On February 20, 2024, scientists at the Salk Institute identified a new reversible, nonhormonal approach to male contraception. The drug, an HDAC (histone deacetylase) inhibitor, blocked sperm production and fertility in male mice without affecting libido or future fertility.
Although most American men say they are interested in male contraceptives, their options remain limited to condoms, which can be unreliable, or invasive vasectomy. Recent attempts to develop drugs that block sperm production, maturation, or fertilization have had limited success, providing incomplete protection or causing severe side effects. New male contraceptive methods are needed, but the complexity of sperm development has made it difficult for researchers to identify a stage that can be targeted safely and effectively.
Scientists at the Salk Institute have now found a new way to interrupt sperm production that is both nonhormonal and reversible. The study, published in the Proceedings of the National Academy of Sciences on February 20, 2024, identified a new protein complex involved in regulating gene expression during sperm production. The researchers showed that treating male mice with an existing class of drugs called HDAC inhibitors could disrupt this protein complex and block fertility without affecting libido.
“Most experimental male contraceptives use a blunt approach to block sperm production, but ours is much more subtle,” said Ronald Evans, professor and director of the Salk Gene Expression Laboratory and March of Dimes Chair in Molecular and Developmental Biology. “This makes it a promising therapeutic approach, and we hope to see it advance to human clinical trials soon.”
The human body produces millions of new sperm every day. To do this, sperm stem cells in the testes continuously replicate until a signal tells them to develop into sperm—a process called spermatogenesis. This signal comes from retinoic acid, a derivative of vitamin A. Pulses of retinoic acid bind to retinoic acid receptors in the cells. When the system is properly synchronized, this activates a complex genetic program that transforms stem cells into mature sperm.
Salk scientists found that for this process to work, the retinoic acid receptor must bind to a protein called SMRT (silencing mediator of retinoic acid and thyroid hormone receptor). SMRT then recruits HDACs, and this protein complex synchronizes the expression of genes involved in sperm production.
Previous research groups tried to stop sperm production by directly blocking retinoic acid or its receptor. However, retinoic acid is important to several organ systems, so disrupting it throughout the body can cause a range of side effects. This is why many previous studies and trials failed to produce a viable drug. Evans and his colleagues instead asked whether they could regulate a molecule downstream of retinoic acid to achieve a more targeted effect.
The researchers first examined a line of genetically engineered mice previously developed in the laboratory. These mice had a mutated SMRT protein that could no longer bind to the retinoic acid receptor. Without this SMRT–retinoic acid receptor interaction, the mice could not produce mature sperm. However, they had normal testosterone levels and mating behavior, indicating that their libido was unaffected.
To determine whether a drug intervention could reproduce these genetic findings, the researchers treated normal mice with MS-275, an oral HDAC inhibitor that has received FDA Breakthrough Therapy designation. By blocking the activity of the SMRT–retinoic acid receptor–HDAC complex, the drug successfully stopped sperm production without obvious side effects. Another notable finding emerged after treatment ended: within 60 days of stopping the drug, the animals fully regained fertility, and all offspring developed normally.
The authors believe that targeting molecules downstream of retinoic acid is key to achieving this reversibility.
Imagine retinoic acid and the genes that produce sperm as two dancers in a waltz. Their rhythm and steps must be coordinated for the dance to proceed smoothly. If something causes the genes to miss a step, the two become unsynchronized and the dance falls apart. In this case, the HDAC inhibitor causes the genes to lose their step, stopping the dance of sperm production.
However, if the dancers regain their rhythm and resynchronize with their partner, the waltz can continue. Similarly, the authors said that removing the HDAC inhibitor allows sperm-producing genes to resynchronize with the pulses of retinoic acid, restarting sperm production when needed.
“It is all about timing,” said co-author Michael Downes, a senior staff scientist in the Evans laboratory. “When we add the drug, the stem cells fall out of sync with the retinoic acid pulses and sperm production stops. Once we stop the drug, however, the stem cells can realign with retinoic acid and sperm production begins again.”
The authors said the drug does not damage sperm stem cells or their genomic integrity. While the drug is present, sperm stem cells simply continue to renew as stem cells. When the drug is removed, the cells can again differentiate into mature sperm.
“When we discovered SMRT and developed this mouse line, we were not necessarily looking to create a male contraceptive. But when we saw that fertility was interrupted, we followed the science and identified a potential therapeutic approach,” said lead author Suk-Hyun Hong, a researcher in the Evans laboratory. “This is a strong example of how fundamental biology research at Salk can lead to major translational impact.”
News | Researchers identify a new target for reversible, nonhormonal male contraception
On February 20, 2024, scientists at the Salk Institute identified a new reversible, nonhormonal approach to male contraception. The drug, an HDAC (histone deacetylase) inhibitor, blocked sperm production and fertility in male mice without affecting libido or future fertility.
Although most American men say they are interested in male contraceptives, their options remain limited to condoms, which can be unreliable, or invasive vasectomy. Recent attempts to develop drugs that block sperm production, maturation, or fertilization have had limited success, providing incomplete protection or causing severe side effects. New male contraceptive methods are needed, but the complexity of sperm development has made it difficult for researchers to identify a stage that can be targeted safely and effectively.
Scientists at the Salk Institute have now found a new way to interrupt sperm production that is both nonhormonal and reversible. The study, published in the Proceedings of the National Academy of Sciences on February 20, 2024, identified a new protein complex involved in regulating gene expression during sperm production. The researchers showed that treating male mice with an existing class of drugs called HDAC inhibitors could disrupt this protein complex and block fertility without affecting libido.
“Most experimental male contraceptives use a blunt approach to block sperm production, but ours is much more subtle,” said Ronald Evans, professor and director of the Salk Gene Expression Laboratory and March of Dimes Chair in Molecular and Developmental Biology. “This makes it a promising therapeutic approach, and we hope to see it advance to human clinical trials soon.”
The human body produces millions of new sperm every day. To do this, sperm stem cells in the testes continuously replicate until a signal tells them to develop into sperm—a process called spermatogenesis. This signal comes from retinoic acid, a derivative of vitamin A. Pulses of retinoic acid bind to retinoic acid receptors in the cells. When the system is properly synchronized, this activates a complex genetic program that transforms stem cells into mature sperm.
Salk scientists found that for this process to work, the retinoic acid receptor must bind to a protein called SMRT (silencing mediator of retinoic acid and thyroid hormone receptor). SMRT then recruits HDACs, and this protein complex synchronizes the expression of genes involved in sperm production.
Previous research groups tried to stop sperm production by directly blocking retinoic acid or its receptor. However, retinoic acid is important to several organ systems, so disrupting it throughout the body can cause a range of side effects. This is why many previous studies and trials failed to produce a viable drug. Evans and his colleagues instead asked whether they could regulate a molecule downstream of retinoic acid to achieve a more targeted effect.
The researchers first examined a line of genetically engineered mice previously developed in the laboratory. These mice had a mutated SMRT protein that could no longer bind to the retinoic acid receptor. Without this SMRT–retinoic acid receptor interaction, the mice could not produce mature sperm. However, they had normal testosterone levels and mating behavior, indicating that their libido was unaffected.
To determine whether a drug intervention could reproduce these genetic findings, the researchers treated normal mice with MS-275, an oral HDAC inhibitor that has received FDA Breakthrough Therapy designation. By blocking the activity of the SMRT–retinoic acid receptor–HDAC complex, the drug successfully stopped sperm production without obvious side effects. Another notable finding emerged after treatment ended: within 60 days of stopping the drug, the animals fully regained fertility, and all offspring developed normally.
The authors believe that targeting molecules downstream of retinoic acid is key to achieving this reversibility.
Imagine retinoic acid and the genes that produce sperm as two dancers in a waltz. Their rhythm and steps must be coordinated for the dance to proceed smoothly. If something causes the genes to miss a step, the two become unsynchronized and the dance falls apart. In this case, the HDAC inhibitor causes the genes to lose their step, stopping the dance of sperm production.
However, if the dancers regain their rhythm and resynchronize with their partner, the waltz can continue. Similarly, the authors said that removing the HDAC inhibitor allows sperm-producing genes to resynchronize with the pulses of retinoic acid, restarting sperm production when needed.
“It is all about timing,” said co-author Michael Downes, a senior staff scientist in the Evans laboratory. “When we add the drug, the stem cells fall out of sync with the retinoic acid pulses and sperm production stops. Once we stop the drug, however, the stem cells can realign with retinoic acid and sperm production begins again.”
The authors said the drug does not damage sperm stem cells or their genomic integrity. While the drug is present, sperm stem cells simply continue to renew as stem cells. When the drug is removed, the cells can again differentiate into mature sperm.
“When we discovered SMRT and developed this mouse line, we were not necessarily looking to create a male contraceptive. But when we saw that fertility was interrupted, we followed the science and identified a potential therapeutic approach,” said lead author Suk-Hyun Hong, a researcher in the Evans laboratory. “This is a strong example of how fundamental biology research at Salk can lead to major translational impact.”
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