A new pathway for reversible male birth control

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 tinkered with. A research team led by the Salk Institute for Biological Studies recently found a non-hormonal and reversible method of interrupting sperm production, which they have described in Proceedings of the National Academy of Sciences (PNAS).

The human body produces several million new sperm per day. To do this, sperm stem cells in the testes continuously 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 the cells, and when the system is aligned just right, this initiates a complex genetic program that turns the stem cells into mature sperm.

The Salk scientists found that for this to work, retinoic acid receptors must bind with a protein called SMRT (silencing mediator of retinoid and thyroid hormone receptors). SMRT then recruits enzymes called HDACs (histone deacetylases), and this complex of proteins goes on to synchronise the 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 multiple organ systems, so interrupting it throughout the body can lead to various side effects — a reason many previous studies have failed to produce a viable drug. Professor Ronald Evans, Director of the Gene Expression Laboratory at Salk, and his colleagues instead asked whether 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 engineered mice that had previously been developed in the lab, 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 mounting behaviour, indicating that their desire to mate was not affected.

To see whether they could replicate 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 stopped sperm production without producing obvious side effects.

Furthermore, within 60 days of going off the drug, the animals’ fertility was completely restored, and all subsequent offspring were developmentally healthy. The researchers say their strategy of inhibiting molecules downstream of retinoic acid is key to achieving this reversibility.

“It’s all about timing,” said co-author Michael Downes, a senior staff scientist in Evans’ lab. “When we add the drug, the stem cells fall out of sync with the pulses of retinoic acid, and sperm production is halted, but as soon as we take the drug away, the stem cells can re-establish their coordination with retinoic acid and sperm production will start up again.”

The authors emphasised that the drug doesn’t damage the sperm stem cells or their genomic integrity. While the drug was present, the sperm stem cells simply continued regenerating as stem cells. When the drug was later removed, the cells could regain their ability to differentiate into mature sperm.

“Most experimental male birth control drugs use a hammer approach to blocking sperm production, but ours is much more subtle,” Evans said. “This makes it a promising therapeutic approach, which we hope to see in development for human clinical trials soon.”

Image caption: Sperm, pictured inside the cross-sectioned tube of the epididymis, were not generated while mice took the HDAC inhibitor drug (top left), but after 60 days off the drug, spermatogenesis was recovered (top right). The bottom row shows sperm at the same time points in a mouse that did not receive the drug. Image credit: Salk Institute.