Following Roe v Wade Overturn, Research Focuses on Male Contraceptives

On the final day of the American Urological Association (AUA) 2024 Annual Meeting, Stephanie T. Page, MD, PhD, co-director of the UW Medicine Diabetes Institute at the University of Washington School of Medicine, shared the latest in male birth control research with a focus on efficacy and user acceptance, paving the way for novel contraceptive options for men.¹ Page also serves as professor of medicine in lipid research as well as head of the division of metabolism, endocrinology, and nutrition.

She started by emphasizing the critical issue of unplanned pregnancies worldwide and in the US. About 50% of global pregnancies are unplanned, mirroring a similar rate in the US. This results in more than 85 million unplanned pregnancies per year in the US alone, with 56 million ending in abortion.

“These unplanned pregnancies have enormous health consequences for women and families, and enormous economic consequences for the global economy,” Page added.

Since the reversal of Roe v Wade and increased constraints on abortion, access to safe abortion has significantly diminished in the US. This has particularly affected women of low socioeconomic status, with 40% of American women now unable to access surgical abortion within 50 miles. The impact extends beyond health consequences, exacerbating poverty, domestic violence, and adversely affecting the well-being of children and families. Further, the loss of access to comprehensive reproductive care—including contraception and cancer screening—due to the relocation of OB/GYN practitioners underscores the broader health implications.

Importantly, these restrictions disproportionately affect women of color, highlighting the exacerbation of health care inequities. Pregnancy-related death is 2 to 3 times more likely in women of color than White women; per 100,000 live births, about 41 Black women, 30 American Indian or Alaskan Native women, and 13 White women die due to pregnancy-related causes, according to CDC data.²

Page stated that to reduce the number of unplanned pregnancies, abortions, and pregnancy-related deaths, the most important tool is contraception.¹ Contraceptives prove to be highly effective in reducing unplanned pregnancies, with inconsistent or non-users accounting for the majority of such pregnancies in the US. By improving both access to and usage of contraceptives, a significant decrease in unplanned pregnancies and the demand for abortion services can be achieved, though it's important to note that this strategy cannot entirely substitute the necessity of accessible and safe abortion services, Page noted.

Birth control pills and condoms | Image credit: TanyaJoy – stock.adobe.com

Male contraception—condoms, vasectomy, and withdrawal—accounts for 28% of contraceptive use in the US. However, more novel methods for men are needed during a time where women are losing access to their options.

“The last innovation in reversible contraception for men was the condom, and that was over 300 years ago,” Page said. “So I think we're really due for some innovation in contraception for men.”

This has raised 2 major questions in the field: will men use these methods, and will women trust them to do so? According to survey results from more than 2000 men, approximately 40% of men in the US said they were open to using a new contraceptive within a year, with this trend growing over time and nearly 80% saying they would be open to it “at some point.”³ Equally noteworthy is that more than 50% of female partners expressed willingness to trust their male partners with a novel contraceptive, indicating a viable market for such products.

“We just need to tap into it,” Page said.

Following the Dobbs decision to overturn of Roe v Wade, the same cohort was asked the same question, and the percentage of US men willing to try a new contraceptive within a year increased by 26%, with 49% of men saying they would be interested. There was also a notable increase in vasectomy interest and uptake at this time.

There are a handful of ongoing clinical trials for hormonal and non-hormonal male contraceptives, including:

• Phase 2b/3 hormonal transdermal gel
• Phase 1/2 dual action daily oral steroids
• Reversible vaso-occlusion
• Retinoic acid receptor antagonists

In the past year and a half, some preclinical studies have also begun, looking into sperm-specific protein targets, fertilization blockers, and sperm motility targets with soluble adenylyl cyclase.¹

“We also know that you don't need to get every man to azoospermia in order to develop an effective contraceptive,” Page emphasized. “In fact, if we can reduce sperm numbers to less than a million per milliliter in the ejaculate from the normal 15 to 200 million sperm per mL, we can achieve contraceptive efficacy similar to the female pill.”

Male hormonal contraceptive research has spanned nearly 5 decades, with 6 efficacy studies involving approximately 2500 couples enrolled for contraception, including a phase 2b study on a daily transdermal gel for hormonal contraception that has recently concluded. These studies have consistently demonstrated the ability to lower sperm concentrations to less than a million per milliliter, achieving highly effective contraception in 95% to 99% of men, comparable to the efficacy of the female pill, with the assurance of reversibility for these methods.

For the recently-completed study on a daily transdermal gel, this innovative approach involves a combination of nesterone—a novel progestin with no estrogenic or androgenic, activity and minimal glucocorticoid activity—and testosterone, potentially leading to fewer side effects compared with other progestins. Unlike traditional methods requiring clinic visits for injections, this study employed a user-controlled approach where men applied the gel themselves daily, demonstrating the ease of use seen with testosterone replacement gels, which are widely utilized in the US. The gel, akin to hand sanitizer in texture, is simply applied to the shoulders after showering, proving to be both convenient and acceptable to users. Page expects the full results of this study to be released later in 2024.

Men have also expressed interest in taking a pill similar to female birth control. Testosterone undecanoate—an oral testosterone replacement method—requires twice-daily dosing, posing challenges for contraception compatibility. The aim is to develop molecules with combined androgenic and progestogenic activity, streamlining pharmacokinetics and potentially reducing manufacturing costs. Studies on dimethandrolone undecanoate have demonstrated promising tolerability and efficacy in suppressing luteinizing hormone and testosterone levels—essential for inhibiting spermatogenesis—without causing hypogonadism symptoms due to exogenous androgen administration.

Moving to non-hormonal contraception, early studies are exploring retinoic acid inhibition—again crucial for spermatogenesis—with preclinical research showing significant suppression in rodents. There are also early human trials focusing on retinoic acid receptor antagonists for male contraception, as well as an increased focus on developing fully-reversible vasectomies by putting a dissolvable polymer into the vas deferens that dissolves on its own or with another injection. There has also been exciting preclinical research targeting sperm motility as a potential non-hormonal method for male contraception, using orally administered soluble adenylate cyclase inhibitors that effectively suppress sperm motility for approximately 3 hours, presenting a promising avenue for on-demand male contraceptives.

In discussing potential side effects, Page noted that hormonal methods will likely exhibit side effects as the female pill including weight gain, mild acne, and changes in libido and mood, though these side effects have been rarely seen in men enrolled in clinical trials. Non-hormonal methods are anticipated to have fewer side effects, though it is uncertain until effects are observed in clinical settings.

References

1. Page ST. Hot off the press/state-of-the-art lecture: approaches to and advances in male contraception in the post-Roe v. Wade era. Presented at: AUA 2024 Annual Meeting; May 3-6, 2024; San Antonio, TX. https://aua2021.app.swapcard.com/event/2024-annual-meeting-san-antonio/planning/UGxhbm5pbmdfMTczMDUxNQ==
2. Petersen EE, Davis NL, Goodman D, et al. Racial/ethnic disparities in pregnancy-related deaths — United States, 2007–2016. MMWR Morb Mortal Wkly Rep. 2019;68:762–765. doi:10.15585/mmwr.mm6835a3
3. Kretschmer S. Demand for novel male contraceptives. Presented at: Reproductive Health Innovation Summit; February 15, 2023; Boston, MA. https://www.malecontraceptive.org/uploads/1/3/1/9/131958006/reproductive_health_summit_male_ct_research_feb2023.pdf