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The idea of a contraceptive pill for men is not new but has until now been limited by problematic side effects. Today, a team from the Salk Institute has discovered a new non-hormonal molecule combining effectiveness, absence of side effects and reversibility.
The idea of shared contraception between men and women is a theme that comes up regularly in research and couples’ discussions. Surveys also show that most men in the United States would not be reluctant to use male contraceptives, but their options to date remain limited to condoms or invasive vasectomies. Multiple recent attempts to develop drugs that block sperm production have had limited success, providing incomplete protection and serious side effects. But a new study could well move the subject forward.
Sperm production, a complex phenomenon
The study, published in Proceedings of the National Academy of Sciences (PNAS) on February 20, implicates a new protein complex in the regulation of gene expression during sperm production. Here’s how.
Every day, sperm stem cells in the testes are produced, until a signal tells them that it is time to develop into sperm, which is called spermatogenesis. This signal comes in the form of retinoic acid, a product of vitamin A. Pulses of retinoic acid bind to retinoic acid receptors in cells, and when the system is perfectly aligned, this triggers a program genetics that transforms stem cells into mature sperm.
Scientists have discovered that for this to work, retinoic acid receptors must bind to a protein called SMRT (silent mediator of retinoid and thyroid hormone receptors). SMRT then recruits HDAC enzymes, and this protein complex then synchronizes the expression of genes that produce sperm.
Modulating the process, not stopping it, the key to reversible treatment
Previously, teams have attempted to stop sperm production by directly blocking retinoic acid or its receptor. But retinoic acid is important for several organ systems. Disrupting it throughout the body can cause various side effects – a reason why many previous studies and trials have failed to produce a viable drug.
The team of Salk Institute researchers instead wondered if they could modulate one of the molecules downstream of retinoic acid to produce a more targeted effect. The researchers first looked at a line of genetically modified mice previously grown in the laboratory, in which the SMRT protein was mutated and could no longer bind to retinoic acid receptors. Without this SMRT-retinoic acid receptor interaction, the mice were not able to produce mature sperm. However, they displayed normal testosterone levels and increasing behavior, indicating that their desire to mate was not affected.
Male mice little affected by this new treatment
To see if they could reproduce these genetic findings with pharmacological intervention, the researchers treated normal mice with MS-275, an oral HDAC inhibitor. By blocking the activity of the SMRT-retinoic acid receptor-HDAC complex, the drug was able to stop sperm production without producing obvious side effects. Another remarkable thing also happened once treatment was stopped: Within 60 days of stopping the pill, the animals’ fertility was completely restored and all subsequent offspring were developmentally healthy.
“When we add the drug, the stem cells are no longer in sync with the pulses of the retinoic acid and sperm production is interrupted. But as soon as we remove the drug, the stem cells can reestablish their coordination with the retinoic acid and sperm production will start again.” The authors claim that the drug does not damage sperm stem cells or their genomic integrity.
“This makes it a promising therapeutic approach, which we hope to see soon developed for human clinical trials” concludes the team. To be continued.