Towards a Male Contraceptive That Doesn’t Target Hormones

Unintended pregnancies may present a pleasant surprise to some, while to others they can impose a significant emotional, physical, and financial burden. They are also a major cause of the roughly 70 million abortions that occur annually worldwide.¹

Contraceptive measures—hormonal pills, intrauterine devices, female condoms, spermicide, intravaginal rings—have mostly only been for women. Men, on the other hand, have limited options.

To counter this disparity, scientists led by Martin Matzuk, a pathologist at the Baylor College of Medicine, investigated a potential contraceptive for men.² In their study, published in Science, they demonstrated how an inhibitor of serine/threonine kinase 33 (STK33)— an enzyme involved in sperm formation—could serve as a promising non-hormonal candidate for birth control in males. This inhibitor was potent at low concentrations, non-toxic, and reversibly inhibited STK33 without altering the size of testes. Their findings present a potential option to develop a male contraceptive in the future to help distribute the biological burden of avoiding pregnancies between both sexes.

Discovering a male contraceptive has in part been so hard because the bar for side effects is very high; men are much less likely to take a contraceptive with side effects, according to Jochen Buck, a pharmacologist at Weill Cornell Medicine, who was not involved in this study. The bar wasn’t as high when the hormonal pill for women was created more than 60 years ago, Buck explained. As targeting testosterone, though effective, might lead to some unwanted side effects, scientists have been looking for non-hormonal methods of male birth control.

“Men need more say in contraception, just like women. In partners, if some women can’t take a contraceptive, the men should be wanting to contribute to the strategy of contraception,” said Matzuk.

In previous studies, researchers had found that STK33 plays a role in sperm formation in mice.³ Scientists had also shown that deleting STK33 in mice led to infertility due to abnormal sperm morphology.⁴ On screening a human family with infertile males, a group of researchers discovered that these males had mutations in the gene encoding STK33.⁵ Since perturbing the protein or its corresponding gene didn’t lead to any permanent abnormalities in the size of the testes in men or mice, Matzuk found this enzyme to be a perfect target for their studies.^3,4 An enzyme inhibitor could temporarily affect sperm morphology and motility, which could easily be tested in a semen.

“For some drugs that are causing more of an effect in the female reproductive tract, you would have to have a clinical trial that involves women and pregnancy as an endpoint. But at least initially, you wouldn’t need it for these kinds of studies. I think that’s a real benefit of this target,” said Matzuk.

Finding an inhibitor that would work best against their enzyme was akin to searching for a needle in a haystack. Using a technique called DNA-encoded library (DEL) screening, the team looked through billions of chemical compounds. They tagged each compound with a unique DNA sequence and combined very high concentrations of STK33 with very low concentrations of the DEL compounds. On isolating the target-compound complexes, scientists could identify the DNA-coded compounds that bound well to the enzyme.

Eventually, they obtained CDD-2807 as the drug of choice. They found that the drug reduced fertility in mice without causing any toxic side effects. Importantly, the effect was reversible, and mice regained their fertility once the treatment was stopped.

A major advantage of this drug when tested on the mice was that it crossed the blood-testes barrier quite smoothly but managed to not slip through the blood-brain barrier. This ensured that not only did it do its job where it should, but it also did not end up accumulating problematically in the brain. Matzuk now plans to test the drug on non-human primate models as the next step.

“We need multiple, different methods, and maybe some people prefer to continuously not have sperm,” said Buck. “There are 10 different methods of female contraception, and at the moment, there is essentially nothing for men with the exception of condoms. And nobody in the world likes condoms, it’s a necessary evil.”