Is that an oral male contraceptive on the horizon?

BioTechniques News
Georgia Bickerton

Male Contraception

A non-hormonal male contraceptive shows promising results in mice, which is 99% effective at preventing pregnancy and has no obvious side effects.  

It’s about time for men to have more than two effective options of contraception – condoms or a vasectomy. Now, a team of researchers led by Gunda Georg at the University of Minnesota (MN, USA) have developed a non-hormonal male contraceptive that inhibits sperm production by blocking a vitamin A receptor. They presented their promising preliminary findings at the American Chemical Society’s spring meeting on the 23rd of March 2022 in San Diego (CA, USA).  

“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, a graduate student who presented this research. Current male contraceptives in clinical trials target testosterone, the male sex hormone, which could lead to side effects, including increased low-density lipoprotein cholesterol levels as well as weight gain and depression, side effects that I’m sure are familiar to those on female contraceptives. “We wanted to develop a non-hormonal male contraceptive to avoid these side effects,” says Noman. At the ASC meeting, Noman adds that “since men do not have to [make the] trade-off between pregnancy and side effects, men are less willing to take a birth control pill that has such significant side effects.”

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There are countless choices of birth control for women, including various coils inserted into the uterus, implants that go under your skin, and, of course, the combined oral contraceptive pill – aka “the pill”. Many of these contraceptives also come with a helping of side effects like migraines, weight gain, spotting between periods, nausea, depression, and ironically, a lower libido. You only need to look at The Lowdown, a website filled with reviews of many different contraceptives, to see how varied experiences are – both positive and negative.  

Clearly, sperm need to step up and come into the firing line with an effective, long-lasting and reversible form of contraception, and finally share the responsibility of birth control. 

Researchers at Georg’s lab developed a non-hormonal male contraceptive by targeting the retinoic acid receptor alpha (RAR-α), one of three proteins that bind to retinoic acid, a form of vitamin A. Retinoic acid plays an important role in cell differentiation, including sperm formation, embryonic development and cell growth. It’s known that depriving male mice of vitamin A leads to infertility and has previously been validated using genetic knockout. The results showed that male mice who had their RAR-α gene removed were sterile, but, importantly, were otherwise healthy.  

Oral compounds that inhibit all retinoic acid receptors (RAR-α, RAR-β and RAR-γ) have been developed by other researchers and result in reversible sterility. However, Georg’s research group and their collaborators wanted to design a drug to specifically inhibit RAR-α, to reduce potential side effects. 

The researchers studied the crystal structures of RAR-α, -β, and -γ when bound to retinoic acid, to identify any structural differences in how these receptors bind to their common ligand, vitamin A. They used these observations to design and synthesize around 100 compounds and analyzed their ability to selectively inhibit RAR-α.  

The frontrunner was a compound called YCT529, which inhibited RAR-α almost 500 times more potently than RAR-β or RAR-γ. YCT529 was given to mice orally for 4 weeks and the researchers reported a greatly reduced sperm count that was 99% effective in preventing pregnancy, without seeing any side effects. Additionally, after 4-6 weeks without taking YCT529, the mice could father pups again.  

While YCT529 seems promising, Georg explains that “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 next-generation compounds will test new structural scaffolds and modify the existing YCT529 compound.  

This non-hormonal contraceptive is now licensed with YourChoice Therapeutics, a birth control start-up, and is undergoing additional studies. The researchers hope that YCT529 will be in a human clinical trial later this year, and if everything goes well, Georg estimates that this male birth control could be available in as soon as 5 years.   

So, it seems that reproductive autonomy for all is on the horizon, and men could finally get their own version of the infamous and revolutionary pill, without the side effects. 

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