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New approaches to male non-hormonal contraception

      Abstract

      A non-hormonal male contraceptive is a contraceptive that does not involve the administration of hormones or hormone blockers. This review will focus on the use of lonidamine derivatives and inhibitors of retinoic acid biosynthesis and function as approaches to male non-hormonal contraception. Two current lonidamine derivatives, adjudin and H2-gamendazole, are in development as male contraceptives. These potent anti-spermatogenic compounds impair the integrity of the apical ectoplasmic specialization, resulting in premature spermiation and infertility. Another approach to male contraceptive development is the inhibition of retinoic acid in the testes, as retinoic acid signaling is necessary for spermatogenesis. The administration of the retinoic acid receptor antagonist BMS-189453 reversibly inhibits spermatogenesis in mice. Similarly, oral dosing of WIN 18,446, which inhibits testicular retinoic acid biosynthesis, effectively contracepts rabbits. Hopefully, one of these approaches to non-hormonal male contraception will prove to be safe and effective in future clinical trials.

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      References

      1. Population Division of the Department of Economic and Social Affairs of the United Nations Secretariat. World Population prospects: the 2008 revision.
        (Available at) (Retrieved 09/30/11)
        • Speidel J.J.
        • Grossman R.A.
        Addressing global health, economic, and environmental problems through family planning.
        Obstet Gynecol. 2011; 117: 1394-1398
        • Singh S.
        • Sedgh G.
        • Hussain R.
        Unintended pregnancy: worldwide levels, trends and outcomes.
        Stud Fam Plann. 2010; 41: 241-250
        • Shah I.
        • Ahman E.
        Unsafe abortion in 2008: global and regional level and trends.
        Reprod Health Matters. 2010; 18: 90-101
        • Singh S.
        • Darroch M.E.
        • Ashford L.S.
        • Vlassoff M.
        Adding it up: the costs and benefits of investing in family planning and maternal and newborn health.
        Alan Guttmacher Institute, New York (NY)2009
        • Piccinino L.J.
        • Mosher W.D.
        Trends in contraceptive use in the United States: 1982:1995.
        Fam Plan Persp. 1998; 30: 4-10
        • Trussell J.
        • Vaughan B.
        Contraceptive failure, method-related discontinuation and resumption of use: results from the 1995 National Survey of Family Growth.
        Fam Plann Perspect. 1999; 31: 64-72
        • Li S.-Q.
        • Goldstein M.
        • Shu J.
        • Huber D.H.
        The no-scalpel vasectomy.
        J Urol. 1991; 145: 341-344
        • Martin C.W.
        • Anderson R.A.
        • Cheng L.
        • et al.
        Potential impact of hormonal male contraception: cross-cultural implications for development of novel male preparations.
        Hum Reprod. 2000; 15: 637-645
        • Heinemann K.
        • Saad F.
        • Wiesemes M.
        • White S.
        • Heinemann L.
        Attitudes towards male fertility control: results of a multinational survey on four continents.
        Hum Reprod. 2005; 20: 549-556
        • Glasier A.F.
        • Anakwe R.
        • Everington D.
        • et al.
        Would women trust their partners to use a male pill?.
        Hum Reprod. 2000; 15: 646-649
        • Cheng C.Y.
        • Silvestrini B.
        • Grima J.
        • et al.
        Two new male contraceptives exert their effects by depleting germ cells prematurely from the testis.
        Biol Reprod. 2001; 65: 449-461
        • Cheng G.Y.
        • Mruk D.
        Testin and actin are key molecular targets of adjudin, an anti-spermatogenic agent, in the testes.
        Spermatogenesis. 2011; 1: 137-146
        • Mok K.-W.
        • Mruk D.D.
        • Lie P.P.Y.
        • Lui W.-Y.
        • Cheng C.Y.
        Adjudin, a potential male contraceptive, exerts its effects locally in the seminiferous epithelium of mammalian testes.
        Reproduction. 2011; 141: 571-580
        • Mruk D.D.
        • Wong C.H.
        • Silvestrini B.
        • Cheng C.Y.
        A male contraceptive targeting germ cell adhesion.
        Nat Med. 2006; 12: 1323-1328
        • Tash J.S.
        • Attardi B.
        • Hild S.A.
        • Chakrasali R.
        • Jakkaraj S.R.
        • Georg G.I.
        A novel potent indazole carboxylic acid derivative blocks spermatogenesis and is contraceptive in rats after a single oral dose.
        Biol Reprod. 2008; 78: 1127-1138
        • Tash J.S.
        • Chakrasali R.
        • Jakkaraj S.R.
        • et al.
        Gamendazole, an orally active indazole carboxylic acid male contraceptive agent, targets HSP90AB1 and EEF1A1, and stimulates II1a transcription in rat Sertoli cells.
        Biol Reprod. 2008; 78: 1139-1152
        • Wolbach S.B.
        • Howe P.R.
        Tissue changes following deprivation of fat soluble A vitamin.
        J Exp Med. 1925; 42: 753-777
        • Vernet N.
        • Dennefeld C.
        • Rochett-Egly C.
        • et al.
        Retinoic acid metabolism and signaling pathways in the adult and developing mouse testis.
        Endocrinology. 2006; 147: 96-110
        • Koubova J.
        • Menke D.
        • Zhou Q.
        • Capel B.
        • Griswold M.D.
        • Page D.C.
        Retinoic acid regulates sex-specific timing of meiotic initiation in mice.
        Proc Natl Acad Sci USA. 2006; 103: 2472-2479
        • Dufour J.M.
        • Kim K.H.
        Cellular and subcellular localization of six retinoid receptors in rat testis during postnatal devlopment: identification of potential heterimeric receptors.
        Biol Reprod. 1999; 61: 1300-1308
        • Lufkin T.
        • Lohnes D.
        • Mark M.
        • et al.
        High postnatal lethality and testis degeneration in retinoic acid receptor alpha mutant mice.
        Proc Natl Acad Sci USA. 1993; 90: 7225-7229
        • Lohnes D.
        • Kastner P.
        • Dierich A.
        • Mark M.
        • LeMeur M.
        • Chambon P.
        Function of retinoic acid receptor gamma in the mouse.
        Cell. 1993; 73: 643-658
        • Kastner P.
        • Mark M.
        • Leid M.
        • et al.
        Abnormal spermatogenesis in RXR beta mutant mice.
        Genes Dev. 1996; 10: 80-92
        • Schulze G.E.
        • Clay R.J.
        • Mezza L.E.
        • Bregman C.L.
        • Buroker R.A.
        • Frantz J.D.
        BMS-189453, a novel retinoid receptor antagonist, is a potent testicular toxin.
        Toxicol Sci. 2001; 59: 297-308
        • Chung S.S.
        • Wang X.
        • Roberts S.S.
        • Griffey S.M.
        • Reczek P.R.
        • Wolgemuth D.J.
        Oral administration of a retinoic acid receptor antagonist reversibly inhibits spermatogenesis in mice.
        Endocrinology. 2011; 152: 2492-2502
        • Chung S.S.
        • Sung W.
        • Wang X.
        • Wolgemuth D.J.
        Retinoic acid receptor alpha is required for synchronization of spermatogenic cycles and its absence results in progressive breakdown of the spermatogenic process.
        Dev Dyn. 2004; 230: 754-766
        • Chung S.S.
        • Wang X.
        • Wolgemuth D.J.
        Male sterility in mice lacking retinoic acid receptor alpha involves specific abnormalties in spermiogenesis.
        Differentiation. 2005; 73: 188-198
        • Heller C.G.
        • Moore D.J.
        • Paulsen C.A.
        Suppression of spermatogenesis and chronic toxicity in men by a new series of bis (dichloroacetyl) diamines.
        Toxicol Appl Pharmacol. 1961; 3: 1-11
        • Coulston F.
        • Beyler A.L.
        • Drobeck H.P.
        The biologic actions of a new series of bis(dichloroacetyl) diamines.
        Toxicol Appl Pharmacol. 1960; 2: 715-721
        • Beyler A.L.
        • Potts G.O.
        • Coulston F.
        • Surrey A.R.
        The selective testicular effects of certain bis-(dichloroacetyl) diamines.
        Endocrinology. 1961; 69: 819-833
        • Heller C.G.
        • Flageolle B.Y.
        • Matson L.J.
        Histopathology of the human testes as affected by bis (dichloroacetyl) diamines.
        Exp Mol Path. 1963; 2: 107-114
        • World Health Organization
        Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men.
        Fertil Steril. 1996; 65: 821-829
        • Amory J.K.
        • Muller C.H.
        • Shimshoni A.J.
        • et al.
        Suppression of spermatogenesis by bisdichloroacetyldiamines is mediated by inhibition of testicular retinoic acid biosynthesis.
        J Androl. 2011; 32: 111-119