Knocking out the RAR-alpha gene in male mice makes them sterile, without any obvious side effects

Saturday, April 16th, 2022

To develop a non-hormonal male contraceptive, researchers targeted a protein called the retinoic acid receptor alpha (RAR-alpha):

This protein is one of a family of three nuclear receptors that bind retinoic acid, a form of vitamin A that plays important roles in cell growth, differentiation (including sperm formation) and embryonic development. Knocking out the RAR-alpha gene in male mice makes them sterile, without any obvious side effects. Other scientists have developed an oral compound that inhibits all three members of the RAR family (RAR-alpha, -beta and -gamma) and causes reversible sterility in male mice, but Georg’s team and their reproductive biology collaborators wanted to find a drug that was specific for RAR-alpha and therefore less likely to cause side effects.

So the researchers closely examined crystal structures of RAR-alpha, -beta and -gamma bound to retinoic acid, identifying structural differences in the ways the three receptors bind to their common ligand. With this information, they designed and synthesized approximately 100 compounds and evaluated their ability to selectively inhibit RAR-alpha in cells. They identified a compound, which was named YCT529, that inhibited RAR-alpha almost 500 times more potently than it did RAR-beta and -gamma. When given orally to male mice for 4 weeks, YCT529 dramatically reduced sperm counts and was 99% effective in preventing pregnancy, without any observable side effects. The mice could father pups again 4-6 weeks after they stopped receiving the compound.

According to Georg, YCT529 will begin testing in human clinical trials 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 says. To identify these next-generation compounds, the researchers are both modifying the existing compound and testing new structural scaffolds. They hope that their efforts will finally bring the elusive oral male contraceptive to fruition.


  1. Pseudo-Chrysostom says:

    Safe and effective male contraception in fact has existed for a long time now; exogenous testoterone taken as a supplement induces reversible reductions in sperm production.

    The thing is these researchers, the incumbent priesthood in general, are not looking to develop male contraception precisely, they’re looking to remove maleness. The only forms of ‘contraception’ they will accept are ones that do not promote maleness in any way.

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