Skip to main content
Top
Published in: Drugs 1/2019

01-01-2019 | Leading Article

Recent Developments in Male Contraception

Authors: Arthi Thirumalai, Stephanie T. Page

Published in: Drugs | Issue 1/2019

Login to get access

Abstract

Unplanned pregnancies are an ongoing global burden, posing health and economic risks for women, children, and families. Advances in male contraception have been historically stymied by concerning failure rates, problematic side effects, and perceived market limitations. However, increased interest in reliable and reversible options for male contraception have resulted in resurgent efforts to introduce novel contraceptives for men. Hormonal male contraception relies on exogenous androgens and progestogens that suppress gonadotropin production, thereby suppressing testicular testosterone and sperm production. In many men, effective suppression of spermatogenesis can be achieved by androgen-progestin combination therapy. Small-scale contraceptive efficacy studies in couples have demonstrated effectiveness and reversibility with male hormonal methods, but side effects related to mood, sexual desire and cholesterol remain concerning. A number of novel androgens have reached clinical testing as potential contraceptive agents; many of these have both androgenic and progestogenic action in a single, modified steroid, thereby holding promise as single-agent contraceptives. Currently, these novel steroids hold promise as both a “male pill” and long-acting injections. Among non-hormonal methods, studies of reversible vaso-occlusive methods (polymers that block transport of sperm through the vas deferens) are ongoing, but reliable reversibility and long-term safety in men have not been established. Proteins involved in sperm maturation and motility are attractive targets, but to date both specificity and biologic redundancy have been challenges for drug development. In this review, we aim to summarize landmark studies on male contraception, highlight the most recent advances and future development in this important field of public health and medicine.
Literature
1.
go back to reference Bearak J, Popinchalk A, Alkema L, Sedgh G. Global, regional, and subregional trends in unintended pregnancy and its outcomes from 1990 to 2014: estimates from a Bayesian hierarchical model. Lancet Glob Health. 2018;6:e380–9.PubMedPubMedCentral Bearak J, Popinchalk A, Alkema L, Sedgh G. Global, regional, and subregional trends in unintended pregnancy and its outcomes from 1990 to 2014: estimates from a Bayesian hierarchical model. Lancet Glob Health. 2018;6:e380–9.PubMedPubMedCentral
2.
go back to reference Finer LB, Zolna MR. Declines in unintended pregnancy in the United States, 2008–2011. N Engl J Med. 2016;374:843–52.PubMedPubMedCentral Finer LB, Zolna MR. Declines in unintended pregnancy in the United States, 2008–2011. N Engl J Med. 2016;374:843–52.PubMedPubMedCentral
3.
go back to reference Sonfield A, Kost K, Gold RB, Finer LB. The public costs of births resulting from unintended pregnancies: national and state-level estimates. Perspect Sex Reprod Health. 2011;43:94–102.PubMed Sonfield A, Kost K, Gold RB, Finer LB. The public costs of births resulting from unintended pregnancies: national and state-level estimates. Perspect Sex Reprod Health. 2011;43:94–102.PubMed
4.
go back to reference Herd P, Higgins J, Sicinski K, Merkurieva I. The implications of unintended pregnancies for mental health in later life. Am J Public Health. 2016;106:421–9.PubMedPubMedCentral Herd P, Higgins J, Sicinski K, Merkurieva I. The implications of unintended pregnancies for mental health in later life. Am J Public Health. 2016;106:421–9.PubMedPubMedCentral
5.
go back to reference Wendt A, Gibbs CM, Peters S, Hogue CJ. Impact of increasing inter-pregnancy interval on maternal and infant health. Paediatr Perinat Epidemiol. 2012;26(Suppl 1):239–58.PubMedPubMedCentral Wendt A, Gibbs CM, Peters S, Hogue CJ. Impact of increasing inter-pregnancy interval on maternal and infant health. Paediatr Perinat Epidemiol. 2012;26(Suppl 1):239–58.PubMedPubMedCentral
8.
go back to reference Drake MJ, Mills IW, Cranston D. On the chequered history of vasectomy. BJU Int. 1999;84:475–81.PubMed Drake MJ, Mills IW, Cranston D. On the chequered history of vasectomy. BJU Int. 1999;84:475–81.PubMed
9.
go back to reference Sundaram A, Vaughan B, Kost K, Bankole A, Finer L, Singh S, Trussell J. Contraceptive failure in the United States: estimates from the 2006–2010 national survey of family growth. Perspect Sex Reprod Health. 2017;49:7–16.PubMedPubMedCentral Sundaram A, Vaughan B, Kost K, Bankole A, Finer L, Singh S, Trussell J. Contraceptive failure in the United States: estimates from the 2006–2010 national survey of family growth. Perspect Sex Reprod Health. 2017;49:7–16.PubMedPubMedCentral
11.
go back to reference World Health Organization Task Force on Methods for the Regulation of Male F. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil Steril. 1996;65:821–829. World Health Organization Task Force on Methods for the Regulation of Male F. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil Steril. 1996;65:821–829.
12.
go back to reference Martin CW, Anderson RA, Cheng L, Ho PC, van der Spuy Z, Smith KB, Glasier AF, Everington D, Baird DT. Potential impact of hormonal male contraception: cross-cultural implications for development of novel preparations. Hum Reprod. 2000;15:637–45.PubMed Martin CW, Anderson RA, Cheng L, Ho PC, van der Spuy Z, Smith KB, Glasier AF, Everington D, Baird DT. Potential impact of hormonal male contraception: cross-cultural implications for development of novel preparations. Hum Reprod. 2000;15:637–45.PubMed
13.
go back to reference Eberhardt J, van Wersch A, Meikle N. Attitudes towards the male contraceptive pill in men and women in casual and stable sexual relationships. J Fam Plann Reprod Health Care. 2009;35:161–5.PubMed Eberhardt J, van Wersch A, Meikle N. Attitudes towards the male contraceptive pill in men and women in casual and stable sexual relationships. J Fam Plann Reprod Health Care. 2009;35:161–5.PubMed
14.
go back to reference Matsumoto AM, Bremner WJ. Stimulation of sperm production by human chorionic gonadotropin after prolonged gonadotropin suppression in normal men. J Androl. 1985;6:137–43.PubMed Matsumoto AM, Bremner WJ. Stimulation of sperm production by human chorionic gonadotropin after prolonged gonadotropin suppression in normal men. J Androl. 1985;6:137–43.PubMed
15.
go back to reference Coviello AD, Bremner WJ, Matsumoto AM, Herbst KL, Amory JK, Anawalt BD, Yan X, Brown TR, Wright WW, Zirkin BR, Jarow JP. Intratesticular testosterone concentrations comparable with serum levels are not sufficient to maintain normal sperm production in men receiving a hormonal contraceptive regimen. J Androl. 2004;25:931–8.PubMed Coviello AD, Bremner WJ, Matsumoto AM, Herbst KL, Amory JK, Anawalt BD, Yan X, Brown TR, Wright WW, Zirkin BR, Jarow JP. Intratesticular testosterone concentrations comparable with serum levels are not sufficient to maintain normal sperm production in men receiving a hormonal contraceptive regimen. J Androl. 2004;25:931–8.PubMed
16.
go back to reference Liu PY, Swerdloff RS, Anawalt BD, Anderson RA, Bremner WJ, Elliesen J, Gu YQ, Kersemaekers WM, McLachlan RI, Meriggiola MC, Nieschlag E, Sitruk-Ware R, Vogelsong K, Wang XH, Wu FC, Zitzmann M, Handelsman DJ, Wang C. Determinants of the rate and extent of spermatogenic suppression during hormonal male contraception: an integrated analysis. J Clin Endocrinol Metab. 2008;93:1774–83.PubMedPubMedCentral Liu PY, Swerdloff RS, Anawalt BD, Anderson RA, Bremner WJ, Elliesen J, Gu YQ, Kersemaekers WM, McLachlan RI, Meriggiola MC, Nieschlag E, Sitruk-Ware R, Vogelsong K, Wang XH, Wu FC, Zitzmann M, Handelsman DJ, Wang C. Determinants of the rate and extent of spermatogenic suppression during hormonal male contraception: an integrated analysis. J Clin Endocrinol Metab. 2008;93:1774–83.PubMedPubMedCentral
17.
go back to reference Nieschlag E. Clinical trials in male hormonal contraception. Contraception. 2010;82:457–70.PubMed Nieschlag E. Clinical trials in male hormonal contraception. Contraception. 2010;82:457–70.PubMed
19.
go back to reference Roth MY, Page ST, Bremner WJ. Male hormonal contraception: looking back and moving forward. Andrology. 2016;4:4–12.PubMed Roth MY, Page ST, Bremner WJ. Male hormonal contraception: looking back and moving forward. Andrology. 2016;4:4–12.PubMed
20.
go back to reference Wang C, Festin MP, Swerdloff RS. Male hormonal contraception: where are we now? Curr Obstet Gynecol Rep. 2016;5:38–47.PubMedPubMedCentral Wang C, Festin MP, Swerdloff RS. Male hormonal contraception: where are we now? Curr Obstet Gynecol Rep. 2016;5:38–47.PubMedPubMedCentral
21.
go back to reference Contraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on methods for the regulation of male fertility. Lancet. 1990;336:955–9. Contraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on methods for the regulation of male fertility. Lancet. 1990;336:955–9.
22.
go back to reference McLachlan RI, McDonald J, Rushford D, Robertson DM, Garrett C, Baker HW. Efficacy and acceptability of testosterone implants, alone or in combination with a 5alpha-reductase inhibitor, for male hormonal contraception. Contraception. 2000;62:73–8.PubMed McLachlan RI, McDonald J, Rushford D, Robertson DM, Garrett C, Baker HW. Efficacy and acceptability of testosterone implants, alone or in combination with a 5alpha-reductase inhibitor, for male hormonal contraception. Contraception. 2000;62:73–8.PubMed
23.
go back to reference Turner L, Conway AJ, Jimenez M, Liu PY, Forbes E, McLachlan RI, Handelsman DJ. Contraceptive efficacy of a depot progestin and androgen combination in men. J Clin Endocrinol Metab. 2003;88:4659–67.PubMed Turner L, Conway AJ, Jimenez M, Liu PY, Forbes E, McLachlan RI, Handelsman DJ. Contraceptive efficacy of a depot progestin and androgen combination in men. J Clin Endocrinol Metab. 2003;88:4659–67.PubMed
24.
go back to reference Gu YQ, Wang XH, Xu D, Peng L, Cheng LF, Huang MK, Huang ZJ, Zhang GY. A multicenter contraceptive efficacy study of injectable testosterone undecanoate in healthy Chinese men. J Clin Endocrinol Metab. 2003;88:562–8.PubMed Gu YQ, Wang XH, Xu D, Peng L, Cheng LF, Huang MK, Huang ZJ, Zhang GY. A multicenter contraceptive efficacy study of injectable testosterone undecanoate in healthy Chinese men. J Clin Endocrinol Metab. 2003;88:562–8.PubMed
25.
go back to reference Gu Y, Liang X, Wu W, Liu M, Song S, Cheng L, Bo L, Xiong C, Wang X, Liu X, Peng L, Yao K. Multicenter contraceptive efficacy trial of injectable testosterone undecanoate in Chinese men. J Clin Endocrinol Metab. 2009;94:1910–5.PubMed Gu Y, Liang X, Wu W, Liu M, Song S, Cheng L, Bo L, Xiong C, Wang X, Liu X, Peng L, Yao K. Multicenter contraceptive efficacy trial of injectable testosterone undecanoate in Chinese men. J Clin Endocrinol Metab. 2009;94:1910–5.PubMed
26.
go back to reference Soufir JC, Meduri G, Ziyyat A. Spermatogenetic inhibition in men taking a combination of oral medroxyprogesterone acetate and percutaneous testosterone as a male contraceptive method. Hum Reprod. 2011;26:1708–14.PubMed Soufir JC, Meduri G, Ziyyat A. Spermatogenetic inhibition in men taking a combination of oral medroxyprogesterone acetate and percutaneous testosterone as a male contraceptive method. Hum Reprod. 2011;26:1708–14.PubMed
27.
go back to reference Behre HM, Zitzmann M, Anderson RA, Handelsman DJ, Lestari SW, McLachlan RI, Meriggiola MC, Misro MM, Noe G, Wu FC, Festin MP, Habib NA, Vogelsong KM, Callahan MM, Linton KA, Colvard DS. Efficacy and safety of an injectable combination hormonal contraceptive for men. J Clin Endocrinol Metab. 2016;101:4779–88.PubMed Behre HM, Zitzmann M, Anderson RA, Handelsman DJ, Lestari SW, McLachlan RI, Meriggiola MC, Misro MM, Noe G, Wu FC, Festin MP, Habib NA, Vogelsong KM, Callahan MM, Linton KA, Colvard DS. Efficacy and safety of an injectable combination hormonal contraceptive for men. J Clin Endocrinol Metab. 2016;101:4779–88.PubMed
28.
go back to reference Zhang FP, Pakarainen T, Poutanen M, Toppari J, Huhtaniemi I. The low gonadotropin-independent constitutive production of testicular testosterone is sufficient to maintain spermatogenesis. Proc Natl Acad Sci USA. 2003;100:13692–7.PubMed Zhang FP, Pakarainen T, Poutanen M, Toppari J, Huhtaniemi I. The low gonadotropin-independent constitutive production of testicular testosterone is sufficient to maintain spermatogenesis. Proc Natl Acad Sci USA. 2003;100:13692–7.PubMed
29.
go back to reference Tom L, Bhasin S, Salameh W, Steiner B, Peterson M, Sokol RZ, Rivier J, Vale W, Swerdloff RS. Induction of azoospermia in normal men with combined Nal-Glu gonadotropin-releasing hormone antagonist and testosterone enanthate. J Clin Endocrinol Metab. 1992;75:476–83.PubMed Tom L, Bhasin S, Salameh W, Steiner B, Peterson M, Sokol RZ, Rivier J, Vale W, Swerdloff RS. Induction of azoospermia in normal men with combined Nal-Glu gonadotropin-releasing hormone antagonist and testosterone enanthate. J Clin Endocrinol Metab. 1992;75:476–83.PubMed
30.
go back to reference Pavlou SN, Brewer K, Farley MG, Lindner J, Bastias MC, Rogers BJ, Swift LL, Rivier JE, Vale WW, Conn PM, et al. Combined administration of a gonadotropin-releasing hormone antagonist and testosterone in men induces reversible azoospermia without loss of libido. J Clin Endocrinol Metab. 1991;73:1360–9.PubMed Pavlou SN, Brewer K, Farley MG, Lindner J, Bastias MC, Rogers BJ, Swift LL, Rivier JE, Vale WW, Conn PM, et al. Combined administration of a gonadotropin-releasing hormone antagonist and testosterone in men induces reversible azoospermia without loss of libido. J Clin Endocrinol Metab. 1991;73:1360–9.PubMed
31.
go back to reference Bagatell CJ, Matsumoto AM, Christensen RB, Rivier JE, Bremner WJ. Comparison of a gonadotropin releasing-hormone antagonist plus testosterone (T) versus T alone as potential male contraceptive regimens. J Clin Endocrinol Metab. 1993;77:427–32.PubMed Bagatell CJ, Matsumoto AM, Christensen RB, Rivier JE, Bremner WJ. Comparison of a gonadotropin releasing-hormone antagonist plus testosterone (T) versus T alone as potential male contraceptive regimens. J Clin Endocrinol Metab. 1993;77:427–32.PubMed
32.
go back to reference Behre HM, Kliesch S, Lemcke B, von Eckardstein S, Nieschlag E. Suppression of spermatogenesis to azoospermia by combined administration of GnRH antagonist and 19-nortestosterone cannot be maintained by this non-aromatizable androgen alone. Hum Reprod. 2001;16:2570–7.PubMed Behre HM, Kliesch S, Lemcke B, von Eckardstein S, Nieschlag E. Suppression of spermatogenesis to azoospermia by combined administration of GnRH antagonist and 19-nortestosterone cannot be maintained by this non-aromatizable androgen alone. Hum Reprod. 2001;16:2570–7.PubMed
33.
go back to reference Page ST, Amory JK, Anawalt BD, Irwig MS, Brockenbrough AT, Matsumoto AM, Bremner WJ. Testosterone gel combined with depomedroxyprogesterone acetate is an effective male hormonal contraceptive regimen and is not enhanced by the addition of a GnRH antagonist. J Clin Endocrinol Metab. 2006;91:4374–80.PubMed Page ST, Amory JK, Anawalt BD, Irwig MS, Brockenbrough AT, Matsumoto AM, Bremner WJ. Testosterone gel combined with depomedroxyprogesterone acetate is an effective male hormonal contraceptive regimen and is not enhanced by the addition of a GnRH antagonist. J Clin Endocrinol Metab. 2006;91:4374–80.PubMed
34.
go back to reference Attardi BJ, Hild SA, Koduri S, Pham T, Pessaint L, Engbring J, Till B, Gropp D, Semon A, Reel JR. The potent synthetic androgens, dimethandrolone (7alpha,11beta-dimethyl-19-nortestosterone) and 11beta-methyl-19-nortestosterone, do not require 5alpha-reduction to exert their maximal androgenic effects. J Steroid Biochem Mol Biol. 2010;122:212–8.PubMedPubMedCentral Attardi BJ, Hild SA, Koduri S, Pham T, Pessaint L, Engbring J, Till B, Gropp D, Semon A, Reel JR. The potent synthetic androgens, dimethandrolone (7alpha,11beta-dimethyl-19-nortestosterone) and 11beta-methyl-19-nortestosterone, do not require 5alpha-reduction to exert their maximal androgenic effects. J Steroid Biochem Mol Biol. 2010;122:212–8.PubMedPubMedCentral
35.
go back to reference Attardi BJ, Pham TC, Radler LC, Burgenson J, Hild SA, Reel JR. Dimethandrolone (7alpha,11beta-dimethyl-19-nortestosterone) and 11beta-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase. J Steroid Biochem Mol Biol. 2008;110:214–22.PubMedPubMedCentral Attardi BJ, Pham TC, Radler LC, Burgenson J, Hild SA, Reel JR. Dimethandrolone (7alpha,11beta-dimethyl-19-nortestosterone) and 11beta-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase. J Steroid Biochem Mol Biol. 2008;110:214–22.PubMedPubMedCentral
36.
go back to reference Attardi BJ, Hild SA, Reel JR. Dimethandrolone undecanoate: a new potent orally active androgen with progestational activity. Endocrinology. 2006;147:3016–26.PubMed Attardi BJ, Hild SA, Reel JR. Dimethandrolone undecanoate: a new potent orally active androgen with progestational activity. Endocrinology. 2006;147:3016–26.PubMed
37.
go back to reference Attardi BJ, Marck BT, Matsumoto AM, Koduri S, Hild SA. Long-term effects of dimethandrolone 17beta-undecanoate and 11beta-methyl-19-nortestosterone 17beta-dodecylcarbonate on body composition, bone mineral density, serum gonadotropins, and androgenic/anabolic activity in castrated male rats. J Androl. 2011;32:183–92.PubMed Attardi BJ, Marck BT, Matsumoto AM, Koduri S, Hild SA. Long-term effects of dimethandrolone 17beta-undecanoate and 11beta-methyl-19-nortestosterone 17beta-dodecylcarbonate on body composition, bone mineral density, serum gonadotropins, and androgenic/anabolic activity in castrated male rats. J Androl. 2011;32:183–92.PubMed
38.
go back to reference Hild SA, Attardi BJ, Koduri S, Till BA, Reel JR. Effects of synthetic androgens on liver function using the rabbit as a model. J Androl. 2010;31:472–81.PubMedPubMedCentral Hild SA, Attardi BJ, Koduri S, Till BA, Reel JR. Effects of synthetic androgens on liver function using the rabbit as a model. J Androl. 2010;31:472–81.PubMedPubMedCentral
39.
go back to reference Hild SA, Marshall GR, Attardi BJ, Hess RA, Schlatt S, Simorangkir DR, Ramaswamy S, Koduri S, Reel JR, Plant TM. Development of l-CDB-4022 as a nonsteroidal male oral contraceptive: induction and recovery from severe oligospermia in the adult male cynomolgus monkey (Macaca fascicularis). Endocrinology. 2007;148:1784–96.PubMed Hild SA, Marshall GR, Attardi BJ, Hess RA, Schlatt S, Simorangkir DR, Ramaswamy S, Koduri S, Reel JR, Plant TM. Development of l-CDB-4022 as a nonsteroidal male oral contraceptive: induction and recovery from severe oligospermia in the adult male cynomolgus monkey (Macaca fascicularis). Endocrinology. 2007;148:1784–96.PubMed
40.
go back to reference Ayoub R, Page ST, Swerdloff RS, Liu PY, Amory JK, Leung A, Hull L, Blithe D, Christy A, Chao JH, Bremner WJ, Wang C. Comparison of the single dose pharmacokinetics, pharmacodynamics, and safety of two novel oral formulations of dimethandrolone undecanoate (DMAU): a potential oral, male contraceptive. Andrology. 2017;5:278–85.PubMed Ayoub R, Page ST, Swerdloff RS, Liu PY, Amory JK, Leung A, Hull L, Blithe D, Christy A, Chao JH, Bremner WJ, Wang C. Comparison of the single dose pharmacokinetics, pharmacodynamics, and safety of two novel oral formulations of dimethandrolone undecanoate (DMAU): a potential oral, male contraceptive. Andrology. 2017;5:278–85.PubMed
41.
go back to reference Thirumalai A, Ceponis J, Amory JK, Swerdloff R, Surampudi V, Liu PY, Bremner WJ, Harvey E, Blithe DL, Lee MS, Hull L, Wang C, Page ST. Effects of 28 days of oral dimethandrolone undecanoate in healthy men: a prototype male pill. J Clin Endocrinol Metab. 2018. https://doi.org/10.1210/jc.2018-01452.CrossRef Thirumalai A, Ceponis J, Amory JK, Swerdloff R, Surampudi V, Liu PY, Bremner WJ, Harvey E, Blithe DL, Lee MS, Hull L, Wang C, Page ST. Effects of 28 days of oral dimethandrolone undecanoate in healthy men: a prototype male pill. J Clin Endocrinol Metab. 2018. https://​doi.​org/​10.​1210/​jc.​2018-01452.CrossRef
43.
go back to reference Kumar N, Didolkar AK, Monder C, Bardin CW, Sundaram K. The biological activity of 7 alpha-methyl-19-nortestosterone is not amplified in male reproductive tract as is that of testosterone. Endocrinology. 1992;130:3677–83.PubMed Kumar N, Didolkar AK, Monder C, Bardin CW, Sundaram K. The biological activity of 7 alpha-methyl-19-nortestosterone is not amplified in male reproductive tract as is that of testosterone. Endocrinology. 1992;130:3677–83.PubMed
44.
go back to reference LaMorte A, Kumar N, Bardin CW, Sundaram K. Aromatization of 7 alpha-methyl-19-nortestosterone by human placental microsomes in vitro. J Steroid Biochem Mol Biol. 1994;48:297–304.PubMed LaMorte A, Kumar N, Bardin CW, Sundaram K. Aromatization of 7 alpha-methyl-19-nortestosterone by human placental microsomes in vitro. J Steroid Biochem Mol Biol. 1994;48:297–304.PubMed
45.
go back to reference von Eckardstein S, Noe G, Brache V, Nieschlag E, Croxatto H, Alvarez F, Moo-Young A, Sivin I, Kumar N, Small M, Sundaram K, International Committee for Contraception Research TPC. A clinical trial of 7 alpha-methyl-19-nortestosterone implants for possible use as a long-acting contraceptive for men. J Clin Endocrinol Metab. 2003;88:5232–5239. von Eckardstein S, Noe G, Brache V, Nieschlag E, Croxatto H, Alvarez F, Moo-Young A, Sivin I, Kumar N, Small M, Sundaram K, International Committee for Contraception Research TPC. A clinical trial of 7 alpha-methyl-19-nortestosterone implants for possible use as a long-acting contraceptive for men. J Clin Endocrinol Metab. 2003;88:5232–5239.
46.
go back to reference Walton MJ, Kumar N, Baird DT, Ludlow H, Anderson RA. 7alpha-methyl-19-nortestosterone (MENT) vs testosterone in combination with etonogestrel implants for spermatogenic suppression in healthy men. J Androl. 2007;28:679–88.PubMed Walton MJ, Kumar N, Baird DT, Ludlow H, Anderson RA. 7alpha-methyl-19-nortestosterone (MENT) vs testosterone in combination with etonogestrel implants for spermatogenic suppression in healthy men. J Androl. 2007;28:679–88.PubMed
47.
go back to reference Sitruk-Ware R, Nath A. The use of newer progestins for contraception. Contraception. 2010;82:410–7.PubMed Sitruk-Ware R, Nath A. The use of newer progestins for contraception. Contraception. 2010;82:410–7.PubMed
48.
go back to reference Mahabadi V, Amory JK, Swerdloff RS, Bremner WJ, Page ST, Sitruk-Ware R, Christensen PD, Kumar N, Tsong YY, Blithe D, Wang C. Combined transdermal testosterone gel and the progestin nestorone suppresses serum gonadotropins in men. J Clin Endocrinol Metab. 2009;94:2313–20.PubMedPubMedCentral Mahabadi V, Amory JK, Swerdloff RS, Bremner WJ, Page ST, Sitruk-Ware R, Christensen PD, Kumar N, Tsong YY, Blithe D, Wang C. Combined transdermal testosterone gel and the progestin nestorone suppresses serum gonadotropins in men. J Clin Endocrinol Metab. 2009;94:2313–20.PubMedPubMedCentral
49.
go back to reference Ilani N, Roth MY, Amory JK, Swerdloff RS, Dart C, Page ST, Bremner WJ, Sitruk-Ware R, Kumar N, Blithe DL, Wang C. A new combination of testosterone and nestorone transdermal gels for male hormonal contraception. J Clin Endocrinol Metab. 2012;97:3476–86.PubMedPubMedCentral Ilani N, Roth MY, Amory JK, Swerdloff RS, Dart C, Page ST, Bremner WJ, Sitruk-Ware R, Kumar N, Blithe DL, Wang C. A new combination of testosterone and nestorone transdermal gels for male hormonal contraception. J Clin Endocrinol Metab. 2012;97:3476–86.PubMedPubMedCentral
50.
go back to reference Misro M, Guha SK, Singh H, Mahajan S, Ray AR, Vasudevan P. Injectable non-occlusive chemical contraception in the male-I. Contraception. 1979;20:467–73.PubMed Misro M, Guha SK, Singh H, Mahajan S, Ray AR, Vasudevan P. Injectable non-occlusive chemical contraception in the male-I. Contraception. 1979;20:467–73.PubMed
51.
go back to reference Guha SK, Ansari S, Anand S, Farooq A, Misro MM, Sharma DN. Contraception in male monkeys by intra-vas deferens injection of a pH lowering polymer. Contraception. 1985;32:109–18.PubMed Guha SK, Ansari S, Anand S, Farooq A, Misro MM, Sharma DN. Contraception in male monkeys by intra-vas deferens injection of a pH lowering polymer. Contraception. 1985;32:109–18.PubMed
52.
go back to reference Guha SK. Biophysical mechanism-mediated time-dependent effect on sperm of human and monkey vas implanted polyelectrolyte contraceptive. Asian J Androl. 2007;9:221–7.PubMed Guha SK. Biophysical mechanism-mediated time-dependent effect on sperm of human and monkey vas implanted polyelectrolyte contraceptive. Asian J Androl. 2007;9:221–7.PubMed
53.
go back to reference Lohiya NK, Manivannan B, Mishra PK. Ultrastructural changes in the spermatozoa of langur monkeys Presbytis entellus entellus after vas occlusion with styrene maleic anhydride. Contraception. 1998;57:125–32.PubMed Lohiya NK, Manivannan B, Mishra PK. Ultrastructural changes in the spermatozoa of langur monkeys Presbytis entellus entellus after vas occlusion with styrene maleic anhydride. Contraception. 1998;57:125–32.PubMed
54.
go back to reference Koul V, Srivastav A, Guha SK. Reversibility with sodium bicarbonate of styrene maleic anhydride, an intravasal injectable contraceptive, in male rats. Contraception. 1998;58:227–31.PubMed Koul V, Srivastav A, Guha SK. Reversibility with sodium bicarbonate of styrene maleic anhydride, an intravasal injectable contraceptive, in male rats. Contraception. 1998;58:227–31.PubMed
55.
go back to reference Lohiya NK, Suthar R, Khandelwal A, Goyal S, Ansari AS, Manivannan B. Sperm characteristics and teratology in rats following vas deferens occlusion with RISUG and its reversal. Int J Androl. 2010;33:e198–206.PubMed Lohiya NK, Suthar R, Khandelwal A, Goyal S, Ansari AS, Manivannan B. Sperm characteristics and teratology in rats following vas deferens occlusion with RISUG and its reversal. Int J Androl. 2010;33:e198–206.PubMed
56.
go back to reference Guha SK. Non-invasive reversal of intraluminal vas deferens polymer injection-induced azoospermia–technology. Asian journal of andrology. 1999;1:131–4.PubMed Guha SK. Non-invasive reversal of intraluminal vas deferens polymer injection-induced azoospermia–technology. Asian journal of andrology. 1999;1:131–4.PubMed
57.
go back to reference Lohiya NK, Manivannan B, Mishra PK, Pathak N, Balasubramanian SP. Intravasal contraception with styrene maleic anhydride and its noninvasive reversal in langur monkeys (Presbytis entellus entellus). Contraception. 1998;58:119–28.PubMed Lohiya NK, Manivannan B, Mishra PK, Pathak N, Balasubramanian SP. Intravasal contraception with styrene maleic anhydride and its noninvasive reversal in langur monkeys (Presbytis entellus entellus). Contraception. 1998;58:119–28.PubMed
58.
go back to reference Manivannan B, Bhande SS, Panneerdoss S, Sriram S, Lohiya NK. Safety evaluation of long-term vas occlusion with styrene maleic anhydride and its non-invasive reversal on accessory reproductive organs in langurs. Asian J Androl. 2005;7:195–204.PubMed Manivannan B, Bhande SS, Panneerdoss S, Sriram S, Lohiya NK. Safety evaluation of long-term vas occlusion with styrene maleic anhydride and its non-invasive reversal on accessory reproductive organs in langurs. Asian J Androl. 2005;7:195–204.PubMed
59.
go back to reference Guha SK, Singh G, Anand S, Ansari S, Kumar S, Koul V. Phase I clinical trial of an injectable contraceptive for the male. Contraception. 1993;48:367–75.PubMed Guha SK, Singh G, Anand S, Ansari S, Kumar S, Koul V. Phase I clinical trial of an injectable contraceptive for the male. Contraception. 1993;48:367–75.PubMed
60.
go back to reference Guha SK, Singh G, Ansari S, Kumar S, Srivastava A, Koul V, Das HC, Malhotra RL, Das SK. Phase II clinical trial of a vas deferens injectable contraceptive for the male. Contraception. 1997;56:245–50.PubMed Guha SK, Singh G, Ansari S, Kumar S, Srivastava A, Koul V, Das HC, Malhotra RL, Das SK. Phase II clinical trial of a vas deferens injectable contraceptive for the male. Contraception. 1997;56:245–50.PubMed
61.
go back to reference Chaki SP, Das HC, Misro MM. A short-term evaluation of semen and accessory sex gland function in phase III trial subjects receiving intravasal contraceptive RISUG. Contraception. 2003;67:73–8.PubMed Chaki SP, Das HC, Misro MM. A short-term evaluation of semen and accessory sex gland function in phase III trial subjects receiving intravasal contraceptive RISUG. Contraception. 2003;67:73–8.PubMed
62.
go back to reference Manivannan B, Mishra PK, Lohiya NK. Ultrastructural changes in the vas deferens of langur monkeys Presbytis entellus entellus after vas occlusion with styrene maleic anhydride and after its reversal. Contraception. 1999;59:137–44.PubMed Manivannan B, Mishra PK, Lohiya NK. Ultrastructural changes in the vas deferens of langur monkeys Presbytis entellus entellus after vas occlusion with styrene maleic anhydride and after its reversal. Contraception. 1999;59:137–44.PubMed
63.
go back to reference Waller D, Bolick D, Lissner E, Premanandan C, Gamerman G. Azoospermia in rabbits following an intravas injection of Vasalgel. Basic Clin Androl. 2016;26:6.PubMedPubMedCentral Waller D, Bolick D, Lissner E, Premanandan C, Gamerman G. Azoospermia in rabbits following an intravas injection of Vasalgel. Basic Clin Androl. 2016;26:6.PubMedPubMedCentral
64.
go back to reference Waller D, Bolick D, Lissner E, Premanandan C, Gamerman G. Reversibility of Vasalgel male contraceptive in a rabbit model. Basic Clin Androl. 2017;27:8.PubMedPubMedCentral Waller D, Bolick D, Lissner E, Premanandan C, Gamerman G. Reversibility of Vasalgel male contraceptive in a rabbit model. Basic Clin Androl. 2017;27:8.PubMedPubMedCentral
65.
go back to reference Wang Z, Widgren EE, Sivashanmugam P, O’Rand MG, Richardson RT. Association of eppin with semenogelin on human spermatozoa. Biol Reprod. 2005;72:1064–70.PubMed Wang Z, Widgren EE, Sivashanmugam P, O’Rand MG, Richardson RT. Association of eppin with semenogelin on human spermatozoa. Biol Reprod. 2005;72:1064–70.PubMed
66.
go back to reference O’Rand MG, Widgren EE, Wang Z, Richardson RT. Eppin: an effective target for male contraception. Mol Cell Endocrinol. 2006;250:157–62.PubMed O’Rand MG, Widgren EE, Wang Z, Richardson RT. Eppin: an effective target for male contraception. Mol Cell Endocrinol. 2006;250:157–62.PubMed
67.
go back to reference Yenugu S, Richardson RT, Sivashanmugam P, Wang Z, O’Rand MG, French FS, Hall SH. Antimicrobial activity of human EPPIN, an androgen-regulated, sperm-bound protein with a whey acidic protein motif. Biol Reprod. 2004;71:1484–90.PubMed Yenugu S, Richardson RT, Sivashanmugam P, Wang Z, O’Rand MG, French FS, Hall SH. Antimicrobial activity of human EPPIN, an androgen-regulated, sperm-bound protein with a whey acidic protein motif. Biol Reprod. 2004;71:1484–90.PubMed
68.
go back to reference Mitra A, Richardson RT, O’Rand MG. Analysis of recombinant human semenogelin as an inhibitor of human sperm motility. Biol Reprod. 2010;82:489–96.PubMed Mitra A, Richardson RT, O’Rand MG. Analysis of recombinant human semenogelin as an inhibitor of human sperm motility. Biol Reprod. 2010;82:489–96.PubMed
69.
go back to reference O’Rand MG, Widgren EE, Beyler S, Richardson RT. Inhibition of human sperm motility by contraceptive anti-eppin antibodies from infertile male monkeys: effect on cyclic adenosine monophosphate. Biol Reprod. 2009;80:279–85.PubMedPubMedCentral O’Rand MG, Widgren EE, Beyler S, Richardson RT. Inhibition of human sperm motility by contraceptive anti-eppin antibodies from infertile male monkeys: effect on cyclic adenosine monophosphate. Biol Reprod. 2009;80:279–85.PubMedPubMedCentral
70.
go back to reference O’Rand MG, Widgren EE, Sivashanmugam P, Richardson RT, Hall SH, French FS, VandeVoort CA, Ramachandra SG, Ramesh V, Jagannadha Rao A. Reversible immunocontraception in male monkeys immunized with eppin. Science. 2004;306:1189–90.PubMed O’Rand MG, Widgren EE, Sivashanmugam P, Richardson RT, Hall SH, French FS, VandeVoort CA, Ramachandra SG, Ramesh V, Jagannadha Rao A. Reversible immunocontraception in male monkeys immunized with eppin. Science. 2004;306:1189–90.PubMed
71.
go back to reference O’Rand MG, Silva EJ, Hamil KG. Non-hormonal male contraception: a review and development of an Eppin based contraceptive. Pharmacol Ther. 2016;157:105–11.PubMed O’Rand MG, Silva EJ, Hamil KG. Non-hormonal male contraception: a review and development of an Eppin based contraceptive. Pharmacol Ther. 2016;157:105–11.PubMed
72.
go back to reference Silva EJ, Hamil KG, O’Rand MG. Interacting proteins on human spermatozoa: adaptive evolution of the binding of semenogelin I to EPPIN. PLoS One. 2013;8:e82014.PubMedPubMedCentral Silva EJ, Hamil KG, O’Rand MG. Interacting proteins on human spermatozoa: adaptive evolution of the binding of semenogelin I to EPPIN. PLoS One. 2013;8:e82014.PubMedPubMedCentral
73.
go back to reference O’Rand MG, Hamil KG, Adevai T, Zelinski M. Inhibition of sperm motility in male macaques with EP055, a potential non-hormonal male contraceptive. PLoS One. 2018;13:e0195953.PubMedPubMedCentral O’Rand MG, Hamil KG, Adevai T, Zelinski M. Inhibition of sperm motility in male macaques with EP055, a potential non-hormonal male contraceptive. PLoS One. 2018;13:e0195953.PubMedPubMedCentral
74.
go back to reference Hild SA, Reel JR, Dykstra MJ, Mann PC, Marshall GR. Acute adverse effects of the indenopyridine CDB-4022 on the ultrastructure of sertoli cells, spermatocytes, and spermatids in rat testes: comparison to the known sertoli cell toxicant Di-n-pentylphthalate (DPP). J Androl. 2007;28:621–9.PubMed Hild SA, Reel JR, Dykstra MJ, Mann PC, Marshall GR. Acute adverse effects of the indenopyridine CDB-4022 on the ultrastructure of sertoli cells, spermatocytes, and spermatids in rat testes: comparison to the known sertoli cell toxicant Di-n-pentylphthalate (DPP). J Androl. 2007;28:621–9.PubMed
75.
go back to reference Koduri S, Hild SA, Pessaint L, Reel JR, Attardi BJ. Mechanism of action of l-CDB-4022, a potential nonhormonal male contraceptive, in the seminiferous epithelium of the rat testis. Endocrinology. 2008;149:1850–60.PubMedPubMedCentral Koduri S, Hild SA, Pessaint L, Reel JR, Attardi BJ. Mechanism of action of l-CDB-4022, a potential nonhormonal male contraceptive, in the seminiferous epithelium of the rat testis. Endocrinology. 2008;149:1850–60.PubMedPubMedCentral
76.
go back to reference Pozor MA, Macpherson ML, McDonnell SM, Nollin M, Roser JF, Love C, Runyon S, Thomas BF, Troedsson MH. Indenopyride derivative RTI-4587-073(l): a candidate for male contraception in stallions. Theriogenology. 2013;80:1006–16.PubMed Pozor MA, Macpherson ML, McDonnell SM, Nollin M, Roser JF, Love C, Runyon S, Thomas BF, Troedsson MH. Indenopyride derivative RTI-4587-073(l): a candidate for male contraception in stallions. Theriogenology. 2013;80:1006–16.PubMed
77.
go back to reference Cheng CY. Toxicants target cell junctions in the testis: insights from the indazole-carboxylic acid model. Spermatogenesis. 2014;4:e981485.PubMed Cheng CY. Toxicants target cell junctions in the testis: insights from the indazole-carboxylic acid model. Spermatogenesis. 2014;4:e981485.PubMed
78.
go back to reference Grima J, Silvestrini B, Cheng CY. Reversible inhibition of spermatogenesis in rats using a new male contraceptive, 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide. Biol Reprod. 2001;64:1500–8.PubMed Grima J, Silvestrini B, Cheng CY. Reversible inhibition of spermatogenesis in rats using a new male contraceptive, 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide. Biol Reprod. 2001;64:1500–8.PubMed
79.
go back to reference Cheng CY, Mruk D, Silvestrini B, Bonanomi M, Wong CH, Siu MK, Lee NP, Lui WY, Mo MY. AF-2364 [1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide] is a potential male contraceptive: a review of recent data. Contraception. 2005;72:251–61.PubMed Cheng CY, Mruk D, Silvestrini B, Bonanomi M, Wong CH, Siu MK, Lee NP, Lui WY, Mo MY. AF-2364 [1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide] is a potential male contraceptive: a review of recent data. Contraception. 2005;72:251–61.PubMed
80.
go back to reference Mruk DD, Wong CH, Silvestrini B, Cheng CY. A male contraceptive targeting germ cell adhesion. Nat Med. 2006;12:1323–8.PubMed Mruk DD, Wong CH, Silvestrini B, Cheng CY. A male contraceptive targeting germ cell adhesion. Nat Med. 2006;12:1323–8.PubMed
81.
go back to reference Tash JS, Attardi B, Hild SA, Chakrasali R, Jakkaraj SR, Georg GI. A novel potent indazole carboxylic acid derivative blocks spermatogenesis and is contraceptive in rats after a single oral dose. Biol Reprod. 2008;78:1127–38.PubMed Tash JS, Attardi B, Hild SA, Chakrasali R, Jakkaraj SR, Georg GI. A novel potent indazole carboxylic acid derivative blocks spermatogenesis and is contraceptive in rats after a single oral dose. Biol Reprod. 2008;78:1127–38.PubMed
82.
go back to reference Vernet N, Dennefeld C, Rochette-Egly C, Oulad-Abdelghani M, Chambon P, Ghyselinck NB, Mark M. Retinoic acid metabolism and signaling pathways in the adult and developing mouse testis. Endocrinology. 2006;147:96–110.PubMed Vernet N, Dennefeld C, Rochette-Egly C, Oulad-Abdelghani M, Chambon P, Ghyselinck NB, Mark M. Retinoic acid metabolism and signaling pathways in the adult and developing mouse testis. Endocrinology. 2006;147:96–110.PubMed
83.
go back to reference Koubova J, Menke DB, Zhou Q, Capel B, Griswold MD, Page DC. Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc Natl Acad Sci USA. 2006;103:2474–9.PubMed Koubova J, Menke DB, Zhou Q, Capel B, Griswold MD, Page DC. Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc Natl Acad Sci USA. 2006;103:2474–9.PubMed
84.
go back to reference Dufour JM, Kim KH. Cellular and subcellular localization of six retinoid receptors in rat testis during postnatal development: identification of potential heterodimeric receptors. Biol Reprod. 1999;61:1300–8.PubMed Dufour JM, Kim KH. Cellular and subcellular localization of six retinoid receptors in rat testis during postnatal development: identification of potential heterodimeric receptors. Biol Reprod. 1999;61:1300–8.PubMed
85.
go back to reference Chung SS, Wang X, Roberts SS, Griffey SM, Reczek PR, Wolgemuth DJ. Oral administration of a retinoic Acid receptor antagonist reversibly inhibits spermatogenesis in mice. Endocrinology. 2011;152:2492–502.PubMedPubMedCentral Chung SS, Wang X, Roberts SS, Griffey SM, Reczek PR, Wolgemuth DJ. Oral administration of a retinoic Acid receptor antagonist reversibly inhibits spermatogenesis in mice. Endocrinology. 2011;152:2492–502.PubMedPubMedCentral
86.
go back to reference Chung SS, Wang X, Wolgemuth DJ. Prolonged oral administration of a pan-retinoic acid receptor antagonist inhibits spermatogenesis in mice with a rapid recovery and changes in the expression of influx and efflux transporters. Endocrinology. 2016;157:1601–12.PubMedPubMedCentral Chung SS, Wang X, Wolgemuth DJ. Prolonged oral administration of a pan-retinoic acid receptor antagonist inhibits spermatogenesis in mice with a rapid recovery and changes in the expression of influx and efflux transporters. Endocrinology. 2016;157:1601–12.PubMedPubMedCentral
87.
go back to reference Heller CG, Moore DJ, Paulsen CA. Suppression of spermatogenesis and chronic toxicity in men by a new series of bis(dichloroacetyl) diamines. Toxicol Appl Pharmacol. 1961;3:1–11.PubMed Heller CG, Moore DJ, Paulsen CA. Suppression of spermatogenesis and chronic toxicity in men by a new series of bis(dichloroacetyl) diamines. Toxicol Appl Pharmacol. 1961;3:1–11.PubMed
89.
go back to reference Amory JK, Muller CH, Shimshoni JA, Isoherranen N, Paik J, Moreb JS, Amory DW Sr, Evanoff R, Goldstein AS, Griswold MD. Suppression of spermatogenesis by bisdichloroacetyldiamines is mediated by inhibition of testicular retinoic acid biosynthesis. J Androl. 2011;32:111–9.PubMed Amory JK, Muller CH, Shimshoni JA, Isoherranen N, Paik J, Moreb JS, Amory DW Sr, Evanoff R, Goldstein AS, Griswold MD. Suppression of spermatogenesis by bisdichloroacetyldiamines is mediated by inhibition of testicular retinoic acid biosynthesis. J Androl. 2011;32:111–9.PubMed
Metadata
Title
Recent Developments in Male Contraception
Authors
Arthi Thirumalai
Stephanie T. Page
Publication date
01-01-2019
Publisher
Springer International Publishing
Published in
Drugs / Issue 1/2019
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI
https://doi.org/10.1007/s40265-018-1038-8

Other articles of this Issue 1/2019

Drugs 1/2019 Go to the issue