Researchers at the University of Minnesota might be on to something different in the realm of male birth control. They're working on a nonhormonal pill for men that would effectively render them infertile while ingesting it.
Female birth control typically works by targeting sex hormones and disrupting ovulation or preventing sperm from reaching the egg, and the research into male birth control to this point has copied that model by targeting testosterone.
"But targeting male sex hormones leads to a lot of side effects, such as weight gain, depression and increased cardiovascular diseases," said Md Abdullah Al Noman, a graduate student at the University of Minnesota, during a press briefing at the American Chemical Society's spring 2022 meeting. "We wanted to develop a nonhormonal male contraceptive to avoid these side effects."
Long story short, they targeted a protein called the retinoic acid receptor alpha (RAR-α). The receptor binds to vitamin A and plays an important role in cell growth, cell differentiation and embryo development. Knock out that receptor and you limit an important factor in fertility and fertilization. It appears to work.
'Targeting male sex hormones leads to a lot of side effects, such as weight gain, depression and increased cardiovascular diseases. We wanted to develop a nonhormonal male contraceptive to avoid these.'
"Mice that no longer have this particular receptor become infertile, but otherwise they are healthy. And that's very important, that you knock out the target that you seek, [and get] the desired effect, but the mice are also viable and healthy," said Gunda Georg, Ph.D., who also spoke as part of the ACS media briefing and whose lab at the University of Minnesota conducted the research.
Georg and her team were aware of three receptors—RAR alpha, beta and gamma—but they targeted alpha specifically because the others showed side effects in previous research. It worked. They identified one compound, out of about 100 they designed, called YCT529 that inhibited RAR-alpha almost 500 times better than it did the beta or gamma receptors. When the compound inhibits the binding of retinoic acid, sperm production is extinguished.
"So that's the mechanism that we used and modified," Noman said.
Computer modeling helped the team predict which compounds would bind to RAR-alpha but not to beta or gamma, and that's how they identified the roughly 100 compounds to try. With YCT529 identified, it was time to test.
"We conducted a mating study," Georg said. "Male mice were given the drug every day and they were together with female mice, and then we observed how many pregnancies took place. Initially, we didn't see an effect, but after we gave this drug for [four] weeks, the pregnancies went down and the efficacy was about 99 percent, meaning it was a very high effect, and so that is really very promising."
She added that you have to be careful about drawing conclusions from these analyses because they were conducted on mice, but the effect is promising, especially given the male mice exhibited no side effects.
That's all good, but there isn't much value in a drug if fertility doesn't return after men stop taking the pill.
"After about two weeks, the mice started to become fertile again," Noman said. "But after about four weeks, they became completely fertile."
The compound has been licensed to YourChoice Therapeutics, whose hope is to get approval for clinical trials from the Food and Drug Administration in the second half of 2022. The documentation and application are being prepared.
"Because it can be difficult to predict if a compound that looks good in animal studies will also pan out in human trials, we're currently exploring other compounds, as well," Georg said.