Clinical Therapeutics/Volume 31, Number 1, 2009
Drug Treatment of Paraphilic and Nonparaphilic
Sexual Disorders
David R.P. Guay, PharmD
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota,
Minneapolis, Minnesota, and Division of Geriatrics, HealthPartners Inc., Minneapolis, Minnesota
ABSTRACT
Background: Paraphilias are characterized by re-
current, intense, sexually arousing fantasies, urges, or
behaviors, over a period of ::::6 months, generally in-
volving nonhuman objects, suffering or humiliation of
oneself or one's partner, or children or other noncon-
senting persons. These fantasies, urges, and behaviors
produce clinically significant distress or impairments
in social, occupational, and other important areas of
functioning.
Objective: The goal of this article was to provide
an in-depth review of the clinical pharmacology of
the main antiandrogens (cyproterone acetate, med-
roxyprogesterone acetate [MPA], and the luteinizing
hormone-releasing hormone [LHRH] agonists) used in
the treatment of the paraphilias, as well as a discus-
sion of the relevant clinical case reports, case series,
and controlled trials. Treatment recommendations are
also provided.
Methods: Relevant publications were identified
through a search of the English-language literature
indexed on MEDLINE/PubMed (1966-September
2008) using the search terms paraphilia. sex offendel:.
hypersexuality. sexual behaviors_. fetish. transvestic
fetishism. sexual addiction. sexual compulsivism. selec-
tive serotonin reuptake inhibitors_. tricyclic antidepres-
sants_. antiandrogens_. cyproterone acetate_. medroxy-
progesterone acetate_. LHRH agonists_. and estrogens.
Additional publications were identified from the bib-
liographies of retrieved publications.
Results: In vitro and in vivo (animal) studies have
revealed that serotonin and prolactin inhibit sexual
arousal, while norepinephrine (via acadrenoceptor acti-
vation), dopamine, acetylcholine (via muscarinic recep-
tor activation), enkephalins, oxytocin, gonadotropin-
releasing hormone, follicle-stimulating hormone,
luteinizing hormone, testosterone/dihydrotestosterone,
and estrogen/progesterone stimulate it. Most of the cur-
rently used pharmacologic treatments of the paraphilias
January 2009
have serotonin and testosterone/dihydrotestosterone
as their targets. Cognitive-behavioral psychotherapy
should be initiated in all offenders. In those at the
highest risk of reoffending, psychotherapy should be
initiated at the same time as drug therapy because
their combination is associated with better results
compared with either as monotherapy (especially in
pedophiles). In offenders committing non-"hands-on"
or violent paraphilias and those at low risk of re-
offending, serotoninergic monotherapies (selective
serotonin reuptake inhibitors [SSRls] or tricyclic an-
tidepressants) are reasonable choices (SSRls are
preferred). In other offenders, initial dual combination
therapy (serotoninergic plus antiandrogenic) is recom-
mended. Progestogens should be used before LHRH
agonists or estrogens. Cyproterone acetate and MPA
are preferred as oral and 1M progestogens, respec-
tively. Failure of dual combination serotoninergicl
progestogen therapy should prompt a change in one
or both of the components (eg, SSRI to tricyclic anti-
depressants or vice versa, or cyproterone acetate to
MPA or vice versa) or the addition or substitution of an
LHRH agonist (leuprolide or triptorelin) for the pro-
gestogen. Estrogens are second- or third-line agents.
Rarely, triple combination therapy is necessary (sero-
toninergic plus LHRH agonist or progestogen plus es-
trogen). It appears that recidivism rates are reduced by
the use of psychotherapy alone, drug therapy alone,
and more so by their combination.
Conclusions: Although some progress has been
made in the therapy of paraphilic and nonparaphilic
sexual disorders, much work remains to be done. The
development of more specific, more effective, and
better-tolerated medications for these disorders should
Accepted for publicatIOn December 8, 2008
dOl:1 OJ 016!J-cIinthera_2009_01_009
0149-2918/$ - see front matter
2009 Excerpta Medica Inc All nghts reserved_
1
 Clinical Therapeutics

be recognized as a program worthy of greater support
from government and pharmaceutical industry sourc-
es. Clinical studies performed to date have largely
been of poor design, making the recommendations
provided in this review tentative at best. (Clin Ther.
2009;31:1-31) 2009 Excerpta Medica Inc.
Key words: sexual behaviors, hypersexuality,
paraphilias, sex offender, selective serotonin reuptake
inhibitors, tricyclic antidepressants, cyproterone,
medroxyprogesterone, LHRH agonists, estrogens.
INTRODUCTION
The paraphilias are characterized by recurrent,
intense, sexually arousing fantasies, urges, or behav-
iors, over a period of ::::6 months, generally involving:
(1) nonhuman objects; (2) suffering or humiliation of
oneself or one's partner; or (3) children or other non-
consenting persons (criterion A). These fantasies, urg-
es, and behaviors also produce clinically significant
distress or impairments in social, occupational, and
other important areas of functioning (criterion B).!
The major types of paraphilias are listed in Table I.!
Stimuli can be either obligatory for erotic arousal and
always a component of the sexual activity, or can be
episodic (eg, only if the individual is stressed) and the
individual does not respond (ie, "is normal") at other
times. For pedophilia, voyeurism, exhibitionism, or
frotteurism, the diagnosis is made only if the individu-
al acts on the sexual urges and/or fantasies, and this
action leads to marked distress or interpersonal diffi-
culties. With the other paraphilias, the diagnosis is
made if the sexual urges and/or fantasies produce the
effects listed in criterion B (see above).!
The most common problems seen in clinics special-
izing in the treatment of paraphilias are pedophilia,
voyeurism, and exhibitionism.! Associated psychiatric
disorders include sexual dysfunction disorder, personali-

Table I. Major types of paraphilias.*

Exhibitionism (302.4)
Fetishism (302.81)
Frotteurism (302.89)
Pedophilia (302.2)
Sexual masochism (302.83)
Sexual sadism (302.84)
Transvestic fetishism (302.3)
Voyeurism (302.82)
Paraphilia NOS (302.9)
Exposure of genitals to unsuspecting strangers (is NOT the same as public
urination).
Use of nonliving objects as a repeatedly preferred or exclusive method of
achieving sexual excitement (eg, leather goods, clothing, undergarments,
fabrics, shoes). (If female clothing is used in cross-dressing [see below] or
devices are used to directly stimulate the genitals leg, vibrator], this is NOT
fetish ism.)
Touching and rubbing against a nonconsenting person.
Children are the sexual target (perpetrator is ::::16 years old and ::::5 years older
than the victim).
Perpetrator receives the humiliation/suffering (practice can even lead to death,
especially during "hypoxyphilia" or sexual arousal during hypoxia).
Perpetrator inflicts the humiliation/suffering on another (generally, severity
increases over time).
Also known as "cross-dressing" or wearing clothing of the other sex (may also
be associated with gender-identity disorder).
Observing sexual activity or naked/disrobing individuals.
Miscellaneous types such as coprophilia (feces/defecation); klismaphilia (enema
use); mysophilia (filth); narratophilia (erotic talk); telephone scatalogia (obscene
telephone calls); urophilia (urine/urination); zoophilia (animals); and necrophilia
(dead persons).

NOS ~ not otherwise specified.

*Numbers In parentheses next to the paraphilia names are the Identification code numbers from the Diagnostic and Statistical
Manual ofMental Disorders, Fourth Edition, Text ReVISion.'

2 Volume 31 Number 1

ty disorder, and depression. Males commit the majori-
ty of all sex crimes.! Females are most frequently, but
not exclusively, diagnosed with sexual masochism; the
male:female frequency ratio ofthis paraphilia is ~20: 1.!
Approximately 50% of perpetrators are married.!
The age predilection is paraphilia-specific. Paraphil-
ias may begin in childhood or early adolescence but
become better defined during adolescence.! For ex-
ample, the onset of paraphilic sexual interest frequent-
ly occurs before 18 years of age. 2 The mean ages of
onset of paraphilias are as follows: transvestic fetish-
ism, 13.6 years; fetishism, 16.0 years; voyeurism,
17.4 years; nonincestuous homosexual pedophilia,
18.2 years; sadism, 19.4 years; and nonincestuous
heterosexual pedophilia, 21.1 years. 2 The onset of
exhibitionism typically occurs before 18 years of age.!
Most paraphilias are usually chronic, unless treated,
lasting for many years (if not a lifetime).! The frequen-
cy of sexual acts may increase or decrease over time
but often diminish with advanced age (::::60 years old).!
The differential diagnosis includes developmental dis-
ability, dementia, personality changes due to general
medical conditions, substance intoxication, manic epi-
sodes, and schizophrenia.!
Actual prevalence/incidence figures are unavailable
for any of the paraphilias. However, surveys have pro-
vided some useful data regarding the epidemiology of
pedophilia. Six percent to 62% of girls and 10% to
30% of boys have reported themselves to be victims
of pedophilic violence during childhood. 2 In one US
survey of 4000 females, 24% stated that they had had
a sexual interaction with a male ::::5 years older than
themselves when they were :c:;14 years old. 2 Intercourse
occurred in only 3 % of cases, with minor petting or
fondling without genital involvement in 31 % of cases.
In a Canadian National Population Survey of 2008
subjects (1005 females, 1003 males), 18.1 % (23.5%
and 12.8% of females and males, respectively) re-
ported that they had been victims of sexual violence
when they were children or adolescents. 2
The majority of recidivism (relapse) data in the
paraphilias exists for pedophilia. Published recidivism
rates among pedophiles range from 10% to 50%, de-
pending on how subjects are grouped. Homosexual
and bisexual pedophiles have higher rates than het-
erosexual pedophiles (50% and 25%, respectively).3
Nonrelated pedophiles exhibit higher rates, while in-
cestuous pedophiles have the lowest rates. Higher
rates of recidivism are also associated with the follow-
January 2009
D.R.P. Guay
ing characteristics: more deviant sexual practices, at-
traction to younger children, display of more socio-
pathic or antisocial personality traits, higher treatment
nonadherence rates, and the greater the number of
paraphilic interests reported by the offender. It is im-
portant to realize that no actuarial or self-report tests
(or combinations thereof) can accurately identify the
future activity of a pedophilic individual. 3
Published rates are probably gross underestimates
because many studies do not report treatment drop-
out numbers, cannot calculate the number of unre-
ported repeat offenses, and do not use polygraph
testing to "confirm" self-reports. Low rates are fre-
quently reported if subjects are only followed up dur-
ing active treatment or only for short periods after the
end of treatment (eg, 1-5 years).3 In some cases, re-
cidivism rates may be exaggerated to support a puni-
tive approach and/or the media misrepresent matters
by sensational reporting of pediatric murder cases. 2
In any proposed theory to explain the development
of the paraphilias, compulsive sexual behaviors, hy-
persexuality, and paraphilic behaviors must be distin-
guishable. Compulsive sexual behaviors, which are
nonparaphilic, include compulsive masturbation, com-
pulsive use of pornography, and promiscuity (the lat-
ter includes satyriasis and nymphomania).4
Although the etiology of the paraphilias is unknown,
the neurophysiology of sexual arousal has been the
subject of much research and has led to the pharma-
cologic approaches used today (as discussed later in
this article). Sexual arousal is dependent on neural
(sensory and cognitive), hormonal, and genetic fac-
tors, and, in humans, the complex influences of cul-
ture and context. 5
Much of the information regarding sexual arousal
has been gained primarily from studies using nonhu-
man models. Several areas in the brain are associated
with sexual arousal: thalamus; basal forebrain; ven-
tral medullary reticular formation; paragigantocellu-
lar reticular nucleus (in ventral medulla); central grey;
ventral tegmental area; central tegmental field of the
midbrain; medial amygdala; medial preoptic area;
basomedial hypothalamus; caudate nucleus; hypotha-
lamic paraventricular nucleus; anterior cingulate,
frontal, parietal, and insular cortices; and cerebellum.
a!-Adrenergic and dopaminergic neurotransmission
enhances sexual arousal, as does parasympathetic
muscarinic neurotransmission. Serotoninergic neu-
rotransmission reduces sexual arousal. Norepineph-
3
 Clinical Therapeutics
rine (via cxl-adrenoceptor activation) and acetylcho-
line (via muscarinic receptor activation) stimulate sexu-
al arousal. Numerous neuropeptides enhance sexual
arousal (enkephalins, oxytocin, gonadotropin-releasing
hormone [GnRH], follicle-stimulating hormone [FSH],
and luteinizing hormone [LH]), either by themselves
or by enhancing production of other compounds.
Hormones that affect sexual arousal include prolactin
(reduces it), testosterone/dihydrotestosterone (increas-
es it), and estrogen/progesterone (increases it).5,6 How-
ever, several treatments studied and believed to be
somewhat useful had no empirical basis when their
formal use began. Examples include various forms of
psychoanalysis and the use of surgical castration in
the late 1800s and early 1900s. 7
The goal of the current article was to provide an
in-depth review of the clinical pharmacology of the
main antiandrogens (cyproterone acetate, medroxy-
progesterone acetate [MPA], and the LH-releasing
hormone [LHRH] agonists) used in the treatment of
the paraphilias, as well as a discussion of the relevant
clinical case reports, case series, and controlled trials.
Treatment recommendations are also provided.
METHODS
Relevant publications were identified through a search
of the English-language literature indexed on MEDLINE/
PubMed (1966-September 2008) using the search
terms paraphilia, sex offendel:, hypersexuality, sexual
behaviors, fetish, transvestic fetishism, sexual addic-
tion, sexual compulsivism, selective serotonin reuptake
inhibitors_, tricyclic antidepressants_, an tiandrogens_,
cyproterone acetate_, medroxyprogesterone acetate_,
LHRH agonists, and estrogens. Additional publica-
tions were identified from the bibliographies of re-
trieved publications.
RESULTS
Nonpharmacologic Therapies
Surgical castration (orchidectomy [removal of the
testes]) reportedly produces definitive results, even in
repeat pedophilic offenders, by reducing recidivism
rates to 2% to 5%.2 However, up to one third of cas-
trated males can still engage in intercourse. 8 Thus, it is
not uniformly effective in producing impotence. 8 Re-
sults can also be reversed by the administration of
exogenous testosterone, allowing reoffense. 3 From the
introduction of surgical castration in Switzerland in
1892 (as a treatment for hypersexuality) until the
4 Volume 31 Number 1
1970s, this procedure was used in many European
countries and the United States. 7 Today, it is available
only in Germany and in certain US states (California,
Florida, Iowa, Louisiana, and Texas as one of the con-
ditions of parole or probation). 9 One significant fac-
tor, considering limited prison health care budgets, is
the substantial difference in cost between one-time
surgical castration and ongoing "chemical castration"
with antiandrogen drug therapy, which costs US
$5000 to US $20,000 per year. This led to the state of
Texas mandating the use of only surgical castration,
the lone state among 9 in the United States allowing
surgical and/or "chemical castration."
Psychotherapy can be divided into individual and
grouplfamily therapy approaches. The former is repre-
sented by insight-oriented, cognitive-behavioral, and
supportive psychotherapies. This type of therapy has
been considered the "gold standard" nonpharmaco-
logic approach to be offered to pedophiles. 8 It is costly
(ie, US $5000-$15,000 per year),10 and the effects in
clinical trials have been extremely variable (including
helpful, not helpful, and/or harmful, even in the same
trial).ll This extreme variability may be related, in
part, to the need for the offender to admit guilt and
accept personal responsibility before success is possi-
ble, the media who bias the public to believe in the
universal failure of these treatments, and the belief
that some humor should always be included in such
therapy but frequently is not. 8 Even offenders with
borderline or mildly impaired intellectual functioning
may benefit from psychotherapy adapted to their spe-
cial needs. l2 Recidivism is likely if a high level of
sexual arousal is present. 8 There is much debate re-
garding the overall effectiveness of psychotherapy for
the long-term prevention of new offenses. 3
A general strategy for the treatment of pedophiles
is the use of a combination of cognitive-behavioral
therapy (addressing distortions and denial), empathy
training, sexual impulse control training, relapse pre-
vention strategies, and biofeedback. 3 A controversial
approach-aversion conditioning and masturbatory
conditioning, targeted to changing an individual's
sexual orientation away from children-is no longer
offered at reputable treatment centers. 3
Pharmacologic Therapies
Table II illustrates the drug treatment of a variety
of problematic contact and noncontact sexual behav-
iors in sex offenders that have been published as case
 D.R.P. Guay

Table II. Case reports and case series on drug treatment of sex offenders.

Targeted Sexual
Drug Behavior (No. of Cases)

Antidepressants
Clomipramine Exhibitionism (4)13-15
Fluoxetine Masturbation (7)16-19
Transvestism (1 )20
Fetishism (1)18
Necrophilia (1)21
Pedophilia (3)17.21
Zoophilia (1)21
Exhibitionism (3)17.22
Voyeurism (3)17.23
Frotteurism (3)17.21.24
Sadism (1 )21
Sertraline Transvestism (1)25
Fetishism (1)25
Pedophilia (1)26
Phenelzine Transsexualism* (2)27
Transvestism* (1)27
Exhibitionism* (1)27
Mirtazapine Fetishism (1)28
Ant ico nvu Isantsjanxio Iyt ics
Topiramate Fetishism (1)29
Masturbation (1)29
Carbamazepine Pedophilia (1)30
Masturbation (1 )30
Narratoph ilia (1 )30
Carbamazepine + clonazepam Pedophilia (1)31
Buspirone Transvestism t (2)32.33
Fetishismt (2)32.33
Masturbationt (1)32
Mood stabilizers
Lithium Transvestismf (1 )34
Masturbation (1 )35
Autoerotic asphyxia (1 )35
Neuroleptics
Clozapine Exhibitionism (2)36
Masturbation (2)36
Opioid antagonists
Naltrexone Masturbation (2)37
Exhibitionism (2)37
Frotteurism (1)37
Antiandrogens
Cyproterone acetate Exhibitionism (9)38.39
Masturbation (2)38.40
Voyeurism (1 )39
Pedophilia (2)41.42
Nymphomania (1)40
Fetishism (1)41
Transvestism (1)41

(continued)

January 2009 5
 Clinical Therapeutics

Table II (continued).

Targeted Sexual
Drug Behavior (No. of Cases)

Medroxyprogesterone acetate Frotteurism (2)43-45

Narratophilia (3)44.46.47
Masturbation (5)43.45.48.49
Pedophilia (15)46.47.49-53
Exh ib itio nism (10)46.47.49.53
Frotteurism (1)53
Rape (3)54
Satyriasis (1 )45
Voyeurism (4)45.47.49
Transvestism (2)47.49
Zoophilia (1)47
M asoch ism (1 )47
Fetishism (3)47.55
Self-bondage (1 )48
Sadism (1 )47
Relapse, during therapy, of
pedophilia (4), rape (3),
exhibitionism (2), and
mastu rbatio n (1 )56.57
Leuprolide acetate Exhibitionism (4)58-60
Masturbation (22)59-63
Rape (46)62-65
Sadomasochism (2)62
Sadism (2)63
Frotteurism (4)61.63
Voyeurism (1 )63
Transvestism (1 )63
Fetishism (1)66
Narratoph ilia (1 )66
Relapse, during therapy,
of pedophilia (1)67

*Cases occurred In patients with social phobia/panic attacks, and phenelzine effect could have
been related to anti phobic and anti panic effects.
tOne case occurred In a patient with generalized anxiety disorder, and busplrone effect could
have been related to anxlolytlc activity.
t Cases occurred In a patient with bipolar disorder, and lithium effect could have been due to
mood stabilization.
Cases occurred In patients with schizophrenia, and c10zaplne effect could have been due to
effect on psychosIs.

reports or case series. 13-67 A class-by-class discussion
of these (and other) agents follows here. With respect
to the antiandrogens, it should be understood that,
with the exception of patients with prostate cancer,
the only adverse-event data available in males are
provided in the clinical case studies, case series, and
controlled trials reviewed in this section. The applica-
bility of metabolic and adverse-event data generated
in males with prostate cancer or females to the subject
population in this article is unknown.

6 Volume 31 Number 1

Antidepressants
A retrospective, open-label review was conducted
of the results of serotoninergic therapy in 13 male
outpatients presenting with paraphilias (n = 5), non-
paraphilic sexual addictions (n = 5), and sexual obses-
sions (n = 3).68 Symptoms were rated using a change
in Clinical Global Impression score (1 = markedly
improved, 2 = moderately improved, 3 = minimally
improved, 4 = unchanged, 5 = minimally worse, 6 =
moderately worse, and 7 = markedly worse). Actual nu-
meric results were not provided. Paraphilic patients re-
ceived fluoxetine 60 mg/d (n = 2) or up to 80 mg/d
(n = 1), fluvoxamine 300 mg/d tapered to 200 mg/d
(n = 1), and clomipramine up to 400 mg/d (n = 1).
Those with nonparaphilic sexual addictions received
fluoxetine 20 to 40 mg/d (n = 2), fluoxetine 80 mg/d
plus fenfluramine 40 mg/d (n = 1), fluoxetine up to
80 mg/d (n = 1), and fluoxetine 80 mg/d tapered to
40 mg/d (n = 1). Those with sexual obsessions re-
ceived fluoxetine 80 mg/d (n = 1) and clomipramine
200 or 300 mg/d (n = 2). Two of 5 patients (40%)
with nonparaphilic sexual addictions reportedly had
some improvement (predominantly in masturbation).
Two of 3 patients (67%) with sexual obsessions re-
portedly had moderate or marked improvement.
None of the 5 patients with paraphilias reported any
benefit. 68
A 16-year-old male with compulsive paraphilic sexu-
al behaviors (pedophilia, fetishism, and masturbation)
was treated with open-label fluoxetine 10 mg/d, which
was increased over the course of 1 week to 30 mg/d and
subsequently to 50 mg/d, then 60 mg/d. 69 The behav-
iors became much improved, with marked decreases in
symptoms and sexual thoughts that subsequently dis-
appeared (no quantitative results were available). Of
interest, serum testosterone concentrations decreased
as the daily fluoxetine dose increased (baseline, 613 to
494 ng/dL [day 10], then 466 ng/dL [day 14]).6 9
In an open-label trial of antidepressant therapy in
10 consecutively evaluated male patients with paraphil-
ias or nonparaphilic sexual addictions, 9 (90%) re-
sponded with improvements in aberrant sexual behav-
iors and depressive symptoms.7 However, the only
quantitative data collected regarding paraphilic signs
and symptoms were the total number of orgasms per
week (which decreased in all patients, from a mean
of 9.2/week at baseline to 2.7/week at the end of
12 weeks; no statistical analysis was performed).
Symptoms that showed a response to therapy included
January 2009
D.R.P. Guay
masturbation (n = 4); pornography (n = 3); hetero-
sexual promiscuity (n = 2); and phone sex, homosexu-
al promiscuity, exhibitionism, homosexual fantasies/
urges, fetishism, sadomasochism, rape fantasies, and
voyeurism (n = 1 each). One patient responded for
only 3 weeks (diagnoses of masturbation, sexual maso-
chism, and transvestic fetishism) and then dropped
out. Seven patients took fluoxetine ranging from 10 to
60 mg/d; 1 patient taking 60 mg/d also received tra-
zodone 150 mg/d. One patient each received imip-
ramine 225 mg/d plus lithium 600 mg/d, imipramine
125 mg/d, and lithium 1500 mg/d. 70
A 27-year-old male with pedophilia and comorbid
dysthymia was treated with open-label fluoxetine
(20 mg/d initially, titrated to 80 mg/d over 6 weeks)
with minimal results. 71 Trifluoperazine was added
and titrated to 6 mg/d; the patient experienced some
symptom relief but disabling akathisia occurred. The
patient's trifluoperazine use was then tapered off, and
he was switched to risperidone 6 mg/d. Within 1 week
of initiation of fluoxetine/risperidone combination
therapy, he was free of all sexual thoughts and urges,
and his mood was reported as improved. No quantita-
tive data were provided; results were clinician's global
impressions. The relative role of each component of
the combination was unknown. 71
Twenty male patients, 10 each with paraphilias and
nonparaphilic sexual behaviors, were evaluated for
depression and abnormal sexual behaviors at baseline
and then every 4 weeks for 12 weeks during open-
label fluoxetine therapy.72 Paraphilias included maso-
chism (n = 6); exhibitionism and phone sex (n = 2
each); and sadism, transvestic fetishism, fetishism, and
frotteurism (n = 1 each). These patients also exhibited
nonparaphilic sexual behaviors, including compulsive
masturbation (n = 6), protracted promiscuity (bisexu-
al, n = 5; heterosexual, n = 1; homosexual, n = 1), in-
volvement in pornography (n = 3), sexual incompati-
bility (n = 2), and phone sex (n = 1). Fluoxetine
therapy was started at 20 mg/d and then titrated every
4 weeks to a maximum of 60 mg/d. At the end of the
12-week trial, the mean (SD) dose was 39.4 (14.8) mg/d.
By week 4, all measures of unconventional sexual be-
havior (paraphilic and nonparaphilic sexual addic-
tions) were significantly reduced compared with base-
line in both groups (intergroup differences were
nonsignificant). For example, pooling the treatment
effects in both groups led to the following pretreat-
ment and posttreatment results for the unconventional
7
 Clinical Therapeutics
behavior variables: total sexual outlet, 10.6/3.6 (P =
0.001); masturbation, 6.4/1.5 (P = 0.005); sexual ac-
tivities, 3.1/0.9 (P = 0.001); desire intensity, 8.5/4.5
(P = 0.001); and sex interest ratio, 87.5/47.6 (P =
0.001). Response was also independent of baseline
depression scores. For most responses, there was a
marked initial drop by week 4, followed by a more
gradual decline thereafter (weeks 8-12),72
A 23-year-old female pedophile was treated with
open-label sertraline 50 mg/d. 73 She experienced a
gradual decline in the frequency and intensity of sexu-
al interest in female children and, by the end of
1 year of therapy, she had very infrequent sexual
thoughts that were easier to resist or stop (12 times/
month at baseline vs 2 times/month at 1 year; no sta-
tistical analysis was performed). Concurrent impulsive
behaviors (eg, temper outbursts, excessive spending)
also responded to therapy. The baseline and 1-year
scores were as follows: Symptom Checklist-90 instru-
ment (measures general level of psychopathology),
50/0:;30; Hamilton Anxiety Rating Scale (based on
score range of 0-64), 11/5; Hamilton Rating Scale
for Depression (based on a score range of 0-56),
7/6; Yale-Brown Obsessive Compulsive Scale (based
on score range of 0-40), 2/0; and 20-term Impulsivity
Scale (based on score range of 20-100),76/46. 73 ,74 All
patient scores (pretreatment and posttreatment) were
within normal limits.
Two case reports of exhibitionism and voyeurism
with treatment using paroxetine were found. 75 No
quantitative data were provided in either case report.
A 29-year-old male exhibitionist initiated therapy
with open-label paroxetine 10 mg at bedtime. Within
4 weeks, his urges to disrobe decreased and the ability
to control urges increased. After a dose escalation to
20 mg at bedtime, the patient requested another dos-
age increase after 3 weeks due to recurrent urges. The
patient did well for 2.5 months with paroxetine 30 mg
at bedtime but was then lost to follow-up. A 50-year-
old male voyeur had experienced symptom relief with
previous fluoxetine and paroxetine treatment. Open-
label paroxetine 10 mg at bedtime was started and,
over the next 4 weeks, the urges were still present, but
the ability to resist them had improved. After a dose
increase to 20 mg at bedtime, the frequencies/intensities
of urges and voyeuristic behaviors decreased. There
were no incidents in the subsequent 3 months. The
patient stopped therapy on his own, and at 4 months'
follow-up, he was still doing well. 75
8 Volume 31 Number 1
Nefazodone therapy of nonparaphilic sexual
obsessions/compulsions was the subject of a retro-
spective, open-label evaluation of 14 male outpatients
(mean age, 45 years; age range, 26-67 years).76 The
mean daily dose of nefazodone was 200 mg (range,
50-400 mg). Nine of the 14 patients (64%) had a
concurrent mood disorder. A rating scale of 1 to 4 was
used to quantitate response: 1 = minimal response or
poor tolerance to drug, 2 = partial control of obsessive
thoughts, 3 = good control of obsessive thoughts, and
4 = remission of obsessive thoughts. Three patients
were withdrawn early from the study due to poor
adherence (n = 1) or adverse events (n = 2 [headaches
and bloating in 1 each]). Eleven patients continued on
therapy long term (mean, 13.4 months). Among these
patients, 45% reported a complete remission of sexual
obsessions/compulsions while 55% reported good
obsession/compulsion control. One patient of the 11
undergoing long-term therapy experienced an adverse
event (dizziness, which dissipated over a few weeks),76
Psychostin1ulants
Adjunctive use of psychostimulants was evaluated
in open-label fashion in 26 male patients with
paraphilia (n = 14) or paraphilia-related disorders
(n = 12) who were being treated with selective sero-
tonin reuptake inhibitors (SSRIs).77 The study lasted
3 years. There were multiple reasons for adding psy-
chostimulant therapy to baseline SSRI therapy. In 17
patients, a retrospective diagnosis of attention-deficit!
hyperactivity disorder (ADHD) with persistent adult
symptoms was made. In 16 patients, residual sexual
pathology was reported despite SSRI use. In 6 pa-
tients, depressive symptoms were present or persisted
despite SSRI use. In 4 patients, SSRI effect in sexual
impulsivity disorder was lost or reduced, and adjunc-
tive therapy was used to treat SSRI-induced adverse
events. To be evaluable, patients had to take combina-
tion therapy for a minimum of 8 weeks. Selected
agents included fluoxetine in 19 patients (mean dose,
49 mg/d), sertraline in 3 (mean dose, 110 mg/d), par-
oxetine in 2 (mean dose, 35 mg/d), and fluvoxamine
in 2 (mean dose, 100 mg/d). Methylphenidate sus-
tained release was the psychostimulant used in all
patients (mean dose, 40 mg/d; range, 20-100 mg/d). A
mean (SD) of 8.8 (11.1) months of SSRI therapy sig-
nificantly reduced the paraphilia/paraphilia-related
disorders total sexual outlet score (by 65 %) and mean
time spent per day on these behaviors (by 75%) (both,

P < 0.001). A mean (SD) of 9.6 (8.2) months of ad-
junctive psychostimulant therapy was associated with
significant additional reductions in mean paraphilia/
paraphilia-related disorders total sexual outlet scores
(by 39%; P = 0.003) and mean time spent per day on
these behaviors (by 44%; P = 0.04), as well as improved
ADHD/depressive symptoms (by clinician and patient
global impressions of change in 82 % of patients). 77
Naltrexone
Twenty-one adolescent male sex offenders received
oral naltrexone in open-label fashion. 78 Inclusion cri-
teria were masturbation at least thrice daily, feeling
unable to control sexual arousal, spending >30% of
awake time in sexual fantasies, and having sexual
fantasies or behaviors that regularly intruded into and
interfered with functioning in a treatment program.
Once all 21 patients had been treated for ::::2 months,
13 had naltrexone therapy withdrawn. A positive re-
sponse to naltrexone was defined as a reduction in
:::: 1 inclusion criterion >30% that persisted for ::::4 months.
Leuprolide was started if naltrexone proved inade-
quate. 78 Fifteen of the 21 patients (71 %) had a positive
response to naltrexone at a mean dose of 160 mg/d.
Positive responses predominantly involved reductions
in time spent in sexual fantasies (from means of 5 to
1 episode/day) and masturbation (from means of 2 times/
day to 2-3 times/week). In poor or nonresponders,
increasing the naltrexone dose to >200 mg/d did not
help. Relapse occurred in the 13 patients in whom
naltrexone was withdrawn when the tapered dose
reached 50 mg/d. Five of 6 naltrexone nonresponders
(83%) benefited from leuprolide therapy (3.75-
7.5 mg 1M monthly). No reports of naltrexone-
associated abnormal results on liver function tests
were found. No statistical analyses of results were
performed. 78
Lithium
Supportive published data for lithium in the man-
agement of abnormal sexual behavior were not avail-
able. Trials to date have been poorly designed, with
small numbers of patients, a lack of clearly defined
outcome parameters, poorly defined and described
comorbidities, a lack of adequate washout periods
from previous medications (eg, estrogens), and an
absence of placebo control groups. At best, lithium
may be weakly effective, and its potential is greatest if
there is a concurrent mood disorder. 79 ,80
January 2009
D.R.P. Guay
Neuroleptics
Neuroleptics, used for their ability to block dopa-
minergic neurotransmission, are generally considered
weak agents for the management of paraphilias, based
on results of open-label trials predating the mid-
1970s; this includes the traditional phenothiazines
(eg, chlorpromazine, thioridazine or fluphenazine de-
pot) and the butyrophenones (eg, haloperidol or ben-
peridol [the latter is not available in the United
States]).81-84 In a placebo-controlled, 3-way crossover
trial lasting 18 weeks (6 weeks/treatment), chlorproma-
zine 125 mg/d and benperidol 1.25 mg/d were com-
pared in 12 pedophiles housed in a security hospital. 82
There were no statistically significant differences be-
tween the 3 treatment phases in most comparisons.
Only in the sexual interest self-ratings (which quanti-
tated the frequency of sexual thoughts on a scale of
0-5) were there significant intertreatment differences
(1. 75 for benperidol, 2.34 for placebo, and 2.65 for
chlorpromazine; the difference between benperidol
and the other 2 agents was significant at P < 0.05 and
the difference between placebo and chlorpromazine
was not). Of interest, extrapyramidal adverse events
occurred during 67% of the benperidol phases. 82
Long-acting oxyprothepine (not available in the Unit-
ed States) has been reported to significantly reduce
penile tumescence compared with baseline (P < 0.05)
during penile plethysmography (spontaneous and post-
erotic exposure).80 Lastly, haloperidol decanoate was
evaluated in an open-label study in 30 sex offend-
ers (mean age, 28 years; mean duration of therapy,
3.1 years [range, 0.67-4.2 years]). Dosing was initi-
ated at 37.5 mg 1M every 4 weeks; 24 patients re-
mained on this dose. The dose of the other 6 patients
was titrated to 75 mg 1M every 4 weeks. Adverse events
were reported in 20% (mainly xerostomia, sleepiness,
and nasal congestion) with minimal extrapyramidal
adverse events (no details were provided). By self-
report, mean sexual appetite, frequency of orgasm, and
frequency of intercourse all decreased and duration of
intercourse increased (no quantitative data were pro-
vided). Results of penile plethysmography revealed a
reduction in sexual reactivity (no statistical analyses
were performed).85
Estrogens
Estrogen therapy has a long history of use in sex
offenders. The first use of oral diethylstilbestrol (DES)
was reported in 1940, followed in that decade and
9
 Clinical Therapeutics
subsequent ones by the use of oral estrone and DES.
DES was the most commonly prescribed oral estrogen
from the late 1950s until the risk of its serious adverse
cardiovascular events (recognized in the 1960s) and
transplacental carcinogenicity (recognized in the
1970s) became known and its use was substantially
curtailed. 86 It was withdrawn from the market in
1997 by its manufacturer (Eli Lilly and Company,
Indianapolis, Indiana).
Bartholomew87 presented anecdotal open-label data
from his database of ~1000 sex offenders (aged 20-
50 years) treated with oral estrogens before 1970.
Initially, oral DES 5 mg thrice daily was used, fol-
lowed in later years by oral ethinyl estradiol 0.05 to
0.10 mg BID. Therapy was tapered over time, and
"drug holidays" were provided to ameliorate gyneco-
mastia. No comment was provided regarding efficacy,
especially in light of the potential adverse effect of
"drug holidays" on effectiveness. To the best of the
author's knowledge, no cases of thromboembolism
had occurred in any patient. 87
Hormonal implants have been used most frequent-
ly in the United Kingdom; the most popular is estra-
diol 100 mg implanted SC. 86 The physiologic target
of therapy was impotence/near impotence. A series of
33 patients selected for hormonal implant therapy
were identified in the literature. 86 Of these patients,
25 (76%) received a full course (ie, greatly decreased
libido occurred), 5 (15%) were partially treated but
withdrew from therapy (3/5 [60%] reoffended), 2
(6%) were judged unsuitable for treatment (both reof-
fended), and 1 (3 %) refused all therapies (and reof-
fended). Only 1 of 25 full-course recipients (4%) had
a repeat sexual offense within 2 years of prison release
(8 [32%] were convicted of nonsexual crimes and in-
carcerated while 16 [64%] had no contact with po-
lice). Dose requirements were highly variable: 100 mg,
n = 1; 200 mg, n = 4; 300 mg, n = 2; 400 mg, n = 5;
500 mg, n = 3; 600 mg, n = 4; 800 mg, n = 3; 1000 mg,
n = 1; 1100 mg, n = 1; and 1200 mg, n = 1. No data
were provided regarding the dosing interval. 86
Estrogen therapy in males is associated with risk.
Although breast cancer in males is extremely rare
(lifetime risk of 1 in 1000), there are case reports of
breast cancer in men receiving estrogens. 88 The major
concerns with oral estrogen therapy in men are car-
diovascular toxicity, including ischemic heart disease
(myocardial infarction, angina, and heart failure),
cerebrovascular disease (stroke and transient ischemic
10
attacks), edema, and thromboembolism (deep venous
thrombosis and pulmonary embolism). The majority
of these adverse-event data originate in studies of es-
trogen therapy of prostate cancer. Although the initial
negative data were associated with high-dose DES
therapy (5 mg/d),8 9 numerous trials using DES doses
of 1 to 3 mg/d had cardiovascular adverse-event rates
ranging from 10% to 35%.90-94 Concurrent adminis-
tration of warfarin 1 mg/d does not appear to lower
these rates. 92 ,95 Similar adverse-event potential exists
with conjugated estrogen (1.25 mg once and thrice
daily) and estradiol (monthly polyestradiol 80-
160 mg 1M plus ethinyl estradiol 0.15 mg/d).95-97
Luteinizing Hormone-Releasing Hormone Agonists
Agonists of LHRH produce complete "chemical
castration" with hypoandrogenism as the only clinical
effect. Their biological effects depend on their dura-
tion of use. Initially, the release of LH and FSH is
stimulated, leading to elevations in sex hormone blood
concentrations. As use continues, gonadotrope re-
sponsiveness to endogenous LHRH is suppressed; the
result is reduced LH and FSH secretion and thus re-
duced sex hormone production. Because of these time-
dependent effects of the LHRH agonists, concurrent
use of a pure antiandrogen (flutamide or one of its con-
geners) is recommended during the initial 1 or 2 months
of LHRH agonist use. Using an oral antiandrogen
counteracts the "flare" of the androgen-dependent
response that occurs with the initial surge in serum
androgen concentrations early during LHRH agonist
therapy. Oral antiandrogen therapy can be stopped
once this phase is over. 98
Leuprolide and triptorelin are synthetic agonists of
the native decapeptide GnRH, a hormone produced
by hypothalamic neurons and secreted directly into
the hypophysioportal circulation. They are approved
for treatment of the following: prostate cancer, central
precocious puberty, endometriosis, uterine fibroids,
breast cancer (in premenopausal women), and infertili-
ty.99 Leuprolide and triptorelin are available as long-
acting depot formulations that are injected every 30,
90, 120, or 180 days, depending on the specific prod-
uct. Leuprolide is available as 3.75- and 11.25-mg
microspheres for 1M depot injection and 7.5-, 22.5-,
30-, and 45-mg micro spheres for SC depot
injection.lOO,lOl Triptorelin is available as 3.75- and
11.25-mg microspheres for 1M depot injection. 102
Table III lists the basic pharmacokinetic properties of
Volume 31 Number 1
"-
III
:::l
l:
III
~
N
o
o
\0
in adults.*
Table III. Mean pharma cokinet ic parame ters of antiand rogens
Cyprot erone Acetate MPA
Parame ter Leupro lide Triptore lin
99,119 -123 138-14 7
Referen ces 98-101 ,104,10 6 98, 99, 102, 103, 105
Tmax = 7 days (I M depot) Tmax = 2.6-2.9 h (PO) Tmax = 8.8 days (SC depot)
Absorp tion Tmax = 3-4 h (1M depot)
PO bioavai lability = 88% = 2.4 days (1M depot)
= 21 days (I M depot)
PO bioavai lability = 0.6%-10%
= 2-7 h (PO)
Can give 1M suspens ion
via PO if liquid form needed
PB 96% PB = 86%
Distrib ution PB = 43%-49 % Vd = 0.4 L/kg =

27 L (IV) Vd = 20.6 L/kg (1M)

Vss =
= 37 L (SC)
Hepatic and renal Hepatic , with major Hepatic via CYP450 3A4
Metabo lism Hepatic to inactive
15~-hy droxy metabo lite. (major metabo lites have
di-, tri-, and pentape ptide CL = 210 mL/min (IV)
tv, = 2.8 h (IV) System ic exposu res to C17, C21 side chain
metabo lites.
parent and 15~-hydroxy modific ations and minor
CL = 7.6 L/h (IV)
metabo lite are similar. ones have C3, C6 side chain
tv, = 2.9 h (IV)
CL = 146 mL/min (1M) modific ations).
= 3.6 h (SC)
Hydrox ylation (2-, 6-,
21-posi tions), reducti on,
demeth ylation occur.
t Y2 = 12-17 h (PO)
= 50 days (SC, 1M depots)

Renal: 40% of dose Renal: 35% of dose Renal: 25%-50 % of dose

Excretion Renal: :::;5% of dose
(metab olites) (15 metabo lites)
CL R = 84 mL/min
Feces/bile: 65% Feces: 5%-10% of dose

(contin ued)
~
(0
:0
CO)
l:
~
........
..... Q
N
:::l
;:;.
~
-l
::r
I'D
P:l
-0
I'D
...;:;.
l:

1II

Table III (continued).

Parameter Leuprolide Triptorelin Cyproterone Acetate MPA

Special Renal DZ: no data Renal DZ: CL t Renal DZ: no data CL t by alcoholic cirrhosis
populations Hepatic DZ: no data (to 87-113 mL/min), Hepatic DZ: no data
CL R t (to 5-20 mL/min), Elderly: CL t 25%,
renal excretion t Vd t 55%, tv, t 2-fold
(to 5%-17% of dose), in elderly patients versus
tv, t (to 7.7 h), and Vd t young (PO dosing).
(to 0.6-0.7 L/kg).
Hepatic DZ: CL t (to 57 mL/min),
CL R t (to 36 mL/min),
renal excretion t (to 62% of dose),
tv, t (to 7.6 h), and Vd t
(to 0.5 L/kg) (Child-Pugh
A + B [mild + moderate]).
If depot formulation used,
no need to dose-adjust
for renal or hepatic DZ.

MPA ~ medroxyprogesterone acetate; PB ~ plasma protein binding; Vss ~ steady-state Vd ; CL ~ total body clearance; CYP450 3A4 ~ cytochrome P450 Isozyme
3A4; CL R ~ renal clearance; DZ ~ disease; J. ~ decreased; i ~ Increased.
*Data from males and females were pooled as there was no Significant gender effect on the kinetiCs of any drug listed. KinetiC data from patients haVing abnor-
mal sexual behaViors are virtually nonexistent.
~
i:
3I'D
.....
CJJ

Z
l:
3
C'"
I'D
....
.....

these agents. 98 ,100,102-106 Most of the clinical trial data
on the use of LHRH agonists in the treatment of ab-
normal sexual behaviors have been generated with
leuprolide followed by triptorelin (usual regimens,
3.75-7.5 mg and 3.75 mg once monthly IM/SC or 1M,
using the long-acting formulations, respectively).
Adverse events include hypogonadism with erectile
failure (2.3 %), decreased testicular volume (4%-20%),
decreased pubiclfacial hair growth (2%-23 %), and
vasomotor instability (hot flashes; 56%-100% ).100,101
Other adverse events include fatigue and malaise (6%-
18% each), weight gain (2%-13%), gynecomastia (2%-
7%), and injection-site reactions (induration [3 %], burn-
ing [16%-35%], redness [2%-13%], itching [1 %-9%],
bruising [3%-12%], and pain [3%_18%]).100,101 Most
concerning is the reduction in bone mineral density
that occurs almost universally due to androgen abla-
tion. Effective prophylactic and therapeutic strategies
for this musculoskeletal effect are being investigated;
they include calcium and vitamin D supplementation,
bisphosphonate and/or parathyroid hormone (or a con-
gener such as teriparatide) therapy, and low-dose an-
drogen supplementation (eg, testosterone enanthate
25-50 mg/month). Low-dose androgen supplementa-
tion may ameliorate erectile failure and thus improve
appropriate sexual relationships with partners. 98 ,99
Injection-site granulomas arising from LHRH ago-
nist administration were originally believed to be rare.
Two recent reports suggest that this is not the case. 107,108
One report found an incidence rate of 4.2% (all 5
[from a total of 118 patients] developing granulomas
had received leuprolide).107 In the other report,108 all
7 patients experienced granulomas within 3 to 5 days
of the first leuprolide injection after being switched
from goserelin to leuprolide. Both reports suggest that
leuprolide was associated with a disproportionate
number of cases. 107,108 Although the etiology of this
reaction is unknown, most theories invoke the vehicle
rather than the drug itself.
In a placebo-controlled, evaluator-blinded, cross-
over trial, cognitive-behavioral psychotherapy was
compared with cognitive-behavioral psychotherapy plus
leuprolide acetate (7.5 mg 1M x 1 dose to start, then
22.5 mg 1M at months 1, 4, 7, and 10) in 5 male pe-
dophilic patients (mean age, 50 years; age range, 36-
58 years).10 9 Each treatment phase lasted 1 year.
Flutamide 250 mg thrice daily was prescribed for
14 days after the first injection of each phase. During
receipt of leuprolide acetate, serum testosterone con-
January 2009
D.R.P. Guay
centrations fell to castrate levels by month 4 (mean,
18.8 ng/dL) and penile tumescence fell significantly
(P = 0.02), but sufficient response remained to detect
pedophilic interest. Patients self-reported reduced pe-
dophilic urges and masturbating to the thoughts of
children (quantitative data and results of statistical
analysis were not reported). Polygraph responses indi-
cated that the patients were not being deceptive. Dur-
ing receipt of placebo, serum testosterone concentra-
tions and physiologic arousal rose back to baseline
values, and patients became deceptive (measured by
polygraph) when questioned about pedophilic urges
and masturbation. The type of pedophilic interest
(age, gender) did not change over the study duration.
After 3 and 6 months on placebo, 2 patients and
1 patient, respectively, restarted leuprolide acetate
therapy due to their high reoffend risk. Adverse events
included injection-site pain in 4 of the 5 patients
(80%); hot flashes in 3 (60%); erectile dysfunction,
total in 2 (40%), partial in 3 (60%); gynecomastia in
1 (20%); and erythema/edema of the upper arm
around the injection site in 1 (20% ).10 9
Twelve patients (mean age, 35.5 years; age range,
20-48 years) with paraphilias or sexual disorders not
otherwise specified (NOS) were treated with open-
label leuprolide acetate 3.75 or 7.5 mg 1M once
monthly (with flutamide 250 mg thrice daily for
30 days, starting on the first day of leuprolide
therapy).l1O Diagnoses included pedophilia (n = 6);
exhibitionism (n = 5); voyeurism (n = 3); sexual disor-
der NOS (n = 2); and masturbation, sexual maso-
chism, and frotteurism (n = 1 each). Treatment lasted
0.5 to 5 years with a subsequent follow-up of 0.5 to
6 years' duration. No quantitative efficacy data or sta-
tistical analyses were provided. All patients reported
reduced sexual arousal, sexual fantasies, exhibitionism,
masturbation in public, and/or sexual interest. Mean
serum testosterone concentrations (n = 8) fell from a
baseline of 493 ng/dL to a nadir of 22 ng/dL at 0.167
to 3 years after commencing therapy. Erectile dysfunc-
tion occurred in all patients while on therapy and for
some months thereafter. In the 3 tested patients, bone
demineralization occurred (after 35-57 months of
drug therapy). Mild gynecomastia occurred in 25% of
patients. 110
Six males (mean age, 25 years; age range, 15-39 years)
with severe paraphilias were treated with open-label
triptorelin 3.75 mg 1M once monthly. 111 Cyproterone
acetate was prescribed concurrently for 10 days to
13
 Clinical Therapeutics
1 year (mean oral dose, 200 mg/d). Concurrent
psychiatric/neurologic comorbidities included mild to
moderate developmental disability (n = 3) and 1 each
of borderline personality disorder, mixed bipolar dis-
order (treated), and histrionic personality disorder. In
the 4 patients who had received cyproterone acetate
previously, 1 experienced partial success (not defined),
2 had no improvement, and 1 withdrew from therapy
due to severe gynecomastia. Five of the 6 patients (83 %)
had a cessation of all deviant behaviors and a marked
decrease (not defined) in the frequency/intensity of sexu-
al fantasies/activities. Plasma testosterone concentra-
tions fell to castrate levels, and serum LH and estradiol
concentrations became undetectable within 1 month of
initiation of therapy. Clinical response was maintained
over a follow-up period of 7 months to 3 years. One
patient stopped therapy after 1 year and relapsed within
10 weeks. One patient reported adverse events (hot
flashes and asthenia), and his bone mineral density also
decreased. No statistical analyses were performed. 111
In another open-label trial by the same authors,
6 males (17-43 years old) with severe paraphilias
were treated with triptorelin 3.75 mg 1M once month-
ly.112 Cyproterone acetate 200 mg/d was initiated
1 week before the initial triptorelin dose and contin-
ued for a minimum of 5 weeks (mean, 19.7 weeks;
range, 1.5-52 weeks) to prevent any "flare" reaction.
Five patients (83%) responded with a cessation of
deviant sexual behaviors and markedly reduced sexual
fantasies/activities for the 1- to 7-year follow-up pe-
riod. For example, mean (SD) incidents of masturba-
tion per week decreased from 40 (10) to 0.6 (0.2)
(P < 0.01) and sexual fantasies per week from 57 (13)
to 0.2 (0.1) (P < 0.01). Mean serum testosterone con-
centrations fell to castrate levels (22.9 to 1.2 nmollL;
P < 0.01), while LH and 17~-estradiol concentrations
also decreased (from 4.5 to <0.5 lUlL and 104.7 to
43 pmollL, respectively; both, P < 0.01). Two patients
abruptly stopped therapy after 1 and 5 years, respec-
tively; both experienced relapses within 8 to 10 weeks.
In another patient, testosterone therapy (oral testos-
terone undecanoate [dose not available] for 18 months
followed by testosterone heptylate 50 mg 1M every
2 weeks for 6 months [to the end of antiandrogen
therapy]) was added to "smooth out" the withdrawal.
Even with normal serum testosterone concentrations
and resumption of normal sexual activities, no relapse
occurred. One patient complained of hot flashes and
asthenia. 112
14
Cyproterone Acetate
Cyproterone acetate was developed in the mid-
1960s as a progestogen. 113 ,114 During early preclinical
toxicity trials, this agent caused feminization of male
fetuses when administered to pregnant rats, an unex-
pected result that led to more intensive investigation
of its pharmacology. Eventually, cyproterone acetate
was marketed as a potent, dose-dependent antiandro-
genic and progestational agent. Three potential mecha-
nisms underly its antiandrogenic effects. llS It com-
petes with testosterone for target-organ receptor-binding
sites (in support of this, the crystal structure of cypro-
terone acetate complexed to the T877A human andro-
gen receptor ligand-binding domain has been deter-
mined I16 ). It also blocks testosterone (and estrogen)
synthesis in the gonads. The progestational activity of
cyproterone acetate blocks the compensatory rise in
gonadotropins expected to follow a decrease in serum
testosterone concentrations. llS This latter effect is in
contrast with that of the pure antiandrogens (eg, cy-
proterone, flutamide and its congeners). When the
latter agents compete with testosterone for binding to
androgen receptors, a compensatory rise in gonado-
tropin secretion occurs; this increase, in turn, stimu-
lates testosterone production and eventually over-
comes receptor blockade. 117 The antiandrogenic effect
of cyproterone acetate is believed to outweigh the
progestational effect in terms of clinical efficacy in the
treatment of the paraphilias; however, it is the proges-
tational effect that allows safe and effective long-term
therapy. Equilibrium between these 2 influences re-
quires many months of treatment (8-15 months on
100 mg/d and 15-20 months on 200 mg/d).llS
Cyproterone acetate has been approved for the
treatment of prostate cancer, central precocious pu-
berty, androgen-induced skin disorders (eg, acne,
seborrhea, idiopathic hirsutism, alopecia), reduc-
tion of the sex drive in sexual deviants, and hot
flashes after orchidectomy.99 It is available as oral
tablets (50 and 100 mg) and a depot formulation for
1M inj ection (100 mg/mL) in many countries. It is
available in the United States only in a low-dosage
form in a combination product with ethinyl estradiol
(orphan drug).
The basic pharmacokinetic properties of cyproter-
one acetate are shown in Table 111. 99 ,11 9-123 Most of
the clinical data regarding its use in abnormal sexual
behaviors have been generated using the oral formula-
tion (usual regimen, 50-200 mg/d; maximum, 600 mg/d).
Volume 31 Number 1

The 1M formulation is usually administered as 300 to
600 mg every 1 or 2 weeks for this indication. During
use for its approved indications, malaise is a common
occurrence early in therapy; flushing, dizziness, de-
pression, venous thromboembolism (VTE), decreased
pubic/facial hair growth, psychotic reactions, and in-
creased (more common) or decreased body weight
have also been reported. No quantitative data on
these adverse events are available, even in the product
prescribing information and data sheets. Gynecomas-
tia, which occurs in ~20% of patients, can be tempo-
rary or permanent, unilateral or bilateral. Radiation-
at a single dose of 1500 cGy per breast-has been
used to prevent or treat painful/tender gynecomastia
caused by cyproterone acetate (275 and 300 mg 1M
every 12 days). After 3 and 6 years of follow-up, the
further development of gynecomastia was halted, and
pain and tenderness were reduced to minimal. 124
Serious hepatotoxicity is not a common finding
with cyproterone acetate. Although large doses of this
agent can produce hepatomas in rats, no evidence ex-
ists that the same happens in humans. 125 Flutamide
and cyproterone acetate may be cross-reactive in
terms of hepatotoxicity risk. 126
A recent study in the United Kingdom assessed the
association of cyproterone acetate and other treat-
ments of prostate cancer with the risk of VTE in pa-
tients with this disease. 127 Cyproterone acetate thera-
py was associated with a greater risk of VTE than was
flutamide/bicalutamide (~3.5-fold) and LHRH ago-
nist or orchidectomy monotherapies (3.35-fold) (both,
P < 0.05). Cyproterone acetate and estrogen mono-
therapies had similar VTE risks (1.25-fold risk with
former vs latter; P = NS). Cyproterone acetate mono-
therapy conferred a lower VTE risk compared with
combination cyproterone acetate plus orchidectomy
or LHRH agonist therapy (40% risk reduction; P <
0.05). VTE risk with the drug was not affected by age.
A history of VTE and recent surgeryltrauma increased
VTE risks of the drug by 4- and 13-fold, respectively
(both, P < 0.05).127
Cyproterone acetate's most serious potential adverse
events are suppression of the hypothalamic-pituitary-
adrenal axis and a reduction in the adrenal response to
stress. Early data were conflicting, but more recent in-
formation is reassuring concerning the adrenal safety of
this agent. In an active surveillance trial (with special
emphasis on liver cancer), 13 of 2506 patients (0.5%)
developed adrenal insufficiency or hyperplasia. 125
January 2009
D.R.P. Guay
All antiandrogens can produce a loss of bone mass,
which leads to osteopenia and osteoporosis. A survey
of bone health was conducted in 5 sex offenders
(mean age, 46.9 years; age range, 36-61 years) under-
going antiandrogen therapy.128 One (20%) had os-
teopenia (on leuprolide plus cyproterone acetate for
3 years followed by leuprolide alone at 11.25 mg every
4 weeks). Two of the 5 patients (40%) had osteoporosis
(both received cyproterone acetate [1 at 75 mg/d for
6 years and the other at 50 mg/d for 10 years]). The
other 2 patients (40%) receiving cyproterone acetate
had normal bone mineral density, probably due to
receipt of much lower drug doses (1 received 24 mg/d
for 2 years and the other 12.5 mg every other day for
1 year).128
Compared with the oral formulation, injectable
cyproterone acetate (via 1M depot injection) has ac-
quired a poor reputation for tolerability based on re-
sults of an open-label trial involving 7 sex offenders. 129
Local pain (at the injection site), joint/muscle pain,
headache, sleep disturbances, and nausea were the
prominent adverse events in these patients.
The effect of open-label oral cyproterone acetate on
sebum excretion rates was evaluated in 20 male sex
offenders (age range, 22-53 years).130 Patients received
cyproterone acetate 25 to 200 mg/d (mean, 100 mg/d)
for 2 to 75 months (mean, 37 months). The mean
sebum excretion rate in treated patients (0.37 rg/cm2/
min) was less than the mean rate in untreated normal
male volunteers of the same age (mean, 1.33 rg/cm2/
min; value ~28% of normal [P < 0.001]). It was also
less than that in normal females (mean, 0.62 rg/cm2/
min; value ~40% of normal [P < 0.001]). There was
no significant correlation of the reduction in sebum
excretory rate with duration of therapy (1' = 0.04).
Results of this study confirmed the potent antiandro-
genic activity of cyproterone acetate and an absence
of tachyphylaxis with <:;,75 months of use. 130
The effects of oral cyproterone acetate on urinary/
serum FSH and LH concentrations were reported in
18 hypersexual males. l3l After receiving cyproterone
acetate 50 mg BID for <:;,15 months, urinary FSH and
LH were not significantly affected (according to the
intent-to-treat analysis). However, if the results of
1 patient with schizophrenia, who had elevated con-
centrations of both markers at baseline, were removed
from the database, both markers were significantly
elevated by cyproterone acetate. After excluding this
1 patient from analysis, the mean urinary FSH concen-
1S
 Clinical Therapeutics
tration was increased from 5.34 to 8.19 ill/mL (P =
0.05) and the mean urinary LH concentration was
increased from 11.04 to 19.00 ill/mL (P = 0.001). Serum
FSH and LH concentrations were not affected by cypro-
terone acetate administration. Results of this study em-
phasized the dual biological effects of cyproterone ace-
tate: antiandrogenic plus progestational. Unlike treatment
with pure antiandrogens, serum gonadotropin concen-
trations do not rise, leading to an "escape phenomenon."
Unlike MPA treatment, serum gonadotropin concentra-
tions do not substantially fall, which leads to virtually
castrate serum testosterone concentrations. 131
The effects of estrogen and cyproterone acetate on
serum concentrations of sex hormone-binding globu-
lin (SHBG), LH, and testosterone were evaluated in
a placebo-controlled, randomized, crossover trial in
11 male sex offenders. 132 Each patient received 5 weeks
of oral cyproterone acetate (50 mg BID), oral ethinyl
estradiol 0.010 mg BID, and placebo; there was a
1-week washout period between phases. Cypro-
terone acetate therapy was associated with a signifi-
cant, although modest, reduction in mean serum tes-
tosterone concentration, from 848 to 221 ng/dL (P <
0.001). In contrast, ethinyl estradiol was associated
with higher mean concentrations of all 3 markers
(LH, from 14.2 to 21.1 ill/mL [P < 0.02]; testoste-
rone, from 848 to 1242 ng/dL [P < 0.02]; and SHBG,
from 5.07 to 11.2 x 10-8 mol/L [P < 0.001]). The
marked increase in SHBG serum concentrations in-
duced by low-dose estrogen administration led to a
reduction in serum free testosterone concentrations
and, in turn, to an elevation in serum LH concentra-
tions. As a result, total testosterone concentrations
rose, partially through enhanced Leydig cell synthesis
and partially from reduced metabolic clearance due to
the increase in SHBG. This returned serum free tes-
tosterone concentrations toward baseline. Results of
this study support the distinctive biological profiles of
cyproterone acetate and estrogen in males, as well as
the controlling variable in the testis-pituitary axis (ie,
free, not total, serum testosterone concentrations). 132
The short-term effects of oral cyproterone acetate
were evaluated in 5 pedophiles (age range, 23-
31 years). 13 3 Outcomes evaluated included nocturnal
penile tumescence, penile responsiveness to erotic
stimulation, and sex hormone concentrations. This
single-blind, placebo-controlled study had 3 parts: an
initial 4-week placebo phase, followed by 8 weeks of
cyproterone acetate 100 mg/d, followed by a 4-week
16
placebo phase. Although all outcome parameters were
affected in a positive manner by the drug, the labora-
tory arousal measures were influenced less by cypro-
terone acetate, and the results were more variable.
Serum testosterone, FSH, and LH concentrations de-
creased from baseline by means of 78%, 42%, and
14%, respectively, during the cyproterone acetate
phases compared with the placebo phases. In the noc-
turnal evaluation, substantial decreases occurred in
the number of full erections (fell by 83 %), the total
number of erections (fell by 37%), nocturnal penile
tumescence AUC (fell by 62%), and the number of
episodes with rigidity >40% (fell by 69%). Penile re-
sponses to audio and video arousal fell by means of
67% and 23 %, respectively, during cyproterone ace-
tate therapy. Little change was noted in the number of
partial erections (pretreatment, 3.2; during cyproter-
one acetate therapy, 4.9) and minimum/maximum
tumescence (pretreatment, 69.1/110.0; during cypro-
terone acetate therapy, 64.8/103.5). By 4 weeks after
discontinuation of cyproterone acetate therapy, all
measures had returned to baseline. There was no men-
tion of adverse events, and no statistical analyses of
results were performed. 133
In a placebo-controlled, double-blind, randomized,
crossover trial conducted in 9 paraphilic males (age
range, 30-68 years), the effects of cyproterone acetate
50 mg BID on penile tumescence, responsiveness to
erotic stimulation, and serum testosterone concentra-
tions were evaluated. 134 The study consisted of five
4-week periods: an initial 4-week, no-treatment peri-
od followed by a placebo/cyproterone acetate period,
then a no-treatment period, then the other placebo/
cyproterone acetate period, and finally a no-treatment
period. The diagnoses in the study population includ-
ed homosexuality (n = 5), hypersexuality and exhibi-
tionism (n = 4 each), voyeurism (n = 2), and fetishism
and incestuous behavior (n = 1 each). Significant re-
ductions occurred in serum testosterone concentra-
tions during cyproterone acetate therapy compared
with no treatment and placebo administration (~30%).
The frequency of spontaneous daytime erections was
significantly reduced during the cyproterone acetate
periods compared with all other periods (P < 0.05).
Spontaneous sexual outlet scores, sexual interest, and
sexual arousal/pleasure during masturbation were
similarly significantly reduced by the active therapy
(all, P < 0.05). Orgasm development during masturba-
tion was suppressed on 21 of 31 occasions (68 %)
Volume 31 Number 1

during cyproterone acetate therapy. The effects of the
drug were fully reversible within 30 days of drug discon-
tinuation. There was no mention of adverse events. 134
Cyproterone acetate was evaluated for the treatment
of sexual "misbehavior" in 9 adult outpatients (5 were
developmentally disabled, 3 were of normal cognition,
and 1 had XXYY chromosomes) and 11 inpatients (all
were developmentally disabled).135 The drug was dosed
orally at 100 mg/d. The chief behaviors included public
masturbation and sexual assaults on females. Of the
9 outpatients, 7 "improved markedly" while 2 "im-
proved but to a lesser degree." Of the 11 inpatients,
6 had "improved markedly," 3 had no response, 1 was
equivocal, and no data were available for 1. One pa-
tient reported 1 adverse event (headache).135
Three hundred paraphilic males were treated for a
minimum of 2 months to a maximum of 8 years with
open-label cyproterone acetate (oral 50-200 mg/d, 1M
300-600 mg every 1 or 2 weeks). 118 The article pro-
vided few quantitative efficacy data and no results of
statistical analyses. Eighty percent of oral cyproterone
acetate 100-mg/d recipients reported the desired de-
gree of sexual inhibition (not defined); 20% required
an increased oral dose of 200 mg/d. The initial mani-
festations of response occurred at the end of the first
week of therapy (ie, decreased libido, erections). Maxi-
mum effect occurred at the end of week 3 of therapy.
Spermatogenesis returned to normal by the end of
month 5 after withdrawal of the oral formulation.
During weeks 2 to 6, the overall prevalence of adverse
events was ~30% (primarily fatigue, hypersomnia,
depressed mood, and decreased activity). Other ad-
verse events included increased weight, reduced body
hair (10%), increased and softened scalp/hair (10%),
decreased skin oiliness (due to reduced sebum ex-
cretion [10%]), and gynecomastia (20%, starting at
months 6-8 ).118
Nineteen relapsed paraphilic males (mean age,
30.4 years; age range, 19-45 years) participated in a
placebo-controlled, double-blind, randomized, cross-
over trial of oral cyproterone acetate 50 to 200 mg/d. 136
After a 1-month baseline phase, there were four
3-month treatment periods during which placebo and
cyproterone acetate treatments were alternated. Mean
serum testosterone and FSH concentrations were sig-
nificantly reduced only during cyproterone acetate
therapy (testosterone-baseline, 23.52 nmollL; on
cyproterone acetate, 12.37 nmollL [P < 0.001]; FSH-
baseline, 10.78 lUlL; on cyproterone acetate, 7.83 IU/L
January 2009
D.R.P. Guay
[P < 0.005]). Neither treatment significantly affected
serum LH concentrations. Serum prolactin concen-
trations were significantly greater during cyprote-
rone acetate (mean, 22.54 flg/L) versus placebo (mean,
10.28 flg/L; P < 0.05) administration. Only cyproter-
one acetate significantly reduced self-reported sexual
arousal (by visual erotic stimuli) (P < 0.01), the sexual
activity score component of the Brief Psychiatric Rat-
ing Scale (BPRS) (P < 0.05), and frequency of mastur-
bation (P < 0.005). Cyproterone acetate and placebo
significantly reduced BPRS total scores (P < 0.001 and
P < 0.005, respectively; cyproterone acetate more so
than placebo, P < 0.05) and the frequencies of sexual
fantasies or dreams (both, P < 0.05; cyproterone ace-
tate vs placebo, P = NS). Neither treatment had a sig-
nificant effect on physiologic response (measured by
phallometry) to visual or fantasized erotic stimuli;
self-reported sexual arousal (by fantasized erotic
stimuli); and Buss-Durkee Hostility Inventory and
sexual interest scores. In addition, the differences be-
tween agents were not significant for the following
potential adverse events: affective equilibrium, general
physical condition, ability to concentrate, and social
adjustment; somatic conditions (12 parameters in-
cluding sleep, appetite, amount of hair on body and
head, hot flashes, sweating, headaches, nausea or
vomiting, and gynecomastia); mood (6 components);
sexual tension, libido, and potency; and all sexual
activities except masturbation. 136
Twenty male pedophiles participated in an evalua-
tion of the effect of open-label cyproterone acetate on
sexual arousal patterns. 137 Assessments were made
pretherapy and after 2 to 3 months on therapy. The
cyproterone acetate dose ranged from 50 to 200 mg/d
(mean, 85.3 mg/d). No adverse-event data were pro-
vided. Three patients were dropped from the trial:
1 due to nonadherence and 2 who were nonresponders
to arousal stimuli at baseline. Of the remaining
17 patients, 7 were classified as having high baseline
serum testosterone concentrations (>28 nmollL; mean
[SD], 34.6 [4.58] nmollL) and 10 as having low base-
line serum testosterone concentrations (<::;28 nmollL;
mean [SD], 21.2 [3.57] nmollL). In the high and low
testosterone groups, mean (SD) serum testosterone
concentrations on therapy fell to 11.3 (6.35) and 9.23
(2.96) nmollL, respectively. These 2 groups responded
differently as measured by phallometry (ie, in terms of
percentages having full erections) to the 4 arousal vi-
suals by analysis of variance. Post hoc analysis found
17
 Clinical Therapeutics
that the significant differences were within the pedo-
philic and coercive visuals (P < O.OS). In the high tes-
tosterone group, arousal fell in 3 of 4 visuals and, in
the low testosterone group, in all 4 visuals. Pooled
analysis revealed the following percentages having full
erections (pretherapy to on-therapy): pedophilic visu-
al, 47.4% to 28.7%; assault visual, 29.1 % to lS.S%;
coercive visual, 37.9% to 23.0%; and adult visual,
39.8% to 29.4%. The reductions in both testosterone
groups for the pedophilic and coercive visuals were
statistically significant (both, P < O.OS); they were not
statistically significant for the other 2 visuals. In terms
of response, patients in the high testosterone group
exhibited a greater reduction from baseline in serum
testosterone concentrations than did those in the low
testosterone group (P < 0.001), but the actual on-
therapy serum testosterone concentrations did not
significantly differ between groups. Results of this
study suggest that cyproterone acetate suppressed de-
viant arousal but did not affect responses to appropri-
ate sexual stimuli (eg, adult visual).137
Medroxyprogesterone Acetate
Compared with cyproterone acetate, MPA is less
potent as an antiandrogen and progestogen and rela-
tively more progestogenic than antiandrogenic (as
opposed to the "balanced" effects with cyproterone
acetate). Unlike cyproterone acetate, MPA can inhibit
gonadotropin secretion and hence testosterone pro-
duction to the extent of complete ablation of the latter
within 1 to 2 weeks after starting therapy. 99
MPA has been approved for the treatment of men-
orrhagia, secondary amenorrhea, and mild to moder-
ate endometriosis; female contraception; catamenial
epilepsy therapy; and the treatment of prostate, breast,
and advanced endometrialJrenal cancers. 138-140
MPA is available as oral tablets (2.S, S, and 10 mg)
and lS0- and 400-mg/mL suspensions for 1M injection.
MPA's basic pharmacokinetic properties are listed in
Table III. 138-147 It should be noted that MPA has poten-
tially clinically relevant inhibitory effects on cyto-
chrome P4S0 isozyme 2C9. 148 Although the oral route
of MPA can be used (usual regimen, 100-S00 mg/d),
erratic oral bioavailability (within and between prod-
ucts and within and between subjects) has made the 1M
formulation preferable. 14 1,145 The majority of clinical
trial data regarding MPA's use in abnormal sexual be-
haviors has been generated using the 1M formulation
(usual regimen, 100-1000 mg once weekly).
18
During use for MPA's approved indications, ad-
verse events included reduced bone mineral density
(virtually 100%), excessive weight gain (18%), head-
ache (9%), malaise S%), dyspepsia S%), VTE
(<1 %), muscle cramps (<1 %), gallstones (<1 %), and
diabetes mellitus (<1 %). More recent adverse-event
data from women receiving the 1M form of the drug
for contraceptive purposes have included details of
the magnitude of the weight gain (means of ~3.S kg
at 2 years, 6 kg at 8 years [dose: 104 mg SC every
90 days for 1 year]), 149 1 case of retinal vein occlusion
(dose: inj ection for contraception not specifically
stated but given 10 weeks before event),150 and its
balanced effects on D-dimer levels and activated par-
tial thromboplastin time values (which have opposing
effects on VTE risk [dose: lS0 mg 1M or 104 mg SC,
both every 90 days for 1 year]).151 This latter result
suggests that MPA's VTE-inducing potential may be
lower than once thought. It is unknown whether these
findings apply to males receiving the drug for abnor-
mal sexual behaviors.
When deciding whether to initiate MPA therapy for
treatment of the paraphilias, consideration of its tox-
icity potential may have greater significance in the
clinician's mind than issues surrounding the agent's clini-
cal efficacy. In an attempt to prevent or ameliorate
adverse events, the dose may be lowered, at the cost of
reduced therapeutic efficacy.
The effects of open-label 1M MPA administration
(100-400 mg/week for::::6 months) on pituitary, adre-
nal, and gonadal functions were evaluated in 9 males
with antisocial (n = 3) or sexually offensive (n = 6)
behaviors. 152 The latter 6 patients had been diagnosed
with the following: pedophilia (n = 3), exhibitionism
and transvestism (n = 2 each), and voyeurism and
homosexual incest (n = 1 each) (1 patient each had
2 and 3 diagnoses concurrently). Five patients were
studied before and during therapy; 4 were studied
only during therapy. Mean serum concentrations of
LH and total testosterone were significantly reduced
by MPA therapy (LH, from 62 to 49 ng/mL [P = 0.02S];
testosterone, from 788 to 138 ng/dL [P = 0.001]). In
addition, MPA produced a significant reduction in mean
24-hour integrated concentrations of cortisol (from
8.4 to 4.2 flg/dL; P < 0.001). However, MPA therapy
did not affect serum FSH concentrations, 24-hour
rhythm and integrated concentrations of growth hor-
mone, and rise in plasma cortisol after insulin-induced
hypoglycemia. Although the circadian rhythm in plas-
Volume 31 Number 1

rna cortisol was suppressed, it was not eliminated.
Five of 9 patients (56%) gained weight during MPA
treatment (mean, 79-86 kg [P = NS]; range, 2-21 kg).
MPA has a suppressive effect on the hypothalamic-
pituitary-adrenal axis that does not appear to be clini-
cally relevant as it can still respond to stress. 152
Other long-term studies on the physiologic effects
of open-label 1M MPA in sex offenders are available.
Twenty-three male patients were treated with ::::300 mg
per week for a mean of 18.1 months (median,
13 months).153 A significant mean weight gain of
11.4 pounds was noted (P < 0.001). Two thirds of
patients gained >5 pounds. Systolic blood pressure
correlated with weight gain (1' = 0.18; P < 0.05) and
correlated with MPA serum concentrations (1' = 0.43;
P < 0.001). Diastolic blood pressure correlated with
weight gain (1' = 0.34; P < 0.001). Serum LH and tes-
tosterone concentrations fell as serum MPA concen-
trations rose (both, P < 0.001 for trend). Testicular
size fell from a mean of 22 to 15 mL in volume (P <
0.001) after 6 months of therapy. Serum FSH changes
were statistically nonsignificant across all 23 patients.
Sperm motility, count, and percentage with normal
morphology decreased significantly with MPA (all,
P < 0.001). Three patients developed cholesterol gall-
stones, 2 requiring cholecystectomy. Glucose and insu-
lin results from the 5-hour glucose tolerance test were
unaffected. One of the 23 patients (4%) developed
overt diabetes mellitus. A few patients reported in-
creased drowsiness, and one had an exacerbation of
migraine headaches (necessitating drug discontinua-
tion). Results of this study indicate the need for moni-
toring of weight, blood pressure, glucose tolerance,
and gallbladder function with the use of MPA.153
The effect of MPA therapy on total thyroxine and
thyroxine-binding globulin concentrations in paraphilic
subj ects was assessed in 14 males (age range, 20-
70 years). 154 The drug was dosed at 500 mg once weekly
via the 1M route. No significant effects were noted
on either laboratory test, whether assessed early (7-
29 days; n = 12) or later (381-415 days; n = 5).
The short-term effects of MPA on lipids, lipopro-
teins, and apolipoproteins were evaluated in 11 para-
philic males (mean [SD] age, 36 [13] years).155 Pa-
tients received MPA 500 mg 1M every week for 2 to
4 weeks. The mean (SD) total MPA dose given over
17 (6) days was 1273 (467) mg. Nonsignificant effects
were noted with the 3 subfractions of high-density lipo-
protein cholesterol. Significant reductions occurred
January 2009
D.R.P. Guay
with total cholesterol (TC) (mean, 12%; P < 0.001),
triglycerides (TG) (mean, 24%; P < 0.005), low-density
lipoprotein (LDL) cholesterol (mean, 13%; P <
0.01), LDL-apolipoprotein B (mean, 15%; P < 0.05),
and apolipoprotein A-I (mean, 7%; P < 0.05). When
the data from 1 patient having significant weight
loss during the study (13 pounds over 20 days) and
1 patient with preexisting hypertriglyceridemia (312 mgl
dL) were excluded from analysis, the mean reductions
in TC, TG, LDL-cholesterol, and LDL-apolipoprotein
B were 10% (P < 0.001), 26% (P < 0.05),9% (P <
0.05), and 14% (P < 0.05), respectively. Also, the re-
duction in apolipoprotein A-I was smaller and no
longer statistically significant. Although this short-
term trial provided reassuring results with respect to
the neutral lipid, lipoprotein, and apolipoprotein ef-
fects of 1M MPA, further trials of longer duration that
also examine cardiovascular outcomes are needed. 155
Forty-eight males with long-standing deviant sexu-
al behavior received open-label MPA therapy for
0:;12 months. 156 Doses were targeted to maintain se-
rum testosterone concentrations <250 ngidL. Study
patients included 39 sex offenders who had been in-
carcerated,4 sexual deviants, 4 compulsive masturba-
tors, and 1 subject confused about his preferred sexual
orientation. The dosing schemata for MPA were as
follows: The initial regimen was 200 mg 1M 2 or
3 times per week for weeks 1 and 2, followed by
200 mg 1M 1 or 2 times per week for weeks 3 through
6 (depending on the clinical response), followed by
100 mg 1M once weekly or 200 mg 1M every 2 weeks
for the next 12 weeks, and 100 mg 1M once weekly to
monthly over the last 7 to 8 months. Serum testoste-
rone concentrations were monitored every 2 weeks
for the first month, then monthly thereafter. Patients
were treated in the inpatient setting for the first
month. One patient left the study due to the develop-
ment of phlebitis. Five patients left against medical
advice (4 had had significant improvement that persisted
after discontinuation of therapy). No quantitative effi-
cacy or statistical analysis data were provided. 156
Forty patients (83%) responded positively to thera-
py, all within 3 weeks (33 in the initial 10 days, 7 from
11 days to 3 weeks).156 Reductions occurred in the
frequencies of sexual fantasies and arousal, the desire
to engage in deviant behaviors, and the frequency and
quality of erections/ejaculation; increased control over
sexual urges also was reported. Psychosocial func-
tional improvement was apparent after 2 to 3 months.
19
 Clinical Therapeutics
The frequency of masturbation decreased after serum
testosterone concentrations had fallen by ~50%. Im-
potence occurred as serum testosterone concentra-
tions approached 25% of baseline concentrations.
Improvement in sexual behaviors was maintained af-
ter treatment ended at 1 year (follow-up ranged up to
4 years). There were no permanent physiologic chang-
es. Seven patients with antisocial personality disorders
had no improvement. 156
Adverse events were reported in all patients. 156
Fatigue was the most common, occurring for 2 or 3 days
after each injection. Twenty-eight of 48 patients (58%)
experienced weight gain (maximum gain, 9.1 kg),
while 14 (29%) had hot flashes, 10 (21 %) had head-
aches, and 7 (15%) had insomnia.
An investigation into the effects of MPA and as-
sertiveness training, individually and together, for the
treatment of genital exhibitionism was performed. 24
The only age data (mean [SD]) provided were for
those who dropped out (24.20 [6.08] years) versus
those who did not drop out (33.64 [10.39] years). No
clear details were provided regarding treatment as-
signment or blinding. MPA was dosed at 100 to 150 mg
orally once daily. The major outcomes assessed were
dropouts and recidivism over 15 weeks. Five patients
were assigned to MPA alone (all dropped out early),
17 to assertiveness training alone, and 15 to a combi-
nation of the 2. The only significant difference be-
tween treatments was the increased dropout rate in
the combination therapy group compared with the
assertiveness training alone group (67% vs 29%, re-
spectively; P < 0.05). The reason(s) for dropping out
were not mentioned, except for a comment regarding
psychological "demasculation" by MPA. Only 2 pa-
tients had adverse events (weight gain and nausea in
1 each).24
Two additional laboratory studies of MPA were
performed due to the "unfair" assessment of MPA in
the previous study.24 The authors felt that the dropout
rates in both groups (MPA, 29%; MPA plus assertive-
ness training, 67%; overall, 47%) were too high to
provide a fair assessment of MPA's efficacy. In one
study, the effects of 7 days of placebo versus oral MPA
(100 mg/d) were evaluated using 5 levels of erotic vi-
sual stimuli. This study was conducted in a double-
blind manner, again using patients being treated for
genital exhibitionism. Oral MPA significantly reduced
mean plasma testosterone concentrations from base-
line (594 ng/dL to mean on-therapy, 247 ng/dL; P <
20
0.01; mean, 58% decrease) while placebo did not.
There were no significant intergroup differences in
penile volume changes or latency of response. Pa-
tients, however, reported being less aroused while tak-
ing oral MPA (P < 0.01). In the other study, this time
using normal heterosexual males in a similar study
design compared with the immediately preceding
study, placebo and oral MPA (100-150 mg/d) were
compared in a double-blind fashion over 3 weeks.
Oral MPA reduced serum testosterone concentrations
significantly more than placebo (mean reductions
from baseline of 68% and 22%, respectively; P <
0.01). There were no significant intergroup differences
in penile measures and self-reported verbal responses
to erotic stimuli. These findings suggest that oral MPA
has little effect on sexual misbehaviors. 24
In an open-label trial with 8 sex offenders, MPA
was administered as a 300- to 400-mg 1M injection
every 10 days.157 Diagnoses included transvestism
(n = 5), pedophilia (n = 2), homosexual incest (n = 1),
exhibitionism (n = 1), and sexual masochism (n = 1).
No quantitative efficacy or statistical analysis data
were provided. Five of the 8 patients (63 %) responded
to therapy (partially or fully [terms not defined]). Two
patients discontinued therapy early (neither due to
adverse events). In 1 patient, there was a poor re-
sponse (minimal effect after 8 weeks on therapy).157
An open-label, retrospective study was performed
to determine whether serum testosterone concentra-
tion monitoring is worthwhile when using MPA in the
treatment of aberrant sexual behavior. 15s Thirteen
paraphilic males (mean [SD] age, 43 [17] years) were
followed up every 3 months. Ten were classified as
pedophiles (4 were incestuous as well) and 3 were
classified as primarily being exhibitionists. Initial
MPA 1M doses were 300, 400, 600, 800, and 900 mg
per week in 5, 1,5, 1, and 1 patient, respectively. Elev-
en of the 13 patients (85%) received ::::6 months of
therapy. The mean (SD) duration of therapy was 96
(67) weeks (range, 4-218 weeks), and mean (SD) drug
dose was 348 (127) mg/week (range, 158-600 mg/
week). After pretreatment, serum testosterone concen-
trations were determined and patients were divided
into low testosterone (255-268 ng/dL; n = 4) and
normal testosterone (345-500 ng/dL; n = 9) groups.
This difference between groups was statistically sig-
nificant (P = 0.006). Eleven of 13 patients (85%) had
testosterone suppression to <100 ng/dL within 6.7
(4.6) (mean [SD]) weeks and to <50 ng/dL within 10.6
Volume 31 Number 1

(6.0) weeks. One patient in the normal testosterone
group had concentrations suppressed to 108 ng/dL
while another did not have a serum testosterone con-
centration determination done before MPA was dis-
continued due to adverse events. Patients with low tes-
tosterone concentrations received therapy for a longer
period (151 [64] weeks) than did those with normal
testosterone concentrations (72 [56] weeks) (P = 0.03).
In the low testosterone group, there was an almost
significant trend between serum testosterone concen-
trations and duration of therapy (1' = -0.54; P = 0.055).
Drug therapy was discontinued due to adverse events
in 1 patient (adverse events were not identified). 158
Older patients took longer to return to baseline
serum testosterone concentrations after drug discon-
tinuation (1' = 0.77; P = 0.002).158 Four parameters in
the multivariate regression analysis (age, pretreatment
serum testosterone concentration, mean weekly MPA
dose, and duration of therapy) correlated with the
time to return to baseline serum testosterone concen-
tration (1':! = 0.71; P < 0.03). All 4 parameters thus
accounted for 71 % of the variance in this outcome.
Age was the most important parameter in this respect,
explaining 46% of the variance.
The low and normal serum testosterone concentra-
tion groups did not differ with regard to the mean
drug dose level (means of 369 and 339 mg/week, re-
spectively).158 There were no significant intergroup
differences in self-reported drug response between the
2 groups: 89% and 67% of the patients with normal
and low serum testosterone levels, respectively, had
deviant sexual fantasies and/or behaviors pretreat-
ment. Of the patients with normal and low testoste-
rone concentrations, 67% and 50%, respectively, had
nondeviant sexual fantasies and/or behaviors during
treatment (only 2 patients, both in the normal testos-
terone concentration group, had sexually deviant
fantasies/behaviors during treatment), and 78 % and
75%, respectively, exhibited nondeviant sexual fanta-
sies and/or behaviors after drug discontinuation. No
results of statistical analysis of efficacy data were
presented. 158
Comparative Trials
Twelve patients exhibiting deviant sexual behaviors
leading to arrest and security hospitalization partici-
pated in an investigator-blinded, random-order, 3-way
crossover trial comparing no treatment, oral ethinyl
estradiol 0.1 mg/d, and oral cyproterone acetate
January 2009
D.R.P. Guay
500 mg BID. 159 Treatment periods lasted for 5 weeks
and were separated by 1-week washout periods.
Results are presented here as no treatment/ethinyl
estradiol/cyproterone acetate. Both drugs significantly
reduced sexual interest scores (frequencies of thoughts,
2.9/1.6/1. 7, respectively; P < 0.001) and sexual activi-
ty scores (count of orgasms, 3.0/1.3/0.8, respectively;
P < 0.01) from baseline. Sexual attitude scores were
not significantly affected by either drug. Only cypro-
terone acetate was significantly associated with de-
creased responses to erotic stimuli (self-ratings [0-5]:
fantasy, 1.17 vs 2.33; slide, 1.00 vs 2.17; film, 2.25 vs
3.58 [P < 0.01], and penile plethysmography [millime-
ter increase in penile diameter]: fantasy, 1.91 vs 3.99;
slide, 2.04 vs 3.96; film, 4.97 vs 5.54 [P < 0.025])
compared with no treatment. The statistical compari-
sons of ethinyl estradiol and cyproterone acetate re-
vealed no significant differences between the treat-
ments. No statistical evidence of a carryover effect
was noted. Only 1 adverse event was reported: depres-
sion commencing on day 3 after the initiation of cy-
proterone acetate. The affected patient requested
withdrawal from the trial. 159
Results of an open-label trial 160 of lithium therapy
in 40 patients exhibiting deviant sexual behaviors
(39 males; mean age, 39 years; age range, 19-53 years;
1 female, 29 years old) were compared with those of
2 previous (unpublished) trials using DES. Among
the 39 males, exhibitionism, pedophilia/ephebophilia,
fetishism, and sexual aggression were noted in 20, 14,
2, and 3 patients, respectively. Hypersexuality leading
to prostitution was diagnosed in the lone female. In
21 of these patients in the previous trials, DES had to
be stopped due to "massive" adverse events; in 19, DES
had to be stopped or was not started due to potential
damage to spermiogenesis or the need to maintain
potency to father children. Lithium was prescribed for
2 to 33 months (mean, 8 months) in 24 patients at a
daily dose of 900 mg and in 16 patients at a daily dose
of 1200 mg. The mean maximum serum lithium con-
centration was 0.76 mEq/L. In these 40 patients, there
were 3 relapses (1 in an ephebophiliac and 2 in exhi-
bitionists, both of whom stopped the drug against
medical advice) (relapse rate of 8%). Adverse events
(gastrointestinal, tremor, and fatigue) occurred in
17 patients (43 %) but necessitated drug withdrawal
in only 8 patients (20%). In the 2 previous DES trials,
relapse rates were 12% and 15% (over mean follow-
up of 17 months and 2 years, respectively). Of the
21
 Clinical Therapeutics
16 patients who relapsed, 10 (63 %) did so after dis-
continuing therapy against medical advice, 3 (19 %)
did so after discontinuing therapy due to adverse events,
and 3 (19%) relapsed for unknown reasons. Adverse-
event rates in the 2 DES trials were 43 % and 84 %,
respectively.
Lithium, DES, and fluphenazine decanoate were
compared in the management of sexual deviancy in
the context of 3 separate open-label trials. 161 One trial
evaluated lithium therapy in 11 patients treated with
900 mg/d for a mean of 5 months. Deviant tendencies
were eliminated in 6 patients (55%); in the other
5 (45%), these tendencies persisted or the patient re-
lapsed after having had an initial complete response.
Adverse events occurred in 2 of the 11 patients (18 %;
both events were nausea). Another trial evaluated DES
therapy in 12 patients treated with 2.5 mg/d for a
mean of 9 months. Deviant tendencies were eliminat-
ed in 5 of 12 (42%) and reduced in 1 (8%); in 6 pa-
tients (50%), these tendencies persisted or the patient
relapsed after experiencing an initial complete re-
sponse. Adverse events occurred in 11 of 12 patients
(92%) (gynecomastia in 5, depression and fatigue in
4 each, nausea in 2, acne in 1, and "disturbed poten-
cy" in 3 of 6 [50%] living in a sexual partnership
[patients could experience ::::1 adverse event]). In the
last trial, 10 patients were treated with fluphenazine
decanoate 12.5 to 25 mg 1M every 2 to 3 weeks for a
mean of 3 to 4 months. Deviant tendencies were elimi-
nated in 5 of the 10 (50%) and reduced in 4 (40%),
while they remained unchanged in 1 (10%). Adverse
events, mainly extrapyramidal symptoms and ortho-
stasis, occurred in 8 of the 10 patients (80% ).161
MPA was compared with cyproterone acetate in a
double-blind, placebo-controlled, 28-week, crossover
trial of pedophilia. 162 Ten patients were enrolled but
3 dropped out during the 4-week, placebo run-in
phase, stating that they "no longer had a problem."
Each patient received seven 4-week phases of therapy
(100 and 200 mg 1M doses of both drugs with inter-
vening placebo washout phases). Seven patients (mean
age, 30 years; age range, 23-37 years) completed the
trial. In addition to pedophilia, patients also experi-
enced sexual sadism (n = 4); transvestism and fetish-
ism (n = 2 each); and exhibitionism, zoophilia, sexual
pyromania, and pediatric/adult rape (n = 1 each). Pa-
tient self-reports used 1- to 5-point scales while penile
responses to audio/video stimuli were measured using
phallometry and measurement of circumferential re-
22
sponse. Both drugs reportedly reduced sexual thoughts/
fantasies, the frequency and pleasure of masturbation,
erections on awakening, level of sexual functioning (in
a dose-dependent manner), penile responses to erotic
stimuli (in a dose-dependent manner), and serum tes-
tosterone concentrations (in a dose-dependent man-
ner). Mean testosterone serum concentrations fell
from 23.2 nmollL with placebo to 11.4 and 7.0 nmollL
with cyproterone acetate 100 and 200 mg/d, respec-
tively. Corresponding testosterone values for MPA
100 and 200 mg/d were 17.2, 11.6, and 9.3 nmollL.
Neither drug reportedly affected preferred sexual ob-
jects or activities in a consistent manner. No specific
adverse events occurred except reduced ejaculate vol-
umes. Five patients preferred MPA while 3 preferred
cyproterone acetate. Unfortunately, no statistical anal-
yses were performed because 25 patients could not be
recruited to the trial over 2 years, and the authors
believed that 10 patients were insufficient to warrant
such analyses. 162
Oral cyproterone acetate and 1M leuprolide acetate
were compared in a complex crossover trial in a
single chronic pedophile. 163 The study sequence was
as follows: placebo for 16 weeks; cyproterone acetate
100 mg/d for 16 weeks; no treatment for 16 weeks;
cyproterone acetate 100 mg/d for 16 weeks; placebo
for 16 weeks; no treatment for 16 weeks; cyproterone
acetate 100 mg/d for 36 weeks; cyproterone acetate
200 mg/d for 42 weeks; no treatment for 10 weeks;
leuprolide acetate 7.5 mg monthly for 24 weeks; and
no treatment for 10 weeks. Serum testosterone con-
centrations fell from baseline values of 17-19 nmollL
to 5 nmollL (on cyproterone acetate 100 mg/d), 4 nmollL
(on cyproterone acetate 200 mg/d), and 1 nmollL (on
leuprolide acetate). Based on phallometry results, cy-
proterone acetate reduced the percentage of full erec-
tions from the 2 baseline values of 30% and 35% to
10% (both doses). Treatment with leuprolide acetate
reduced this percentage to zero. Self-reported sexual
arousal (derived from 5 variables) fell from a baseline
value of 2.75 to 1.7 (cyproterone acetate 100 mg/d),
1.5 (cyproterone acetate 200 mg/d), and 1.0 (leupro-
lide acetate). Self-reported erection scores fell from
a baseline value of 3.0 to 1.75 (cyproterone acetate
100 mg/d), 1.4 (cyproterone acetate 200 mg/d), and
1.1 (leuprolide acetate).163
A double-blind, crossover trial compared clomipra-
mine and desipramine in the treatment of paraphilias
and/or compulsive masturbation. 164 The 15 study pa-
Volume 31 Number 1

tients ranged in age from 29 to 52 years (mean [SD],
31 [9] years) and diagnoses included phone sex (n =
7); exhibitionism, transvestism, and compulsive mas-
turbation (n = 4 each); frotteurism (n = 3); voyeurism
and pedophilia (n = 2 each); and zoophilia, klis-
maphilia, and sexual sadism (n = 1 each). Both drugs
were initiated at 25 to 50 mg/d, followed by titration,
based on response, to a maximum of 250 mg/d. Treat-
ment phases lasted for 5 weeks. Four of the 15 pa-
tients responded positively (defined as a ::::50% im-
provement in any outcome parameter) during the
2-week, single-blind, placebo run-in phase and were
withdrawn. Of the 11 patients proceeding to the
double-blind phase, 3 failed to complete the study
(none had adverse events as the cause of withdrawal).
In the 8 "completers," the mean maximum daily dose
of clomipramine was 163 mg (range, 75-250 mg) and
for desipramine it was 213 mg (range, 100-250 mg).
Both drugs significantly reduced the severity of behav-
iors compared with baseline (mean score, 6.6) and
placebo (mean score, 6.0) (clomipramine [mean score,
2.6], P :s; 0.005; desipramine [mean score, 1.9], P :s;
0.002; intertreatment comparison, P = NS). Delayed
ejaculation, erectile dysfunction, and pain on ejacula-
tion were noted in 5, 5, and 1 clomipramine recipients
and 1, 3, and 1 desipramine recipients, respectively.
After 6 to 9 months of follow-up, 3 of 8 patients
(38%) were still receiving therapy. Two of these 3 pa-
tients (67%) had stopped or decreased the dose of the
assigned drug and, after experiencing a paraphilic re-
lapse, restarted therapy. 164
A retrospective analysis was conducted of the re-
sults of therapy in paraphilics treated with 3 SSRIs
used in a sexual behavior clinic between 1991 and
1995. 165 Results were compared over the initial 12 weeks
of therapy with fluoxetine, fluvoxamine, and sertra-
line. Records were not eligible for review if the patient
had received any previous SSRI (n = 16), did not re-
turn for follow-up (n = 9), was taking cyproterone
acetate concomitantly (n = 6), or exhibited psychotic
symptoms (n = 5). Ninety-five records were eligible
for review. However, 17 patients were no longer eli-
gible by week 4: 4 had left against medical advice,
3 had started cyproterone acetate therapy, 3 had with-
drawn due to adverse events, 3 felt better and subse-
quently stopped therapy, 2 were lost to follow-up due
to incarceration, 1 had a change in SSRI, and 1 had
miscellaneous reasons. By the end of 12 weeks, only
58 records remained eligible (17 patients received flu-
January 2009
D.R.P. Guay
oxetine [29%],25 patients received sertraline [43%],
and 16 patients received fluvoxamine [28%]). More
than 75% of patients also received concurrent psy-
chosocial therapy (36% received 1 type, 43 % received
::::2 types). Mean (range) age was 36 (17-72) years,
and the mean number of paraphilias per patient was
1.6. The major paraphilias represented included pedo-
philia (74%), atypical paraphilias (24%), exhibitionism
(14%), and sexual sadism (12%). Associated findings
included frotteurism, fetishism, voyeurism, transvestic
fetishism, and sexual masochism. Major concurrent
psychopathologic conditions included borderline per-
sonality disorder (31 %), depression (28 %), alcohol
dependence (17%), and adjustment disorder (16%).
No quantitative data were presented in the results. 165
Dosing information was not provided in the arti-
cle. 165 No significant intertreatment differences were
found using the Global Improvement Scale. When data
were pooled across all 3 SSRIs, the improvements from
baseline to week 4 (P < 0.001), week 4 to week 8
(P < 0.001), and week 8 to week 12 (P < 0.05) were
all significant. Paraphilic fantasies were reported in
76% of patients at baseline. By weeks 4, 8, and 12, the
proportions of the population having fantasies had
dropped to 58%,58%, and 31 %, respectively. When
pooled across all 3 agents, the reductions in intensity
were significant from baseline to week 4 (P < 0.001)
and week 4 to week 8 (P < 0.05) but not from week 8
to week 12. Similar findings were noted for reductions
in fantasy frequency. The frequency and intensity of
fantasies fell similarly with all 3 SSRIs (P = NS for all
pairwise comparisons).165
Adverse events (::::1 at each specified time) occurred
in 40%,30%, and 23% of patients at weeks 4, 8, and
12, respectively. 165 Insomnia and delayed ejaculation
occurred in 8 each; headache in 7; drowsiness in 6;
reduced sexual drive in 4; and diarrhea and nausea in
3 patients each. Adverse-event frequency and severity
were similar for the 3 agents (results of statistical
analyses were not provided).
DISCUSSION
Methodologic Difficulties in Sex Offender Research
Numerous deficiencies exist within the clinical ef-
ficacy literature in sex offender research. A major
problem is the presence of strong sampling biases, as
most investigators recruit subjects from prisons or le-
gally mandated sex therapy groups. Subjects from
these 2 settings may not be willing to incriminate
23
 Clinical Therapeutics
themselves on self-report surveys. Prison populations
exclude those not arrested, those whose offense was
not judged severe enough to warrant incarceration,
those able to control their impulses, and, potentially,
those more financially successful and thus better able
to prevail in legal troubles through retention of a pri-
vate lawyer. These sources of subjects introduce the
possibility that the findings of lower intellect, person-
ality disorders, and overall reduced level of function-
ing may be representative of sex offenders who are
arrested compared with the sex offender group as a
whole. 3
Another common deficiency is the small sample siz-
es, which lead not only to type II statistical errors (ie,
false-negatives) but also to a lack of generalizability
due to significant differences between the treatment
groups in sex offender and/or victim demographics. 3
The randomized controlled trial (RCT) is consid-
ered the "gold standard" design for evaluation of
treatment outcomes. However, problems occur when
the RCT design is adapted to psychological treat-
ments. Unlike the administration of medications
wherein the client-physician interaction is minimal,
psychological therapy involves numerous, more com-
plex factors (eg, an ongoing relationship between the
therapist and patient over an extended period). Mar-
shall and Marshall,166 in their review of the RCT de-
sign in sex offender research, found that many practi-
cal and ethical problems emerge when the RCT design
is considered. For example, the simple randomization
implicit in RCT designs can never result in the com-
plex matching of both static actuarial factors as well
as dynamic factors in study groups. In addition, the
negative influence of allocation to no treatment, rang-
ing from disappointment to anger and resentment,
could be expected to confound results. Also, parole
boards and prisons are unlikely to change policies to
accommodate the RCT design, especially if nontreat-
ment groups are deemed necessary. The public would
likely be nonsupportive of this design if the RCT were
conducted in nonincarcerated individuals. Subjects
may refuse to enroll if there is a chance of allocation
to nontreatment. This loss of potential subjects would
compromise the scientific merit of the study. The use
of a rigid approach to study procedures, implicit in an
RCT design, with study manuals to guide interven-
tions would compromise the effectiveness of the
(cognitive-behavioral) therapist. The therapist can
have a significant impact on therapeutic outcomes if
24
he or she can adapt treatment to the learning style and
interpersonal approach of each client and adjust
therapy to the day-to-day fluctuations in the client's
mood and motivation. Strict adherence to study
manuals reduces the generalizability of the results of
RCTs to usual clinical practice. In summary, RCT de-
signs do not allow many of the features of an effective
therapist-patient relationship (eg, flexibility in the ap-
plied treatments, "freedom" of the therapist to adapt
as discussed previously, ability to vary the number and
lengths of sessions).
There are 2 major ethical dilemmas for the investi-
gator who uses RCT study designs: the issue of ran-
domization to placebo of the prison population (a
group very vulnerable to possible coercion) and the
need to provide the nontreatment group with treat-
ment at the earliest possible date consistent with the
needs of the trial. Marshall and Marshall 166 have ad-
vanced 2 alternative designs for use in sex offender
studies: incidental designs and actuarially based evalu-
ations. With incidental designs, the "incidental" non-
treatment group is selected from the same population
as the treatment group, the source being those not
treated because limited resources prevent the treat-
ment of all offenders or historical "controls" from
facility archives. From the perspective of rigor, this
"level 4 design" is close to the rigor of an RCT design
(which is a level 5 design). In actuarially based evalu-
ations, the actual recidivism rates of treated subjects
are compared with the expected recidivism rates from
actuarial risk assessment instruments. This is the only
acceptable study design when all (or almost all) sub-
jects enter treatment. Although several academic
groups have echoed these recommendations, it is still
too early to tell whether they will be accepted by re-
searchers in the field. 166
Antiandrogen Treatment Protocols
Protocols for the use of cyproterone acetate, MPA,
and leuprolide acetate in the treatment of deviant
sexual behaviors have been published. 167 For cypro-
terone acetate, pretreatment laboratory testing should
include determinations of serum testosterone, LH,
FSH, and prolactin; a liver function test panel; com-
plete blood count; and glucose. An electrocardiogram
should be obtained, and weight and blood pressure
measured. Contraindications include thromboembolic
disorders, liver failure, and active pituitary pathology.
The dosage range recommended is 50 to 600 mg/d
Volume 31 Number 1

(orally) or 300 to 600 mg weekly or every other week
(by 1M injection). Follow-up involves determination
of serum testosterone concentrations (monthly for
4 months, then every 6 months) and serum LH and
FSH (every 6 months). Patients should be monitored
for increases in weight and blood pressure. If hepato-
toxicity is suspected, liver function tests are required.
If serum testosterone concentrations fall significantly,
bone mineral densitometry should be obtained annually.
For MPA, the protocol is identical to that of cypro-
terone acetate except for the dosage range to be used:
100 to 500 mg/d (orally) and 100 to 1000 mg weekly
(by 1M injection).
For leuprolide acetate and triptorelin, there are
pretreatment tests in addition to those recommended
above: renal function testing (blood urea nitrogen and
creatinine), bone mineral densitometry, and an SC test
dose of 1 mg (to check for anaphylaxis and less severe
forms of allergy). Contraindications include osteopo-
rosis and active pituitary pathology. Follow-up is simi-
lar to that presented above, with the additional need
for renal function tests every 6 months and bone min-
eral densitometry annually. The dose range to be used
is 3.75 to 7.5 mg monthly (by IM/SC injection, de-
pending on the product).
Ethical Aspects of Ablative Therapies
Physical (orchidectomy) and chemical (hormonal)
ablative therapies are attended by several ethical is-
sues centered on the concept of human rights that
should be discussed. Human rights protect what are
considered essential attributes of human beings: per-
sonal freedom, material subsistence, personal security,
elemental equality, and social recognition. These rights
have been codified in the United Nations' Universal
Declaration of Human Rights and in 2 subsequent
international covenants (1966).168 By committing a
sexual assault, the perpetrator has abused the human
rights of his or her victim. Subsequent restrictions
placed on the perpetrator represent a withdrawal of
his or her human rights (eg, incarceration as a punish-
ment for a criminal act and in the interests of preserv-
ing the safety of the public). Newer restrictions such
as civil commitment, registration, and public notifica-
tion, although welcome by the general public, also
affect the human rights of the perpetrator. In addition,
surgical and chemical castration has a negative effect
on the perpetrator's human rights. The legality of
these forms of castration is decided on a state-by-state
January 2009
D.R.P. Guay
basis. In addition, even if these procedures are legally
available in a given jurisdiction, the ability of a pris-
oner of the state to provide truly informed consent for
them is questionable (this topic has been thoroughly
reviewed with respect to prisoners in research 16 9 ). In
some way, the human rights of all participants (victim,
perpetrator, and general public) must be safeguarded.
A recent in-depth article focused on the human rights
of the sex offender in the context of treatment and
rehabilitation. 170
Treatment Recommendations for Sex Offenders
During the search for published materials for this
review, no formal practice guidelines were identified
for the treatment of paraphilias. The following recom-
mendations, which must be individualized on the ba-
sis of clinical exigency and pragmatism, are those of
the author, based on a synthesis of the evidence re-
viewed in this article as well as >20 years of clinical
experience. These suggestions are also predicated on
medical clearance to use antiandrogen or estrogen
therapies, if necessary. It should be noted that the
quality of the evidence base supporting the use of all
of these agents is rather poor and that there can be no
set rules in the pharmacotherapeutic approach to the
paraphilic and nonparaphilic sexual disorders.
Psychotherapy is useful in virtually all offenders
and should be initiated as soon as possible. In those at
the highest risk of reoffending (those with multiple
victims, multiple paraphilias, deviant sexual interests,
use of force, male victims, age dO years at the time of
release, central nervous system dysfunction, psychiat-
ric illness, sexual violence under institutional condi-
tions, and a history of treatment failure), pharmaco-
logic therapy should be initiated at the same time. The
combination of psychotherapy plus drug therapy is
associated with better results compared with either as
monotherapy, especially in pedophiles. 3,8
In those offenders committing non-" hands-on" or
violent paraphilias and those at low risk of reoffend-
ing, the use of serotoninergic monotherapies (eg,
SSRls or tricyclic antidepressants [TCAs], especially
tertiary amines such as clomipramine, amitriptyline,
and imipramine) are reasonable choices. In those at
moderate or high levels of risk of reoffending, initial
dual combination therapy (serotoninergic plus antian-
drogenic) is recommended. Due to better tolerability,
SSRls should be used before TCAs, and progestogens
should be used before LHRH agonists or estrogens.
2S
 Clinical Therapeutics
Among progestogens, oral cyproterone acetate (usu-
ally 50-200 mg/d in 2 divided doses) is a better choice
(if available) than oral MPA (100-500 mg/d) if the
oral route is desired (due to the supporting clinical
trial evidence of the former). If the 1M route is desired,
1M MPA (initially 100 mg once weekly with titration to
effect) may be a better choice than 1M cyproterone ace-
tate (due to the supporting clinical trial evidence and
tolerability of the former). Failure of dual combina-
tion serotoninergic/progestogen therapy should prompt
a change in one or both of the components (eg, SSRI
to TeA or vice versa, or cyproterone acetate to MPA
or vice versa) or the addition or substitution of an
LHRH agonist (leuprolide or triptorelin) for the pro-
gestogen. In a minority of patients, the use of triple
combination therapy (serotoninergic plus LHRH ago-
nist or progestogen plus estrogen) may be necessary.
Estrogens should be considered second- or third-line
agents and can be administered orally (ethinyl estra-
diol 0.05-0.10 mg once daily or conjugated equine
estrogens 0.625-1.25 mg once daily) or topically
(ethinyl estradiol 0.05-0.10 mg daily as a transdermal
patch). There is no longer a role for DES.
In the situation where a rapid onset of effect is de-
sired, 1M progestogens may be useful. Oral/topical
agents and long-acting LHRH agonists have too slow
an onset of effect to be safely used.
CONCLUSIONS
Some progress has been made in the therapy of
paraphilic and nonparaphilic sexual disorders, with
both psychotherapy and drug therapy-and especially
their combination-contributing to this progress;
however, much work remains to be done. The devel-
opment of more specific, more effective, and better-
tolerated medications for these disorders should be
recognized as a program worthy of greater support
from government and pharmaceutical industry sourc-
es. Because the clinical studies performed to date have
largely been of poor design, the recommendations
provided in this review are tentative at best.
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