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BPH Therapies and Sexual Function

Presented by: Anmar Nassir

Quality of Life and BPH


Factors affecting Quality of Life in BPH patients:
Nocturia, Impact of LUTS on daily activities, Anxiety about a possible prostate cancer, Sexuality

Calais da Silva F, Marquis P, Deschaseaux P et al. Eur urol, 1997, 31(3) : 272-280.

Erectile Dysfunction is Associated with LUTS and BPH


ED (n=853) Diabetes Hypertension Pelvic surgery LUTS Smoker Regular alcohol
Epidemiology of ED in Germany/Cologne: Co-morbidity Braun M et al., Int J Impot Res 2000; 12:305-311

No ED (n=3581) 3.2% 13.6% 2.4% 37.7% 34.6% 42.4%

20.2% 32.0% 18.8% 72.2% 29.6% 37.5%

MSAMMSAM-7
Multinational Survey of the Aging Male
Objective: To evaluate in populations of men aged 5080 years: 50
 Incidence of LUTS and their severity  Importance of sexuality and incidence of sexual disorders  Possible relationship between LUTS and sexual disorders, including impact of coco-morbidities (diabetes, hypertension)
Rosen R et al. Eur Urol 2003; 44: 637649

MSAMMSAM-7
The largest study on sexual impact of LUTS

Materials and methods (1) Patients: More than 14,000 men aged 50 to 80 years in 7 countries (USA, UK, France, Germany, Italy, Spain and The Netherlands) In each country, the sample was representative of the target population
Rosen R et al. Eur Urol 2003; 44: 637649

MSAMMSAM-7

Materials and methods (2) Postal questionnaire


 Demographic characteristics  I-PSS and quality of life index  Dan-PSS sex (6 questions) Dan IIEF (15 questions)  Co-morbidities CoRosen R et al. Eur Urol 2003; 44: 637649

MSAMMSAM-7
The largest study on sexual impact of LUTS

Materials and methods (3)  34,800 questionnaires sent  14,254 questionnaires returned  12,815 questionnaires evaluable & analysed (89.9%)

Rosen R et al. Eur Urol 2003; 44: 637649

MSAMMSAM-7: 83% of men between 5080 50


are sexually active
92% 83% 83% 65%

100 90 80 70 60 50 40 30 20 10 0

Total

5059 50

60 6069

7080 70

Age
Rosen R et al. Eur Urol 2003; 44: 637649 / Data on file

Average number of sexual intercourse / activities per month


8 7 6 5 4 3 2 1 0

7.6 5.9 5.3 3.0

Total

5059 50

60 6069

7080 70

Age
Rosen R et al. Eur Urol 2003; 44: 637649

DAN-PSS sex
Prevalence of functional problems

Erection (reduced / none)

49%

Ejaculation (reduction / none)

46%

Ejaculation (pain / discomfort)

7%
Among total sample (n=12,815)

Rosen R et al. Eur Urol 2003; 44: 637649

DAN-PSS sex
Bothersomeness of functional problems

Erection (reduced / none)

78%

Ejaculation (reduction / none)

55%

Ejaculation (pain / discomfort)


Among men with functional problems
Rosen R et al. Eur Urol 2003; 44: 637649

88%

Sexual Activity in the Ageing Male MSAM-7


12,815 men aged 50-80 y. Representative sample 10
Mean Sexual Activity per Mo
8.8 8.3 7.9 6.8 5.9 5.9 5.0 3.7 2.8 3.6 2.5 2.6 5.0 3.3 7.4 6.0 4.8 3.0 8.8 7.8

8 6 4 2 0

4.9

US

FR

DE 50-59 y.

IT 60-69 y.

NL 70-80 y.

SP

UK

Rosen R et al. Eur Urol 2003; 44: 637649

Sexual impact of LUTS


MSAM-7: LUTS have a negative impact MSAMon sexual function
reducing sexual activity LUTS have a negative impact by reducing stiffness of erection decreasing volume of ejaculate
Rosen R et al. Eur Urol 2003; 44: 637649

Severity of LUTS Impacts Sexual Activity


60 50 40 30 20 10 0 50-59 years IPSS 0 60-69 years 1-7 8-19 70-79 years 20-35 points
7% 9% 11% 9% 27% 21% 15% 17% 30% 35% 33%

2,372 French men IIEF


48%

Richard F et al., J Urol 2000; 163:249A

Surgery and Instrumental Procedures may Impact Sexual Function


% % 16 14 12 10 8 6 4 2 0
OPEN TURP TUIP ILC TUNA TUMT

100

Impotence

90 80 70 60 50 40 30 20 10 0
OPEN

Retrograde ejaculation

TURP TUIP

TUMT

ILC

TUNA

McConnell - BPH Clinical Practice Guidelines, 1994

What is the Impact of Medical Therapies? Are there Differences Between Medical Therapies?

5E-Reductase
Impotence Double-Blind Placebo-Controlled Studies
VA study
(Lepor et al)

PROWESS
(Marberger et al)

PLESS study
(McConnell et al)

Duration Placebo n=305

1yr Fina n=310 %

2 yrs Placebo n=1,591 % 5.0 9.0 NA 2.0 2.8 4.7 NA 0.6 4.0 6.6 NA 2.1 3.4 3.7 0.8 0.1 Fina n=1,577

Year 1 Placebo n=1,376 % 6.4 8.1 3.7 0.8 Fina n=1,384

Decreased libido Impotence Decreased ejaculation Ejaculation disorder

1.0 5.0 NA 1.0

Sexual Function
Direct Comparative Studies (E1Blocker/Finasteride)
10

VA: 1 Year
10

ALFIN: 6 months
p=0.04
% 5

Ejaculatory Abnormality

p<0.001
% 5

0 10

0 10

p=0.05

Decreased Libido

ns
% 5

0 10

0 10

p=0.05

p<0.002
% 5

Impotence

Pbo
Lepor H et al. NEJM 1996;335:533 Debruyne FMJ et al. Eur Urol 1998;34:169

T+F

F F: Finasteride Pbo: Placebo

A+F A: Alfuzosin T: Terazosin

E1-Blockers
Impotence Double-Blind Placebo-Controlled Studies

VA (n=1,229) % Terazosin Doxazosin Alfuzosin Placebo 6.0 5.0

PREDICT (n=1,094) % 5.8 3.3

ALFORTI (n=447) % 10mg: 0.0 0.6

ALFUS (n=536) % 10mg: 2.8 15mg: 1.1 1.1

Sexual Function with Alfuzosin: ALFORTI Study


Placebo Alfuzosin Alfuzosin
10mg OD 2.5mg TID

n=154 Abnormal ejaculation Impotence Decreased libido 0% 0.6% 0.6%

n=143 0% 0% 0%

n=150 0% 0% 0.7%

Van Kerrebroeck et al., Eur Urol 2000; 37:306-313

E1-Blockers
Ejaculatory Disorders US Pivotal Studies with Tamsulosin
Alfuzosin
Tamsulosin (3 months) Abnormal ejaculation (%) 20 15 10 5 0
6%

Alfuzosin OD (3 months)
18%

*p < 0.001

20 15

ns

10 5
0% 0.6%

0%

0.6%

Pbo

Tam 0.4 mg

Tam 0.8 mg

Pbo

Alf 10 mg

Alf 15 mg

Lepor et al. Urology 1998;51:892-900

Roehrborn et al. Urology 2001;58:953

E1-Blockers
Ejaculatory Disorders Long-Term Studies with Tamsulosin
Alfuzosin
US open study with tamsulosin 0.4-0.8 mg OD * 0.4Mean exposure time: 16 months Tamsulosin European open study with tamsulosin 0.4 mg OD ** Mean exposure time: 4 years Tamsulosin

30%

4.9%

European open study with alfuzosin 10 mg OD *** Mean exposure time: 9 months Alfuzosin

0.6%

*Narayan P. et al. Urology 1998 **Schulman C. et al J Urol 2001 ***Van Kerrebroeck et al. Eur Urol. 2000

E1-Blockers
Ejaculatory Disorders Long-Term Studies with Tamsulosin
Alfuzosin
van Kerrebroeck et al. Eur Urol 2002 Exposure time Abnormal Ejaculation Impotence Decreased Libido 12 months % 0.6 1.4 0.3 Alfuzosin 10 mg Narayan et al. Urology 2001 16 months % 30 6 NA Tamsulosin 0.4-0.8 mg Schulman et al. J Urol 2001 4 years % 4.9 5.4 1.2 Tamsulosin 0.4 mg

DAN-PSSsex
Reduced Ejaculate, a Problem
In % 100 90 80 71 70 60 50 40 30 20 10 0 39 54 44 66 54 66 85 80 76

Men with ejaculatory dysfunction (n=6,023)

52

50

LUTS
50 - 59 years 60 - 69 years 70 - 79 years

Alfuzosin has the Lowest Impact on Sexuality

Does Alfuzosin have a Beneficial Effect on Sexuality ?

Sexual Function Following 1 Year Treatment with Alfuzosin


7 6 5 4 3 2 1 0 < 65 years 65-70 years > 70 years Moderate symptoms Severe symptoms

Lukacs B et al. Urology, 1996; 48 (5): 731-740

Alfuzosin 10 mg XL may Improve Sexual Dysfunction


n = 310 D0 Weighted score
3

Dend * 2.3 2.0 ** 1.7

* p vs D0 < 0.01 ** p vs D0 < 0.05

2.6

2.3 * 1.5

Reduced erection

Reduced ejaculate

Painful ejaculate

DAN-PSSsex -

J. Urol. 2006, 176, 1051-1056

How can BPH Interfere with Sexuality?


Treatments Local Factors Deterioration in Sexuality Deterioration in QoL Correlated Factors eg. age

Anxiety

Deterioration in Self-Image

How might E-Blockers Impact on Sexuality?


Pharmacological Impact ? Local Factors Reduction of Anxiety

Sexuality Improvemen t in QoL Improvement in Self-Image

ABEJAC Study
Materials and Methods Using a randomized, 3-way crossover design, the effects of 5 days of treatment with 0.8 mg tamsulosin daily, 10 mg alfuzosin daily and placebo on ejaculation in healthy adult men were compared. The primary end points of the study were ejaculate volume and sperm concentration in post-ejaculate urine on each treatment. The healthy volunteers who completed the study were 48.
J Urol. 2006 Oct;176(4 Pt 1):1529-33.

ABEJAC Results
Change in ejaculate volume
Change in ejaculate volume (ml)
3 2 1 0 -1 -2 *Tam vs Pbo, p<0.001 Tam vs Alfu, p<0.001

Change in urine sperm conc. (million/ml)

Change in urine sperm concetration


p=ns

2 +1.7 +1.4 +1.2 1

+0.4

+0.3

-2.4
-3

0 Mean sd value at baseline 48 0.5 million/ml Tamsulosin 0.8 mg OD

Mean

* sd value at baseline
3.4 1.4 ml Placebo Alfuzosin 10mg OD

J Urol. 2006 Oct;176(4 Pt 1):1529-33.

ABEJAC Results
% with decreased ejaculate volume >20%
90%
100 *Tam vs Pbo, p<0.001 Tam vs Alfu, p<0.001 80

% subjects with no ejaculation


100 80

% of subjects

% of subjects

60 40 20 0

60

35%

40

21%
20

13%

0%

0%

Placebo
J Urol. 2006 Oct;176(4 Pt 1):1529-33.

Alfuzosin 10mg OD

Tamsulosin 0.8 mg OD

Intent to treat population

ABEJAC Conclusions
Nearly all volunteers (90%) receiving tamsulosin 0.8mg had a significant reduction in ejaculate volume and 1 out of 3 had no ejaculation. This reduced ejaculation with tamsulosin is not due to retrograde ejaculation.

Conversely, with alfuzosin 10mg once daily, the percentage of subjects with reduced ejaculation is similar to placebo.

1Giuliano

et al. BJU Int. 2004 : 93:605-8 et al. J.Pharmacol. Exp. Therap. 2005 3Giuliano et al. EAU 2005 (abstract 141)
2Tambaroa

ABEJAC Conclusions
The mechanism by which tamsulosin impairs ejaculation may be a peripheral effect on seminal vesicles and/or on vas deferens1-2. A central effect is also plausible as tamsulosin shows an important affinity for 5HT1A and D2-like receptors that are both involved in the central control of ejaculation3.

1Giuliano

et al. BJU Int. 2004 : 93:605-8 et al. J.Pharmacol. Exp. Therap. 2005 3Giuliano et al. EAU 2005 (abstract 141)
2Tambaroa

Effects of Alfuzosin and Tamsulosin on Sperm Parameters in Healthy Men

Short-Term, Randomized, Double-Blind, Placebo-Controlled, Crossover Study. Sperm parameters were evaluated in healthy men receiving tamsulosin, alfuzosin, and placebo

Published-Ahead-of-Print on February 5, 2009 by Journal of Andrology

Study design
48 healthy men received 5 days of tamsulosin 0.8 mg once daily (QD), alfuzosin 10 mg QD, and placebo in a randomized, double-blind, 3-way crossover study with a 10-14-day washout period between treatments.

Published-Ahead-of-Print on February 5, 2009 by Journal of Andrology

End points of the study

The mean (SE) changes from baseline in semen sperm concentration, semen sperm count, semen viscosity, semen fructose, sperm motility, and sperm morphology on Day 5 of treatment.

Published-Ahead-of-Print on February 5, 2009 by Journal of Andrology

Results
The total sperm count in semen decreased from baseline with tamsulosin -54.6 (24.0) million] but not with placebo [81.5 (18.8) million] or alfuzosin [46.2 (19.0) million]. The percentage of men with normal semen viscosity was lower with tamsulosin (65%) than with placebo (98%) or alfuzosin (92%). The change from baseline in semen sperm concentration was 3.1 (8.3) million/mL with tamsulosin, 15.0 (6.5) million/mL with alfuzosin, and 24.4 (6.5) million/mL with placebo.
Published-Ahead-of-Print on February 5, 2009 by Journal of Andrology

Results
The change from baseline in semen fructose was comparable for all treatments. The percentage of motile sperm decreased 13.8% from baseline to Day 5 of treatment with tamsulosin compared with decreases of 2.3% with placebo and 0.4% with alfuzosin. The percentage of abnormal sperm increased marginally with tamsulosin (0.6%) but not with placebo (-2.8%) or alfuzosin (-3.9%).
Published-Ahead-of-Print on February 5, 2009 by Journal of Andrology

Safety results
The most common adverse events were
dizziness
(alfuzosin 11%, tamsulosin 14%, placebo 0%)

orthostatic hypotension
(alfuzosin 25%, tamsulosin 11%, placebo 5%).

Published-Ahead-of-Print on February 5, 2009 by Journal of Andrology

Conclusion
The results suggest that tamsulosin has a negative impact on sperm in healthy men. Studies on the effects of alpha1adrenergic blockers on sperm in men with BPH are warranted.

Published-Ahead-of-Print on February 5, 2009 by Journal of Andrology

How can we Explain Differences Between E1-Blockers ?

Potential Targets for E-Blockers


CNS Spinal cord centers Prostate Seminal vesicle Vas deferens Penis

Hendry et al. in Erectile Dysfunction. Jardin et al. (eds), Health Publication Ltd, Plymouth, 1999:477-50.

)nim( EMIT
021001 08 06 04 02 0 02- 04- 06- 080
.v.i ,gk/gm 4.0 .v.i ,gk/gm 1.0 .v.i ,gk/gm 30.0

021 001 08 06 04 02 0 02- 04- 06- 080


.v.i ,gk/gm 4.0 .v.i ,gk/gm 1.0

02 04 06 08 001 021 041

02 04 06 08 001 021 041

nisozareT

nisozarP

Rouquier et al, Eur. J. Pharmacol, 1994, 261, 59-64

021001 08 06 04 02 0 02- 04-06- 080


.v.i ,gk/gm 4.0 .v.i ,gk/gm 1.0

02 04 06 08 001 021 041

nisozuflA

Alfuzosin Does not Penetrate the Blood-Brain Barrier

The Physiology Of Ejaculation: The Emission Phase


Emission: seminal vesicle (50-80%) prostate (15-30%) Cowpers gland testis (<0.1%)
Mann and Lutwak-Mann. Male reproductive function and semen. Berlin:Springer-Verlag;1981:171-93.

E1-ARs and Seminal Emission


The E1-AR subtype involved in contraction of the human vas deferens and seminal vesicle is most probably the E1A-AR.
SV is responsible for 70% of the amount of ejaculate

Silva MA et al. Eur J Pharmacol 1999

E1-ARs and the Control of Bladder Neck Contraction


The Two Functions of the Bladder Neck: - Maintain urinary continence - Prevent seminal fluid from being forced into the bladder (retrograde ejaculation) The contractile tone of bladder neck smooth muscle is mediated primarily by the sympathetic innervation via release of noradrenaline and action on E1-ARs, The degree to which an E1-AR antagonist relaxes the bladder neck may give rise to retrograde ejaculation.

Effects of E-Blockers on Seminal Vesicle Pressure

120

*p <0.001

80

*
40

0 Vehicle 3 10 3 10

Tamsulosin ( g/kg)
F. Giuliano et al. , ISSIR 2002

Alfuzosin ( g/kg)

Differential Effects of E-Blockers on Ductus Deferens Contraction

K.-E. Andersson

Peripheral Mechanisms Involved in Erection


E-AR Antagonism All E1-AR subtypes (E1A, E1B, E1D, E1L) can be demonstrated in human penile erectile tissues It has not been established if one subtype is more important than the others

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