Ponco Birowo,

Division of Urology Departement of Surgery Faculty of Medicine

University of Indonesia/
Department of Urology Cipto Mangunkusumo Hospital
 Arrousal
 Erection
 Ejaculation
 Orgasm
 Organic
 The inability to attain and/or maintain an
erection sufficient for satisfactory sexual
performance.

Persistent 3 months

Remember, both partners in a relationship are affected.

National Institute of Health. JAMA. 1993

 20 – 30 million in USA

 > 150 million worldwide

 The risk increases with age

40%
Minimal ED
20%
Moderate ED

0% Complete ED

40 years 70 years
Massachusetts Male Aging Study. J Urol. 1994
 Periaqueductal Grey
Midbrain
Visual, auditory and
olfactory cerebral
afferents

Medial Preoptic Area

Paraventricular Hypothalamus
Nucleus

Mucosal sensory receptors

(Krause finger Corpuscle)
Diabetes Mellitus
Hypertension
Vascular
Ischemic Heart Disease Disease
Dyslipidaemia
Depression
National Institutes of Health. JAMA. 1993
Lue TF. N Engl J Med. 2000
 Organic (most common, 70%)
◦ Vascular
◦ Hormonal
◦ Neurological
◦ Medications
 Psychogenic
 Mixed psychogenic and organic
Drugs Associated with Erectile Dysfunction

A Physician Guide to the Management of ED. ESIR. 2001

Lue T, Giugliano F, Montorsi F, et al. J Sex Med. 2004.
6 bulan terakhir 1 2 3 4 5
Bagaimana kepercayaan anda untuk Sangat rendah Rendah Sedang Baik Sangat baik
mencapai dan mempertahankan
ereksi?
Ketika ereksi dengan stimulasi Hampir tidak Kurang dari Setengah Lebih dari Hampir
seksual, seberapa sering ereksi anda pernah/tidak setengahnya setengah selalu/selalu
cukup keras untuk penetrasi? pernah

Selama hubungan seksual, seberapa Hampir tidak Kurang dari Setengah Lebih dari Hampir
sering anda dapat mempertahankan pernah/tidak setengahnya setengah selalu/selalu
ereksi setelah penetrasi? pernah

Selama hubungan seksual, seberapa Sangat-sangat Sangat sulit Sulit Tidak terlalu Tidak sulit
sulit anda mempertahankan ereksi sulit sulit
hingga selesai hubungan?

Seberapa sering hubungan seksual Hampir tidak Kurang dari Setengah Lebih dari Hampir
anda memuaskan? pernah/tidak setengahnya setengah selalu/selalu
pernah
 ED Classification according IIEF-5 Score:
◦ Severe (5-7),
◦ Moderate (8-11),
◦ Mild – Moderate (12-16),
◦ Mild (17-21),
◦ No ED (22-25).
 Hypertension • Thyroid
 DM dysfunction
 Smoking • Uraemia
Alcohol
• Pelvic surgery /

Medications
trauma

 Depression, anxiety
 Hypogonadysm
• Partner problems
• Libido
• Nocturnal erection
 Blood pressure
 Cardiac, thyroid, testicular, prostate
examination
 Penile anatomical abnormalities
 Gynecomastia
 Exercise treadmill test (if cardiac risk factors
are present)
 Fasting glucose
 HbA1C
 Fasting lipid profile
 Blood chemistry
 Serum testosterone
 Hemogram

Additional test (optional):

 ECG
 Share the same pathophysiology
(vasculopathy, endothelial dysfuntion)
 Patients with CVD and CVD’s risk factors has
increasing risk of having ED
 ED may be a manifestation of a CVD, even as
a sentinel of silent CVD
90%
80%
70%
60%
50%
No CVD
40%
CVD
30%
20%
10%
0%
40-49 50-59 60-69 >70
Grover SA, Lowensteyn I, Kaouache M, et al. Arch Intern Med. 2006
 Low Risk:
•< 3 major cardiac risk
factors
•Uncomplicated past MI
(>8 weeks ago)
•Mild valvular disease
Intermediate Risk:
•> 3 major cardiac risk
•Recent MI (2-6 weeks)
•NYHA class II
High Risk:
•Unstable angina
•Recent MI (<2 weeks)
•Uncontrolled
hypertension
•Moderate to severe
valve disease

Jackson G, Rosen RC, Kloner RA, et al. J Sex Med. 2006

 Age,
 Male gender,
 Hypertension,
 Diabetes mellitus,
 Cigarette smoking,
 Dyslipidemia,
 Sedentary lifestyle,
 Family history of premature CAD

2nd Princeton Consensus on Sexual Dysfunction and Cardiac Risk

The Stages of Heart Failure –
New York Heart Association (NYHA)
Classification
Class Patient Symptoms
Class I (Mild) No limitation of physical activity. Ordinary physical activity
does not cause undue fatigue, palpitation, or dyspnea
(shortness of breath).

Class II (Mild) Slight limitation of physical activity. Comfortable at rest,

but ordinary physical activity results in fatigue,
palpitation, or dyspnea.

Class III Marked limitation of physical activity. Comfortable at rest,

(Moderate) but less than ordinary activity causes fatigue, palpitation,
or dyspnea.

Class IV (Severe) Unable to carry out any physical activity without

discomfort. Symptoms of cardiac insufficiency at rest. If
any physical activity is undertaken, discomfort is
increased.
 Patients with DM has more prevalence of ED
compared with non-DM

Etiology

Penile arterial narrowing and

Somatic and
clossure  penile hypotension
autonomic nerve
& cavernous arterial
dysfunction
insufficiency
100%
90%
80%
70%
60%
50% No DM
40% DM
30%
20%
10%
0%
40-49 50-59 60-69 >70

Grover SA, Lowensteyn I, Kaouache M, et al. Arch Intern Med. 2006

 LUTS and BPH reported in up to 72% men with
ED.
 Independent risk factors for each other
 Treatment of one condition can influence the
other
 • Treat reversible causes
• Lifestyle modification (weight loss, tobacco cessation, exercise)
1st line • PDE-5 inhibitor

• Intracavernous injection
• Medicated Urethral System for Erection
2nd line • Vacuum erection device

• Surgical prosthesis
• Some men respond to hormonal therapy, penile
3rd line revascularization or sex therapy
 First line therapy otherwise contraindicated
 Broad spectrum of therapy
 Rates of successful sexual intercourse:
 57% (PDE-5i) VS 21% (Placebo)
 Adverse effects:
◦ Headache, flushing, dyspepsia, backpain, blue
vision, priapism
 No increase in MI or mortality rates, stokes
and syncope
 Myocardial infarction within 90 days
 Angina: unstable or during sexual activities
 NYHA class II within 6 months
 Stroke within 6 months
 Hypotension (<90/50) or uncontrolled
hypertension (>170/100)
 Uncontrolled arrythmias
 Tendency to develop priapism
 Heredity degenerative retinal disorders
 Nitrates: absolutely contraindicated with all
PDE-5i
 Drugs that prolong the QT interval:
predispose to ventricular arrythmia
 Cytochrome P450 CYP3A4 inhibitors: increase
plasma levels of PDE-5i
 Cytochrome P450 CYP3A4 inducers: decrease
plasma levels of PDE-5i
 Maleable
 Inflatable
 ED is a prevalent and undertreated condition
that has many comorbiditiers (CVD, DM,
LUTS, BPH)
 ED is a marker of CVD
 PDE-5 inhibitors are the recommended 1st
line therapy for ED
When To refer to Urologist
 Patient desires surgery
 Fails non surgical treatment
 Not comfortable with 2nd line
 Fails 2nd line therapy
 Patients with low Testosterone who desire
preserve fertility potential
 Patients with penile abnormality (peyronie’s)
ED:
 Erectile Dysfunction = Endothelial Dysfunction
 Erectile Dysfunction = Emotional Dysfunction
 Erectile Dysfunction = Endocrinal Dysfunction
 New PDE 5 Inhibitors
 New Mechanisms of PDE5i
 New Preparation of PDE5 Inhibitors
 Combination therapy
 ESWT
 Future Treatment
Palit, V. & Eardley, I. Nat. Rev. Urol. 2010
Palit, V. & Eardley, I. Nat. Rev. Urol. 2010
Tadalafil has a apoptotic efect. EMPa = apoptotic endothelial microparticles
Tadalafil effect on cGMP production in diabetic
rat
 Endothelial progenitor cells (EPCs) are bone
marrow derived cells required for endothelial
repair.
 Decreased production and/or impaired action
NO play a role in the pathogenesis of
atherosclerotic CVD and ED in DM patient.
 Hyperglycemic conditions  formation and
accumulation of advanced glycation end
products (AGE) have been known to
progress tissue damage in diabetes.
 Inhibitor of PDE-5, could block the
deleterious effects of AGE in human umbilical
vein endothelial cells (HUVEC)
Anti Inflammatory effect: production of ROS (Reactive Oxygen
Species)
The POTENT studies

Sperling H, Debruyne F, Boermans A, Beneke M, Ulbrich E, Ewald S. J Sex Med. 2010

The POTENT studies
Efficacy and safety of Levitra ODT
(orodispersible tablet)

Sperling H, Debruyne F, Boermans A, Beneke M, Ulbrich E, Ewald S. J Sex Med. 2010

 Placebo
25 Levitra ODT
*
21.1 * Levitra film-coated
domain score at LOCF

* 19.2 tablet 10 mg
20 18.3
LS mean IIEF-EF

Levitra film-coated
15 14.1 tablet 20 mg
12.3
Baseline
10

0
n= 33 34 60 63 62
2 8 1 0 3
Levitra ODT Levitra film-coated
clinical trials tablet clinical trials

*p<0.0001 Levitra vs placebo; IIEF-EF, erectile function domain of the International

Index of Erectile Function; ITT, intent-to-treat; LOCF, last observation carried forward;
LS, least scores
Sperling H, Debruyne F, Boermans A, Beneke M, Ulbrich E, Ewald S. J Sex Med. 2010
 * * Placebo
* * *
Levitra ODT
domain score at LOCF

*
* * Levitra film-coated
LS mean IIEF-EF

tablet 10 mg
Levitra film-coated
tablet 20 mg
Baseline

n= 160 168 172 180 55 59 46 407 423 433 139 148 144
Age: <65 ≥65 <45 years 45 to <65 years ≥65 years
years years
Levitra ODT Levitra film-coated
clinical trials tablet clinical trials

*p<0.0001 Levitra vs placebo; IIEF-EF, erectile function domain of the International

Index of Erectile Function; ITT, intent-to-treat; LOCF, last observation carried forward;
LS, least scores Sperling H, Debruyne F, Boermans A, Beneke M, Ulbrich E, Ewald S. J Sex Med. 2010
 Placebo (n=340) Levitra ODT (n=355)
<65 years ≥65 years <65 years ≥65 years
Adverse event (AE), n (%) (n=165) (n=175) (n=173) (n=182)
Treatment-emergent AEs 34 (20.6 40 (22.9 71 (41.0 64 (35.2
) ) ) )
Drug-related, treatment-emergent AEs 12 (7.3) 13 (7.4) 47 (27.2 39 (21.4
) )
Treatment-emergent AEs leading to 0 (0) 2 (1.1) 3 (1.7) 2 (1.1)
discontinuation
Serious AEs 1 (0.6) 1 (0.6) 1 (0.6) 3 (1.6)
Drug-related,
Serious AEs withtreatment-emergent
outcome of death AEs <65
0 years
(0) ≥65
0 years
(0) <65
0 years
(0) ≥65
0 years
(0)
occurring in >1% of safety population, n (%) (n=165) (n=175) (n=173) (n=182)
Back pain 0 (0) 0 (0) 2 (1.2) 2 (1.1)
Dizziness 0 (0) 0 (0) 5 (2.9) 3 (1.6)
Dry mouth 1 (0.6) 0 (0) 0 (0) 2 (1.1)
Dyspepsia 0 (0) 0 (0) 4 (2.3) 4 (2.2)
Fatigue 0 (0) 0 (0) 0 (0) 2 (1.1)
Feeling hot 0 (0) 0 (0) 3 (1.7) 0 (0)
Flushing 1 (0.6) 1 (0.6) 16 (9.2) 11 (6.0)
Headache 2 (1.2) 3 (1.7) 26 (15.0 23 (12.6
) )
Nasal congestion 0 (0) 0 (0) 9 (5.2) 2 (1.1)
Pharmaceutical product complaint 2 (1.2) 2 (1.1) 0 (0) 0 (0)
Supraventricular extrasystoles 2 (1.2) 0 (0) 0 (0) 1 (0.5)
Sperling H, Debruyne F, Boermans A, Beneke M, Ulbrich E, Ewald S. J Sex Med. 2010
PDE5I plus:
 Vacuum constrictions device
 Intraurethral alprostadil
 Intracavernous injection
 Androgen suplementation
 α-adrenergic receptor antagonists
 Others: PLG, PLG + ALC, PT-141, trazodone,
pentoxifylline, vit E

Sperling H, Debruyne F, Boermans A, Beneke M, Ulbrich E, Ewald S. J Sex Med. 2010

 Hydrogen sulfide
 Gene Therapy
Palit, V. & Eardley, I. Nat. Rev. Urol. 2010
d'Emmanuele di Villa Bianca R, Sorrentino R, Mirone V, Cirino G. Nat Rev Urol.
 H2S-donating derivative of sildenafil (ACS6)
vs sildenafil: ACS6 and sildenafil relaxed
rabbit corpus cavernosum strips to the same
extent

d'Emmanuele di Villa Bianca R, Sorrentino R, Mirone V, Cirino G. Nat Rev Urol.

 Gene therapy involves the transfer of genetic
material to a target cell or tissue using a viral
vector or other nonviral methods.
 Most of the published work in this area
concerns the induction of potassium channel
over expression via gene therapy.
 From several potassium channels in penile
SMC: maxi-K channel has been the subject of
most research interest

Palit, V. & Eardley, I. Nat. Rev. Urol. 2010

Melman A, Int J Impot Res (2006)
Palit, V. & Eardley, I. Nat. Rev. Urol. 2010
Melman A, Int J Impot Res (2006)
 1st human trial for gene transfer with hMaxi-
K, n=6 (@3 dose 500 µg & 100 µg), injected
intracavernously.* Preliminary results : safe,
without AR

*Melman A et al. Eur Urol

Other potential gene therapy targets,
 vascular endothelial growth factor (increased
penile vascularity)1,2
 nitric oxide synthase (for patients with
defective nitric oxide production)3
 superoxide dismutase (prevention of neural
injury)4,5
 vasoactive intestinal poly peptide6
 calcitonin gene-related peptide7 1. Gholami, S. S. et al. J. Urol. 2003.

 PDE58
2. Rogers, R. S. et al Int. J. Impot. Res. 2003.
3. Liu, W. J. et al. Asian J. Androl. 2005.
4. Eng, W. et al. Methods Mol. 2010.
5. Azadzoi, K. M., et al BJU Int. 2009.
6. Shen, Z. J. et al. BJU Int. 2005.
7. Bivalacqua, T. J., et al. Biol. Reprod 2001.
8. Gonzalez-Cadavid, N. F. & Rajfer, Exp. Gerontol. 2004.
 There are at least 5 new PDE 5 inhibitors
 New Mechanisms of PDE5 inhibitors are
investigated
 New Preparation of PDE5 Inhibitors available
(ODT)
 Combination therapy are needed in PDE5i failure
 Future therapy in ED needs more investigation
 Nenden Rosdiana MD
 Mrs. Tri Darani

Department of Urology
“Cipto Mangunkusumo” Hospital /
Faculty of Medicine, University of Indonesia
 5-HT 5-HT Theoretical Background
5-HT 5-HT 5-HT

4 6 7
Smooth muscle Cell
RELAXATION
[Ca2+]

GS
+ PKA
A cAMP
AC T
P
- [Ca2+] CONTRACTION
IP3
Gi
+
PLCß Gq/II
PIP2

1A 1B 1E 1F 2A 2B 2C
5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT

1Raymond JR et al, Pharmachol Theurapeutics 2001 5-HT 5-HT 5-HT

2Abdel-Hamid IA, DDT 2005
Neue Rathaus @Hannover