For years, scientists have faced challenges in developing a safe, effective male contraceptive that doesn’t rely on hormones. However, a new breakthrough may bring them closer to creating a non-hormonal option, thanks to an enzyme previously overlooked in reproductive studies.
Unintended pregnancies are a global concern, with millions of abortions occurring annually. Contraceptive methods—such as hormonal pills, intrauterine devices, and female condoms—have traditionally been developed with women in mind, leaving men with limited options. In response to this disparity, a team of researchers led by Martin Matzuk, a pathologist at the Baylor College of Medicine, has made significant strides in exploring a male contraceptive that doesn’t rely on hormonal manipulation.
Published in Science, the study showcases how an inhibitor targeting the enzyme serine/threonine kinase 33 (STK33)—an enzyme crucial for sperm formation—could be a viable candidate for male birth control. The inhibitor demonstrated effectiveness at low concentrations, did not cause toxicity, and could temporarily disrupt sperm formation without affecting testicular size. This finding opens the door to developing a male contraceptive that helps share the responsibility of preventing unintended pregnancies.
The Difficulty of Male Contraceptive Development
Creating a male contraceptive has proven difficult for several reasons, one of which is the high expectation for minimal side effects. Unlike the hormonal pill for women, which was developed over 60 years ago, men are less likely to tolerate side effects from birth control methods, according to Jochen Buck, a pharmacologist at Weill Cornell Medicine. As testosterone-targeted methods can cause unwanted effects, researchers have increasingly focused on non-hormonal solutions.
Matzuk, who believes men should be more involved in contraceptive decisions, expressed that a shared responsibility in contraception benefits both sexes, especially when some women may be unable to take hormonal birth control. Previous studies had already identified STK33’s role in sperm production in mice, and mutations in the STK33 gene were linked to infertility in human males. Since interfering with STK33 didn’t cause lasting harm to testicular size, Matzuk and his team targeted this enzyme for further study.
Targeting STK33: A New Approach to Male Birth Control
The discovery that inhibiting STK33 could affect sperm motility and morphology without permanent testicular damage opened up new possibilities. Unlike other contraceptive methods that require extensive clinical trials involving female reproductive systems and pregnancy, testing an STK33 inhibitor would focus solely on male fertility, streamlining the research process.
Finding the right inhibitor, however, proved challenging. The researchers used a technique known as DNA-encoded library (DEL) screening to sift through billions of chemical compounds, ultimately identifying CDD-2807 as the most promising candidate. When tested on mice, the drug successfully reduced fertility without causing toxic side effects. Notably, the drug’s effects were reversible—mice regained fertility once treatment ceased.
An important feature of the drug was its ability to cross the blood-testes barrier while not affecting the brain, ensuring it targeted the reproductive system without accumulating in the brain, potentially avoiding unwanted side effects.
The Road Ahead
Building on these results, Matzuk’s team plans to test the drug on non-human primates next, as part of the ongoing effort to develop a male contraceptive. While many contraceptive options exist for women, men currently have limited alternatives beyond condoms, which are often less favored. According to Buck, there is a need for multiple contraception methods, and a male contraceptive could offer men more control over reproductive health.
The development of a non-hormonal male contraceptive marks a significant step forward in balancing the contraceptive options available to both men and women, with the potential to ease the burden of unintended pregnancies globally.
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