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Emerging approaches to male contraception

2021; Elsevier BV; Volume: 115; Issue: 6 Linguagem: Inglês

10.1016/j.fertnstert.2021.03.047

1556-5653

Arthi Thirumalai, John K. Amory,

Sperm and Testicular Function

Despite significant interests in contraception by men, effective methods of male contraception are limited to vasectomy and condoms. Recently, there have been several promising advances in male contraceptive research. This review will update readers on recent research in both hormonal and nonhormonal approaches to male contraception. Hormonal approaches to male contraception have been stymied by adverse effects, formulations requiring injections or implants, a 5% to10% nonresponse rate, as well as poor understanding of user acceptability. In the last several years, research has focused on novel, orally bioavailable androgens such as dimethandrolone undecanoate and 11β-methyl-19-nor-testosterone. Additionally, combinations of a topical testosterone gel combined with a gel containing segesterone acetate, a potent progestin, have shown promise in clinical trials recently. Simultaneously, significant preclinical progress has been made in several approaches to nonhormonal male contraceptives, including compounds that inhibit sperm motility such as eppin, compounds that inhibit retinoic acid binding or biosynthesis, and reversible approaches to obstruction of the vas deferens. It is imperative for these areas of research to continue making strides so that there is a gamut of contraceptive options for couples to choose from. Some of these approaches will hopefully reach clinical utility soon, greatly improving contraceptive choice for couples. Despite significant interests in contraception by men, effective methods of male contraception are limited to vasectomy and condoms. Recently, there have been several promising advances in male contraceptive research. This review will update readers on recent research in both hormonal and nonhormonal approaches to male contraception. Hormonal approaches to male contraception have been stymied by adverse effects, formulations requiring injections or implants, a 5% to10% nonresponse rate, as well as poor understanding of user acceptability. In the last several years, research has focused on novel, orally bioavailable androgens such as dimethandrolone undecanoate and 11β-methyl-19-nor-testosterone. Additionally, combinations of a topical testosterone gel combined with a gel containing segesterone acetate, a potent progestin, have shown promise in clinical trials recently. Simultaneously, significant preclinical progress has been made in several approaches to nonhormonal male contraceptives, including compounds that inhibit sperm motility such as eppin, compounds that inhibit retinoic acid binding or biosynthesis, and reversible approaches to obstruction of the vas deferens. It is imperative for these areas of research to continue making strides so that there is a gamut of contraceptive options for couples to choose from. Some of these approaches will hopefully reach clinical utility soon, greatly improving contraceptive choice for couples. Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/32478 Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/32478 The development of female contraceptive methods had great impacts on fertility rate, women’s health, the role of women in society, and sexual practices of adults and adolescents (1Tyrer L. Introduction of the pill and its impact.Contraception. 1999; 59: 11S-16SAbstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Failure rates of these methods range from 20% (2Trussell J. Contraceptive failure in the United States.Contraception. 2011; 83: 397-404Abstract Full Text Full Text PDF PubMed Scopus (951) Google Scholar), depending on the method, with numerous reversible options. However, a significant proportion of women have contraindications to the currently available female contraceptives or experience adverse effects from the use of these methods, resulting in method discontinuation. The only effective and reversible male contraception option is condoms, the use of which is associated with a 13% on year failure rate of unintended pregnancy (3Sundaram A. Vaughan B. Kost K. Bankole A. Finer L. Singh S. et al.Contraceptive failure in the United States: estimates from the 2006–2010 National Survey of Family Growth.Perspect Sex Reprod Health. 2017; 49: 7-16Crossref PubMed Scopus (145) Google Scholar). As a result of the shortcomings of the current female contraceptives and very limited male contraceptive options, the rates of unplanned pregnancy have largely remained at approximately 44% globally for some time (4Shah I. Ahman E. Unsafe abortion in 2008: global and regional levels and trends.Reprod Health Matters. 2010; 18: 90-101Crossref PubMed Scopus (81) Google Scholar, 5Bearak 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-e389Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar), accounting for roughly 100 × 106 unintended pregnancies yearly. Interestingly, surveys of couples have shown that most men and women would be likely to accept and use safe and effective male contraceptive methods were they to become available (6Martin C.W. Anderson R.A. Cheng L. Ho P.C. van der Spuy Z. Smith K.B. et al.Potential impact of hormonal male contraception: cross-cultural implications for development of novel preparations.Hum Reprod. 2000; 15: 637-645Crossref PubMed Scopus (174) Google Scholar, 7Heinemann 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: 549-556Crossref PubMed Scopus (147) Google Scholar, 8Eberhardt 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: 161-165Crossref PubMed Scopus (27) Google Scholar, 9Glasier A. Acceptability of contraception for men: a review.Contraception. 2010; 82: 453-456Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). In this article, we will review the most recent advances in the field of male contraceptive research, work aimed at reducing the currently high rate of unintended pregnancy. In men, the hypothalamic-pituitary-testicular axis regulates the production of testosterone (T) and sperm (Fig. 1, left panel). The hypothalamus releases gonadotropin-releasing hormone, which stimulates the pituitary to release gonadotropins—luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates the Leydig cells of the testes to produce T and FSH stimulates the Sertoli cells, the function of which is necessary for sperm production. In addition, testosterone binds to androgen receptors (ARs) in the pituitary that suppress the release of LH and FSH in a highly regulated feedback loop. Hormonal contraceptive methods exploit this feedback inhibition (Fig. 1, right panel) by providing exogenous androgens that bind to ARs in the brain and inhibit the release of LH and FSH. Gonadotropin suppression turns off the stimulation of the Leydig and Sertoli cells in the testes, markedly lowering intratesticular T biosynthesis and Sertoli cell function, leading to a cessation of spermatogenesis in most men. At the same time, the exogenously administered T binds to ARs in other tissues, preventing the development of signs and symptoms of hypogonadism. Clinical trials of various hormonal male contraceptive regimens have revealed that the addition of a progestin to the androgen enhances the speed and magnitude of gonadotropin suppression (10Liu P.Y. Swerdloff R.S. Anawalt B.D. Anderson R.A. Bremner W.J. Elliesen J. et al.Determinants of the rate and extent of spermatogenic suppression during hormonal male contraception: an integrated analysis.J Clin Endocrinol Metab. 2008; 93: 1774-1783Crossref PubMed Scopus (77) Google Scholar) and may even directly inhibit spermatogenesis (11Lue Y. Wang C. Lydon J.P. Leung A. Li J. Swerdloff R.S. Functional role of progestin and the progesterone receptor in the suppression of spermatogenesis in rodents.Andrology. 2013; 1: 308-317Crossref PubMed Scopus (28) Google Scholar). As a result, most male contraceptive regimens use both androgens and progestins. It takes approximately 72 days to produce mature sperm from the spermatogonial stem cells (12Heller C.H. Clermont Y. Kinetics of the germinal epithelium in man.Recent Prog Horm Res. 1964; 20: 545-575PubMed Google Scholar), which is why male contraceptives that inhibit sperm production, such as hormonal methods, are associated with a 2 to3 month delay in the onset of efficacy. Similarly, sperm production is only restored several months after discontinuation of a hormonal method. After sperm are produced, they are stored in the epididymis until ejaculation, only gaining their full motility and capacity to fertilize the egg once within the female urogenital tract. Nonhormonal approaches to male contraception have focused on interrupting different steps in these processes, ranging from interfering with sperm production to blocking sperm transport during ejaculation or impairing the ability of the sperm to gain motility after ejaculation. The clinical trials testing androgen/progestin male contraceptive trials conducted to date have been elegantly summarized in prior reviews (13Nieschlag E. Clinical trials in male hormonal contraception.Contraception. 2010; 82: 457-470Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 14Wang C. Festin M.P. Swerdloff R.S. Male hormonal contraception: Where are we now?.Curr Obstet Gynecol Rep. 2016; 5: 38-47Crossref PubMed Google Scholar, 15Amory J.K. Male contraception.Fertil Steril. 2016; 106: 1303-1309Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). The lessons learned from these trials were that marked gonadotropin suppression to concentrations well below the lower limit of the normal range is required, but not sufficient, for effective suppression of spermatogenesis. For one regimen, only men who suppressed FSH and LH serum levels to ≤1 IU/L had suppression of sperm concentrations to <1 × 106 sperm/mL of ejaculate (16Roth M.Y. Ilani N. Wang C. Page S.T. Bremner W.J. et al.Characteristics associated with suppression of spermatogenesis in a male hormonal contraceptive trial using testosterone and Nestorone gels.Andrology. 2013; 1: 899-905Crossref PubMed Scopus (27) Google Scholar), a concentration of sperm associated with a roughly 1% rate of unintended pregnancy (17Contraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on Methods for the regulation of male Fertility.Lancet. 1990; 336: 955-959Abstract PubMed Scopus (469) Google Scholar). Normally, sperm concentrations in men exceed 15 × 106 sperm/mL of ejaculate. Ideally, male contraceptive regimens would suppress sperm production to zero (azoospermia); however, achieving high rates of azoospermia has proven very difficult. For example, only 70% of men achieved this target in 1 large male hormonal contraceptive trial (17Contraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on Methods for the regulation of male Fertility.Lancet. 1990; 336: 955-959Abstract PubMed Scopus (469) Google Scholar, 18World Health Organization Task Force on Methods for the Regulation of Male FertilityContraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men.Fertil Steril. 1996; 65: 821-829Abstract Full Text PDF PubMed Google Scholar). The good news is that the efficacy at prevention of unintended pregnancy is <1% when azoospermia is achieved, a rate similar to the most effective female methods available currently (2Trussell J. Contraceptive failure in the United States.Contraception. 2011; 83: 397-404Abstract Full Text Full Text PDF PubMed Scopus (951) Google Scholar). In the most recent male hormonal contraceptive trials, sperm concentrations of 80% of men who received 8 mg/day of segesterone acetate along with T had suppression of their gonadotropin levels to ≤1 IU/L, 69% of whom suppressed their gonadotropins levels to 88% had their sperm concentrations suppressed to <1 × 106 sperm/mL of ejaculate, in contrast to only 23% of men receiving T gel alone (32Ilani N. Roth M.Y. Amory J.K. Swerdloff R.S. Dart C. Page S.T. et al.A new combination of testosterone and Nestorone transdermal gels for male hormonal contraception.J Clin Endocrinol Metab. 2012; 97: 3476-3486Crossref PubMed Scopus (67) Google Scholar). The gel was largely well tolerated without significant safety concerns. Five of 99 men in the study discontinued treatment because of adverse events—one for irritability and nightmares, one for decreased libido, one for increased appetite, one for mood swings, and one for an asthma exacerbation (32Ilani N. Roth M.Y. Amory J.K. Swerdloff R.S. Dart C. Page S.T. et al.A new combination of testosterone and Nestorone transdermal gels for male hormonal contraception.J Clin Endocrinol Metab. 2012; 97: 3476-3486Crossref PubMed Scopus (67) Google Scholar). Acne was reported by 21% of men, headache by 17%, weight increase by 7%, and insomnia by 6% of men during drug exposure (33Ilani N. Liu P.Y. Swerdloff R.S. Wang C. Does ethnicity matter in male hormonal contraceptive efficacy?.Asian J Androl. 2011; 13: 579-584Crossref PubMed Scopus (22) Google Scholar). Next, segesterone acetate was formulated as a combination gel (segesterone acetate 8.3 mg and T 62.5 mg), and the combination product demonstrated gonadotropin suppression similar to that of the two gels used alone after 28 days of treatment (84% men with FSH and LH levels ≤1 IU/L)(34Anawalt B.D. Roth M.Y. Ceponis J. Surampudi V. Amory J.K. Swerdloff R.S. et al.Combined Nestorone-testosterone gel suppresses serum gonadotropins to concentrations associated with effective hormonal contraception in men.Andrology. 2019; 7: 878-887Crossref PubMed Scopus (13) Google Scholar). Given the promising results of this product, a phase IIB efficacy trial using the combined segesterone acetate/T gel is currently underway in 13 sites spanning 4 continents: North America, South America, Europe, and Africa. To our knowledge, this trial is the first large-scale, male hormonal contraceptive efficacy trial using a self-administered product. The trial is recruiting 400 couples who will undergo an initial period of sperm suppression until they exhibit a sperm concentration of <1 × 106/mL of ejaculate. At this point, men with adequate sperm suppression will enter a 52-week efficacy phase in which they will only use the study product for contraception. The primary outcome of the study is the rate of unintended pregnancy, with key secondary outcomes being mood and sexual function as assessed by validated questionnaires. Dimethandrolone undecanoate (DMAU) is a modified T derivative that is being studied as a once-daily oral male hormonal contraceptive. Orally dosed DMAU is cleaved by esterases in vivo to the active drug dimethandrolone (DMA). The undecanoate ester both enhances oral absorption when ingested with a fat-containing meal and extends the half-life. DMA does not require 5α-reduction for its action (35Attardi B.J. Hild S.A. Koduri S. Pham T. Pessaint L. Engbring J. et al.The potent synthetic androgens, dimethandrolone (7α, 11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone,do not require 5alpha-reduction to exert their maximal androgenic effects.J Steroid Biochem Mol Biol. 2010; 122: 212-218Crossref PubMed Scopus (20) Google Scholar) and is not aromatized to an estrogen in vivo (36Attardi B.J. Pham T.C. Radler L.C. Burgenson J. Hild S.A. Reel J.R. 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: 214-222Crossref PubMed Scopus (26) Google Scholar). Another unique aspect of DMA is that it binds both ARs and progesterone receptors (PRs) with a relative binding affinity 4 times that of T at the AR and 18% that of progesterone at the PR (37Attardi B.J. Hild S.A. Reel J.R. Dimethandrolone undecanoate: a new potent orally active androgen with progestational activity.Endocrinology. 2006; 147: 3016-3026Crossref PubMed Scopus (52) Google Scholar). Animal studies showed that orally administered DMAU was able to reversibly suppress gonadotropins, spermatogenesis, and fertility in rodents while still preserving androgenic characteristics (38Attardi B.J. Marck B.T. Matsumoto A.M. Koduri S. Hild S.A. 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: 183-192Crossref PubMed Scopus (27) Google Scholar, 39Hild S.A. Marshall G.R. Attardi B.J. Hess R.A. Schlatt S. Simorangkir D.R. et al.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: 1784-1796Crossref PubMed Scopus (38) Google Scholar, 40Hild S.A. Attardi B.J. Koduri S. Till B.A. Reel J.R. Effects of synthetic androgens on liver function using the rabbit as a model.J Androl. 2010; 31: 472-481Crossref PubMed Scopus (26) Google Scholar). A first-in-men study of single doses of DMAU (at doses ranging from 100 to 800 mg/orally/day) showed that the drug was well tolerated when dosed once daily. Similar to oral testosterone undecanoate, oral DMA requires coadministration with a fat-containing meal to optimize absorption (41Surampudi P. Page S.T. Swerdloff R.S. Nya-Ngatchou J.J. Liu P.Y. Amory J.K. 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: 579-587Crossref PubMed Scopus (26) Google Scholar, 42Ayoub R. Page S.T. Swerdloff R.S. Liu P.Y. Amory J.K. Leung A. 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: 278-285Crossref PubMed Scopus (26) Google Scholar). A subsequent 28-day daily oral dosing study of DMAU showed suppression of T serum levels to castrate levels in treated men and suppression of gonadotropin serum levels to ≤1 IU/L in all treated groups (43Thirumalai A. Ceponis J. Amory J.K. Swerdloff R. Surampudi V. Liu P.Y. et al.Effects of 28 days of oral dimethandrolone undecanoate in healthy men: a prototype male pill.J Clin Endocrinol Metab. 2019; 104: 423-432Crossref PubMed Scopus (21) Google Scholar). In addition, this study showed the drug to be mostly well tolerated by trial participants. DMA is a potent androgen. Therefore, androgenic effects such as weight gain (1.5–3.8 kg), increase in hematocrit (up to 2%), and reduction in high-density lipoprotein-cholesterol level (6–15 mg/dL) were noted among study subjects (43Thirumalai A. Ceponis J. Amory J.K. Swerdloff R. Surampudi V. Liu P.Y. et al.Effects of 28 days of oral dimethandrolone undecanoate in healthy men: a prototype male pill.J Clin Endocrinol Metab. 2019; 104: 423-432Crossref PubMed Scopus (21) Google Scholar). Among the participants who received the active drug, 11% reported headache, 11% reported decreased libido, and 7% reported acne (43Thirumalai A. Ceponis J. Amory J.K. Swerdloff R. Surampudi V. Liu P.Y. et al.Effects of 28 days of oral dimethandrolone undecanoate in healthy men: a prototype male pill.J Clin Endocrinol Metab. 2019; 104: 423-432Crossref PubMed Scopus (21) Google Scholar). No participants discontinued treatment because of adverse events (43Thirumalai A. Ceponis J. Amory J.K. Swerdloff R. Surampudi V. Liu P.Y. et al.Effects of 28 days of oral dimethandrolone undecanoate in healthy men: a prototype male pill.J Clin Endocrinol Metab. 2019; 104: 423-432Crossref PubMed Scopus (21) Google Scholar). Given these results, DMAU holds the promise of being a once-daily orally bioavailable prototyp