1. BPH Therapies and Sexual Function Presented by: Anmar Nassir

2. 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.

3. Diabetes20.2%3.2% Hypertension32.0%13.6% Pelvic surgery18.8%2.4% LUTS72.2%37.7% Smoker29.6%34.6% Regular alcohol37.5%42.4% ED (n=853) No ED (n=3581) Erectile Dysfunction is Associated with LUTS and BPH Epidemiology of ED in Germany/Cologne: Co-morbidity Braun M et al., Int J Impot Res 2000; 12:305-311

4. MSAM-7 Multinational Survey of the Aging Male Objective: To evaluate in populations of men aged 50–80 years: Incidence of LUTS and their severity Incidence of LUTS and their severity Importance of sexuality and incidence of sexual disorders Importance of sexuality and incidence of sexual disorders Possible relationship between LUTS and sexual disorders, including impact of co-morbidities (diabetes, hypertension) Possible relationship between LUTS and sexual disorders, including impact of co-morbidities (diabetes, hypertension) Rosen R et al. Eur Urol 2003; 44: 637–649

5. MSAM-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: 637–649

6. Materials and methods (2) Postal questionnaire Demographic characteristics Demographic characteristics I-PSS and quality of life index I-PSS and quality of life index Dan-PSS sex (6 questions) Dan-PSS sex (6 questions) IIEF (15 questions) IIEF (15 questions) Co-morbidities Co-morbiditiesMSAM-7 Rosen R et al. Eur Urol 2003; 44: 637–649

7. Materials and methods (3) 34,800 questionnaires sent 34,800 questionnaires sent 14,254 questionnaires returned 14,254 questionnaires returned 12,815 questionnaires evaluable & analysed (89.9%) 12,815 questionnaires evaluable & analysed (89.9%) MSAM-7 The largest study on sexual impact of LUTS Rosen R et al. Eur Urol 2003; 44: 637–649

8. % of men with sexual activity in the last 4 weeks 83% 92% 83% 65% 0 10 20 30 40 50 60 70 80 90 100 Total 50–59 60–69 70–80 Age MSAM-7: 83 % of men between 50–80 are sexually active Rosen R et al. Eur Urol 2003; 44: 637–649 / Data on file

9. Average number of sexual intercourse / activities per month Average number of sexual Intercourse/activities per month 5.9 7.6 5.3 3.0 0 1 2 3 4 5 6 7 8 Total 50–59 60–69 70–80 Age Rosen R et al. Eur Urol 2003; 44: 637–649

10. Among total sample (n=12,815) 46% 7% 49% Erection (reduced / none) Erection (reduced / none) Ejaculation (reduction / none) Ejaculation (reduction / none) Ejaculation (pain / discomfort) Ejaculation (pain / discomfort) DAN-PSS sex Prevalence of functional problems Rosen R et al. Eur Urol 2003; 44: 637–649

11. Among men with functional problems DAN-PSS sex ‘Bothersomeness’ of functional problems55% 88% 78% Erection (reduced / none) Erection (reduced / none) Ejaculation (reduction / none) Ejaculation (reduction / none) Ejaculation (pain / discomfort) Ejaculation (pain / discomfort) Rosen R et al. Eur Urol 2003; 44: 637–649

12. 7.8 6.8 8.8 8.3 7.9 7.4 8.8 4.8 6.0 5.0 5.9 4.9 3.0 3.3 2.6 2.5 3.6 3.7 2.8 0 2 4 6 8 10 USFRDEITNLSPUK 50-59 y.60-69 y.70-80 y. Mean Sexual Activity per Mo 12,815 men aged 50-80 y. Representative sample Sexual Activity in the Ageing Male MSAM-7 Rosen R et al. Eur Urol 2003; 44: 637–649

13. MSAM-7: LUTS have a negative impact on sexual function reducing sexual activity reducing stiffness of erection decreasing volume of ejaculate LUTS have a negative impact by Sexual impact of LUTS Rosen R et al. Eur Urol 2003; 44: 637–649

14. 0 10 20 30 40 50 60 % Sexually inactive patients 7% 9% 11% 27% 50-59 years 9% 15% 17% 21% 60-69 years 30% 35% 33% 48% 70-79 years Richard F et al., J Urol 2000; 163:249A 01-78-1920-35 points IPSS 2,372 French men IIEF Severity of LUTS Impacts Sexual Activity

15. 0 2 4 6 8 10 12 14 16 % OPENTURPTUIPILCTUNATUMT 0 10 20 30 40 50 60 70 80 90 100 OPENTURPTUIPILCTUNA TUMT Impotence Retrograde ejaculation % McConnell - BPH Clinical Practice Guidelines, 1994 Surgery and Instrumental Procedures may Impact Sexual Function

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

17. VA study (Lepor et al) PROWESS (Marberger et al) PLESS study (McConnell et al) Duration1yr Placebo Fina n=305 n=310 % 2yrs Placebo Fina n=1,591 n=1,577 % Year 1 Placebo Fina n=1,376 n=1,384 % Decreased libido 1.0 5.02.8 4.03.46.4 Impotence5.0 9.04.7 6.63.78.1 Decreased ejaculation NA 0.8 3.7 Ejaculation disorder 1.0 2.00.6 2.10.1 0.8 5  -Reductase  Impotence Double-Blind Placebo-Controlled Studies

18. Ejaculatory Abnormality Decreased Libido Impotence VA: 1 Year 0 5 10 % 0 5 % 0 5 % Pbo F T T+F p<0.001 p=0.05 ALFIN: 6 months 0 5 10 % 0 5 % 0 5 % FAA+F p=0.04 ns p<0.002 Debruyne FMJ et al. Eur Urol 1998;34:169 F: Finasteride A: Alfuzosin Pbo: Placebo T: Terazosin Lepor H et al. NEJM 1996;335:533 Sexual Function  Direct Comparative Studies (  1 Blocker/Finasteride)

19. VA (n=1,229) PREDICT (n=1,094) ALFORTI (n=447) %% ALFUS (n=536) % Terazosin6.0 - - - Doxazosin5.8 - - Alfuzosin - - 10mg: 0.0 10mg: 2.8 15mg: 1.1 Placebo5.03.3 0.6 1.1  1 -Blockers  Impotence Double-Blind Placebo-Controlled Studies

20. 10mg OD n=143 0% Alfuzosin 0% Van Kerrebroeck et al., Eur Urol 2000; 37:306-313 Placebo n=154 2.5mg TID n=150 Impotence0.6%0% Decreased libido0.6%0.7% Alfuzosin Abnormal ejaculation0% Sexual Function with Alfuzosin: ALFORTI Study

21. 0 5 10 15 20 Abnormal ejaculation (%) Tamsulosin (3 months) *p < 0.001 Alfuzosin OD (3 months) 0 5 10 15 20 ns Lepor et al. Urology 1998;51:892-900 * Tam 0.8 mg 18% Pbo 0% Pbo 0% Alf 10 mg 0.6% Alf 15 mg 0.6% Tam 0.4 mg 6% * Roehrborn et al. Urology 2001;58:953  1 -Blockers  Ejaculatory Disorders US Pivotal Studies with Tamsulosin  Alfuzosin

22. *Narayan P. et al. Urology 1998 **Schulman C. et al J Urol 2001 ***Van Kerrebroeck et al. Eur Urol. 2000 0.4-0.8 mg OD US open study with tamsulosin 0.4-0.8 mg OD * Mean exposure time: 16 months Tamsulosin 0.4 mg OD European open study with tamsulosin 0.4 mg OD ** Mean exposure time: 4 years Tamsulosin European open study with alfuzosin 10 mg OD *** Mean exposure time: 9 months Alfuzosin 30% 0.6%  1 -Blockers  Ejaculatory Disorders Long-Term Studies with Tamsulosin  Alfuzosin 4.9%

23. van Kerrebroeck et al. Eur Urol 2002 Narayan et al. Urology 2001 Schulman et al. J Urol 2001 Exposure time 12 months 16 months4 years % % % Abnormal Ejaculation Impotence 1.4 6 5.4 Decreased Libido 0.3 NA 1.2 Alfuzosin 10 mg Tamsulosin 0.4-0.8 mg Tamsulosin 0.4 mg 0.6 30 4.9  1 -Blockers  Ejaculatory Disorders Long-Term Studies with Tamsulosin  Alfuzosin

24. DAN-PSSsex Reduced Ejaculate, a Problem 0 10 20 30 40 50 60 70 80 90 100 No Mild Moderate Severe No Mild Moderate Severe No Mild Moderate Severe In % 39 54 71 85 44 52 66 80 54 50 66 76 50 - 59 years 60 - 69 years 70 - 79 years LUTS Men with ejaculatory dysfunction (n=6,023)

25. Alfuzosin has the Lowest Impact on Sexuality… Does Alfuzosin have a Beneficial Effect on Sexuality ?

26. Sexual Function Following 1 Year Treatment with Alfuzosin 0 1 2 3 4 5 6 7 < 65 years65-70 years> 70 years Moderate symptomsSevere symptoms Improvement in Sexual Score Lukacs B et al. Urology, 1996; 48 (5): 731-740

27. Alfuzosin 10 mg XL may Improve Sexual Dysfunction DAN-PSSsex - J. Urol. 2006, 176, 1051-1056 1 2 3 Weighted score Reduced erection Reduced ejaculate Painful ejaculate D0Dend 2.0 1.7 2.6 * 2.3 * 1.5 * pvsD0 < 0.01 ** p vsD0 < 0.05 ** n = 310

28. Local Factors Treatments Deterioration in QoL Deterioration in Self-Image Deterioration in Sexuality Correlated Factors eg. age How can BPH Interfere with Sexuality? Anxiety

29. Improvemen t in QoL Sexuality How might  -Blockers Impact on Sexuality? Reduction of Anxiety Pharmacological Impact ? Local Factors Improvement in Self-Image

30. 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.

31. Placebo Alfuzosin 10mg OD Tamsulosin 0.8 mg OD Mean±sd value at baseline 3.4±1.4 ml Mean±sd value at baseline 48±0.5 million/ml +0.4 +0.3 -2.4 * +1.4 +1.2 +1.7 *Tam vs Pbo, p<0.001 Tam vs Alfu, p<0.001 p=ns Change in ejaculate volume Change in urine sperm concetration ABEJAC Results -3 -2 0 1 2 3 Change in ejaculate volume (ml) J Urol. 2006 Oct;176(4 Pt 1):1529-33.

32. Intent to treat population Placebo Alfuzosin 10mg OD Tamsulosin 0.8 mg OD % subjects with no ejaculation 0% 35% % with decreased ejaculate volume >20% 13% 21% 90% *Tam vs Pbo, p<0.001 Tam vs Alfu, p<0.001 * ABEJAC Results 0 20 40 60 80 100 % of subjects J Urol. 2006 Oct;176(4 Pt 1):1529-33.

33. –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. ABEJAC Conclusions 1 Giuliano et al. BJU Int. 2004 : 93:605-8 2 Tambaroa et al. J.Pharmacol. Exp. Therap. 2005 3 Giuliano et al. EAU 2005 (abstract 141)

34. –The mechanism by which tamsulosin impairs ejaculation may be a peripheral effect on seminal vesicles and/or on vas deferens 1-2. –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 ejaculation 3. ABEJAC Conclusions 1 Giuliano et al. BJU Int. 2004 : 93:605-8 2 Tambaroa et al. J.Pharmacol. Exp. Therap. 2005 3 Giuliano et al. EAU 2005 (abstract 141)

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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

41. Conclusion The results suggest that tamsulosin has a negative impact on sperm in healthy men. Studies on the effects of alpha1- adrenergic blockers on sperm in men with BPH are warranted. Published-Ahead-of-Print on February 5, 2009 by Journal of Andrology

42. How can we Explain Differences Between  1 -Blockers ?

43. Potential Targets for  -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.

44. Alfuzosin Does not Penetrate the Blood-Brain Barrier Rouquier et al, Eur. J. Pharmacol, 1994, 261, 59-64

45. The Physiology Of Ejaculation: The Emission Phase Mann and Lutwak-Mann. Male reproductive function and semen. Berlin:Springer-Verlag;1981:171-93. Emission: seminal vesicle (50-80%) prostate (15-30%) Cowper’s gland testis (<0.1%)

46.  1 -ARs and Seminal Emission The  1 -AR subtype involved in contraction of the human vas deferens and seminal vesicle is most probably the  1A -AR. –SV is responsible for 70% of the amount of ejaculate Silva MA et al. Eur J Pharmacol 1999

47.  1 -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  1 -ARs, The degree to which an  1 -AR antagonist relaxes the bladder neck may give rise to retrograde ejaculation.

48. Effects of  -Blockers on Seminal Vesicle Pressure 0 40 80 120 Vehicle310 *p <0.001 310 Tamsulosin (µg/kg) Alfuzosin (µg/kg) * * F. Giuliano et al., ISSIR 2002

49. Differential Effects of  -Blockers on Ductus Deferens Contraction K.-E. Andersson

50. Peripheral Mechanisms Involved in Erection  -AR Antagonism All  1 -AR subtypes (  1A,  1B,  1D,  1L ) can be demonstrated in human penile erectile tissues It has not been established if one subtype is more important than the others