penis (phentolamine
mesylate and sibutramine).
64
The importance of AGEs
in cardiovascular disease and ED has prompted
development and testing of ALT-711, an orally bio-
available non-enzymatic breaker of AGE cross-links.
Treatment with this agent signicantly increased
arterial compliance and reduced pulse pressure in
patients with systolic hypertension.
74
It seems reason-
able to suggest that this treatment might also be
effective in men with ED, especially in those patients
with diabetes who have been shown to have increased
concentrations of AGEs in penile tissues.
51
Gene therapy
Increased understanding of the molecular mechanisms
involved in penile erectile function and how they may
be impaired in men with ED has prompted investi-
gations into gene therapy. The importance of NO in
erectile function has prompted transfer of the gene for
eNOS in aged rats.
75
Champion and associates showed
that adenoviral-mediated gene transfer of eNOS could
reverse at least some symptoms of age-related ED in
60-week-old rats. Five days after gene transfer, eNOS
protein, mRNA, and cGMP levels in the corpora caver-
nosa were signicantly increased, and the erectile
Figure 18.11 Successful endothelial nitric oxide synthase
(eNOS) transfection in the animal produces an improvement
in intracavernosal pressure upon electrical stimulation.
C
h
a
n
g
e

i
n

c
a
v
e
r
n
o
s
a
l

p
r
e
s
s
s
u
r
e

(
m
m
H
g
)
0
Control eNOS
transfected
P <0.05
80
20
40
60
TABLE 18.2 PDE5 inhibitors: selectivity for
PDE5 vs other PDE isoenzymes.
PDE Sildenal Tadalal Vardenal
Isoenzyme
PDE1 80 >4500 500
PDE2 >8750 >14 800 44 290
PDE3 4630 >14 800 >7140
PDE4 2190 >14 800 43 570
PDE6 (rod) 11 187 25
(cone) 10 193 4
PDE7 6100 >14 800 >214 000
PDE8 8500 >14 800 >214 000
PDE9 750 >14 800 4150
PDE10 2800 >14 800 21 200
PDE11 780 5 1160
Therapies for ED in the Elderly 251
response to cavernosal nerve stimulation was signi-
cantly increased. These results raise the possibility that
transfer of the gene for eNOS may provide a new
therapeutic intervention for ED.
76
This same group evaluated the effects of gene transfer
for prepro-CGRP as therapy for ED in another group
of aged rats.
76
As noted above, levels of this peptide are
decreased in the penis of old rats.
35
Five days after
transfection, the aged rats had an approximately three-
fold increase in cavernosal CGRP levels. In addition,
cAMP levels in the corpora cavernosa were signicantly
increased. More importantly, there was a signicant
increase in the erectile response to cavernosal nerve
stimulation in the transfected animals.
It was noted above that aging-associated ion-channel
abnormalities may play a role in the development of
ED. Specically, Melman and Christ suggested that
alterations in the expression, regulation, and/or func-
tion of potassium (K
+
) channels and gap junctions may
be involved in the etiology of diabetes- and/or age-
related ED.
32
They tested the potential importance of a
specic K
+
channel, maxi-K, in diabetes-associated ED
in the following way. First, they rendered rats diabetic
with a single subcutaneous injection of streptozotocin.
Two months after the streptozotocin injection and
verication of a profound penile neuropathy, animals
received a single intracavernous injection of the DNA
encoding the K
+
channel maxi-K or the pcDNA vector
only. After an additional 23 months, the rats were
tested with an intracavernous nerve stimulation
protocol. Despite the presence of signicant neuro-
pathy, the nerve stimulation responses were dramati-
cally greater in the maxi-K-transfected animals than in
controls that received only the pcDNA. This result is
consistent with the conclusion that increasing maxi-K
channel expression in cavernosal tissues may reverse
diabetes-associated pathologic changes in penile
function.
All of the results summarized in this section are
consistent with the possibility that gene therapy may
provide effective treatment for patients with ED. Given
that ED may be a heterogeneous disease, it is likely
that transfer of different genes may be required in
different patients.
CONCLUSIONS
ED is a common condition with a prevalence that
increases dramatically with age. It seems likely that
both the normal aging process and the age-related
accumulation of risk factors for ED contribute to this
increased prevalence in older men. At present,
inhibition of PDE5 with oral agents such as sildenal
appears to be the treatment of choice. These drugs have
been shown to be safe and effective in elderly men
with ED, and sildenal has demonstrated efcacy in
patients who have many of the comorbidities observed
in older men with ED. New treatments, in particular
transfection with genes for key mediators of erectile
function that are known to be downregulated in elderly
men, also hold signicant promise. The results reviewed
here underscore the remarkable progress in the treat-
ment of ED that has taken place in the past decade. It
is likely that further research into the neural and
vascular mechanisms involved in penile erection will
continue to result in new safe, effective, and convenient
therapies for men with this condition.
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INTRODUCTION
Following Masters and Johnsons groundbreaking
work in the early 1970s there was a flurry of scientic
inquiry into the etiology and treatment of female
sexual dysfunction. This early excitement stalled in the
late 1980s and early 1990s. It was not until after the
introduction of sildenal for the treatment of erectile
dysfunction that a second renewed wave of scientic
enthusiasm regarding female sexual dysfunction
evolved, leading to the advancement of new models
and treatments.
This chapter will present the major etiological and
treatment models for female sexual dysfunction. It will
address both the psychological and biological issues
relevant to a holistic biopsychosocial model of female
sexuality.
THE EARLY YEARS
William Masters and Virginia Johnson, in 1966, were
recognized for providing the rst description of the
human sexual response as it applies to both men and
women.
1
Through direct observations and physical
measurements, they identied the gross physical and
physiological reactions to sexual stimuli and proposed
a linear model with four separate yet successive phases:
excitement, plateau, orgasm, and resolution. Albeit
arbitrary and inadequate for understanding the ne
psychogenic aspects of the sexual response, these
divisions provided a useful framework for future
description and study. In addition to the development
of their sexual response model, Masters and Johnson
recognized gender-specic differences between the
male and female sexual response. With the exception
of variations in the duration of response, the male
sexual response was described by a single cycle that can
be represented graphically, as shown in Figure 19.1.
This was in contrast to the female, where three
different response patterns were noted, but also with
the recognition that an innite variety of responses
exist with variations in both intensity and duration of
response (Fig. 19.2).
The Masters and Johnson models for male and
female sexuality were similar in that they were linear
and phasic; they began with arousal and ended with
orgasm. By studying women having intercourse in a
clinical research setting they documented the physio-
logical parameters of female orgasm. They found there
were variations in form but not separate clitoral or
vaginal orgasms, as proposed by psychoanalytic theory.
Helen Singer Kaplan
24
and Harold Lief
5
expanded
on Masters and Johnsons work by proposing the
concept of desire to account for women and men
who lacked the motivation to be sexual.They proposed
desire as the initial phase, or the inciting factor respon-
sible for triggering a three-phase sexual response cycle:
desire, arousal, and orgasm. Desire, for both men and
women, was thought to be a spontaneous event, which
directly elicited the physiological responses of arousal
and orgasm. A biphasic nature of these physiological
responses to sexual stimulation was described: genital
and generalized vasocongestion, seen as penile erection
in the male and vaginal lubrication and labial/clitoral
swelling in the female; and reflexive myotonic reactions
resulting in ejaculation in the male and orgasm in both
sexes. Desire, however, was thought to be the necessary
precursor for initiating these physiological responses.
Kaplan perpetuated the linear phasic models of
Masters and Johnson, leading clinicians to think of
female sexual dysfunctions as discrete entities with
little overlap between dysfunctions.
Dening Female Sexual Dysfunction
Suzette E. Sutherland and Stanley E. Althof
CHAPTER 19
Figure 19.1 The male sexual response cycle. From
Masters WH and Johnson VE. Human sexual response.
Boston: Little Brown, 1966. By kind permission of
Lippincott, Williams & Wilkins.
Orgasm
Plateau
Excitement
Refractory
period
Refractory
period
R
e
s
o
l
u
t
i
o
n
R
e
s
o
l
u
t
i
o
n
Further investigation into sexual response patterns
has led to a greater understanding of differing gender-
specic responses. This has resulted in the develop-
ment of alternate models for women. In 1991 Leonore
Tiefer recognized the non-genital components of
female sexual satisfaction respect, mutuality,
emotional bonding, intimacy as the motivational
forces for engaging in sexual activity.
6
In her recent
women-centered New View denitions of sexual
problems among women, the psychobiosocial
aspects emotional, physical, cultural, and relational
of the sexual experience are emphasized.
7,8
This con-
cept, known as the demedicalization of sexuality,
advocates a non-medical framework for sexuality
theory which is meaning-centered rather than
function-centered, and grounded in humanistic
rather than in biological foundations.
7
Unlike women, men exhibit a strong objective and
physically visible correlation between subjective and
objective (genital) sexual arousal and response.
1,2
With
sexual stimulation, genital vasocongestion leads to
penile rigidity; continued stimulation leads to orgasm
with ejaculation. In contrast to this, female sexual
arousal and response are not only difcult to measure
but are often not readily perceived as such by the
woman.
9
Furthermore, Laan and Everaerd noted a
discrepancy between objective and subjective sexual
arousal in women.
10
A disconnection between objective
and subjective (mental) arousal was observed in their
laboratory studies. These ndings further support the
notion that sexuality is more contextual for women as
compared to men.
Rosemary Basson recently put this context-
centered perspective into an elegant non-linear
model of female sexual response (Fig. 19.3).
11,12
The
emphasis is on the responsive nature of womens sexual
desire (as opposed to spontaneous); arousal and desire
occur simultaneously, each enhancing the other in
an interactive pattern. Many women are sexually
neutral and consciously decide to be sexual and/or
receptive to sexual overtures that have been made.
This decision is primarily in response to a greater need
for a sense of emotional attachment. In Bassons model,
a yearning for emotional and relational intimacy
provides the motivational force for physical and sexual
behavior.
PREVALENCE STUDIES ON FEMALE
SEXUAL PROBLEMS AND
DYSFUNCTIONS
The National Health and Social Life Survey (NHSLS),
conducted in the early 1990s, reported epidemio-
logical data on sexual dysfunction in the USA.
13
This
population-based analysis was the rst of its kind in
almost 50 years to shed light on the widespread nature
of sexual problems in society, especially among women.
The survey included 1749 women and 1410 men, aged
1859 years. A higher prevalence of sexual problems
overall was reported among women (43%) as com-
pared to men (31%). One-third of women identied
problems with sexual interest and desire, one-fourth
reported a lack of orgasmic experiences, and one-fth
complained of difculties with vaginal lubrication.
Overall, 20% of women reported sex as an unpleasant
experience (Fig. 19.4). Due to the cross-sectional
design of the NHSLS, conclusions about causality or
risk factors for sexual dysfunction were not possible.
However, subsequent multivariate analysis identied
258 Dening Female Sexual Dysfunction
Orgasm
Plateau
Excitement
A B C (C)
(A)
(B)
R
e
s
o
l
u
t
i
o
n
R
e
s
o
l
u
t
i
o
n
R
e
s
o
l
u
t
i
o
n
Figure 19.2 The female sexual
response cycle. From
Masters WH and Johnson VE.
Human sexual response.
Boston: Little Brown, 1966. By
kind permission of Lippincott,
Williams & Wilkins.
several independent predictors of female sexual dys-
function.
14
Increasing age (especially postmenopausal),
lower level of educational attainment, unmarried
status, poor physical or emotional health, and prior
negative sexual experiences were all associated with
an increased incidence of sexual problems. For many
women female sexual dysfunction caused profound
physical, psychological, and emotional concerns,
resulting in a signicant impairment in quality of life.
Previous estimates of sexual dysfunction among
healthy women vary widely. In a review of 23 studies
on the incidence and prevalence of female sexual dys-
function by Spector and Carey, a 510% prevalence
for lifelong inhibited orgasm among the community
samples was reported, with 70% of these women
anorgasmic with intercourse.
15
The majority of womens
complaints, however, were decreased sexual desire and
arousal. Studies completed with community samples
revealed difculties associated with sexual desire and
arousal in up to 50% of women, while analysis of the
clinical samples noted these same complaints in up to
80% of women.
In 1978 Frank et al. published a study on 100
ethnically homogenous happily married couples in
which 63% of the women experienced dysfunction with
sexual performance relating to arousal or orgasm.
16
Sexual difculties were dened as those parameters
relating to the emotional tone of the sexual relation-
ship (inability to relax, lack of sexual interest or desire,
insufcient foreplay before intercourse, insufcient
tenderness after intercourse) and were reported by
77% of the women.
The men in Franks study tended to underestimate
the problems reported by their wives.While difculties
with getting and maintaining excitement during sexual
encounters was reported by one-third of the wives,
only half of their husbands recognized this problem in
their partner. For women, dysfunctions in sexual
Sexual
desire
To continue
Enhanced
intimacy
More arousal and
pleasure and positive
outcome emotionally
and physically
Intimacy
needs
Biological and
psychological factors
affect processing
of stimuli
Seeking out
and being
receptive to
Sexual
arousal
Sexual
stimuli
Figure 19.3 Alternative model of
female sex response cycle. From
Basson R. Using a different
model for female sexual response
to address womens problematic
low sexual desire. J Sex Marit
Ther 2001; 27:395403.
Reproduced by permission of
Taylor & Francis Inc.
Figure 19.4 Male and female
frequency of reported sexual
problems. From Laumann EO,
Gagnon JH, Michael RT,
Michaels S. The social
organization of sexuality. Sexual
practices in the United States,
Chicago. Copyright 1994
University of Chicago Press.
Reproduced by permission of the
University of Chicago Press.
Experience pain during sex
Sex not pleasurable
Unable to achieve orgasm
Lacked interest in sex
Anxiety about performance
Climax too early
Men unable to keep an erection
Women have trouble lubricating
0 5 10 15 20
Women
Men
25 30 35
Prevalence Studies on Female Sexual Problems and Dysfunctions 259
arousal, as well as the number of sexual difculties,
most strongly correlated with overall sexual dissatis-
faction. This nding supports the notion that women
may have a greater need for the emotional intimacy
associated with sexual behaviors, and are therefore
disappointed when the physical encounter does not
generate a greater sense of connection.
Another survey study by Rosen et al. in 1993
identied a number of sexual problems among 329
healthy women (ages 1873 years) from an outpatient
gynecology setting.
17
Among these problems were
sexual anxiety or inhibition (38%), lack of sexual
pleasure (16%), orgasmic difculties (15%), lubrication
difculties (13.5%), and dyspareunia (11%). Increasing
age (especially postmenopausal women) and non-
married status were signicant predictors of sexual
dissatisfaction. In spite of these reported difculties,
68.6% of the women viewed their sexual relationship
overall as satisfactory, reinforcing the multidimensional
aspect of female sexuality and the importance of
relationship factors for normal female sexual function.
A renewed interest in female sexual dysfunction
blossomed following the successful experience of oral
pharmacotherapy with sildenal citrate (Viagra) for
the treatment of male erectile dysfunction.
18,19
With
promising clinical research suggesting the importance
of neurohemodynamic events in female sexual
physiology, similar to those seen in males, the efcacy
of a vascular medication for the treatment of female
sexual dysfunction was hopeful.
9,20,21
Preliminary data
on the use of Viagra in women have not been optimistic,
largely owing to a reported 50% placebo effect.
22
This
again points to the multifactorial nature of female
sexual functioning, emphasizing the psychological and
emotional, as opposed to purely physical, aspects.
CLASSIFICATION OF FEMALE SEXUAL
DYSFUNCTION
Classication systems for female sexual dysfunction
are based on the linear and discrete model initially
promulgated by Masters and Johnson
1
and Kaplan
2
that includes disorders of desire, arousal, orgasm, and
sexual pain. Three major classication systems exist,
including the World Health Organizations Inter-
national Classication of Disease (ICD-10) system of
1992,
23
the Diagnostic and Statistical Manual of
Mental Disorders (DSM-IV-TR) of the American
Psychiatric Association classications of 2000,
24
and
the more recent reclassication system developed by
the American Foundation of Urologic Disease (AFUD)
Consensus Panel in 2000.
25
According to the ICD-10,
sexual dysfunction is dened as the various ways in
which an individual is unable to participate in a sexual
relationship as he or she would wish.
23
Seven
categories were devised, which include: (1) a lack or
loss of sexual desire (F52.0); (2) sexual aversion dis-
order (F52.1); (3) failure of genital response (F52.2);
(4) orgasmic dysfunction (F52.3); (5) non-organic vagin-
ismus (F52.5); (6) non-organic dyspareunia (F52.5);
and (7) excessive sexual drive (F52.7).
The DSM-IV-TR denes sexual dysfunction as
disturbances in sexual desire and/or the psycho-
physiological changes that characterize the sexual
response cycle and cause marked distress and inter-
personal difculty.
24
The dysfunctions listed in DSM-
IV-TR include: (1) hypoactive sexual desire disorder
(302.71); (2) sexual aversion disorder (302.79); (3)
female arousal disorder (302.72); (4) female orgasmic
disorder (302.73); (5) dyspareunia (302.76); and (6)
vaginismus (306.51). Additionally, in order to qualify
for any of these diagnoses, the woman must also be
personally, not just interpersonally, distressed by the
dysfunction. A separate diagnostic category for sexual
dysfunction due to a general medical condition
24
was included for any sexual performance difculties
secondary to the physiologic consequences of a
medical condition.
Criticism of the DSM-IV-TR stems from its excessive
focus on genital response while minimizing the
emotional and interpersonal aspects of sexual
encounters, which seem to be of greater importance
to women than the physical genital response.
26
By
separating psychogenic dysfunctions from medical or
substance-related dysfunctions it perpetuates the
psychogenicorganic dichotomy rather than reflecting
a more holistic biopsychosocial model. It is also
criticized for reflecting a heterosexual, phallocentric
model, where intercourse is considered the gold
standard or point of reference for many of the
diagnoses.
7,26
Furthermore, the DSM-IV-TR and ICD-
10 classications do not reflect the extensive overlap
commonly seen among women presenting with sexual
dysfunction.
27
In an attempt to address many of the shortcomings
of these previous classication systems for female
sexual dysfunction, a multidisciplinary, international
committee of experts and in the eld of female
sexuality convened to evaluate and revise the existing
denitions and classications.
25
Their aim was to
develop a new consensus-based system of diagnostic
criteria that would include psychogenic- and organic-
based disorders.They sought to make recommendations
regarding guidelines for clinical evaluation, measurable
endpoints and outcomes for therapy and clinical trials,
and to identify and prioritize future areas for research.
The nal consensus classication system that
emerged maintained the same four major disorder
categories of desire, arousal, orgasm, and sexual pain
as previously used in both the ICD-10 and the DSM-
IV-TR. This was done in an effort to preserve some
continuity in both the clinical and research settings.
The individual psychologically based denitions, how-
ever, have been redened to include medical risk
factors and etiologies of female sexual dysfunction.
This change reflects recent advances seen in basic and
clinical research. In an attempt to move away from the
previous phallocentric model of sex, a new category
for non-coital sexual pain disorders was created.
Enthusiasm about an additional new diagnostic
category designated to reflect sexual satisfaction dis-
orders was generated, but insufcient epidemiological
and clinical data in this area prevented the panel from
reaching a consensus for its inclusion.
The AFUD Consensus Panel Classications and
Denitions of Female Sexual Dysfunction follow:
I. Sexual desire disorders
A. Hypoactive sexual desire disorder: the persistent or
recurrent deciency (or absence) of sexual fantasies/
thoughts, and/or desire for or receptivity to sexual
activity, which causes personal distress.
B. Sexual aversion disorder: the persistent or recur-
rent phobic aversion to and avoidance of sexual
contact with a sexual partner, which causes personal
distress.
II. Sexual arousal disorder
The persistent or recurrent inability to attain or main-
tain sufcient sexual excitement, which causes personal
distress, and may be expressed as a lack of subjective
excitement, or genital (lubrication/swelling) or other
somatic responses.
III. Orgasmic disorder
The persistent or recurrent difculty, delay in, or
absence of attaining orgasm following sufcient sexual
stimulation and arousal, which causes personal
distress.
IV. Sexual pain disorders
A. Dyspareunia
The recurrent or persistent genital pain associated with
sexual intercourse.
B. Vaginismus
The recurrent or persistent involuntary spasm of the
musculature of the outer third of the vagina that inter-
feres with vaginal penetration, which causes personal
distress.
C. Other sexual pain disorders (non-coital)
The recurrent or persistent genital pain induced by
non-coital sexual stimulation.
Each classication receives additional subtyping to
describe the disorder as:
A. Lifelong versus acquired type.
B. Generalized versus situational type.
C. Etiologic origin (organic, psychogenic, mixed,
unknown).
A criterion for personal distress as a quality-of-life
measure was included for most of the diagnostic
categories. This criterion emphasizes the subjective
nature of female sexual dysfunction and thereby afrms
the importance of relying on patient self-reports as
a signicant endpoint in clinical trials, rather than
focusing solely on physiological or anatomical (genital)
data. Furthermore, the substitution of personal
distress for interpersonal distress (included in
DSM-IV-TR) was intended to focus on the womans
concerns rather than those of her partner. Current
validated self-report instruments, such as the Female
Sexual Function Index (FSFI)
28
and the Brief Index of
Sexual Functioning for Women (BISF-W),
29,30
do not
incorporate an evaluation of personal distress. How-
ever, following the recent development and validation
of the Female Sexual Distress Scale (FSDS), a measure
of sexually related distress and its impact on quality of
life is now possible.
31
Hypoactive sexual desire disorder was broadened to
include a lack of receptivity to sexual activity initiated
by a sexual partner. The concept of receptivity, how-
ever, is left without specic denition. The new de-
nition also includes the persistent lack or deciency
of sexual desire, which therefore excludes situational
fluctuations in desire or sexual interest.
Sexual arousal disorder was expanded beyond the
objective physiologic parameters of genital arousal
to acknowledge the strong subjective component of
normal female sexual function. The new denition for
sexual arousal disorder now includes subjective and
non-genital objective somatic excitement and arousal
responses, or lack thereof. Orgasmic disorder was
broadened to include difculty and delay in attain-
ing orgasm, rather than just the absolute absence of
orgasm.
Sexual pain disorder was also broadened to include
an additional category for pain associated with sexual
stimulation that does not include vaginal penetration
or coitus. Moving away from traditional phallocentric
notions of normal sexual activity, this recognizes the
importance and satisfaction of non-coital sexual activity
for many women.
Commentary on the AFUD
classication system
While the new AFUD classication system represents
a signicant step forward in conceptualizing female
sexual dysfunction, several authors have voiced
Classification of Female Sexual Dysfunction 261
concerns regarding the diagnosis, the criterion sets,
and larger conceptual issues. A summary of the major
modications of the DSM-IV-TR nosologies and the
controversies regarding the revisions or lack thereof
are summarized below:
Does it truly provide an international
perspective?
Although introduced as an international group, the
participants of the consensus panel were primarily
Caucasian as well as North American and/or European.
Representation from Eastern European, Asian, Pacic
Islanders, Australian, and South American cultures was
lacking.
32
The cultural differences and attitudes
towards sexuality vary vastly and the new system may
not be sufciently culturally sensitive. For example,
reports of sexual desire disorders in Asian females
would indicate that the incidence is statistically lower
than that seen in the USA. Such statistics, however, are
undoubtedly affected by cultural practices, as fewer
Asian women consider decreased sexual desire a
problem, and therefore do not seek counsel.
33
The influence of commercial interests?
This endeavor was made possible by educational
grants from various pharmaceutical companies who
have a vested interest in developing pharmacological
solutions for female sexual dysfunction. The nancial
incentive to medicalize female sexual dysfunction
and further research along a path that undoubtedly
takes a predominantly physiological course has some
mental health practitioners concerned.
3437
However, in keeping with the biopsychosocial
model of female sexual function, scientific advances in
physiological and sociological domains are needed.
More of the same?
Overall, the Consensus Panel did not stray far from the
classication system of the DSM-IV-TR, although the
descriptions of each dysfunction were updated and
broadened.
27
Admittedly, this was done to maintain
continuity for the sake of furthering research and
clinical efforts. As there is no evidence-based research
that supports the DSM-IV-TR system, maintaining the
framework could possibly allow for the continuation of
inherent problems within it, and the continuation of
existing myths about female sexuality.
38
Are the criterion sets a list of symptoms or
distinct diagnoses?
Writers criticize the DSM-IV-TR, and therefore the
Consensus Panel, as being a symptom-oriented, rather
than a preferred diagnosis-oriented classication
system.
39
As a list of symptoms (which are not necess-
arily synonymous with diagnoses), this classication
system may prove useful in the clinical setting, but
may leave a functional void in the formation of
distinct diagnoses, management schemes, or research
endeavors. A fully functional diagnostic classication
system would in theory have provided more thera-
peutic, prognostic, and scientic signicance.
Organic categories
Incorporation of the organic category into the
specication of female sexual dysfunction was a useful
alteration, which should inspire research on the etiology
of sexual disorders in women.
40
The inclusion of both
organic and psychogenic causes of sexual dysfunction
is in line with the generally accepted multifactorial or
biopsychosocial view of female sexuality.
38,41
Personal distress
The criterion for personal distress has been met
with mixed reviews. For those who believe it is the
extent to which a disorder subjectively impacts the
patient that denes the dysfunction, it is a welcome
addition.
32,4143
Likewise, the removal of interpersonal
difculty previously seen in the DSM-IV-TR has been
applauded, as it takes the focus away from the couple,
and any inherent or interpersonal problems associated
with sexual incompatibility, and places it on the
individual.
40
Others, however, do not feel that the absence of dis-
tress nullies the presence of the disorder.
38,44,45
This
argument centers around the lack of a personal distress
criterion for other non-sexual disorders in the DSM-
IV-TR such as obsessivecompulsive disorder, bipolar
disorder, or substance abuse. Similarly, a personal
distress criterion is not required for medical diagnoses
such as hypertension, diabetes, and coronary artery
disease. Because the patient does not experience
personal distress about the dysfunction, does that mean
it does not exist? If a problem is present, it should be
identied as such and given a rightful diagnosis, regard-
less of the subjective degree of bother experienced
by the patient. Distress should not guide a diagnosis,
although clearly the womans subjective distress is one
of the primary motivators for treatment.
27
Perhaps this
controversy could be bridged by adding a specier to
the diagnosis, such as with or without personal distress
or syntonic versus dystonic.
44
Receptivity
The inclusion of receptivity to the category of hypo-
active sexual desire disorder was another welcome
addition. Traditionally, sexual desire has been dened
by cognitive and/or psychological factors such as spon-
taneous sexual thoughts, fantasies, or urges. Many
women, however, may not have spontaneous feelings
or expressions of desire, but are responsive or receptive
to the sexual advances of a partner.
41,46
This idea is in
keeping with the alternative female sexual response
cycle described by Basson, which is intimacy-based.
11,12
In this model, sexual arousal is not spontaneous, but
follows the cognitive and physical acceptance of sexual
stimulation. This new model challenges the traditional
linear model where a psychological state (i.e., sexual
desire) leads to a physiological response (i.e., sexual
arousal).
13
A linear relationship between the psycho-
logical and physiological aspects of the sexual response
pattern is more readily apparent in men than in
women. It was the recognition of these gender-specic
differences which led to the development of Bassons
non-linear female sexual response model.
Receptivity, however, is neither clearly explained
nor dened.A woman may be receptive to the sexual
advances of her partner, without being emotionally or
physically invested in the activity.
46
A receptive but
reluctant woman may be engaging in sexual activity
to appease or placate her partner in order to main-
tain harmony within the relationship. Would her
receptiveness preclude her from classication within
the new Consensus Panel classication system?
Clearly sexual desire problems are not without
context (i.e., when? how? with whom?), and the
important subjective components cannot be ignored.
47
A complete objective medical, physical, or physio-
logical approach to a woman with decreased sexual
desire would be deemed inappropriate. For many
women, the motivational aspects associated with
enhanced nurturing and intimacy provide the primary
incentive for sexual contact. Likewise, intimacy, affec-
tion, and nurturing touch, rather than spontaneous
sexual thoughts or desire, provoke arousal, which in
turn generates desire. The desire category may benet
from an expansion, which includes motivational aspects
other than sexual fantasies/thoughts.
39,41,46
In keeping with this idea, Levine recently proposed
a tripartite motivational model of sexual desire com-
prised of wish, drive, and motive.
48
Wish represents
the cognitive aspirations of sexual desire, motive the
psychological, and drive the more biological.
Subjective mental excitement
The inclusion of subjective or mental excitement, as
well as non-genital somatic responses to the denition
of sexual arousal, was another welcome addition.Again
the importance of the cognitive element of female
sexual desire and arousal is acknowledged.
40,41,49
And
although physiological excitement in the form of
genital swelling and lubrication is an important aspect
of healthy sexual arousal, recent advances in basic and
clinical science have revealed the concomitant import-
ance of non-genital, somatic responses in women.
9,20,21
Non-coital pain
Moving away from an exclusively intercourse-focused
classication system led to the introduction of a non-
coital sexual pain category. This extension of the exist-
ing category addresses recurrent or persistent genital
pain following non-coital stimulation.
43
This new
category acknowledges other non-phallocentric sexual
behaviors that are not focused on intercourse.
8
Sexual pain versus genital pain
A controversy exists regarding the labeling of pain
disorders: sexual versus genital.
50
Sexual pain denotes
that it occurs during a specic behavior, while genital
pain characterizes the pain by location rather than by
activity. With the exception of dyspareunia and vagin-
ismus, all other chronic pain syndromes in the DSM-
IV-TR are classied according to their anatomical
location, not by the activity with which they interfere
(i.e., intercourse). The reproducibility of pain on
physical examination outside the context of sexual
activity supports a nosological change from sexual
pain to genital pain. With this in mind, Binik suggests
dyspareunia should be classied according to the
specic anatomical location or origin of pain (i.e.,
vestibule, vaginal vault, supercial, deep), which would
further emphasize the physical nature of dyspareunia
and vaginismus as opposed to the psychological.
51
On
the other hand, Basson advocates in favor of a sexual
pain disorder category, but makes a recommendation
for further subtyping of dyspareunia according to
the stage of penile entry or penile movement that is
associated with pain.
41
Vaginismus versus penetration disorder
A close look at the current denition of vaginismus
reveals that it does not actually require the presence
of pain. The term vaginismus focuses on the inter-
ference of vaginal penetration or intercourse due to
vaginal spasms. Objective data dening the etiology
and exact location of the overactive muscular activity
within the pelvis that inhibits penetration are however
lacking. Furthermore, there are other painful conditions
that prevent penetration, such as vulvar vestibulitis,
which are not specically associated with vaginal
spasms. With this in mind, a suggestion for substituting
vaginismus with penetration disorders was intro-
duced, which would include all physical conditions
that discourage or prevent vaginal penetration.
43,52
For
those women who describe a purely psychological fear
about penetration with minimal actual introital stimu-
lation, the term PARVE phobic anxiety regarding
vaginal entry has been proposed.
41
Sexual satisfaction
Finally, the concept of a sexual satisfaction category
was discussed, although ultimately not included in
Classification of Female Sexual Dysfunction 263
the new consensus conference report. According to
McCabe, a sexual satisfaction disorder could be seen as
a breakdown in the resolution phase of the sexual
response cycle.
40
For Tiefer, the issue of sexual satis-
faction is central to a woman-centered classication
system and should denitely be included.
34
A disjunc-
tion between sexual function and sexual satisfaction
has often been noted among women. Most womens
perceptions of the quality of their sexual relations are
heavily influenced by the affective tone of the relation-
ship itself, as opposed to the quality of the sexual
performance.
16
Inclusion of a sexual satisfaction dis-
order would provide the incentive for further research
in this area.
SUMMARY
Research into the nosology, etiology, and treatment of
female sexual dysfunction is nally receiving attention
and nancial support. It is evolving into a reenergized
and exciting area of medicine. Once a eld limited to
the discipline of mental health, recent advances in basic
science and clinical research have uncovered important
anatomical and physiological aspects that comprise
normal and abnormal human sexual function, lending
further credence to the need for a biopsychosocial
model. The appropriateness of a multidisciplinary
approach for the understanding and treatment of
female sexual dysfunction is now acknowledged.
Adequate evaluation and treatment, addressing both
cognitive and physiologic aspects of female sexual
function, would benet from input from both medical
and mental health practitioners.
The need for more research in the area of female
sexual function is evident. First, however, strategic
planning is necessary to assist academic centers and
pharmaceutical centers to organize and prioritize their
efforts and nancial resources.
53
The importance of an
appropriate nosological diagnostic system to further
this goal has previously been emphasized. To this end,
the Consensus Panel has provided the eld of female
sexual dysfunction with an important step, as it provides
a clear and functional nomenclature for clinical and
scientic purposes. The next 10 years will surely prove
exciting as we see the continued development of new
models and treatments for female sexual dysfunction.
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INTRODUCTION
Past research regarding androgen deciency in men
has been extensive, elucidating complications such as
osteopenia, diminished libido, increased fat mass, and
decreased muscle mass.
1
Consideration that androgen
deciency in women could lead to such conditions, as
well as general disruption of hormonal homeostasis,
has been limited by the notion that circulating levels in
women are less signicant than in men. Androgens are
essential for the development of female reproduction
as immediate precursors of estrogen biosynthesis.
Androgens affect bone density, libido, muscle mass and
strength, mood, energy, and adipose tissue distribution.
As with men, low levels of androgens will alter these
mechanisms with detriment to a womans overall well-
being. In recognition of these ndings, the Princeton
Consensus Statement dened female androgen insuf-
ciency as consisting of a pattern of clinical symptoms
in the presence of decreased bioavailable testosterone
and normal estrogen status.
2
In order to garner a more
comprehensive appreciation for female androgen
deciency, the following abilities are essential:
1. Understand basic testosterone physiology in
women.
2. Identify the symptoms of androgen deciency.
3. Know the possible medical causes.
4. Recognize what, when, and how to order tests in
the laboratory.
5. Apply a decision-making algorithm to diagnose
female androgen insufciency prior to considering
treatment options.
ANDROGEN PRODUCTION (Fig. 20.1)
The group of C19 steroids, collectively referred to as
androgens, includes testosterone, androstenedione,
dehydroepiandrosterone (DHEA), dehydroepiandros-
terone sulfate (DHEA-S), and 5-dihydrotestosterone
(DHT). Of these steroids, testosterone and DHT have
stronger androgenic activity. It is generally accepted
that women produce a mean of approximately 300 g
testosterone daily. Newer isotope dilution techniques
estimate the mean production closer to 400 g/day,
3
but this is controversial. Androgen synthesis is multi-
factorial. The female body generates androgens directly
in the adrenal glands and in the ovaries.
4,5
Greater
than half of these androgens, however, are converted
in the peripheral tissues from precursors made in the
adrenal glands and ovaries.
6,7
Much of the testosterone
and DHT produced in women is synthesized in periph-
eral tissues and detected as circulating metabolites.
SYMPTOMS OF ANDROGEN
DEFICIENCY (Table 20.1)
A series of signs and symptoms may guide a clinician
to suspect androgen insufciency. Women and men
most commonly complain of decreased sexual desire.
Other factors related to health, relationships, and
chronic illness interplay, and may tend to confuse the
diagnosis. The most frequently encountered symptom
complex associated with androgen deciency includes
decreased libido, increased fatigability, and diminished
vaginal lubrication. Laumann et al.
8
corroborated this
in a large epidemiological study and claimed that
Female Androgen Insufciency Syndrome
Dinamarie C. Garcia-Banigan and Andre T. Guay
CHAPTER 20
Adrenal
Testosterone
Testosterone
Peripheral tissues
DHEA
50%
25%
Ovary
Testosterone
25%
Androstenedione
Figure 20.1 Sites of androgen production in women.
DHEA, dehydroepiandrosterone.
decreased sexual desire was the most common
presenting symptom in all decades between ages 18
and 59 years. The loss of libido or sexual desire may
include a lessened desire to engage in sexual activity
or intimacy as well as a decrease in fantasizing and
sexual dreaming. This may coincide with a lack of
motivation in general. Often, it is difcult to distin-
guish the separation between depression and sexual
dysfunction. Flat mood and affect are symptoms that
correlate with a general diminished sense of well-
being, and lowered mood may be a consequence of
androgen deciency, a reaction to lowered libido, or
both. In postmenopausal women, similar symptoms
may be seen with estrogen deciency. Symptoms in a
woman receiving estrogen replacement would then be
more likely secondary to androgen deciency. This con-
clusion is made after fully assessing other confounders,
such as relationship or marital discourse, concurrent
illness, medication side-effects, and previously existing
depression or depression as the result of poor sexual
performance.
An International Consensus Development
Conference
9
on female sexual dysfunction dened
hypoactive sexual desire disorder as the persistent or
recurrent deciency (or absence) of sexual fantasies/
thoughts and/or desire for the receptivity to sexual
activity, which causes personal distress. Clinicians
must acknowledge the many components of sexual
desire in women. These include level of sexual expe-
rience and knowledge, past encounters, expectations,
cultural beliefs, partner availability, hormonal status,
and general health.
10
Decreased frequency of sexual fantasies often
accompanies the lack of sexual desire. Some women
may report decreased energy and overcompromised
well-being, both subjective elements. Studies have
found that testosterone replacement in premenopausal
and postmenopausal women restores well-being.
11,12
Lower androgen levels are associated with greater
vaginal atrophy and lessened vaginal lubrication.
13,14
Concomitantly, women report decreased vaginal lubri-
cation consistent with the nding that lower androgen
levels are associated with greater vaginal atrophy.
14
Muscle weakness and difculty in achieving sexual
arousal and orgasm, often requiring prolonged stimu-
lation to the point of irritation, are present compared
to prior sexual history.
CAUSES OF ANDROGEN
INSUFFICIENCY (Table 20.2)
The most logical indication for androgen replacement
is surgical menopause. After hysterectomy and bilateral
oopherectomy, testosterone levels decrease by half
since only the adrenal glands are left to produce testos-
terone. Similarly, patients with premature ovarian
failure also experience decient androgen levels.
Medical oophorectomy damages cells secondary
to chemotherapy or radiation therapy. Gonadotropin-
releasing hormone (GnRH) antagonist therapy yields
the same result. Treatment with cortisone or steroid-
containing medications suppresses pituitary secretion
of adrenocorticotropic hormone (ACTH), therefore
decreasing adrenal androgen production.
Exogenous oral estrogens used as contraceptive pills
or hormone replacement therapy decrease ovarian
production of androgens and their precursors. Oral
estrogen suppresses the elevated gonadotropins,
luteinizing hormone (LH) and follicle-stimulating hor-
mone (FSH), found during menopause, thus lowering
testosterone production by the ovary. It also increases
sex hormone-binding globulin (SHBG), which binds
testosterone and decreases the free fraction, i.e., the
metabolically active component that can reach the
tissues. This scenario mimics other situations of
elevated SHBG levels, such as pregnancy, cirrhosis,
excess thyroid hormone, anorexia nervosa, or anti-
epileptic medications.
268 Female Androgen Insufciency Syndrome
TABLE 20.1 Clinical symptoms consistent with androgen insufciency.
Decreased sexual desire Decreased vaginal lubrication
Decreased desire to engage in sexual activity Decreased vaginal vasocongestion
Decreased desire to be intimate Decreased intensity and delayed orgasms
Decreased fantasies and/or sexual dreams Decreased muscle strength
Decreased sexual arousal Decreased sleep
Decreased sexual pleasure Decreased sense of well-being
Decreased energy Increased menopausal symptoms
Decreased motivation Flat mood
Adapted from references 2, 10, 14, and 37.
Hypopituitarism, from any etiology, leads to androgen
and estrogen suppression and pituitary decline.
15
Both
the adrenal gland and ovary production are curtailed.
These women, irrespective of age, menopausal status,
and exogenous estrogen use are severely affected
compared to healthy counterparts.
16
Acute critical illness will decrease gonadotropin
levels, even in postmenopausal women whose levels
are usually elevated.
17
Chronic illnesses suppress the
central gonadotropin axis, leading to hindered testos-
terone production. In acute, chronic, and severe
systemic illnesses, the body often conserves energy
and shifts the production of androgens to cortisol and
epinephrine (adrenaline).
18,19
Adrenal insufciency, whether primary, secondary,
or part of the multiple endocrine deciency syndrome,
will decrease DHEA-S production. This leads to
decreased peripheral conversion to form testosterone.
Women with adrenal insufciency will have symptoms
of androgen deciency coinciding with abnormal
DHEA-S and testosterone levels.
20
Replacement with
oral DHEA-S reverses these symptoms.
21
A group of women still warranting further investi-
gation are the younger, menstruating, otherwise healthy
women who do not take oral contraceptives, yet have
decreased androgens and precursors. These women are
symptomatic, with the presenting complaint usually
reduced libido.
19
Much more study is needed with this
population, to conrm the entity and to study its extent
in the population.
LABORATORY TESTING (Table 20.3)
Once a physician identies a compilation of symptoms
suggestive of androgen insufciency, in conjunction
with adequate estrogens and appropriate medical con-
ditions, the next step is to support the diagnosis with
biochemical evidence. As discussed earlier, testos-
terone is normally present in women at lower levels
than in men, and even lower for those women with
true androgen insufciency. The assays currently avail-
able to assess testosterone levels unfortunately lack
precision, especially at the lower ranges, and do not
have validated normal ranges in women. A more
sensitive assay has been developed; however, it is more
expensive and difcult to perform. The reliability in
many regional labs may be questionable.
22
Despite
these limitations, the free testosterone test is considered
the most reflective measure of testosterone available
to the tissues. The total testosterone assay performed
for decades in males lacks accuracy since it is affected
by shifts in its main binding protein, SHBG.
23
In
women, free testosterone levels are needed for accu-
rate diagnosis of testosterone deciency, because a
greater proportion of testosterone is bound to SHBG
in women than in men. In most men, total testosterone
levels are sufcient for diagnosis of androgen deciency.
Therefore, medications and diseases that influence
SHBG levels affect testosterone levels in women more
profoundly than in men.
1
Estradiol levels may raise
SHBG, with the effect varying widely in women
depending upon gonadal status and medication use.
1
In contrast, obesity, insulin, growth hormone, gluco-
corticoids, and androgens decrease SHBG values.
Equilibrium dialysis, considered by some to be the
gold standard for measuring free testosterone, should
be done if other methods lead to confusion about the
diagnosis. It is not considered a rst-line test due to
TABLE 20.2 Potential causes of androgen
insufciency in women.
Ovarian insufciency
Oophorectomy
Chemotherapy
Radiation therapy
Menopause
Premature ovarian failure
Adrenal insufciency
Adrenalectomy
Addisons disease
Multiple endocrine deciency syndrome
Hypothalamicpituitary Insufciency
Hypopituitarism, organic (tumor, hypophysitis,
idiopathic necrosis)
Hypothalamic amenorrhea (functional)
Hyperprolactinemia
Drug-related
Estrogen replacement therapy (HRT)
Oral or injectable contraceptive products
Corticosteroids
GnRH agonists or antagonists
Antiandrogenic agents (cimetidine, flutamide,
cyproterone acetate, spironolactone)
Chronic illness
AIDS wasting
Anorexia nervosa
Immunologic disorders (rheumatoid arthritis,
systemic lupus erythematosus)
Acute stress/illness
Increased sex hormone-binding globulin
Idiopathic
GnRH, gonadotropin-releasing hormone; AIDS, acquired
immune deciency syndrome.
Laboratory Testing 269
expense, specialized equipment, limited distribution,
and time demand. Other methods have been evaluated
as possible rst-line tests to order.
24
Salivary testos-
terone has not gained widespread support, because the
normal range seems excessively large and has question-
able accuracy in the lower ranges.
25
The bioavailable testosterone assay measures the free
fraction of testosterone, the fraction loosely bound to
albumin and, ergo, more readily available for tissue
use. This test is limited by level of difculty, time con-
sumption, expense, and operator error.
26
In the USA, the most commonly performed assay is
the analog free testosterone assay. The results are
reproducible and less labor-intensive.
27
Compared to
the equilibrium dialysis assay, however, the analog free
testosterone assay only measures approximately 30%
of the circulating free testosterone in women. Despite
this, Vermulen et al. found a high correlation between
the analog free testosterone value and that from the
equilibrium dialysis method of free testosterone
determination.
23
It is felt by some not to be accurate
enough.
Further discussion has supported the use of the free
androgen index (FAI) as perhaps the best screening
tool. The calculation for FAI is:
Total testosterone in ng/dl (0.0347)
(100)
Sex hormone-binding globulin (nmol/l)
= free androgen index (nmol/l)
The free androgen index may be used as a primary
test. Alternatively, physicians may perform either the
free or bioavailable testosterone. A free testosterone
by equilibrium dialysis may be sent as conrmation to
a major reference laboratory.
The next great hurdle entails comparing the results
of the FAI with a known normal range of androgen
levels for women. At this time, no precise ranges for
women, especially an age-related tool, exist. Zumoff
et al.,
28
with the most quoted study, established
decreasing total testosterone levels with age (n = 33).
Labrie et al.
29
noted a similar trend; however, they
found that levels do not decrease further after meno-
pause. Adashi
30
demonstrated a decrease in testos-
terone production across the menopausal transition,
but later testosterone levels change only minimally.
Longscope and Baker
31
further showed that the mean
concentration of testosterone was not correlated with
menopausal status. Burger et al.
32
found that total
testosterone did not vary with time relative to an
average womans nal menstrual period, at least over
6 years following the termination of menses.
Androgen precursors may also serve as a guide.
The chief precursor of testosterone in the ovary is
androstenedione, which lessens with age and changes
during the normal menstrual cycle, comparable to
testosterone. Considering this similarity, testosterone
is usually measured alone. Androstenedione assays,
however, are reliable and not controversial, so they
may be used if the result of a testosterone evaluation
appears questionable.
29
The chief androgen precursor in the adrenal gland,
DHEA, is chiefly measured in the sulfated form,
DHEA-S. DHEA-S has a longer half-life, resulting in
more stable levels. Many studies have shown a
reduction in DHEA-S levels with age for both men and
women.
25,29,3236
Guay et al.
37
recently showed that
DHEA-S negatively correlated with age in women
from ages 20 to 49 who were screened for sexual dys-
TABLE 20.3 Mean hormone levels ( SE), and ranges in women without sexual dysfunction (n = 60).
Age 2029 (n = 17) 3039 (n = 23) 4049 (n = 20)
DHEA-S (g/dl) 195.6 ( 18.7) 154.9 ( 15.9) 140.4 ( 15.7)
Range (mean SE) 176.9214.3 139.0170.8 124.7156.1
SHBG (nmol/l) 51.1 ( 7.5) 48.5 ( 3.9) 52.7 ( 5.7)
Range (mean SE) 43.658.6 44.652.4 47.058.4
Total testosterone (ng/dl) 51.5 ( 6.0) 33.7 ( 6.1) 32.8 ( 5.8)
Range (mean SE) 45.557.5 27.639.8 27.038.6
Analog free testosterone (pg/ml) 1.51 ( 0.12) 1.10 ( 0.08) 1.02 ( 0.12)
Range (mean SE) 1.391.63 1.021.18 0.901.14
Free androgen index (FAI) 4.34 ( 0.62) 2.5 ( 0.46) 2.46 ( 0.48)
Range (mean SE) 3.724.96 2.042.96 1.982.94
DHEA-S, dehydroepiandrosterone sulfate; SHBG, sex hormone-binding globulin.
function (Table 20.3). DHEA-S does not vary in con-
centration within the various stages of menstruation.
DHEA-S is not bound to SHBG in any degree, nor is it
affected by estrogen therapy.
Measuring the level of SHBG has become more
important, especially if the FAI is considered the best
screening test for androgen deciency in women.
SHBG levels are not controversial, and are relatively
simple to perform with good reproducibility.The major
limitation is the cost of both the total testosterone and
the SHBG assays.
The Princeton Consensus recommends the measure-
ment of two of three essential values for clinical assess-
ment of both androgen production and bioavailability.
Testosterone values should be obtained in the morning
hours and during the middle third of the menstrual
cycle when the androgens are at their highest in
normally cycling premenopausal women.
3,38
The free
testosterone index (total testosterone divided by SHBG)
correlates with bioavailable testosterone and may be a
substitute evaluation. Free testosterone assays, assessed
directly or via analog methods, are not well validated
for women.
THE DECISION-MAKING ALGORITHM
(Table 20.4)
With the preceding information, physicians can use the
rst part of the decision-making algorithm presented
by the Princeton Consensus Conference on female
androgen deciency to determine if criteria are
fullled to diagnose female androgen deciency prior
to initiating treatment. Care must be taken to rule out
other causes of the symptoms, which are commonly
decreased libido and decreased energy. To differentiate
these symptoms from depression and/or relationship
problems is very important.
ANDROGEN THERAPY
There are no approved methods of replacing testos-
terone in women in the USA, and indeed, in most
countries of the world. In the USA, Estratest is
available, which is conjugated estrogen plus methyl
testosterone. The only indication for its use, however,
is to treat vasomotor symptoms during menopause not
controlled with estrogen alone.
Despite adequate information about androgens,
and despite an approved product, women have not
been given them for decades.
39
Much of the data is in
menopausal women. Greenblatt et al. reported on this
in 1950.
40
Sherwin
41
reviewed the literature and
concluded that the addition of androgen to estrogen
replacement has additive benecial effects. There are
many studies that have showed good results. One of
the main criticisms has been the notion that oftentimes
the levels of androgens have been supraphysiological,
with the fear of exacerbated side-effects.
Men have received intramuscular injections of long-
acting testosterone esters for decades, and some women
have received small doses. The problem with this
method of delivery is that the levels of testosterone do
rise above normal for several days before gradually
decreasing. Subcutaneous pellets are approved for use
in men in the USA, but seldom implemented. These are
used more in the UK and Australia, and some women
have received low-dose pellets.
Testosterone patches have been used in men for
several years, but the doses are inflexible and too
high for women. A testosterone patch has been in
phase II clinical trials for women.
42
The results were
mixed but promising, especially when tried in women
with acquired immune deciency syndrome (AIDS)
wasting.
43
Further studies are ongoing for this
technique.
TABLE 20.4 Decision-making algorithm for
considering androgen therapy in women.
Q: Does the woman have symptoms consistent
with androgen insufciency?
A: If yes, initiate evaluation.
Q: Is there an alternative explanation or cause for
these symptoms?
A: If yes, manage as appropriate. If no, evaluate
further.
Q: Is the woman in an optimum estrogen state?
A: If yes, continue evaluation. If no, initiate
estrogen replacement.
Q: Does the woman have laboratory values,
collected ideally, consistent with a diagnosis of
androgen deciency?
A: If yes, continue evaluation. This should include
assessment of at least two of three measures of
total testosterone, free testosterone, or sex
hormone-binding globulin. Androgen values
should be in the lowest quartile of normal
ranges for reproductive-age women. If no,
consider alternative treatments or referral.
Q: Does the woman have a specic treatable
cause for androgen insufciency?
A: If yes, treat the specic cause. If no, consider a
trial of androgen replacement therapy.
Adapted from Bachman G, Bancroft J, Braunstein G et al.
Female androgen insufciency: the Princeton consensus
statement on denition, classication, and assessment.
Fertil Steril 2002; 77:660665.
Androgen Therapy 271
Several pharmaceutical companies are in the process
of developing topical gels for testosterone replace-
ment. These may offer less skin irritation than a patch
and may be able to be titrated, allowing flexible dosing
that could be monitored with blood tests. Testosterone
creams have been prescribed for many years by gyne-
cologists. These are effective when applied directly on
atrophic vaginal tissue, but systemic absorption has
been questionable, as reflected by very little change in
androgen blood levels.
DHEA has been studied more in recent years. It
is available without a prescription but also without
assurance of quality and consistency between lots.
DHEA-S is marketed as a food supplement. It is
readily absorbed into the system and readily measured
as DHEA-S. It does cross the placenta, raising fears of
virilization of a female fetus. Premenopausal women
who might wish to use this should be under close
supervision and have adequate birth control. Labrie
and colleagues emphasize that DHEA is the most
abundant steroid in both men and women. It is very
important, especially in the postmenopausal state, due
to its peripheral conversion to both estrogens and
androgens.
44,45
These areas are controversial and will
require more study and verication. As an adrenal
androgen primarily, it was logical for Arlt et al. to study
women with adrenal insufciency and nd a benecial
effect with its replacement.
46
DHEA replacement has
also been shown, in some early trials, to treat bone and
other tissues, to help resolve symptoms associated with
sexual dysfunction, to affect behavior, and to affect
positively dysthymia.
7,4749
These studies are early but
promising. One challenge is obtaining a pharmaceutical-
grade DHEA for use in studies.
Treatment of women with androgen insufciency is
a goal that is attainable, after development of adequate
tools to diagnose and to treat the condition. Although
many studies were imperfect for one reason or another,
it seems clear that androgen treatment in decient
women will have many benets. There is some early
evidence that androgen levels may have a negative
correlation with vascular calcications.
50
There is also
evidence that androgens may improve endothelium-
dependent as well as endothelium-independent vascular
flow in postmenopausal women.
51
More research is
needed in these areas before we can make denitive
statements about the usefulness and safety of androgen
replacement therapy in women.
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22. Sinha-Hakim I, Arver S, Beall G et al. The use of a
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27. Wilke T, Utley D. Total testosterone, free-androgen index,
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after oophorectomy. N Engl J Med 2000; 343:682688.
43. Miller K, Corcoran C, Armstrong C et al. Transdermal
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44. Labrie F, Belanger A, Cusan L et al. Physiological
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46. Arlt W, Callies F, Van Vlijmen J et al. Dehydro-
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47. Munarriz R, Talakoub L, Flaherty E et al. Androgen
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dehydroepiandrosterone affects behavior in hypopituitary
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INTRODUCTION
Well-designed, random-sample, community-based
epidemiologic investigations of women with sexual
dysfunction are limited. Current data reveal that up to
76% of women have some type of sexual dysfunction.
1,2
US population census data suggest that approximately
10 million American women aged 5074 self-report
complaints of diminished vaginal lubrication, pain and
discomfort with intercourse, decreased arousal, and
difculty achieving orgasm. Recently, a national survey
of almost 1700 women and 1500 men between the
ages of 18 and 59 revealed that sexual dysfunction is
more prevalent in women (43%) than in men (31%)
and is associated with various psychodemographic
characteristics such as age, education, and poor physical
and emotional health. More importantly, female sexual
dysfunction (FSD) is associated with negative sexual
relationship experiences.
3
NOSOLOGY
Broadly speaking, sexual dysfunction in women is
dened as disorders of sexual desire, arousal, orgasm
and/or sexual pain, which result in signicant personal
distress and may have an impact on the quality of life.
While each specic condition of FSD is uniquely dened,
there is often great overlap in afflicted patients. The
denition and classication of sexual dysfunction in
women were initially based on knowledge of male
sexuality but more recently have incorporated an
increased understanding of what is unique to women.
In their pioneering work in the 1960s,William Masters
and Virginia Johnson described sexual response in
both men and women as occurring in four phases:
excitement, plateau, orgasm, and resolution.
4
The
three-phase model espoused by Helen Kaplan in 1974
consisted of desire, arousal, and orgasm and empha-
sized the temporal sequencing and coordination of the
phases.
5
These two models, which recognized that
sexual response has both psychological and somatic
components, became the basis for the Diagnostic and
Statistical Manual-IV (DSM-IV) denitions of sexual
dysfunction.
An intimacy-based sex response cycle exclusive to
women proposed by Rosemary Basson et al.
6
recog-
nizes that earlier models do not reflect the complexity
of womens sexual response and assigns emotional
intimacy a key role alongside sexual stimuli. Recently,
an interdisciplinary consensus conference panel, com-
prising 19 experts in FSD, developed a new diagnostic
and classication system of sexual disorders. Although
it is based on the four major categories used in the
DSM-IV disorders of desire, arousal, orgasm, and
sexual pain the system has several important inno-
vations. Denitions are expanded to include physical
as well as psychological causes of FSD and a personal
distress criterion is used for most diagnostic categories.
In addition, the panel added to the category of sexual
pain disorders a new diagnosis of non-coital sexual
pain disorder.
ANATOMY
There is a paucity of data concerning the anatomy,
physiology, and pathophysiology of sexual function in
women.The female external genitalia consist of various
structures. The vagina is a midline cylindrical organ
that connects the uterus with the external genitalia.
The vaginal wall consists of three layers: (1) an inner
mucous-type stratied squamous cell epithelium
supported by a thick lamina propria, that undergoes
hormone-related cyclical changes; (2) the muscularis,
composed of outer longitudinal smooth-muscle bers
and inner circular bers; and (3) an outer brous layer,
rich in collagen and elastin, which provides structural
support to the vagina. The vulva, bounded by the
symphysis pubis, the anal sphincter, and the ischial
tuberosities, consists of labial formations, the interlabial
space, and erectile tissue. The labial formations are
two paired cutaneous structures: (1) the labia majora
are fatty folds covered by hair-bearing skin that fuses
anteriorly with the mons veneris, or anterior promi-
nence of the symphysis pubis, and posteriorly with the
perineal body or posterior commissure; (2) the labia
minora are smaller folds covered by non-hair-bearing
skin laterally and by vaginal mucosa medially, that
fuses anteriorly to form the prepuce of the clitoris, and
Female Sexual Dysfunction
Ricardo Munarriz, Noel N. Kim, Abdul Traish, and Irwin Goldstein
CHAPTER 21
posteriorly in the fossa navicularis. The interlabial
space is composed of the vestibule, the urinary meatus,
and vaginal opening and is bounded by the space
medial to the labia minora, the fossa navicularis, and
the clitoris. The clitoris is a 713-cm Y-shaped organ
comprised of glans, body, and crura.
7
The body of the
clitoris is surrounded by tunica albuginea and consists
of two paired corpora cavernosa composed of
trabecular smooth muscle and lacunar sinusoids.
Finally, the vestibular bulb consists of paired structures
located beneath the skin of the labia minora and
represents the homologue of the corpus spongiosum in
the male.
There is limited understanding of the precise location
of autonomic neurovascular structures related to the
uterus, cervix, and vagina. Uterine nerves arise from
the inferior hypogastric plexus formed by the union
of hypogastric nerves (sympathetic T10L1) and the
splanchnic bers (parasympathetic S2S4). This plexus
has three portions: the vesical plexus, the rectal plexus,
and the uterovaginal plexus (Frankenhausers ganglion),
which lies at the base of the broad ligament, dorsal to
the uterine vessels, and lateral to the uterosacral and
cardinal ligament. This plexus provides innervation
via the cardinal ligament and uterosacral ligaments
to the cervix, upper vagina, urethra, vestibular bulbs,
and clitoris. At the cervix, sympathetic and para-
sympathetic nerves form the paracervical ganglia.
The larger one is called the uterine cervical ganglion.
It is at this level that injury to the autonomic bers of
the vagina, labia, and cervix may occur during hyster-
ectomy. The pudendal nerve (S2S4) reaches the
perineum through Alcocks canal and provides sensory
and motor innervation to the external genitalia.
PHYSIOLOGY OF GENITAL SEXUAL
AROUSAL
Large gaps exist in our knowledge of how the central
nervous system controls female sexual function.
Limited data suggest that descending supraspinal
modulation of female genital reflexes emanates from:
(1) brainstem structures such as the nucleus para-
gigantocellularis (inhibitory via serotonin), locus
ceruleus (norepinephrine (noradrenaline), nocturnal
engorgement during rapid eye movement sleep) and
midbrain periaqueductal gray; (2) hypothalamic struc-
tures such as the medial preoptic area, ventromedial
nucleus, and paraventricular nucleus; and (3) forebrain
structure such as the amygdala. Multiple factors inter-
act at the supraspinal levels to influence the excitability
of spinal sexual reflexes such as: (1) gonadal hormones;
(2) genital sensory information via the mylenated
spinothalamic pathway and the unmyelinated spino-
reticular pathway; and (3) input from higher cortical
centers of cognition.
The sexual arousal responses of the multiple genital
and non-genital peripheral anatomic structures are
largely the product of spinal cord reflex mechanisms.
The spinal segments are under descending excitatory
and inhibitory control from multiple supraspinal sites.
The afferent reflex arm is primarily via the pudendal
nerve. The efferent reflex arm consists of coordinated
somatic and autonomic activity. One spinal sexual
reflex is the bulbocavernosus reflex involving sacral
cord segments S2S4 in which pudendal nerve stimu-
lation results in pelvic floor muscle contraction.
Another spinal sexual reflex involves vaginal and
clitoral cavernosal autonomic nerve stimulation, result-
ing in clitoral, labial, and vaginal engorgement.
In the basal state, clitoral, corporal, and vaginal
smooth muscles are under contractile tone. Following
sexual stimulation, neurogenic and endothelial release
of nitric oxide (NO) plays an important role in clitoral
cavernosal artery and helicine arteriolar smooth-muscle
relaxation.
6
This leads to a rise in clitoral cavernosal
artery inflow, an increase in clitoral intracavernosal
pressure, and clitoral engorgement. The result is extru-
sion of the glans clitoris and enhanced sensitivity.
In the basal state, the vaginal epithelium reabsorbs
sodium from the submucosal capillary plasma transu-
date. Following sexual stimulation, a number of neuro-
transmitters, including NO and vasoactive intestinal
peptide (VIP), are released, modulating vaginal vascular
and non-vascular smooth-muscle relaxation. Dramatic
increase in capillary inflow in the submucosa over-
whelms Na-reabsorption, leading to 35 ml of vaginal
transudate, enhancing lubrication essential for pleasur-
able coitus. Vaginal smooth-muscle relaxation results
in increased vaginal length and luminal diameter,
especially in the distal two-thirds of the vagina. VIP
is a non-adrenergic, non-cholinergic neurotransmitter
that plays a role in enhancing vaginal blood flow, lubri-
cation, and secretions.
8
EXPERIMENTAL MODELS FOR
INVESTIGATION OF FEMALE SEXUAL
GENITAL AROUSAL
In vivo animal studies
Data derived from in vivo animal models indicate that
estrogen but not androgens modulate genital blood
flow, vaginal lubrication, and vaginal tissue structural
integrity. It should be noted that estradiol levels used
in these studies were supraphysiological, with potential
pharmacologic effects different from those achieved
physiologically.
914
Although estrogen replacement
276 Female Sexual Dysfunction
increases vaginal lubrication and restores vaginal epi-
thelial integrity, this therapy may not be appropriate
for all patients, due to the associated risk of breast and
endometrial cancer. Limited data are available on the
effects of vasoactive substances on genital hemo-
dynamics. Park et al. demonstrated that injection of
papaverine hydrochloride and phentolamine mesylate
into the vaginal spongy muscularis layer increased
vaginal wall pressure and vaginal blood flow.
12
We
have shown that sildenal administration caused a
signicant increase in genital blood flow and vaginal
lubrication in intact and ovariectomized animals.
15
However, this response was more pronounced in
animals treated with estradiol. These data suggested
that the NOcyclic guanosine monophosphate (cGMP)
pathway is involved, at least in part, in the physiologic
mechanism of female genital arousal and that sildenal
facilitates this response in an in vivo animal model.
16
The effects of apomorphine, a non-selective dopamine
receptor agonist, on genital blood flow were investigated
by Tarcan et al., who suggested that systemic adminis-
tration of apomorphine improved clitoral and vaginal
engorgement by increasing clitoral intracavernosal and
vaginal wall arterial inflow.
17
In summary, data derived
from in vivo animal models indicate that vasoactive
agents play a role in genital arousal. Although sildenal
and apomorphine enhanced genital blood flow in the
animal model, clinical use of vasoactive agents remains
controversial.
Organ bath studies
Data reported from several laboratories suggest that
NO is a key pathway in mediating clitoral smooth-
muscle relaxation.
18,19
However, in the vagina, NO
appears to play only a partial role in mediating smooth-
muscle relaxation.
20
VIP also induces vaginal smooth-
muscle relaxation, yet its exact functional role remains
to be determined.
2125
Functional -adrenergic
receptors are expressed in the vagina and mediate nor-
adrenaline (norepinephrine)-induced contraction.
2628
We have observed that androgens but not estrogens at
pharmacological doses enhanced smooth-muscle
relaxation.
29
Further studies with hormonal manipu-
lations at physiological doses are necessary to establish
the role of hormones on vaginal smooth-muscle
relaxation.
Cell culture studies
Park et al. and Traish et al. subcultured and charac-
terized human and rabbit vaginal and clitoral smooth-
muscle cells and investigated the synthesis of second
messenger cyclic nucleotides in response to vaso-
dilators and determined the activity and kinetics of
phosphodiesterase (PDE) type 5.
30,31
These studies
suggest that cultured human and rabbit vaginal smooth-
muscle cells retained their metabolic functional
integrity and this experimental system should prove
useful in investigating the signaling pathways that
modulate vaginal smooth-muscle tone. Investigation
of the distribution of NO synthase (NOS) in the rat
vagina in response to ovariectomy and estrogen
replacement was recently performed using immuno-
histochemical analyses with neuronal NOS (nNOS)
and endothelial NOS (eNOS) antibodies.
32
Estrogen
replacement resulted in a signicant increase in eNOS
and nNOS expression, when compared with NOS in
intact animals. It was suggested that estrogen plays a
critical role in regulating vaginal NOS expression of
the rat vagina and that NO may modulate both vaginal
blood supply and vaginal smooth musculature. More
recent studies have shown the opposite observation.
They found that rabbit vaginal NOS activity was
considerably reduced by treatment with estradiol or
estradiol and progesterone.
33,34
This discrepancy in
NOS regulation by estrogen in these studies may be
due to species differences or to methods for assess-
ment of NOS expression and activity. We have used
both immunochemical (Western blots) and enzymatic
activity assays to determine regulation of vaginal NOS
in the rabbit model. In this study we demonstrated that
NOS was predominantly expressed in the proximal
vagina.
35
The reason for this tissue distribution is yet
to be determined. We further observed that ovari-
ectomy enhanced NOS activity in the proximal vagina,
suggesting specic regulation of NOS by sex steroid
hormones. Treatment of ovariectomized animals with
estrogens resulted in decreased expression and activity
of NOS in vaginal tissue, consistent with the research
by Al-Hijji et al.
33
In contrast, treatment of ovari-
ectomized animals with androgens resulted in increased
NOS expression and activity.These observations suggest
that NOS in vaginal tissue is regulated by androgens
and estrogens in an opposite manner.
DIAGNOSIS OF FEMALE SEXUAL
DYSFUNCTION
The cornerstone of the patient evaluation is a com-
prehensive and detailed sexual, medical, and psycho-
social history, physical examination, and focused
laboratory testing. Specialized diagnostic tests such as
biothesiometry or genital vascular studies (duplex
Doppler ultrasound), although not always indicated,
may corroborate the impressions discovered on the
initial evaluation. It should be stressed that the
secondary psychologic reaction to these organic factors
Diagnosis of Female Sexual Dysfunction 277
must not be ignored. Validated sexual questionnaires,
such as the Female Sexual Function Index and the
Sexual Distress Scale, may be helpful tools in the
evaluation of sexual function.
Sexual, medical, and psychosocial
history
A detailed and comprehensive sexual history should
include past and present assessment of sexual desire
(libido), arousal, and orgasmic capabilities. In addition
to physiologic sexual responses, overall sexual satis-
faction should also be assessed. Patients generally
dont volunteer this information; in consequence, start
with general questions such as are you sexually
active?, have you noticed any change in your sexual
interest? and then move on to more personal
questions, trying to overcome any resistance to giving
an honest answer. Also assess overall sexual satis-
faction, keeping in mind that under the new consensus
development conference diagnostic system, a sexual
problem is generally considered dysfunction only when
it causes signicant personal distress.
The medical history should focus questions on the
patients medical illness (chronic/medical illness (e.g.,
diabetes, anemia, renal failure), neurological illness
(e.g., spinal cord injury, multiple sclerosis, lumbosacral
disk disease), endocrinologic illness (e.g., hypogonadism,
hyperprolactinemia, thyroid disorders), atherosclerotic
vascular risk factors (e.g., hypercholesterolemia,
hypertension, diabetes, smoking, family history),
medications/recreational drug use (e.g., antihyper-
tensives, antidepressants, alcohol, cocaine), pelvic/
perineal/genital trauma (e.g., bicycling injury), genital
pain, surgical (e.g., hysterectomy, laminectomy,
vascular bypass surgery), and psychiatric history (e.g.,
depression, anxiety)).
Given the personal, interpersonal, social, and
occupational implications of sexual problems, a brief
psychosocial history is mandatory in every patient.
Current psychological state, self-esteem, history of
sexual trauma/abuse, as well as past and present
relationships and social and occupational performance
should be addressed.
While nothing can replace the personal interview,
several validated instruments are available for assess-
ing subjective sexual function.
Physical examination
In addition to a detailed vascular and neurologic
examination, a careful and systematic examination of
the external genitalia using magnifying surgical loops
and cotton-bud evaluation of the external genitalia
may conrm aspects of the medical history (e.g.,
vestibular adenitis (Fig. 21.1AC) and neuropathies),
and occasionally reveal unsuspected physical ndings
such as paraclitoral neuromas.
Laboratory testing
Laboratory testing is strongly recommended. Standard
serum chemistries, complete blood count, and lipid
proles may elucidate vascular risk factors such as
hypercholesterolemia, diabetes, and renal failure.
Serum thyroid-stimulating hormone determination
may be indicated in select cases.
The integrity of the hypothalamicpituitarygonadal
axis should be examined in every patient with sexual
dysfunction. Adrenal and ovarian androgens, estrogens
and follicle-stimulating hormone and luteinizing hor-
mone testing are strongly recommended. It is unclear
which testosterone assay (total, free, and bioavailable)
is the best; however there is a consensus that at least
one of these assays should be performed. Total andro-
gen production is best reflected by the total testos-
terone, but the available testosterone is best measured
by free testosterone value, as determined by equilib-
rium dialysis. Whenever total or free testosterone is
measured, the value of circulating sex hormone-binding
globulin (SHBG) has to be taken into consideration.
To evaluate adrenal androgen status, it is recommended
to obtain dehydroepiandrosterone (DHEA) sulfate
levels. Androgen values should ideally be determined
in the morning and in the mid-third of the menstrual
cycle, but this recommendation makes clinical practice
extremely difcult. Although pituitary adenomas are
a rare cause of sexual dysfunction, this potentially life-
threatening disease and reversible cause of sexual dys-
function should not be forgotten.
Specialized diagnostic testing
Diagnostic modalities such as duplex Doppler ultra-
sound, vaginal and clitoral temperature and vibration
sensory testing, and selective pudendal arteriogram
expand the physician and patient understanding of the
pathophysiologic mechanisms, but disadvantages such
as invasiveness, cost, the associated risks and compli-
cations, and lack of normative data have limited the
use of specialized testing.
Vaginal and clitoral warm, cold, and vibratory
sensory thresholds can be reliably measured with a
Thermal Sensory Analyzer/Vibratory Sensory Analyzer
system (TSA-3000 and VSA-3000; Medoc, Israel) and
compared to currently available validated normograms,
allowing quantitative neurologic assessment of the
female genitalia.
34
This non-invasive valuable diag-
nostic tool has been proven helpful in the management
of women with sexual dysfunction.
Non-invasive vascular testing of women with sexual
dysfunction has been reported by several investigators.
These include vaginal photoplethysmography and
genital duplex Doppler ultrasound. Vaginal photo-
plethysmography, the most widely used vascular testing
technique, measures vaginal mucosal engorgement and
vaginal blood volumes, providing quantitative data on
the extent of vaginal vasocongestion.
3336
The major
drawbacks of this diagnostic tool are that it provides
arbitrary rather than absolute units of measurement.
In addition, it is susceptible to subject movement arti-
fact and baseline drift.
The role of duplex Doppler ultrasonography in the
management of women with sexual dysfunction
remains to be determined. Although several investi-
gators have reported small patient series using duplex
Doppler ultrasound before and after stimulation (visual
and vibratory) as a diagnostic tool in females with sexual
dysfunction, there is no standardized ultrasonographic
technique to maximize diagnostic information. We
routinely obtained volumetric and hemodynamic data
before and after audiovisualsexual stimulation by
placing an 11 MHz small-parts probe on the side of the
clitoris. Clitoral shaft diameter is measured from the
medial tunica albuginea of the corporal body across
the septum to the lateral tunica albuginea of the contra-
lateral corporal body. The angle of the clitoral shaft
formed by the suspensory ligament is the sonographic
landmark used for volumetric measurements. Main-
taining this sonographic landmark, the small-parts
probe is then swept laterally to evaluate the hypo-
echoic, ill-dened, carrot-shaped corpus spongiosum
that possesses a thin, occasionally visualized tunica and
a corpus spongiosum diameter is measured. Hemo-
dynamic data (peak systolic (PSV), end-diastolic
(EDV), and resistive index (RI) values) from the corpus
spongiosum and cavernosal arteries are measured
(Fig. 21.1D,E) We have found that the increase in
pre- and postarousal clitoral and corpus spongiosum
diameters directly correlated with an increase in both
the pre- and postarousal clitoral and corpus spongiosum
end-diastolic velocity values, suggesting that end-
diastolic velocity values have an important physiologic
implication as a direct determinant of genital engorge-
ment. One of the limitations of the current ultra-
sonographic methodology is the lack of standardized
use of topical vasoactive agents to maximize genital
smooth-muscle relaxation. Several investigators are
performing genital duplex Doppler ultrasounds before
and after audiovisualsexual stimulation in combination
with topical application of 2% alprostadil with more
consistent hemodynamic and volumetric data.
37,38
Diagnosis of Female Sexual Dysfunction 279
Figure 21.1 AC Vestibular adenitis; DE clitoral and spongiosal hemodynamic changes.
A B C
D E
TREATMENT OF FEMALE SEXUAL
DYSFUNCTION
Patient and partner education is a critical component
in the management of FSD and should be carried out
whenever possible. The results of the history, physical
examination, laboratory testing, and the need for
additional diagnostic testing should be reviewed in
detail with the patient and her partner, and if indicated,
appropriate referrals should be made. Patient and
partner education not only facilitates physician
patientpartner communication, but also enhances
patient compliance and treatment adherence.
Modifying reversible causes
Health professionals should work with patients to
modify reversible causes of FSD such as psychogenic
FSD, hormonal imbalances, hyperprolactinemia, specic
drug-related FSD (e.g., selective serotonin reuptake
inhibitors (SSRIs)), vascular or neurologic sexual
dysfunction secondary to blunt perineal trauma, and
anorgasmia due to pudendal neuropathy.
Sex steroid hormones
The role of sex steroid hormones in reproductive
function has been extensively investigated and has
signicantly contributed to successful clinical manage-
ment of women with infertility by sex hormones or
hormone analogs. However, the role of sex steroid
hormones in regulating vaginal arousal has been
poorly investigated. At present, there is no rationale
for pharmacologic management of women with sexual
dysfunction by sex hormones or hormone analogs.
Bachmann et al.
39
reported that estrogen deciency
associated with the postmenopausal state results in loss
of collagen and adipose tissue in the vulva, attenuated
maturation of vaginal epithelial cells, thinning and loss
of elasticity of the vaginal wall with loss of premeno-
pausal ridges, bleeding and ulceration of the vaginal
epithelium after minor trauma, delayed onset of
lubrication with sexual stimulation, and an increase
in vaginal pH leading to heightened vulnerability to
urogenital pathogens and flora.
39
Sarrel
4042
reported
that women with plasma estradiol levels less than
50 pg/ml had signicantly more complaints of vaginal
dryness, frequency, and intensity of dyspareunia and
burning compared to women with estradiol values
greater than 50 pg/ml. Several investigators have
shown that treatment with estradiol increases vaginal
blood flow and lubrication, improves epithelial matu-
ration indices, normalizes vaginal pH, and prevents
vaginal atrophy.
40,43,44
Androgen insufciency, in women who are
adequately estrogenized, is also associated with sexual
dysfunction.
41,4547
Androgen replacement in women
with sexual dysfunction is associated with changes in
the external genitalia, including increased sensitivity,
engorgement, and hypertrophy of the clitoris and
vulvar hyperemia.
4850
It has been reported that
women with higher levels of testosterone had signi-
cantly greater levels of vaginal blood flow responses to
erotic stimuli compared to those with lower levels of
testosterone.
51,52
Exogenous administration of andro-
gens has resulted in a signicant increase in subjective
ratings of sexual arousal in postmenopausal women.
53
In oophorectomized women treated with testosterone,
those who had a higher ratio of testosterone to SHBG
had higher sexual arousal.
45
Shifren et al.
54
have
shown that transdermal testosterone improved sexual
function and psychological well-being in women who
have undergone oophorectomy and hysterectomy.
Arlt et al.
55
have shown that treatment of women with
adrenal insufciency with DHEA improved overall
well-being and sexual function. Munarriz et al.
56
have
shown that androgen replacement therapy with DHEA
in women with sexual dysfunction and androgen
insufciency signicantly decreased sexual distress,
signicantly increased sexual function in the domains
of desire, arousal, lubrication, satisfaction, and orgasm,
and normalized androgen blood levels to values within
the physiologic range.
Hyperprolactinemia
The treatment of hyperprolactinemia in women
with sexual dysfunction consist of: (1) the cessation
of medication causing hyperprolactinemia (e.g.,
estrogens, -methyldopa); (2) the administration of
bromocriptine; or (3) the surgical ablation or extir-
pation of a pituitary prolactin-secreting tumor.
Iatrogenic/drug-induced
Psychotropic agents such as SSRIs, neuroleptics, and
antipsychotics have been associated with sexual dys-
function in women. In addition, luteinizing hormone-
releasing hormone agonist and antiandrogens,
commonly used in the treatment of endometriosis,
infertility, and uterine bromas, are also associated
with sexual dysfunction.
Psychogenic
Patients with destructive behaviors, alcoholism,
cigarette smoking, and recreational drug use, should
be counseled on the potential etiologic role of these
factors in FSD.
Genital pain
Genital pain is a highly prevalent (14%), incapacitating,
and devastating condition associated with signicant
personal distress and diminished quality of life. Genital
neuromas and vestibular adenitis may be successfully
treated by excising the affected area.
First-line therapy
First-line interventions, characterized by ease of
administration, reversibility, non-invasive nature, and
low cost, include oral erectogenic agents (e.g., sildenal,
apomorphine, oral phentolamine), vacuum erection
devices, and psychosexual or couples therapy.
Oral vasoactive agents
Sildenal
The introduction of sildenal in 1998 revolutionized
the management of men with erectile dysfunction and
empowered women with sexual dysfunction to seek
medical attention. This potent and selective PDE5
inhibitor, which blocks the hydrolysis of cGMP,
enhances the accumulation of cGMP, and potentiates
the relaxant effects of NO in the clitoris, is not currently
approved by the US Food and Drug Administration
(FDA) for use in women. Sildenal has been utilized in
the treatment of women with sexual arousal disorders
with mixed results.
57,58
Kaplan et al.
58
reported on 33 consecutive post-
menopausal women with sexual dysfunction who
entered an open-label, non-randomized study with
50 mg sildenal. Efcacy was assessed at weeks 4, 8,
and 12 using a nine-item, self-administered Index of
Female Sexual Function and a global efcacy question.
They concluded that, despite positive changes in
vaginal lubrication and clitoral sensitivity, the overall
sexual function did not improve signicantly.
Caruso et al.
57
recently reported the results of a
double-blinded, placebo-controlled, cross-over study
of 53 normal-cycling premenopausal women (i.e.,
normal ovulatory cycles and normal levels of sexual
steroid hormones). They found that sildenal treat-
ment (25 and 50 mg) signicantly improved sexual
function (arousal and orgasm, overall pleasure, satis-
faction due to intercourse frequency, frequency of
intercourse, and erotic fantasy), but without any statis-
tically signicant difference between the two drug
dosages. At the end of the study 70.5% of women
were willing to continue the sildenal treatment.
Basson and coworkers published data concerning
efcacy and safety results of sildenal treatment in
estrogenized and estrogen-decient women com-
plaining of sexual dysfunction, also including sexual
arousal disorders.
59
A total of 577 estrogenized and
204 estrogen-decient women were randomized to
treatment. Differences in efcacy between sildenal
and placebo were not statistically signicant for any
patient or partner endpoints; in other words, sildenal
did not seem to produce any genital physiological
effect, such as improving the sexual response in both
estrogenized and estrogen-decient women.
Phentolamine
Phentolamine is a non-specic
1
- and
2
-adrenergic
antagonist, which promotes the relaxation of smooth
muscle of the vessel walls. Rosen et al. conducted a
placebo-controlled, single-blinded study on six post-
menopausal women suffering from low lubrication and
difculties in reaching arousal for at least 6 months.
60
The intake of 40 mg of oral phentolamine was safe and
well tolerated and capable of promoting improvements
in physical excitement from an objective (i.e., increase
in VPA after vaginal photoplethysmography) and
subjective point of view, with a statistically signicant
variation in vaginal lubrication as well as in local
perception of pleasure.
Apomorphine
Apomorphine, a dopamine receptor non-selective
agonist (D2>D1), produces penile erection by activating
the dopaminergic pathway in the central nervous
system. Tarcan and coworkers recently reported that
the systemic administration of apomorphine can
improve clitoral and vaginal engorgement by increasing
clitoral intracavernosal and vaginal wall artery inflow
in rabbit.
17
Topical vasoactive agents
Alprostadil
In the literature there are several studies concerning the
use of topical alprostadil in women with sexual arousal
disorders. Becher and coworkers used alprostadil
0.2% gel, associated with a factor promoting the skin
permeability (NextACT; NexMed, Robbinsville, NJ),
over the clitoris in women with sexual dysfunction.
61
All women enrolled showed labial and clitoral engorge-
ment, 72% (12/18) reported a pleasant sensation of
warmth, and only 2/18 (11%) described a mild local
burning. The color duplex ultrasonography investi-
gation showed a signicant modication of the hemo-
dynamic parameters (namely, (PSV), EDV, and RI).
A placebo-controlled study reported the results of
a single intravaginal dose of alprostadil gel (0.05%,
0.1%, or 0.2%) in eight women with sexual arousal
disorders.
62
Intravaginal prostaglandin E
1
induced an
improvement of the subjective vaginal excitement
sensation, local erythema, and genital engorgement
as well as an increase of the photoplethysmographic
vaginal parameters after audiovisualsexual stimu-
lation. The most frequent adverse events were itching
and mild vaginal burning.
Bechara et al., in a case-control study, reported
that the topic application of 1 g alprostadil 0.2%
(NextACT) over the clitoris of women with sexual
arousal or orgasmic disorders signicantly changed
Treatment of Female Sexual Dysfunction 281
the local hemodynamic parameters as shown by color
duplex ultrasonography investigation.
38
This rigorously
controlled study demonstrated an increase over base-
line of the clitoral PSV in all three groups considered.
This improvement was much more signicant when
patients were compared with controls (P > 0.005 and
P > 0.001 for women with sexual arousal and orgasmic-
phase disorders, respectively).
Neal et al. suggested the possibility of applying
an increasing dosage of alprostadil (from 50 to 400 g)
over the clitoris, the periurethral area, the vaginal
introitus, and the internal surface of the small labial
folds in a randomized, double-blinded, placebo-
controlled, cross-over study.
63
Alprostadil was locally
well tolerated and promoted a signicant vasodilation
(i.e., mild to moderate genital erythema which was
statistically signicant compared to placebo).
Topical alprostadil treatment has also recently been
reported to be efcacious for both premenopausal
and postmenopausal women.
64,65
Indeed, Shabsigh
and coworkers reported the results of a multicenter,
at-home, phase II, randomized, placebo-controlled,
cross-over study that evaluated the efcacy of a topical
cream containing placebo or alprostadil (500, 1000
or 1500 g) with a proprietary skin permeation
enhancer.
64
The authors showed a mean arousal success
rate with a dosing trend (43%, 52%, and 61% for the
three dosages, respectively) but also an unexpected
relatively large placebo effect (54%). Genital edema,
burning, and itching were the most frequent adverse
events, peculiarly observed with escalating dose preva-
lence. Costabile and coworkers, on the other hand,
in response to prostaglandin E
1
described a signi-
cantly greater genital vasocongestion than placebo in
a randomized, placebo-controlled, cross-over study
enrolling 79 naturally or surgical postmenopausal
women with sexual arousal disorders.
65
Overall,
topical alprostadil applied to the clitoris and vulva, in
comparison with a topical placebo, was associated
with signicant objective changes and dose-dependent
increase in subjective sexual responses, namely
increased level of sexual arousal, satisfaction with
sexual arousal, and sexual satisfaction.
Phentolamine
Rubio-Aurioles et al. showed that physiological readings
and subjective reports were signicantly different from
placebo in women using estrogen replacement therapy
with 40 mg phentolamine in vaginal solution.
66
Vacuum devices
At the present time, EROS therapy is the only FDA-
approved treatment of women with sexual dysfunction.
EROS therapy is designed to increase blood flow to the
clitoris, facilitating clitoral engorgement and enhancing
peripheral genital sexual arousal. It is generally
accepted that clitoral stimulation and engorgement
are important aspects of female sexual arousal. It is
believed that the difculty or inability to achieve
maximal clitoral tumescence may be related to and
associated with other symptoms of female sexual
arousal disorder.
12
During use in women with sexual arousal or
orgasmic disorders, the EROS device is placed over the
clitoris, providing three levels of gentle vacuum suction
(low, medium, and high). The postulated increase in
blood flow to the clitoris is associated with increased
sensation and enhanced sexual arousal, including
increased vaginal lubrication and labial engorgement.
In women with sexual arousal disorder, use of the
EROS therapy device has been shown to improve
sexual function and satisfaction.
67,68
Sexual therapy
Sexual therapy addressing relationship distress, sexual
performance concerns, and dysfunctional communi-
cation patterns is likely to enhance sexual functioning.
It is recommended to involve both patient and partner
in the sexual therapy. Sexual therapy is also indicated
and benecial in patients or couples who desire to
resume sexual activity after a prolonged period of
abstinence. Lastly, sexual therapy is effective in
addressing psychological reactions to the medical or
surgical treatment.
Second- and third-line therapies
Unfortunately, there are no second- or third-line
therapies available for the management of women with
sexual dysfunction.
Indications for referral
Physicians with appropriate training in sexual medi-
cine should manage the vast majority of women with
sexual dysfunction. However, there are several indi-
cations for referrals:
1. Young patients with a history of pelvic/perineal
trauma.
2. Patients with anorgasmia due to traumatic pudendal
neuropathy or hysterectomy.
3. Patients with genital pain due to neuromas,
vestibular adenitis, and myofascial pain syndrome.
4. Patients with aortic aneurysm or bulbosacral disk
disease that requires vascular or neurosurgical
intervention.
5. Patients with complicated endocrinopathies.
6. Patients with complicated psychiatric or psycho-
sexual disorders (e.g., refractory depression,
transsexualism).
7. Patient or physician request for specialized
evaluation.
8. Medicolegal reasons (occupational or iatrogenic
injuries).
CONCLUSIONS
Sexual dysfunction in women is a highly prevalent
disorder, which results in signicant personal distress
and may have an impact on the quality of life. Studies
concerning the anatomy, physiology, and patho-
physiology of female sexual function and dysfunction
are limited.A collaborative and comprehensive psycho-
logic and medical evaluation, continuous patient and
partner education, modication of reversible causes,
and individualized pharmacotherapy are strongly
recommended.
ACKNOWLEDGMENTS
Supported by grants R01-DKJ6846 and K01-
DK02696 from the National Institute of Diabetes and
Digestive and Kidney Diseases.
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References 285
A
acetylcholine 20
ACTH, in sexual function 13
adrenergic system in control of ejaculation 51
age-related changes see elderly
AIDS 204
alcohol, and erectile dysfunction 256
alprostadil
erectile dysfunction 1512
female sexual dysfunction 2812
amantadine, in retarded ejaculation 75
ametamine, in retarded ejaculation 76
aminergic control of sexual function 1012, 12
dopamine 1012, 12
norepinephrine 10
serotonin 89, 9
androgen deciency 989, 98
see also female androgen insufciency syndrome
androgen replacement therapy 967, 2079
adverse effects
benign prostatic hypertrophy 20910
cardiovascular risk 210
hematopoiesis 210
prostatic cancer 210
sleep apnea 210
benecial effects 99101, 99
body composition 208
bone 99, 208
cardiovascular system 100, 209
cognition and mood 99100, 209
immune system 209
lipid metabolism 2089
muscle mass and strength 99, 100
sexual function 99100, 208
contraindications 213
dosage 212
monitoring 212
testosterone preparations 21213, 212
testosterone regulation of prostate cells 209
in women 2712
androgen resistance 956
androgens 1315, 85105
actions of 89
adverse effects 96, 1012
age-related changes 245
central effect 1415
mechanisms of action 2034
metabolism 889
target organ changes in aging males 99
use in eugonadal men 978
see also androgen replacement therapy; testosterone
andropause 98, 211
antidepressants, and erectile dysfunction 25
antihypertensives, and erectile dysfunction 25
antipsychotics, and erectile dysfunction 25
anxiety, and premature ejaculation 63
apomorphine
retarded ejaculation 76
arousability 65
arrhythmia, phosphodiesterase inhibitors in 176
arteriogenic erectile dysfunction 21
atherosclerosis, and erectile dysfunction 26, 161
B
bed nucleus of stria terminalis 67
benign prostatic hypertrophy 20910, 2489
bladder, nerve supply 47
body composition
effects of androgen therapy 208
effects of testosterone deciency 207
bone
effects of androgen therapy 99, 208
brachytherapy see radiation therapy
brain-derived neurotrophic factor, gene therapy 188
Brief Index of Sexual Functioning for Women
(BISF-W) 261
bromocriptine, in retarded ejaculation 76
bupropion, in retarded ejaculation 75, 76
buspirone, in retarded ejaculation 75, 76
C
calcitonin gene-related peptide, gene therapy 1878
cardiovascular system
effects of androgen therapy 100, 209, 210
and erectile dysfunction 248
Index
cavernosal erectile dysfunction 212
cavernous nerves 24
cell-based gene therapy 189
cholinergic system in control of ejaculation 51
chronic renal failure, and erectile dysfunction 27
Cialis 11516, 116
cimetidine, and erectile dysfunction 25
cirrhosis, and testicular function 94, 95
clomipramine
premature ejaculation 38, 678
structure 68
cocaine, in retarded ejaculation 76
cognition
colchicine 194
coronary artery disease, phosphodiesterase inhibitors
in 1714, 173, 174
Cowpers glands 43
cryptorchidism, unilateral 94
cyproheptadine, in retarded ejaculation 75
D
dehydroepiandrostenedione replacement 1001
dehydroepiandrosterone
plasma levels 270
delayed puberty 93
L-deprenyl, in retarded ejaculation 76
depression, sildenal therapy 112
diabetes mellitus, and erectile dysfunction 26,
1623, 163, 248
sildenal therapy 111
dihydrotestosterone, age-related changes in 245
L-dopa, in retarded ejaculation 76
dopamine
control of ejaculation 489
control of sexual function 1012, 12
median preoptic area 11
nucleus accumbens 1011
paraventricular nucleus 11
spinal cord 1112
drug-induced erectile dysfunction 256
dry ejaculation 74
dyslipidemia, and erectile dysfunction 1612, 162
dyspareunia 261
E
ejaculation 4357
drug effects on 324
functional brain imaging 524, 53, 54
nervous control 448, 44
afferent pathways 44
cerebral control 445, 45
sensory receptors and areas 44
spinal motor centers 458, 46, 47
neurochemical control 4851
adrenergic control 51
cholinergic control 51
dopaminergic system 489
GABAergic control 51
serotonergic system 4951, 50
nitric oxide in 512
physiology 434, 43, 59, 60
premature see premature ejaculation
see also ejaculatory dysfunction
ejaculatory control 646
abnormal levels of sex hormones 65
arousability 65
evolutionary 64
genetic predisposition 65
6-hydroxytryptamine receptor sensitivity 656
hyperexcitable ejaculatory reflex 65
penile hypersensitivity 645
psychodynamic theories 64
ejaculatory dysfunction 5984
dry ejaculation 74
failure of emission/retarded ejaculation 747,
75, 76
inhibited mail orgasm 78
premature ejaculation see premature ejaculation
retrograde ejaculation 74
spinal cord injuries 778, 77
ejaculatory reflex, hyperexcitability of 65
ejection 43, 59
elderly
comorbidity 2479
epidemiology 2412, 241
gene therapy 2512
penile erection 2424, 242, 243, 244
penile function 2457, 246, 247
penile structure 245
phosphodiesterase inhibitors 24951, 250, 251
sildenal therapy 112, 24951, 250, 251
systemic changes 2445, 245
serum testosterone in 2056, 205, 206
sexual dysfunction in 112, 2056, 205, 206
EMDA 194
emission 43, 59
failure of 747, 75, 76
endocrinologic erectile dysfunction 223
enterochromafn cells 49
classication 21
drug-induced 256
elderly 24154
comorbidity 2479
gene therapy 2512
288 Index
erectile dysfunction (Contd)
penile erection 2424, 242, 243, 244
penile function 2457, 246, 247
penile structure 245
phosphodiesterase inhibitors 24951, 250, 251
systemic changes 2445, 245
endocrinologic 223
gene therapy 18390
brain-derived neurotrophic factor 188
calcitonin gene-related peptide 1878
cell-based 189
nitric oxide synthase 1867
non-viral gene transfer 185
potassium channels 1889
vascular endothelial growth factor 188
viral gene transfer 1845
incidence 20
intracavernosal therapy 1218
MUSE 1256
papaverine 1245
penile anatomy 1223, 122
phentolamine 125
prostaglandin E
1
1234
as marker for concomitant conditions 166
multiple risk factors 165
neurogenic 235
pathophysiology 207
phosphodiesterase inhibitor therapy 10713
post-radiation therapy 148
post-radical prostatectomy 147
prevalence 1920
primary care issues 22933
in prostate cancer 14558
psychogenic 27, 23540
evaluation 2368
goals of treatment 236
outcome studies 2389
treatment 2368
and smoking 25, 1634, 164
systemic disease 267
atherosclerosis 161
cardiovascular disease 248
chronic renal failure 27
depression 249
diabetes mellitus 26, 1623, 163, 248
dyslipidemia 1612, 162
hyperlipidemia and atherosclerosis 26
hypertension 267, 1601
vacuum devices and penile implants 12943
vasculogenic
arteriogenic 21
venogenic (cavernosal) 212
erection see penile erection
estrogens
plasma levels 912
external genitalia 85
nerve supply 47
F
female androgen insufciency syndrome 26774
androgen production 267
androgen therapy 2712
causes 2689, 269
decision-making algorithm 271
laboratory testing 26971, 270
symptoms 2678, 268
female sexual dysfunction 11314, 113, 25765,
27585
anatomy 2756
classication 2604
AFUD system 2614
non-coital pain 263
orgasmic disorder 261
personal distress 262
receptivity 2623
sexual desire disorders 261
sexual pain disorders 261
subjective mental excitment 263
diagnosis 2779
laboratory testing 278
physical examination 278, 279
sexual, medical and psychosocial history 278
specialized testing 278
epidemiology 114
experimental models 2767
historical aspects 2578, 257, 258
nosology 275
oral pharmacotherapy 113, 114
pathophysiology 114
physiology of genital sexual arousal 276
prevalence 25860, 259
treatment 2803
rst-line therapy 2812
indications for referral 2823
modication of reversible causes 2801
second- and third-line therapies 282
sexual therapy 282
Female Sexual Function Index (FSFI) 261
female sexual response 258
feminization 94
brinolytic system, effects of testosterone deciency
207
fluoxetine
structure 68
follicle-stimulating hormone
plasma levels 91
free androgen index 270
FSH see follicle stimulating hormone
functional brain imaging of ejaculation 524, 53, 54
G
GABAergic system in control of ejaculation 51
gene therapy 18390
with brain-derived neurotrophic factor 188
with calcitonin gene-related peptide 1878
cell-based 189
in elderly patients 2512
with nitric oxide synthase 1867
non-viral gene transfer 185
with potassium channels 1889
with vascular endothelial growth factor 188
genital pain 261, 263, 2801
Global Efcacy Question 11113
GnRH see gonadotropin-releasing hormone
gonadotropin-releasing hormone, response to 91
gonadotropins
regulation of 867
response to stimulation 91
H
hematopoiesis
hemochromatosis 94
HIV 204
hyperlipidemia, and erectile dysfunction 26
hyperprolactinemia 23, 280
hypertension
and erectile dysfunction 267, 1601
phosphodiesterase inhibitors in 1746, 175
hypogonadism 20318
approach to diagnosis 21012
andropause 98, 211
questionnaires 211
serum endocrine evaluations 21112
conditions characterized by 2046, 204
age-related decline in serum testosterone 2056,
205, 206
see also androgen replacement therapy
hypothalamic-pituitary disorders 934
hypothalamic-pituitary-gonadal axis 205, 206
hypothalamus 45
medial preoptic area 7, 36, 445
paraventricular nucleus 5, 78, 11, 44
I
iatrogenic sexual dysfunction 280
IC351 11516, 116
immune system
incomplete puberty 93
insulin, age-related changes 245
interferon- 194
International Index of Erectile function 11011
intracavernosal therapy 1218
and priapism 219
intravaginal ejaculation latency time 35, 60, 61
iontophoresis 194
K
Kallmann syndrome 204
Klinefelter syndrome 94, 204
Krause-Finger corpuscles 44
L
Leydig cell hyperplasia 923
LH see luteinizing hormone
limbic system
in ejaculation 49
in penile erection 56, 6, 7
lipid metabolism, effects of androgen therapy
2089
luteinizing hormone
plasma levels 90
M
male menopause 98
medial amygdala 67
medial preoptic area 56, 7
ejaculation 445
premature ejaculation 36
in sexual behaviour 11
medical urethral system for erection see MUSE
melanocyte-stimulating hormone, in sexual function
13, 14
mood
multiple sclerosis, sildenal therapy 111
muscle mass, effects of androgen therapy 99, 100
MUSE 1256, 125
myotonic dystrophy 204
N
nerve grafting 152
neurogenic erectile dysfunction 235
neurophysin 45
nitrates, phosphodiesterase inhibitor interactions
1767, 176, 177
290 Index
nitric oxide 20, 160
in ejaculation 512
in sexual function 12
nitric oxide synthase 160
gene therapy 1867
endothelial NOS 1867
inducible NOS 187
neuronal NOS 186
transfection 251
nocturnal erections 20
non-coital pain in women 263
non-viral gene tranfer 185
noradrenaline see norepinephrine
norepinephrine in control of sexual function 10
NOS see nitric oxide synthase
nucleus accumbens 7
in sexual function 1011
O
orchitis 204
viral 94
orgasm 43, 59
inhibited 78
orgasmic disorders in women 261
osteoporosis 206
oxytocin in sexual function 13
P
PABA 194
papaverine, erectile dysfunction 1245, 125
paragigantocellular reticular nucleus 45
paraventricular nucleus 5, 78
ejaculation 44
in sexual behaviour 11
paroxetine
premature ejaculation 38, 701, 71
structure 68
pelvic fracture 24
pelvic parasympathetic nervous system 46
pelvic sympathetic nervous system 46
penile erection
anatomy 159
central neurophysiology 318
bed nucleus of stria terminalis 67
limbic system 56, 6, 7
medial amygdala 67
median preoptic area 7, 11
nucleus accumbens 7
paraventricular nucleus 78
spinal reflex 4, 5
dysfunction see erectile dysfunction
mechanism of 2424, 242, 243, 244
physiology of 1078
penile hypersensitivity 645
penile implants 13140
complications
corporal cross-over 1378
corporal and urethral perforation 138
erosion 139
glans bowing 140
infection 1389
mechanical malfunction 137
reservoir herniation 13940, 139, 140
history 1312
indications 132
inflatable prostheses
multicomponent prostheses 1345, 134, 135
perioperative care 1356
unitary self-contained cylinders 134
semirigid/rod prostheses 1323, 133
surgical approaches 1367
penile relaxation 160
penis
age-related changes 2457, 246, 247
anatomy 1223, 122
peripheral innervation 35, 4, 5
spinal reflex 4, 5
see also erectile dysfunction; penile erection
Peyronies disease 191202
clinical manifestations 1923, 192
diagnosis 193
differential diagnosis 193
follow-up 1934
investigations 192
medical treatment 1946, 194
intralesional 1956
oral 1945, 194
topical 196
pathophysiology 1912
surgical treatment 1969, 197, 198
phentolamine
female sexual dysfunction 281, 282
phosphodiesterase inhibitors 10719, 1701
cardiovascular safety 1708
in elderly patients 250
hemodynamic effects 1716
arrhythmias 175
coronary artery disease 1714, 173, 174
healthy men 171, 172
nitrate interactions 1767, 177
pituitary tumors 204
potassium channels, in gene therapy 1889
Prader-Labhart-Willi syndrome 204
precocious puberty 923
premature ejaculation (Contd)
course of rapidity 36
denition of
intravaginal ejaculation latency time 35, 60,
612, 61
number of thrusts 601
partner satisfaction 62
voluntary control 62
drug therapy 389
as-needed treatment with anesthetic topical
ointments 389
as-needed treatment with antidepressants 38
new developments 39
serotonergic antidepressants 38
ejaculation threshold hypothesis 356
etiology 624, 63
anxiety 63
early sexual experience 634
frequency of intercourse 64
evidence-based medicine 334
drug treatment 34
psychotherapy 334
genetic aspects 378
historical development of theories 312
neuroanatomy 367, 37
new theory of 35
operational denition 345, 35
serotonin neurotransmission 32
treatment 6674
clomipramine 678, 68
fluoxetine 6970
paroxetine 701, 71
phosphodiesterase inhibitors 713
psychosexual counselling 667
SSRIs 689, 72
surgery 734
topical 73
see also ejaculatory control
priapism 21928
complications 226
denition 219
diagnosis 223
epidemiology and etiology 21921, 221
intracavernosal injection with erectogenic
agents 219
malignancy 2201
medications and drugs 220
neurological factors 220
sickle-cell hemoglobinopathies 21920
systemic illness 220
total parenteral nutrition 220
trauma 221
pathophysiology 2213
high-flow 2223
low-flow 2212
treatment 2236, 224, 225
prostaglandins 20
in erectile dysfunction 1234, 125
prostate
adverse effects of testosterone on 209
benign prostatic hypertrophy 20910
testosterone regulation of 209
prostate cancer 14558, 210
epidemiology 1458, 147, 148
follow-up and treatment 1513, 153
pathophysiology 14851, 149, 150
and priapism 2201
sildenal after radiation therapy 112
psychogenic erectile dysfunction 27, 23540
evaluation 2368
outcome studies 2389
treatment 2368
psychogenic sexual dysfunction 280
psychosexual counselling 667
psychotherapy 334
puberty 92
delayed/incomplete 93
precocious 923
Q
quinelorane, in retarded ejaculation 76
R
radiation therapy
erectile dysfunction after 148
sildenal after 112, 1523, 153
radical prostatectomy
prevalence of erectile dysfunction 147
retarded ejaculation 747, 75, 76
retrograde ejaculation 74
S
selective androgen receptor modulators 213
selective serotonin reuptake inhibitors, in premature
ejaculation 38, 689, 72
Semans manoeuvre 667
semen analysis 91
serotonin receptors 32
and premature ejaculation 656
serotonin structure 68
serotoninergic system
control of ejaculation 4951, 50
control of sexual function 89, 9
sertraline
structure 68
292 Index
sex hormone-binding globulin 203
plasma levels 270
sex hormones
abnormal levels of 65
see also androgens; estrogens; testosterone
sexual activity, cardiovascular effects 16670
cardiovascular risks 1679, 168, 169
hemodynamic and metabolic parameters 1667,
167
risk stratication 16970, 170
sexual desire disorders in women 261
sexual function
in females 11314, 113
neurotransmitter control
ACTH 13
amines 812
dopamine 1012, 12
melanocyte-stimulating hormone 13, 14
nitric oxide 12
norepinephrine 10
oxytocin 13
serotonin 89, 9
sexual pain disorders in women 261
sexual therapy 282
sickle-cell hemoglobinopathies, and priapism 21920
sildenal 10715
-blocker interaction 178
cardiovascular effects 11415
contraindications 1089
dosage 108
efcacy 11013
depression 112
diabetes 111
Global Efcacy Question 11113
increased age 112
International Index of Erectile Function 11011
long-term 113
multiple sclerosis 111
post-radiation therapy 112, 1523, 153
radical prostatectomy 11112
spinal cord injury 111
TURP 112
in elderly patients 24951, 250, 251
female sexual dysfunction 11314, 113, 281
xed-dose studies 109
flexible-dose studies 109
long-term open-label studies 110
non-responders 113
pharmacokinetics 116
pharmacology 108
precautions 109
safety 10910, 109, 174, 175
structure 250
see also phosphodiesterase inhibitors
sleep apnea, androgen-induced 210
smoking, and erectile dysfunction 25, 1634, 164
spermatogenesis 8990
spinal cord injury 234
ejaculatory dysfunction 778, 77
spinal cord in sexual function 1112
spinal reflex 4, 5
SSRIs see selective serotonin reuptake inhibitors
systemic disease and erectile dysfunction 267
atherosclerosis 161
cardiovascular disease 248
chronic renal failure 27
depression 249
diabetes mellitus 26, 1623, 163, 248
dyslipidemia 1612, 162
hyperlipidemia and atherosclerosis 26
T
tadalal 11516, 116, 251
structure 250
tamoxifen 194
testes
abnormal function 923
adult males 93
delayed/incomplete puberty 93
precocious puberty 923
puberty 92
anatomy 856, 85
biopsy 91
disorders of 948
acquired 945
androgen replacement therapy 967
androgen resistance 956
developmental defects 94
systemic disease-related 95
evaluation of function 901
plasma LH levels 90
plasma testosterone levels 90
response to GnRH 91
response to gonadotropin stimulation 91
normal function 92
regulation of function 8690, 86
androgen action 89
androgen metabolism 889
gonadotropin regulation 867
spermatogenesis 8990
testosterone synthesis 87, 88
testosterone transport 878
testicular torsion 94
testicular tumors 204
testosterone
in adult sexual function 1314
age-related deciency 2056, 205, 206, 245
bone and osteoporosis 2067
cardiovascular, brinolytic and immune systems
207
cognition and mood 207
hematopoiesis 207
sexual function 206
and erectile dysfunction 23
metabolism 15, 889, 203
plasma levels 270
preparations 21213, 212
regulation of prostate cells 209
serum levels 90
range of 211
supplementation 98
synthesis 87, 87, 88
transport 878
see also androgen replacement therapy
testosterone deciency 2067
bone and osteoporosis 2067
cardiovascular, brinolytic and immune systems
207
cognition and mood 207
hematopoiesis 207
sexual function 206
total parental nutrition, and priapism 220
trabeculae 3
transurethral resection of prostate, sildenal therapy
112
triiodothyronine, age-related changes 245
TURP see transurethral resection of prostate
V
vacuum devices 12931
complications 1301
economics 130
history 129
indications 12930
mechanism of action 12930, 130
patient satisfaction 131
vaginismus 261, 263
vardenal 11617, 251
structure 250
varicocele 94
vas deferens, nerve supply 47
vascular endothelial growth factor, gene therapy
188
vasoactive intestinal peptide 20
venogenic (cavernosal) erectile dysfunction 212
verapamil 194
Viagra see sildenal
virilizing syndromes 92
vitamin E 194
Y
yohimbine, in retarded ejaculation 75
294 Index

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