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Sunday, April 14, 2024

A Novel Male Birth Control Could Be an ‘On-Off Switch for Sperm’

Before a sperm can fertilize an egg, it faces a long journey: Propelled by the back and forth movement of its tail, it needs to swim all the way through the female reproductive tract to the fallopian tube, where it meets an egg. But in a new study, researchers who want to develop on-demand male contraceptives say they’ve figured out a way to prevent pregnancy: temporarily stop the sperm from swimming.

In a paper published today in Nature Communications, the researchers announced that when they injected 52 male mice with an experimental compound called TDI-11861, it temporarily inhibited an enzyme that helps sperm move. When they paired the males off with females to mate, no pregnancies occurred. (The same number of male mice treated with a control substance impregnated almost one-third of their mates.) The effects lasted for up to two and half hours. At around three hours, some sperm started moving again, and by 24 hours, nearly all sperm recovered normal movement. The authors say the results point the way to a short-term birth control option for men.

“It’s pretty clear that this is an on-off switch for sperm,” says Lonny Levin, a professor of pharmacology at Weill Cornell Medicine in New York, and an author on the paper. “We thought inhibiting this would be a great way to stop sperm in their tracks, prevent them from ever leaving the vagina and getting to the promised land to fertilize an egg.” 

But injecting a drug before sex isn’t exactly an appealing idea, so the researchers also tested an oral version in male mice and confirmed that the drug immobilized sperm when delivered this way. This method of birth control doesn’t contain hormones, as pills for women do. The idea is that it could be taken shortly before sex, rather than daily. “I think this is really one of the biggest advancements for non-hormonal contraceptives in recent times,” says Christopher Lindsey, a program official in the National Institute of Child Health and Human Development, which partly funded the work. 

Levin and his collaborator Jochen Buck, also a professor of pharmacology at Weill Cornell, didn’t initially set out to find a male contraceptive. They were studying a regulatory enzyme called soluble adenylyl cyclase, or sAC, which is found in almost every cell. When they genetically engineered mice to lack this enzyme, they found that the males were infertile. The enzyme appears to play a major role in activating a sperm cell’s ability to swim.

That led the researchers on a new quest to develop a potential male contraceptive by designing compounds that could block sAC. But because this enzyme is present elsewhere in the body—and may be necessary for other cellular functions—they didn’t think it would be a good idea to shut it off permanently.

In 2018, Melanie Balbach, a postdoctoral associate in their lab, gave one of those experimental compounds to mice and found that it produced sperm that could not propel themselves forward. “They didn't move. They didn't twitch,” Levin says. But that compound lost its effect once it entered the female reproductive tract. So the researchers kept testing compounds that would keep sperm immobile. 

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Over time, they refined TDI-11861. In mice, the drug didn’t appear to interfere with sexual functioning or cause any side effects. And most importantly, the sperm were normal again a day later. 

Of course, there is a big caveat: Mice are not people. But humans also have the sAC enzyme, and in males, it’s also involved in sperm movement. Buck and Levin are reassured that the strategy might be safe in people by another team’s report from 2019, which described two infertile men with mutations in the gene that makes sAC. The men were otherwise healthy, except for having a higher risk of kidney stones. (Mice bred without this gene have elevated eye pressure, which wasn’t a problem found in the men without the gene.) 

To test the safety of their compound, the Cornell team continuously infused it into male and female mice via a pump for six weeks. They noted no side effects, including no kidney issues. They’re now testing the compound in rabbits, which have reproductive organs that are more similar to those of humans. 

Many efforts to create male contraceptives have used hormones—primarily testosterone—to suppress sperm production. But like hormonal birth control for women, these drugs can have an array of negative side effects, including mood swings, weight gain, and decreased libido. Both female and male hormonal birth control also take weeks to become fully effective at preventing pregnancy. A trial sponsored by the National Institutes of Health that’s testing a hormonal gel for men is showing promising results, but the gel must be applied daily to the shoulders to keep sperm levels low enough for effective contraception. 

Some men might prefer a non-hormonal, temporary option. “I think it’s a really wonderful idea and would be very much appreciated by a lot of people who would not maybe want to take a pill every day,” says Gunda Georg, a professor of medicinal chemistry at the University of Minnesota, who researches male and female contraceptives and wasn’t involved in the new work. “I think we need to have many different options for contraception for men and also for women.” 

Georg’s lab developed a non-hormonal pill, dubbed YCT529, that targets a protein called retinoic acid receptor alpha and is involved in sperm formation. In mice, it greatly reduced sperm counts and was 99 percent effective at preventing pregnancy after being given daily for four weeks. 

While Buck and Levin are also working toward a pill, these are less efficient at delivering drugs than injections. The stomach tends to degrade them, and Levin says the current version of their compound would need to be a pretty large pill. The researchers have launched a company, Sacyl Pharmaceuticals, to further refine their sAC inhibitors and advance them to human clinical trials. “We're trying to get a compound that will be a nice, small pill,” Levin says. 

They also acknowledge that the current compound wears off too quickly, which could result in unwanted pregnancies if not taken at exactly the right time, so they’re hoping to extend the window of effectiveness to 18 hours or so. While there’s still a lot of testing ahead, if all goes well, maybe it will play a role in future Valentine’s Days. “Presumably, you could take this over dinner, and then within an hour, similar to Viagra, you would be ready to engage in sexual activity,” Lindsey says. 

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