Women who want to control their reproduction usually complain that they, not men, are responsible for avoiding pregnancy, except when men use condoms or undergo invasive vasectomy surgery.
With unwanted pregnancies costing billions of dollars annually in the US alone and increasing restrictions on abortion, the socioeconomic and health benefits of improved birth control are very important to many couples.
Ironically, surveys show that most American men are interested in using male contraceptives, but they have almost no options. Recent attempts to develop drugs that block sperm production, maturation, or fertilization have had limited success, providing incomplete protection or severe side effects. New approaches to male contraception are needed, but because sperm development is so complex, researchers have struggled to identify parts of the process that can be safely and effectively tweaked.
Now scientists at the Salk Institute in California have discovered a new method of interrupting sperm production that is both non-hormonal and reversible. The study, just published in the Proceedings of the National Academy of Sciences under the title “Targeting Nuclear Receptor Corepressors for Reversible Male Contraception,” discovered a new protein complex in the regulation of gene expression during sperm production. The researchers demonstrated that treating male mice with an existing class of drugs called HDAC (histone deacetylase) inhibitors could interrupt the function of this protein complex and block fertility without affecting libido.
“Most experimental male birth control drugs use a sledgehammer approach to block sperm production, but ours is much more subtle,” said senior author Prof. Ronald Evans, director of the Gene Expression Laboratory and head of molecular biology and developmental biology at Salk. “This makes it a promising therapeutic approach that we hope to soon see in development for human clinical trials.”
The human body produces several million new sperm per day. To do this, the sperm stem cells in the testicles constantly make more of themselves until a signal tells them it’s time to turn into sperm, a process 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 positioned correctly, this initiates a complex genetic program that turns stem cells into mature sperm.
The Salk scientists discovered that for this to work, the retinoic acid receptors must bind to a protein called SMRT (retinoid and thyroid hormone receptor silencing mediator), which then recruits HDACs, and this complex of proteins continues to synchronize expression of genes that produce sperm.
Previous groups have tried to stop sperm production by directly blocking retinoic acid or its receptor, but retinoic acid is important to several systems in the body, so disrupting it throughout the body can lead to various side effects. This is the reason why many previous studies and attempts have failed to create a viable drug. Instead, Evans and his colleagues asked if they could modulate one of the molecules downstream of retinoic acid to produce a more targeted effect.
How did scientists discover an alternative method of male birth control?
The researchers first looked at a line of genetically modified laboratory mice that had previously been developed in which the SMRT protein had mutated and could no longer bind to retinoic acid receptors. Without this SMRT-retinoic acid receptor interaction, the mice were unable to produce mature sperm, but showed normal testosterone levels and increased behavior, indicating that their desire to mate was not affected.
To see if they could reproduce these genetic results with pharmacological intervention, the researchers treated normal mice with MS-275, an oral HDAC inhibitor with FDA breakthrough status. By blocking the activity of the SMRT-retinoic acid receptor-HDAC complex, the drug successfully stops sperm production without causing obvious side effects.
Another remarkable thing also happened after the treatment was stopped; within 60 days of stopping the pill, the animals’ fertility was fully restored and all subsequent offspring were developmentally healthy. The researchers said their strategy of inhibiting molecules downstream of retinoic acid was key to achieving this reversibility.
“Think of retinoic acid and the genes that make sperm like two dancers in a waltz. Their rhythm and steps must be coordinated with each other for the dance to work. But if you throw in something that causes the genes to miss a step, the two suddenly fall out of sync and the dance falls apart. In this case, the HDAC inhibitor causes the genes to misstep, stopping the dance of sperm production,” they said. However, if the dancer can find his footing and get back in step with his partner, the waltz can resume. Likewise, the authors say that removing the HDAC inhibitor allows the sperm-producing genes to resynchronize with the retinoic acid pulses, bringing sperm production back as desired.
“It’s all about timing,” says co-author Michael Downs, a senior scientist in Evans’ lab. “When we add the drug, the stem cells go out of sync with the retinoic acid pulses and sperm production stops, but as soon as we remove the drug, the stem cells can regain coordination with the retinoic acid and sperm production.” will start again.”
The authors say the drug does not damage sperm stem cells or their genomic integrity. As long as the drug was present, the sperm stem cells simply continued to regenerate as stem cells, and when the drug was later removed, the cells could regain their ability to differentiate into mature sperm.
“We didn’t necessarily want to develop male contraceptives when we discovered SMRT and generated this line of mice, but when we saw that their fertility was interrupted, we were able to follow the science and find a potential therapeutic,” concludes first author Suk-Hyun Hong, a researcher at Evans Lab. “This is a great example of how Salk’s seminal biological research can lead to major translational impact.”
