Scientists have potentially achieved a significant milestone towards developing a male contraceptive pill, a major advancement for birth control for men.
Pioneered by researchers at the University of Minnesota, the non-hormonal male contraceptive pill innovation has been demonstrated to prevent 99% of pregnancies in mice without inducing any noticeable side effects. This advancement looks to alleviate the burden of birth control that women have primarily carried due to a lack of contraceptive options for men.
The project received support and funding from the National Institutes of Health and the Male Contraceptive Initiative.
Limitations of current birth control
There is presently a range of effective birth control options for women, including pills, patches, and intrauterine devices, resulting in women bearing the majority of the burden for preventing pregnancy.
For men, birth control is limited, with there being only two effective options – male condoms and vasectomy. However, these methods have limitations; condoms can only be used once, and a vasectomy is a surgical procedure that is considered a permanent form of male sterilisation.
Despite vasectomies sometimes being reversed, this surgery can be expensive and is not always successful. This highlights the need for effective, long-lasting, but reversible birth control, such as a male contraceptive pill.
Md Abdullah Al Noman, a graduate student in the lab of Gunda Georg, PhD, at the University of Minnesota, said: “Scientists have been trying for decades to develop an effective male oral contraceptive, but there are still no approved pills on the market. Scientists have been trying for decades to develop an effective male oral contraceptive, but there are still no approved pills on the market.”
Designing a non-hormonal male contraceptive pill
The team targeted a protein called the retinoic acid receptor alpha (RAR-α) to develop their male contraceptive pill. This protein is part of a family of three nuclear receptors that bind retinoic acid, a type of vitamin A that is essential in cell growth, differentiation, including sperm formation, and embryonic development. Eliminating the RAR-α gene in male mice makes them sterile and does not cause any negative side effects.
Other researchers have created an oral compound that inhibits all three members of the RAR family (RAR-α, -β and -γ), causing sterility in mice that is reversible. However, the Minnesota team wanted to identify a specific drug for RAR-α, making it less likely to cause side effects.
The researchers analysed crystal structures of RAR-α, -β and -γ bound to retinoic acid, discovering structural differences in how the three receptors attach to their common ligand. This enabled the team to design and synthesise 100 compounds and assess their proficiency at inhibiting RAR-α in cells.
From this, the scientists isolated a compound, which they labelled as YCT529, that effectively inhibited RAR-α almost 500 times more potently than it did RAR-β and -γ. When administered orally to male mice for four weeks, YCT529 significantly mitigated sperm counts and was 99% effective at preventing pregnancy without causing side effects, and the mice were able to father pups again four to six weeks after stopping the treatment. Georg explained that her team will begin testing YCT529 in human clinical trials in the third or fourth quarter of 2022.
She said: “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.”
The team is hopeful that through modifying existing compounds and testing new structural scaffolds, they will be able to make the elusive male contraceptive pill commercially available.
