A non-hormonal male contraceptive that works well in mice and doesn’t have any obvious side effects.

Women have a number of birth control options, ranging from pills to patches to intrauterine implants, and they bear the brunt of the responsibility for avoiding conception.

However, men’s birth control options — and hence responsibilities — may be expanding shortly. Scientists have developed non-hormonal male contraception that efficiently prevents pregnancy in mice while having no noticeable adverse effects.

Male condoms and vasectomy are currently the only two effective birth control alternatives available to males. Condoms, on the other hand, are single-use only and prone to failure. Vasectomy, on the other hand, is a surgical treatment that is considered a permanent method of male sterilization. Although vasectomies can be reversed in rare cases, the procedure is costly and not always successful. As a result, men require a contraceptive that is effective, long-lasting, and reversible, comparable to the birth control pill for women.

“Scientists have been trying for decades to develop an effective male oral contraceptive, but there are still no approved pills on the market,” explains Md. Abdullah Al Noman, who is presenting the work at the ACS 2022 meeting.

The majority of drugs currently in clinical trials target the male sex hormone testosterone, which could contribute to weight gain, depression, and higher levels of low-density lipoprotein (LDL) cholesterol.

“We wanted to develop a non-hormonal male contraceptive to avoid these side effects,” adds Noman.

The researchers used a protein called the retinoic acid receptor alpha (RAR-α) to develop their non-hormonal male contraception. This protein belongs to a group of three nuclear receptors that bind retinoic acid, a kind of vitamin A that helps cells grow, differentiate (including sperm production), and create embryos. Male mice that have the RAR-α gene knocked out are sterile, with no noticeable adverse effects. Other researchers have created an oral compound that inhibits all three RAR family members (RAR-α, -β and -γ) and causes reversible sterility in male mice, but Georg’s group and their reproductive biology collaborators wanted to find a drug that was specific for RAR-α and thus less likely to cause side effects.

Thus, the researchers studied the crystal structures of RAR-α, -β and -γ coupled to retinoic acid in detail, discovering structural variations in how the three receptors bind to their shared ligand.

They used this information to design and manufacture about 100 chemicals, which they then tested for their capacity to specifically block RAR-α in cells. They discovered a chemical called YCT529 that inhibited RAR-α nearly 500 times more effectively than RAR-β and -γ.

YCT529 significantly lowered sperm counts and was 99 percent efficient in preventing conception in male mice when given orally for four weeks. After stopping receiving the chemical, the mice might father pups again after 4-6 weeks.

According to Georg, human clinical trials for YCT529 will commence in the third or fourth quarter of 2022.

“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 adds.

The researchers are altering current drugs and testing novel structural scaffolds to find these next-generation chemicals. They are hopeful that their efforts will result in the development of the long-awaited oral male contraception.

Source: ACS Spring 2022

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