Non-Hormonal Male Contraceptive May Prevent Pregnancy Without Adverse Effects

A non-hormonal male contraceptive effectively prevents pregnancy in mice and without any obvious adverse events, according to the results of a study presented at the American Chemical Society Spring 2022.

The male contraceptive would add form of birth control for men to the only other 2 effective options: male condoms and vasectomies. Condoms, however, are single-use and prone to failure, while vasectomies are a surgical procedure that is considered a permanent form of male sterilization.

Although vasectomies can sometimes be reversed, reversal is expensive and not reliable. Forms of oral birth control are limited to females, with most also being hormonal.

“Scientists have been trying for decades to develop an effective male oral contraceptive, but there are still no approved pills on the market,” Md Abdullah Al Noman, PhD, who presented the findings at the meeting and is a graduate student at the Institute for Therapeutics Discovery and Development at the University of Minnesota, said in a statement. “We wanted to develop a non-hormonal male contraceptive to avoid these side effects.”

Most of the compounds that are being tested target the male sex hormone, testosterone, which could lead to adverse effects (AEs), such as depression, increased low-density lipoprotein cholesterol levels, and weight gain.

The non-hormonal contraceptive differs by targeting a protein called the retinoic acid receptor alpha (RAR-α), investigators said.

The protein is 1 of 3 nuclear receptors that bind retinoic acid, a form of vitamin A that plays a key role in cell growth, differentiation, which includes sperm formation, and embryonic development.

Taking out the RAR-α in male mice makes them sterile, and there are no obvious AEs that investigators noted.

Other investigators have developed an oral compound that inhibits all 3 members of the RAR family and causes reversible sterility in male mice. However, the team in this study wanted to specifically target RAR-α, because it is least likely to cause AEs.

Investigators studied crystal structures of RAR-α, -β, and -γ that were bound to retinoic acid and identified the structural differences in the ways the 3 receptors bind to their common ligand.

They designed and synthesized approximately 100 compounds and evaluated their abilities to selectively inhibit RAR-α in cells. A specific compound identified was YCT529, which inhibited RAR-α almost 500 times more than it did with RAR-β, and -γ.

When the mice were given YCT529 orally for 4 weeks, it dramatically reduced sperm counts and was 99% effective in preventing pregnancies. About 4 to 6 weeks after stopping the compound, the mice could father pups again.

YCT529 will begin testing in human trials in the third or fourth quarter of 2022, and investigators said they are also exploring other compounds.

Investigators said that they are both modifying the existing compound and testing new structural scaffolds and hope that their efforts will launch a male contraceptive.

Reference

A non-hormonal pill could soon expand men’s birth control options. News release. March 23, 2022. Accessed March 24, 2022. https://www.eurekalert.org/news-releases/945816