Hormonal male contraception.

gonadotropin releasing hormone analogs modified androgens progestin spermatogenesis suppression testosterone

Journal

Andrology
ISSN: 2047-2927
Titre abrégé: Andrology
Pays: England
ID NLM: 101585129

Informations de publication

Date de publication:
17 Jul 2024
Historique:
revised: 22 06 2024
received: 19 02 2024
accepted: 02 07 2024
medline: 17 7 2024
pubmed: 17 7 2024
entrez: 17 7 2024
Statut: aheadofprint

Résumé

Male contraception with exogenously administered hormones suppresses both luteinizing hormone and follicle stimulating hormone leading to low intratesticular testosterone concentration. This results in reversible suppression of spermatogenesis and marked decrease in sperm output in the ejaculate and preventing pregnancy in the female partner. Studies of testosterone administered alone or in combination of another gonadotropin suppressive agent such as a progestin or gonadotropin releasing hormone (GnRH) analog showed decisively that the exogenous hormone administrations are effective in suppressing sperm output with few adverse events that are not anticipated. In contraceptive efficacy studies, testosterone alone or combined with a progestin are as effective in preventing pregnancies as female contraceptive methods. Hormone combinations for male contraception are in late-phase clinical trials and hold the promise of being the new, reversible contraception method for men in over half a century. Lessons learned from the male hormonal contraceptive development pave the way for new targeted approached to regulate male fertility.

Identifiants

pubmed: 39016284
doi: 10.1111/andr.13699
doi:

Types de publication

Journal Article Review

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

© 2024 American Society of Andrology and European Academy of Andrology.

Références

Moore AM, Novak AG, Lehman MN. KNDy neurons of the hypothalamus and their role in GnRH pulse generation: an update. Endocrinology. 2023;165(2):bqad194. doi:10.1210/endocr/bqad194
McLachlan RI, O'Donnell L, Meachem SJ, et al. Hormonal regulation of spermatogenesis in primates and man: insights for development of the male hormonal contraceptive. J Androl. 2002;23(2):149‐162.
Smith LB, Walker WH. The regulation of spermatogenesis by androgens. Semin Cell Dev Biol. 2014;30:2‐13. doi:10.1016/j.semcdb.2014.02.012
Hikim AP, Wang C, Leung A, Swerdloff RS. Involvement of apoptosis in the induction of germ cell degeneration in adult rats after gonadotropin‐releasing hormone antagonist treatment. Endocrinology. 1995;136(6):2770‐2775.
Thirumalai A, Amory JK. Emerging approaches to male contraception. Fertil Steril. 2021;115(6):1369‐1376. doi:10.1016/j.fertnstert.2021.03.047
Coviello AD, Bremner WJ, Matsumoto AM, et al. Intratesticular testosterone concentrations comparable with serum concentrations are not sufficient to maintain normal sperm production in men receiving a hormonal contraceptive regimen. J Androl. 2004;25(6):931‐938.
Steinberger E, Smith KD, Rodriguez‐Rigau LJ. Suppression and recovery of sperm production in men treated with testosterone enanthate for one year. A study of a possible reversible male contraceptive. Int J Endrol. 1978;1:748‐760.
Swerdloff RS, Campfield LA, Palacios A, McClure RD. Suppression of human spermatogenesis by depot androgen: potential for male contraception. J Steroid Biochem. 1979;11(1B):663‐670.
Cunningham GR, Silverman VE, Thornby J, Kohler PO. The potential for an androgen male contraceptive. J Clin Endocrinol Metab. 1979;49(4):520‐526.
Nieschlag E, Hoogen H, Bolk M, Schuster H, Wickings EJ. Clinical trial with testosterone undecanoate for male fertility control. Contraception. 1978;18(6):607‐614.
World Health Organization Task Force on Methods for the Regulation of Male Fertility. 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(8721):955‐959.
World Health Organization Task Force on the regulation of male fertility. Contraceptive efficacy of testosterone‐induced azoospermia and oligozoospermia in normal men. Fertil Steril. 1996;65(4):821‐829.
Gu YQ, Wang XH, Xu D, et al. A multicenter contraceptive efficacy study of injectable testosterone undecanoate in healthy Chinese men. J Clin Endocrinol Metab. 2003;88(2):562‐568.
Gu Y, Liang X, Wu W, et al. Multicenter contraceptive efficacy trial of injectable testosterone undecanoate in Chinese men. J Clin Endocrinol Metab. 2009;94(6):1910‐1915. doi:10.1210/jc.2008‐1846
Meriggiola MC, Farley TM, Mbizvo MT. A review of androgen‐progestin regimens for male contraception. J Androl. 2003;24(4):466‐483.
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(7):1708‐1714. doi:10.1093/humrep/der138
Mommers E, Kersemaekers WM, Elliesen J, et al. Male hormonal contraception: a double‐blind, placebo‐controlled study. J Clin Endocrinol Metab. 2008;93(7):2572‐2580.
Turner L, Conway AJ, Jimenez M, et al. Contraceptive efficacy of a depot progestin and androgen combination in men. J Clin Endocrinol Metab. 2003;88(10):4659‐4667.
Lue Y, Wang C, Lydon JP, Leung A, Li J, Swerdloff RS. Functional role of progestin and the progesterone receptor in the suppression of spermatogenesis in rodents. Andrology. 2013;1(2):308‐317. doi:10.1111/j.2047‐2927.2012.00047.x
Liu PY, Swerdloff RS, Anawalt BD, et al. Determinants of the rate and extent of spermatogenic suppression during hormonal male contraception: an integrated analysis. J Clin Endocrinol Metab. 2008;93(5):1774‐1783.
Kamischke A, Venherm S, Ploger D, von Eckardstein S, Nieschlag E. Intramuscular testosterone undecanoate and norethisterone enanthate in a clinical trial for male contraception. J Clin Endocrinol Metab. 2001;86(1):303‐309.
Meriggiola MC, Costantino A, Saad F, et al. Norethisterone enanthate plus testosterone undecanoate for male contraception: effects of various injection intervals on spermatogenesis, reproductive hormones, testis, and prostate. J Clin Endocrinol Metab. 2005;90(4):2005‐2014.
Behre HM, Zitzmann M, Anderson RA, et al. Efficacy and safety of an injectable combination hormonal contraceptive for men. J Clin Endocrinol Metab. 2016:jc20162141. doi:10.1210/jc.2016‐2141
Mahabadi V, Amory JK, Swerdloff RS, et al. Combined transdermal testosterone gel and the progestin nestorone suppresses serum gonadotropins in men. J Clin Endocrinol Metab. 2009;94(7):2313‐2320. doi:10.1210/jc.2008‐2604
Ilani N, Roth MY, Amory JK, et al. A new combination of testosterone and nestorone transdermal gels for male hormonal contraception. J Clin Endocrinol Metab. 2012;97(10):3476‐3486. doi:10.1210/jc.2012‐1384
Anawalt BD, Roth MY, Ceponis J, et al. Combined nestorone‐testosterone gel suppresses serum gonadotropins to concentrations associated with effective hormonal contraception in men. Andrology. 2019;7(6):878‐887. doi:10.1111/andr.12603
Yuen F, Wu S, Thirumalai A, et al. Preventing secondary exposure to women from men applying a novel nestorone/testosterone contraceptive gel. Andrology. 2019;7(2):235‐243. doi:10.1111/andr.12577
Amory JK, Blithe DL, Sitruk‐Ware R, et al. Design of an international male contraceptive efficacy trial using a self‐administered daily transdermal gel containing testosterone and segesterone acetate (Nestorone). Contraception. 2023;124:110064. doi:10.1016/j.contraception.2023.110064
Behre HM, Nashan D, Hubert W, Nieschlag E. Depot gonadotropin‐releasing hormone agonist blunts the androgen‐induced suppression of spermatogenesis in a clinical trial of male contraception. J Clin Endocrinol Metab. 1992;74(1):84‐90.
Behre HM, Klein B, Steinmeyer E, McGregor GP, Voigt K, Nieschlag E. Effective suppression of luteinizing hormone and testosterone by single doses of the new gonadotropin‐releasing hormone antagonist cetrorelix (SB‐75) in normal men. J Clin Endocrinol Metab. 1992;75(2):393‐398.
Tom L, Bhasin S, Salameh W, et al. Induction of azoospermia in normal men with combined Nal‐Glu gonadotropin‐releasing hormone antagonist and testosterone enanthate. J Clin Endocrinol Metab. 1992;75(2):476‐483.
Swerdloff RS, Bagatell CJ, Wang C, et al. Suppression of spermatogenesis in man induced by Nal‐Glu gonadotropin releasing hormone antagonist and testosterone enanthate (TE) is maintained by TE alone. J Clin Endocrinol Metab. 1998;83(10):3527‐3533.
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(12):2570‐2577.
Matthiesson KL, Stanton PG, O'Donnell L, et al. Effects of testosterone and levonorgestrel combined with a 5alpha‐reductase inhibitor or gonadotropin‐releasing hormone antagonist on spermatogenesis and intratesticular steroid concentrations in normal men. J Clin Endocrinol Metab. 2005;90(10):5647‐5655.
Page ST, Amory JK, Anawalt BD, et al. 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(11):4374‐4380.
Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen‐deprivation therapy in advanced prostate cancer. N Engl J Med. 2020;382(23):2187‐2196. doi:10.1056/NEJMoa2004325
Taylor AP, Lee H, Webb ML, Joffe H, Finkelstein JS. Effects of testosterone and estradiol deficiency on vasomotor symptoms in hypogonadal men. J Clin Endocrinol Metab. 2016;101(9):3479‐3486. doi:10.1210/jc.2016‐1612
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(2‐3):297‐304.
Beri R, Kumar N, Savage T, Benalcazar L, Sundaram K. Estrogenic and progestational activity of 7alpha‐methyl‐19‐nortestosterone, a synthetic androgen. J Steroid Biochem Mol Biol. 1998;67(3):275‐283.
Anderson RA, Martin CW, Kung AW, et al. 7Alpha‐methyl‐19‐nortestosterone maintains sexual behavior and mood in hypogonadal men. J Clin Endocrinol Metab. 1999;84(10):3556‐3562.
von Eckardstein S, Noe G, Brache V, et al. 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(11):5232‐5239.
Nieschlag E, Kumar N, Sitruk‐Ware R. 7alpha‐methyl‐19‐nortestosterone (MENTR): the population council's contribution to research on male contraception and treatment of hypogonadism. Contraception. 2013;87(3):288‐295. doi:10.1016/j.contraception.2012.08.036
Attardi BJ, Hild SA, Koduri S, et al. 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(4):212‐218. doi:10.1016/j.jsbmb.2010.06.009
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(2):183‐192. doi:10.2164/jandrol.110.010371
Attardi BJ, Engbring JA, Gropp D, Hild SA. Development of dimethandrolone 17beta‐undecanoate (DMAU) as an oral male hormonal contraceptive: induction of infertility and recovery of fertility in adult male rabbits. J Androl. 2011;32(5):530‐540. doi:10.2164/jandrol.110.011817
Surampudi P, Page ST, Swerdloff RS, et al. Single, escalating dose pharmacokinetics, safety and food effects of a new oral androgen dimethandrolone undecanoate in man: a prototype oral male hormonal contraceptive. Andrology. 2014;2(4):579‐587. doi:10.1111/j.2047‐2927.2014.00216.x
Ayoub R, Page ST, Swerdloff RS, et al. 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(2):278‐285. doi:10.1111/andr.12303
Wu S, Yuen F, Swerdloff RS, et al. Safety and pharmacokinetics of single‐dose novel oral androgen 11beta‐methyl‐19‐nortestosterone‐17beta‐dodecylcarbonate in men. J Clin Endocrinol Metab. 2019;104(3):629‐638. doi:10.1210/jc.2018‐01528
Thirumalai A, Ceponis J, Amory JK, et al. Effects of 28 days of oral dimethandrolone undecanoate in healthy men: a prototype male pill. J Clin Endocrinol Metab. 2019;104(2):423‐432. doi:10.1210/jc.2018‐01452
Yuen F, Thirumalai A, Pham C, et al. Daily oral administration of the novel androgen 11β‐MNTDC markedly suppresses serum gonadotropins in healthy men. J Clin Endocrinol Metab. 2020;105(3):e835‐847. doi:10.1210/clinem/dgaa032
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 Global health. 2018;6(4):e380‐e389. doi:10.1016/S2214‐109X(18)30029‐9
Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular safety of testosterone‐replacement therapy. N Engl J Med. 2023;389(2):107‐117. doi:10.1056/NEJMoa2215025
Heinemann K, Saad F, Wiesemes M, White S, Heinemann L. Attitudes toward male fertility control: results of a multinational survey on four continents. Hum Reprod. 2005;20(2):549‐556.
Martin CW, Anderson RA, Cheng L, et al. Potential impact of hormonal male contraception: cross‐cultural implications for development of novel preparations. Hum Reprod. 2000;15(3):637‐645.
Kretschmer S. Demand for novel male contraceptives. Male Contracpetive Initiative; 2023. Accessed February 10, 2024. https://www.malecontraceptive.org/uploads/1/3/1/9/131958006/reproductive_health_summit_male_ct_research_feb2023.pdf

Auteurs

Christina Wang (C)

Division of Endocrinology, Department of Medicine, Harbor-UCLA Medical Center, and Clinical and Translational Science Institute, The Lundquist Institute, Torrance, California, USA.

Cristina Meriggiola (C)

Division of Gynecology and Human Reproduction Physiopathology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Hermann M Behre (HM)

Center for Reproductive Medicine and Andrology, University Medicine Halle, Halle, Germany.

Stephanie T Page (ST)

Division of Metabolism, Endocrinology and Nutrition, UW Medicine Diabetes Institute, University of Washington School of Medicine, Seattle, Washington, USA.

Classifications MeSH