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Target for Reversible, Non-Hormonal Male Birth Control Identified in Mice

An illustration of sperm cells.
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Researchers from the Salk Institute have uncovered a protein complex that regulates gene expression during sperm production and discovered an oral non-hormonal drug that reversibly stops this process in mice, without obvious side effects.

Expanding options for contraception

Nearly half of pregnancies are unintended and the burden of contraception remains largely on women. These methods can be invasive – such as intra-uterine devices (IUDs) and implants – or cause unpleasant side effects – such as the hormonal contraceptive pill.

On the other hand, contraceptive options targeted to men are limited to condoms and vasectomy. In one study, 28.5–71.4% of men expressed willingness to try male fertility control methods – but their development has been slow. One of these studies encountered side effects and was stopped early, while the complex nature of sperm development also makes it generally difficult to target effectively.

Sperm are produced from stem cells in the testes in a process called spermatogenesis. These stem cells self-replicate until they receive a signal in the form of retinoic acid, derived from vitamin A. Retinoic acid binds to retinoic acid receptors on the stem cells, as well as another protein – SMRT (silencing mediator of retinoid and thyroid hormone receptors). This recruits histone deacetylase (HDAC) enzymes to kick-start a complex genetic program to mature the stem cells into sperm cells.

Previous studies that have tried to block retinoic acid or its receptor to prevent sperm production have failed, as retinoic acid is important for the function of several other organ systems.

In the current study, researchers found that using a more targeted approach – using a drug to inhibit HDAC instead of retinoic acid – halted sperm production temporarily and effectively in healthy mice. The study – published in PNAS – was led by senior author Prof. Ronald Evans, director of the Salk Institute’s Gene Expression Laboratory.

“We discovered that a protein that forms a complex with HDAC, namely SMRT, is a critical component in sperm formation in our mouse model,” Evans explained, speaking to Technology Networks. “We used an HDAC inhibitor to disrupt the SMRT–HDAC protein complex to interfere with the cycling levels of retinoic acid during sperm development.”

Drug successfully and reversibly prevents sperm production in mice

The researchers first used genetically modified mice that were engineered to have a SMRT protein that was unable to bind to retinoic acid receptors. This left them unable to produce mature sperm, but their testosterone levels were unaffected.

“Unlike female contraceptives that prevent ovulation, a male contraceptive has to either stop the formation of sperm or its function to prevent fertilization of the egg,” said Evans. “After puberty, millions of sperm are continually produced in males every day and only one sperm is required to fertilize an egg. Therefore, the challenge is to achieve efficient, transient male infertility without affecting the sex hormone axis (for example, libido).”

Evans and colleagues then explored whether this could be achieved by blocking this molecular interaction using a drug to inhibit HDAC. HDAC inhibitors are an existing drug class approved by the US Food and Drug Administration (FDA) to treat some types of blood cancer. For this study, the researchers focused on an experimental oral HDAC inhibitor named MS-275.

Treating healthy mice with MS-275 successfully stopped sperm production with no obvious side effects. In the presence of the drug, the sperm stem cells continued self-renewing as stem cells. After the drug was withdrawn, the stem cells regained the ability to differentiate into mature sperm. “When you stop taking the HDAC inhibitor, the SMRT–HDAC protein resumes its function, [and] normal sperm production resumes,” Evans explained.

The findings also showed that within 60 days of halting the drug treatment, sperm production was restored. The animals’ subsequent offspring were also all developmentally healthy.

Additional pre-clinical studies required

Though this study was effective in healthy mice, much more research needs to be done to pave the way for potential human studies. Evans highlights that first, further investigation in non-human primates is required to confirm the findings observed in this mouse study. Nevertheless, there is optimism that these HDAC inhibitors will be effective in other clinical studies, as Evans adds that mammalian sperm development is similar across both rodents and primates.

“We are optimistic that the efficacy of HDAC inhibitors as male contraceptives will not be diminished in future clinical studies. As with the development of many drugs, the safety concern has to be first addressed in non-human primates,” said Evans.

Reference: Hong SH, Castro G, Wang D, et al. Targeting nuclear receptor corepressors for reversible male contraception. PNAS. 2024;121(9):e2320129121. doi: 10.1073/pnas.2320129121

Prof. Ronald Evans was speaking to Dr. Sarah Whelan, Science Writer for Technology Networks.

About the interviewee:

Prof. Ronald Evans is director of the Gene Expression Laboratory and March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute. He holds a BA in bacteriology and a PhD in microbiology and immunology from the University of California, Los Angeles. At Salk, Evans’ research focuses on the role of hormones, both under normal conditions and in disease.