New approach to contraceptive pills for men

New approach to contraceptive pills for men

The active ingredient inhibits sperm formation. © ThorstenSchmitt / iStock

Contraception could finally become a men’s issue. A new drug effectively inhibits sperm production in male mice, a study has shown. The active ingredient binds to a specific gene switch in the testes and thus temporarily blocks sperm production. This did not affect the animals’ libido or general fertility. The switch could therefore be a new approach to developing a non-hormonal pill for men that has fewer side effects than previous active ingredients for women. Even taking it once a week may be enough.

Today, women have numerous contraceptive options. However, the most reliable methods such as the pill, a hormone injection and the IUD are based on hormones and sometimes have drastic side effects. For men, family planning options are even more limited: They have the choice between condoms, which are rather unreliable to use, and surgical vasectomies, which usually cannot be reversed. Despite numerous development approaches, there is still no “pill for men” due to insufficient effectiveness or excessive hormonal side effects.

A research group led by Suk-Hyun Hong from the Salk Institute for Biological Studies in California has now tested a different, non-hormonal approach. To do this, the researchers examined a specific protein complex, which includes the retinoic acid receptor (RAR), the silencing mediator for retinoid and thyroid hormone receptors (SMRT) and histone deacetylases (HDACs). The RAR receptor is known to be regulated by retinoid acid and contributes to the maturation of sperm stem cells. Turning it off has also produced promising results in a previous study. Hong’s team now wanted to find out exactly what role the SMRT mediator plays in this complex during sperm production and whether it would also be a good target. To do this, the scientists developed special male mice whose SMRT proteins can no longer bind to the RAR receptor. They then observed sperm maturation in the epididymis.

Sperm maturation in the epididymal tubules
Cross sections of the epididymal tubules show typical sperm maturation in untreated mice (top left). After treatment with a drug that blocks the activity of the RAR-SMRT gene repressor complex, maturing sperm are absent in the epididymis (top right). After 60 days without the drug, sperm begin to mature again in the epididymal tubules (bottom right), which are similar to control mice of the same age (bottom left). © Suk Hyun Hong

Drug inhibits sperm production

In fact, the experiments found that the mice no longer produced mature sperm without an intact RAR-SMRT complex. However, this did not change their sexual behavior and the animals’ sperm stem cells were not affected. At the cellular level, the researchers found that some genes that are only periodically active in the sperm ducts of unchanged mice were chronically activated in the experimental mice. This suggests that the SMRT-RAR complex plays a key role in sperm maturation and production in the testes. The same picture emerged when the researchers treated unchanged mice with a drug from the histone deacetylase inhibitor class (MS-275), which interferes with the RAR-SMRT complex: sperm production was effectively blocked without increasing libido affect. After discontinuation of the active ingredient, the animals’ normal sperm production resumed.

Hong and his colleagues conclude: In order for mature sperm to form from stem cells in the body of male mammals, specific genes are alternately activated and suppressed. The regulation of this mechanism occurs via the RAR-SMRT protein complex. When “off” this complex suppresses many of the genes relevant to sperm production. However, if retinoid acid binds to the gene switch, the RAR-SMRT complex dissolves and the target genes can be translated into proteins.

Contraceptive pills only need to be taken once a week

What is particularly interesting is that this switch can be temporarily disabled by a medication taken orally. “The results suggest that the RAR-SMRT complex may be a viable target for reversible, non-hormonal contraception for men,” the scientists write. In other words: The genetic switch is a good starting point for a “male pill” that is likely to have fewer side effects than previous approaches. “Given the long half-life of MS-275 in humans, even taking a contraceptive pill once a week is possible,” the study says. However, follow-up experiments and clinical studies are still necessary before such an active ingredient can come onto the market.

Source: Suk-Hyun Hong (Salk Institute for Biological Studies) et al., Proceedings of the National Academy of Sciences (PNAS), doi: 10.1073/pnas.2320129121

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