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New Contraceptives for Men

New Contraceptives for Men. SWEET Seminar December 2007. Kirsten Thompson, Director Male Contraception Coalition Kirsten@MaleContraceptives.org www.IMCCoaltion.org. What we’ll cover today. Why family planning remains relevant Why male contraceptives are important

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New Contraceptives for Men

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  1. New Contraceptives for Men SWEET SeminarDecember 2007 Kirsten Thompson, DirectorMale Contraception CoalitionKirsten@MaleContraceptives.orgwww.IMCCoaltion.org

  2. What we’ll cover today • Why family planning remains relevant • Why male contraceptives are important • Evidence of a male contraceptive market • 5 male contraceptives in or approaching clinical trials

  3. What is a contraceptive? • Is contraception inherently inconvenient? • What doesn’t a contraceptive do?

  4. The big picture • Worldwide, fertility is declining • Desired family size is a moving target • Unmet need remains substantial • Method mix is a quality indicator • Dissatisfaction / discontinuation / lack of compliance with existing methods

  5. Do men want new options? We get letters every day from men around the world asking: “How can I get access to these new contraceptives?”

  6. Do men want new options? Over 40% of US couples rely on the currently available male contraceptives Source: CDC (2006) Health, United States

  7. Surveys say “Yes” • In 12 countries, the majority of men would use a new hormonal male contraceptive • 50% of US men • Men are motivated by desire to share family planning responsibility & have direct control over their fertility Sources: Martin (2000) Human Reproduction 15(3): 637-45.Heinemann (2005) Human Reproduction 20(2): 549-56.MCC (2007) Male Contraception Quarterly 3: 1-4.

  8. What do women think? Only 2-3% wouldn’t trust their partners to use a male contraceptive Sources: Glasier (2000) Human Reproduction 15(3): 646-9. MCC (2007) Male Contraception Quarterly 3: 1-4. KFF (1997) Men’s Role in Preventing Pregnancy.

  9. Which male contraceptives are closest to market? Three methods are in clinical trials: • RISUG • The Intra Vas Device (IVD) • Male hormonal contraceptives Two interesting pre-clinical leads: • Adjudin • RAR antagonist

  10. Vas-based methods

  11. RISUG – What is it? • A polymer gel injected into the vasa deferentia • Partially blocks the lumen and disrupts passing sperm • Now in Phase III clinical trials in India

  12. RISUG – How effective is it? • Extremely effective (>99%) 200+ men have been treated with RISUG 2 pregnancies: 1 due to improper delivery, 1 due to marital infidelity • Long-lasting The first clinical trial volunteers received RISUG in 1992; Informal follow-up visits show they still have effective contraception today Sources: Guha (1993) Contraception 48(4): 367-75. Guha (1997) Contraception 56(4): 245-50.

  13. RISUG – Side effects • Transient, painless scrotal swelling which resolves with no intervention within 2 weeks • Prostate indicators all healthy after 8 years of RISUG use in Phase II trial volunteers • Zero clinical trial attrition to date Source: Sharma (2001) Reproduction 122(3): 431-6.

  14. RISUG – How is it reversed? • Reversal proven in monkeys after 1½ years of use, all had normal sperm count within 3 months of reversal • Sodium bicarbonate solution • Multiple injections and reversals effective in monkeys • Not yet (formally) tested in men Sources: Lohiya (2000) Int J of Andrology 23(1): 36-42. Lohiya (2005) Contraception 71(3): 214-26.

  15. The IVD – What is it? • US design in Phase I trials: dual silicone plugs inserted into the vas block sperm • Chinese design has completed Phase II trials: single urethane stent filled with nylon mesh allows vasal fluid to pass but traps sperm

  16. IVD – How effective is it? • US design awaiting completion of trial; past designs 90-100% effective • Chinese design 100% effective, no pregnancies in 123 couples in 1 year • Like vasectomy, effective after 3 months • Sperm count required to confirm

  17. IVD – Side effects • Similar to “no scalpel vasectomy”, but less frequent and less severe • 10% reported mild pain, 3% developed granulomas • No spontaneous reversal, no congestive epididymitis • Higher satisfaction rate than NSV Source: Song (2006) Int J Andrology 29(4): 489-95.

  18. IVD – How is it reversed? • Reversal proven in primates after 7 months of use, all had normal sperm count within 1 month of reversal • Another 20 minute out-patient procedure required to remove, as opposed to 3-4 hours of microsurgery for vasovasostomy • Not yet tested in men Source: Zaneveld (1999) In Rajalakshmi & Griffin (eds.), Male Contraception: Present and Future, p. 293.

  19. Hormonal methods • Men’s and women’s hormones are analogous in function • LH stimulates T production in Leydig cells • FSH stimulates spermatid production when T is present • Blood-testis barrier regulates internal testes environment

  20. MHCs – What are they? • Supra-physiological dose of testosterone suppresses testicular production of T and halts spermatogenesis • May include a progestin for faster, more complete suppression • No orally available T; delivery via implants, depot injections, transdermal gels and patches

  21. MHCs – Formulations T-only formulations are more effective for Asian men

  22. MHCs – Formulations T + progestin formulations effective for all

  23. MHCs – How effective are they? • Varies by formulation and population • Two important trials: • WHO’s monthly im depot TU 97.7% effective in Chinese men • Monash Medical Center’s T pellets every 4 months + im DMPA every 3 months 100% effective in Australian men • 3-10% “Non-responders” Sources: Gu (2003) JCEM 88(2):562–568. Turner (2003) JCEM 88(10):4659–4667.

  24. MHCs – “Non-responders” • Central mystery of MHCsSome men keep producing sperm despite extreme suppression of FSH and LH • Theories: • genetic differences in androgen regulation • phytoestrogens in the diet • INSL3 production Source: Amory (2007) J Andrology E-pub ahead of print.

  25. MHCs – Side effects • Similar to side effects experienced by women on hormonal contraceptives • Mild weight gain, increase in lean muscle mass, acne • Drop in HDL cholesterol level with some androgens • No prostate over-stimulation observed in studies up to 18 months

  26. MHCs – How are they reversed? • Stop treatment, hormones begin rebound, spermatogenesis reinitiates • Meta analysis showed all formulations reliably reversible within 3-5 months • Minimum 2½ month recovery due to lag for production of mature sperm Source: Liu (2006) The Lancet 367: 1412–20.

  27. Interesting leads - Adjudin • Non-toxic lonidamine analog • Disrupts cellular bridges between spermatids and Sertoli cells • Clever targeted delivery by attaching Adjudin to a modified FSH • Population Council researchers working to improve delivery method and bring down production costs Source: Mruk (2006) Nature Medicine 12(11):1323-8.

  28. Interesting leads – RAR antagonist • Retinoic acid required for sperm production • 1 week of RAR antagonist treatment blocks sperm production for 3 months • 100% effective, no observable side effects, fully reversible • Researchers at Columbia University testing in other animal models Source: Wolgemuth (2007) Future of Male Contraception abstract.

  29. In summary • Men & women are ready for better options • Promising products in the pipeline • Investment in contraceptive technologies should remain part of the reproductive health agenda

  30. For more information • Explanations of emerging male contraceptives MaleContraceptives.org • Research community forumIMCCoalition.org

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