Is there a Future for Male Contraception?

Transcription

1 Hormonal Contraception for Men Past and Future Regine Sitruk -Ware, MD Rockefeller University Population Council, New-York, NY European Society for Contraception Istanbul, Turkey, May 3-6, 2006 Use of Contraceptive Methods in Western Europe and USA (%) Methods W. Europe USA Oral contraceptives IUD 10 <1 Sterilization 6 37 Condom 6 13 Barrier (female) <1 2 Natural/other 4 6 Is there a Future for Male Contraception? Is there a demand? Are men interested? Source: UN 2004 Mexico 1024 USA 1500 Spain Men Study Germany 1021 France 725 Sweden 1023 Indonesia 1000 Decision on Contraceptive Method Both 72% Man 7% Argentina 1000 Brazil 1000 Heinemann et al, Hum Reprod 2005 Woman 21% Courtesy of FaridSaad Schering; Heinemann et al, Hum Reprod

2 % Willingness to Use New Male Method Europe U.S.A. Latin America Indonesia All Respondents Courtesy of FaridSaad Schering; Heinemann et al, Hum Reprod % 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Preferred Application Forms Desirable Uncertain Disapproving Daily Pill Daily Jelly Monthly Injection Annual Implant Courtesy of FaridSaad Schering; Heinemann et al, Hum Reprod 2005 Fýrst study-testosterone Injections New Hormonal Approaches Efficacy study on 271 men (WHO1990) T enanthate IM 200mg/week 63% reached azoospermia and used the method for contraception High efficacy [1 Pregnancy/ 1486 months; 0.8% w/yr] Side-effects of androgen: Acne (9), aggressiveness (3) Implanon (2) + TU IM 1000mg /4-6w Implanon + T pellets DMPA + T pellets every 3-4 mo Efficacy study in China TU 1g then 0.5g /4w 1,000 couples 9 pregnancies GnRH antagonist 12w + T Injections MENT implant + progestins 2

3 Selective Androgen Receptor Modulators for Male Contraception Should not convert into DHT: No effect on prostate Should aromatize in E2: Maintenance of bone and libido Should be active at low doses Androgen Metabolism in Prostate Testosterone (T) Dihydrotestosterone (DHT) Potency: 7 MEthyl 19-NorTestosterone (MENT) for Male Contraception A tissue-selective selective androgen OO 7a -methyl, 19-norT (MENT) 5a -reduced OO HH not reduced No change OO CH 3 OO CH 3 MENT will not undergo 5 -reduction but can be aromatized in estrogen 3

4 Rat osteoporosis model Prostate weights were lower with both low and mid dose of MENT. High dose induces prostate hypertrophy. MENT, at all doses prevented ORX-induced acceleration of bone remodeling (osteocalcin & DPD) and bone loss at spine, femur & total body. Coll with University of Leuven, B MENT implants Clinical study in volunteers MENT Implant Three doses tested, 1, 2, or 4 implants (400, 800 or 1,600 µg/d) 36 subjects followed for 6, 9 or 12 months Samples for MENT,T, LH, FSH, Sperm count, testicular and prostate volume at month 1, 2, 4, 6, 9, 12 S.Von Eckardstein et al JCEM 2003: 88:

5 Wang et al MENT (M) +Levonorgestrel (L) Conclusions 1) MENT Ac implants are a promising method for sustained supression of gonadotropins and spermatogenesis. 2) They can be effective for at least one year. 3) After initial suppression of spermatogenesis, the dose required is lower for continued suppression. 4) Dose-finding and efficacy/safety studies are warranted Progestin effect on FSH in men (E.Nieschlag et al, Ch.Wang et al) Dose-finding study testing the antigonadotropic effect of various progestins used for male contraception and tested at different doses with and without T in male volunteers Discovery of New targets The OMIC revolution Genomics and Proteomics to identify» Genes regulating specific reproductive targets» Enzymes, proteins, receptors, cofactors» Specific to the sperm or the ovum» Drugable by small molecules» Leading to non-hormonal methods of contraception Some Promising Targets on the Horizon Sperm proteins help entry in oviduct Motility-related targets : GAPDS (a sperm-specific glycolytic enzyme located in fibrosheatof flagellum) Binding to Zona Pellucida : ZP receptor on acrosome Proteins in Adherens junctions Epididymal factors 5

6 Further reading Anderson RA & Baird DT Endocrine Review, 2002; 23: 735 Kamischke A & Nieschlag E Trends in Pharm Sci, 2004; 25: 49 Collaborators and Co -Investigators Population Council Narender Kumar Sushma Kumar Esther Wu Irving Sivin K Sundaram YY Tsong Grants USAID, NIH CONRAD Mellon Foundation Hewlett Foundation ICCR R Anderson H. Croxatto & G. Noe F. Alvarez & V. Brache S. von Eckardstein A. Kamische Ebo Nieschlag Christina Wang Other Universities John Amory William Bremner Ron Swerdloff 6