What Is Going On With Male Contraception?

In 1960, the first hormonal birth control pill was marketed to women; 60 years later, women have a wide variety of options for family planning, while men remain limited to options with variable efficacy. For example, condoms, although cheap and widely available, have a failure rate of approximately 18% and vasectomies, although efficacious, are limited by cost, time to azoospermia, and the potential for failed reversal.¹

Comparatively, there are a wide variety of female contraceptive options that are both efficacious and reversible. The focus on the development of female contraceptive options has, logically, been driven by the significant physical, economic, and social impact a resulting pregnancy has on a female. However, one article showed that almost 50% of surveyed men in the United States expressed willingness to use new methods.²

Research on hormonal male contraception began with 2 hallmark studies on testosterone enanthate. The first one was funded by the National Institutes of Health (NIH) In the 1970s and focused on the effects on sperm concentration. The other was conducted almost 20 years later in the 1990s and funded by the World Health Organization (WHO). This study focused on the efficacy of lower sperm concentrations as a contraceptive method.^3,4

Although these studies confirmed that suppressing spermatogenesis would result in similar contraception results when compared with female options, subsequent studies that focused on combining androgen and progestins were limited by administration frequency, cost, and adverse effects (AEs). The most common AEs across these studies were acne, mood changes, injection site pain, and libido changes. Although most of these AEs were considered to be mild or moderate and similar to the effects seen with comparable female methods, the WHO Human Reproduction Program Research Project Review Panel recommended discontinuing some studies before completion.⁵ Ultimately, these 2 studies created the foundation for many of the regulations and expectations for current hormonal male contraception research, including parameters for sperm concentration and tolerability, while simultaneously influencing the interest in non-hormonal options.

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In recent years, interest in this topic has become increasingly apparent. The most recent advancement for hormonal male contraception is NES/T (Testosterone plus Nestorone), a gel that utilizes the previously established efficacy of the androgen and progestin combination and the minimal AEs associated with its once daily, transdermal application.⁶ With an estimated primary completion for the phase 2b trial in September 2023, this could be the first male contraception option to reach phase 3. Although it has taken more than 50 years of funding by NIH, WHO, and others to get to this point, nonprofits like the Male Contraceptive Initiative have continued to advocate for expanding research towards non-hormonal methods to increase the potential impact of more male contraceptive options in the future.

In February 2023, the Male Contraceptive Initiative’s advocacy efforts led to the research article by Balbach et. al. describing a promising, non-hormonal option for male contraception which sparked conversation regarding hormonal and nonhormonal methods once again. What makes this method unique is that, rather than suppressing spermatogenesis, it targets a soluble adenylyl cyclase that is specific to sperm motility, displayed 100% contraceptive efficacy within 30 minutes to 2.5 hours after administration, and produced similar pregnancy rates 24 hours after administration (87% vs 96%). In comparison, one of the limiting factors of hormonal methods is the longer time to azoospermia which have an estimated suppression phase up to 6 months, or 20 weeks in the case of NES/T.^3,6 Furthermore, because the targeted adenylyl cyclase is unique to sperm expressed in the testis in addition to the contraceptive’s transient “on demand” use intention, there is potential for fewer systemic AEs compared to hormonal options which have a wide variety of targets throughout the body and, therefore, are associated with metabolic effects.^3,7 Although this medication has yet to be studied in human trials, it is an encouraging addition to the future of male contraception.

The expansion of male contraceptive methods is a necessary addition to reproductive health, especially when considering that approximately 40% of pregnancies are unintended despite improvements to female contraceptive methods.^1,2 By increasing the variety of efficacious and safe choices, the unintended pregnancies in the United States could be reduced by up to 7.5%, or almost 400,000, with the addition of male contraceptive options.² Overall, although the development has been ongoing for almost 50 years, the hormonal and non-hormonal options undergoing pre-clinical and clinical trials are indicative of a future with more reproductive autonomy for patients.

About the Authors

Ginny Snipes is a class of 2025 PharmD candidate at the Auburn University Harrison College of Pharmacy.

Marilyn Bulloch, PharmD, BCPS, FCCM, SPP, is an associate clinical professor and director of strategic operations at the Auburn University Harrison School of Pharmacy.

References

1. Handelsman DJ. Male Contraception. Endotext [Internet]. 2022 Dec 8 [cited 2023 Mar 18]. Available from: https://pubmed.ncbi.nlm.nih.gov/25905319/
2. Dorman E, Perry B, Polis C, et al. Modeling the impact of novel male contraceptive methods on reduction in unintended pregnancies in Nigeria, South Africa, and the United States. Contraception [Internet]. 2017 Sep 5 [cited 2023 Mar 18]; 97(1):62-69. Available from: https://www.contraceptionjournal.org/article/S0010-7824(17)30430-4/fulltext
3. Swerdloff RS, Campfield LA, Palacios A, McClure RD. Suppression of human spermatogenesis by depot androgen: potential for male contraception. J Steroid Biochem [Internet]. 1979 Jul [cited 2023 Mar 18];11(1B):663-70. Available from:https://pubmed.ncbi.nlm.nih.gov/491631/
4. Contraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on methods for the regulation of male fertility. Lancet [Internet]. 1990 Oct 20 [cited 2023 Mar 18];336(8721):955-9. Available from: https://pubmed.ncbi.nlm.nih.gov/1977002/
5. Wang C, Festin MP, Swerdloff RS. Male Hormonal Contraception: Where Are We Now? Curr Obstet Gynecol Rep [Internet]. 2016 [cited 2023 Mar 18];5:38-47. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762912/#CR29
6. Study of daily application of nestorone and testosterone combination gel for male contraception. ClinicalTrials.gov [Internet]. Updated 2023 Mar 16 [cited 2023 Mar 18]. Available from: https://clinicaltrials.gov/ct2/show/NCT03452111
7. Balbach M, Rossetti T, Ferreira J, et al. On-demand male contraception via acute inhibition of soluble adenylyl cyclase. Nat Commun [Internet]. 2023 Feb 14 [cited 2023 Mar 18];14:637. Available from: https://www.nature.com/articles/s41467-023-36119-6