Unintended pregnancies account for nearly half of all pregnancies in the United States, and the burden of preventing them has historically fallen on women (1). Existing options for women, such as hormonal pills, intrauterine devices, and implants, can be invasive or come with side effects. Men, on the other hand, have far fewer choices, limited primarily to condoms and vasectomy, which is usually a permanent procedure.

Men have had no opportunity really to have this kind of contraception. When there is surgery involved or condoms, it’s not very romantic, nor do they always work. This is simple. You don't have to think about it. There's no fumbling around. It really does check off the kinds of things that you want in that it's also relatively safe. 
- Ronald Evans, Salk Institute

Researchers at the Salk Institute led by geneticist Ronald Evans found a glimmer of hope for a new era in contraception. They identified a protein complex essential for sperm production and successfully halted sperm production in male mice using an existing class of drugs (2). This discovery paves the way for the development of a potentially long-acting, reversible, and nonhormonal male contraceptive pill.

"Men have had no opportunity really to have this kind of contraception," Evans said. "When there is surgery involved or condoms, it’s not very romantic, nor do they always work. This is simple. You don't have to think about it. There's no fumbling around. It really does check off the kinds of things that you want in that it's also relatively safe.”

Spermatogenesis is a complex choreography orchestrated by hormones and cellular signals within the testes. The stem cells there continuously self-renew until they receive a chemical cue, retinoic acid, to mature into sperm. This signal involves retinoic acid receptors on the stem cells interacting with another protein called silencing mediator of retinoid and thyroid hormone receptors (SMRT). The SMRT protein then recruits histone deacetylase (HDAC) enzymes, which trigger a genetic program that transforms the stem cells into mature sperm.

Previous attempts to develop male contraceptives by blocking retinoic acid or its receptor proved unsuccessful because retinoic acid plays a vital role in multiple organs. Evans’ team employed a more targeted approach by going one step further down the pathway. Rather than targeting the retinoic acid receptor, they decided to test if inhibiting the SMRT protein complex formation prevented HDAC enzyme recruitment to ultimately block sperm production. 

The researchers first used genetically engineered mice with a mutated SMRT protein that was unable to bind to retinoic acid receptors. Although these mice were infertile, they displayed normal testosterone levels and mating behavior, indicating that impairing SMRT function did not affect libido.

Next, they investigated whether a drug could achieve the same effect. As a proof of principle, they used MS-275, an existing oral HDAC inhibitor already approved by the FDA for certain cancers (3). Treating healthy mice with MS-275 successfully halted sperm production without any obvious side effects. Importantly, the drug did not harm sperm stem cells. These stem cells continued to self-renew, and upon stopping the drug, they regained the ability to differentiate into mature sperm.

The researchers also showed that within 60 days of stopping the drug, sperm production in the mice returned to normal, and all subsequent offspring were developmentally healthy. This highlighted the reversibility of the approach, an important feature for clinical translatability. 

"This would be a fantastic option for men in long-term relationships where they want to take the burden away from the woman, and he simply takes an additional pill,” said Jochen Buck, a pharmacologist from Weill Cornell Medicine who was not involved in the study.

While these findings are promising, further research, including studies in nonhuman primates, is necessary before human trials can begin. However, the researchers are optimistic because mammalian sperm development is similar across rodents and primates.

Evans added that while the development of the hormonal birth control pill was transformational for female contraception, “they couldn't correct the problem for men, but now we actually have cracked it.”

References

1. Lawrence B. & Zolna Mia R. Declines in Unintended Pregnancy in the United States, 2008–2011. NEJM  374, 843–852 (2016).
2. Hong, S.-H. et al. Targeting nuclear receptor corepressors for reversible male contraception. PNAS  121, e2320129121 (2024).
3. Hess-Stumpp, H., Bracker, T. U., Henderson, D. & Politz, O. MS-275, a potent orally available inhibitor of histone deacetylases—The development of an anticancer agent. Int J Biochem Cell Biol  39, 1388–1405 (2007).