Male contraceptive effective in mice

Numerous male contraceptives have been touted and tested, but generally trials have failed to get off the ground because of seemingly insurmountable side-effects like acne, mood disorders and libido impacts – side-effects women regularly experience on the widely prescribed contraceptive pills. 

Solving the dual problem of the overwhelmingly female burden of contraception and the unappealing nature of prescribing side-effect laden medicines for men has thus been a key focus of chemists and pharmacological researchers.

In a new study presented today at the spring meeting of the American Chemical Society (ACS), a team of researchers from the University of Minnesota have obtained promising results in a trial testing a non-hormonal male contraceptive on mice. 

“Scientists have been trying for decades to develop an effective male oral contraceptive, but there are still no approved pills on the market,” says Md Abdullah Al Noman, who presented the findings at the meeting. 

Most compounds currently undergoing clinical trials target the male sex hormone testosterone, and can produce undesirable side effects like weight gain, depression and increased cholesterol levels. 

“We wanted to develop a non-hormonal male contraceptive to avoid these side-effects,” says Noman, a graduate student in the lab of Gunda Georg, at the University of Minnesota, US.

To develop their non-hormonal male contraceptive, the researchers targeted a protein called the retinoic acid receptor alpha (RAR-α). The protein is part of a family of three nuclear receptors that bind retinoic acid, a form of vitamin A that plays a key role in cell growth, cell differentiation and embryonic development.

Knocking out the RAR-α gene in male mice makes them sterile, without any currently obvious side-effects. Previous research has led to the development of oral compounds that inhibit all three members of the RAR family (RAR-α, -β and -γ), but the authors of the new study wanted to develop a drug that targeted RAR-α specifically, rather than a broad-brush approach, to reduce the likelihood of side-effects.

The team designed and synthesised approximately 100 compounds and evaluated their ability to selectively inhibit RAR-α in cells. They identified a compound, YCT529, that inhibited RAR-α some 500 times more potently than it did RAR-β and -γ. When given to male mice for four weeks, the compound dramatically reduced sperm counts and was 99% effective in preventing pregnancy.

The mice were able to father pups again 4-6 weeks after they stopped receiving the compound.

The results are a promising first step in the road to making the burden of contraception more equitable, but they’re extremely preliminary. 

While animal studies are an important early phase in developing drugs for human consumption, and can sometimes translate into successes at the human trial stage, not all drugs that show promise in mice translate into effective human medicines, because, quite obviously, mice and men have different physiologies.

Moreover, while the male mice regained their fertility, the trial was short, so the long-term effects of such inhibition would need to be studied.

But lab head Georg, who is also a consultant with YourChoice Therapeutics, says the team will begin testing their compound on humans in clinical trials by the end of 2022, as well as exploring other potentially effective compounds.

“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,” she says.