The effort to create a male contraceptive pill has been full of obstacles. Targeting hormones or sperm production can produce difficult side effects, not the least of which is changes in libido. But a new paper shows that you might be able to get better results by focusing not on the sperm but on where they travel. If the pill could be worked out, it could mean an effective male contraceptive.
With female contraceptives so widespread, you would think the male version might not be far behind. But in fact, the male pill has a lot more to contend with. Instead of releasing one egg a month, males produce thousands of sperm in one go. And while female eggs may be produced only once and released roughly every 28 days, male sperm are produced over and over again, roughly every 45 to 70 days. Decreasing male hormones like testosterone to stop sperm production and function produces side effects that many men will not tolerate, like loss of libido (what’s the good of a contraceptive if you lose the desire to use it?). If you give a drug that reduces sperm production, will it affect sperm production after you stop taking the drug?
These are all problems that might arise when you’re focusing on the sperm itself, how much are made and how they move. But what if you focused instead on their route out of the body? For example, one method under development targets the vas deferens, the tube that sperm travel through during ejaculation. The method involves the insertion of a silicone plug into the vas deferens, stopping sperm from getting through. But it’s still a surgical intervention.
So how do you target sperm transport without physically blocking tubes? Carl White and researchers from Australia and England focused on the receptors that control tube width. The vas deferens is made of smooth muscle. This smooth muscle contracts during ejaculation, forcefully ejecting sperm from its storage spot in the cauda epididymis into the urethra. The contraction happens as receptors in the smooth muscle, called P2X1-purinoceptors and alpha 1a-adrenergic receptors, respond to ATP and norepinephrine, chemical signals from neurons that signal ejaculation time has come.
So what if you cut off those receptors? Would it change fertility? And would it do it without affecting libido or causing other side effects? To look at this, White and colleagues deleted the genes for P2X1-purinoceptors and alpha 1a-adrenergic receptors in mice. The resulting mice, described December 2 in the Proceedings of the National Academy of Sciences, made it to adulthood just fine … and were completely infertile. While they produced viable sperm, the sperm did not make it to the urethra to be ejaculated.
But the mice were still rarin’ to go. To quote from the results section, “male mice exhibited normal sexual behavior for this background strain of mouse in terms of precoital chasing, sniffing, mounting of mates, pelvis thrusting with appropriate vigor and frequency.” (I added the italics for emphasis. How many times will you see that in a scientific paper? I can only imagine the faces of the reviewers…) No problems with libido here. It makes me wonder what “appropriate vigor and frequency” is for a mouse.
Despite their, ahem, vigor, the mice ejaculated no sperm. In fact, they appeared to produce no ejaculate at all. When mice mate, the male leaves a vaginal plug in the female, made of secretions from several glands. When the P2X1-purinoceptors and alpha 1a-adrenergic receptors were gone, the mice could not produce the plug, which suggests that the secretions were not being ejaculated either. Without ejaculate, the mice clearly had no sperm, though the authors noted that “a lack of ejaculate has the potential to be disconcerting.” While it might indeed be disconcerting in humans, I have to wonder about the mice.
In spite of the dry ejaculation, the knockout mice were otherwise pretty normal. This is particularly surprising, as the alpha 1a-adrenergic receptor plays an important role in regulating things like blood pressure. The mice did have slightly lower blood pressure but appeared to be able to make up the difference. The mice also produced sperm (which they couldn’t ejaculate) that were fully functional when used in IVF with a mouse egg.
But these are mice with knocked out genes. What does this mean for human male contraceptives? The authors hope that this study will help pave the way for effective contraceptive drugs. Alpha 1a-adrenergic receptor antagonists (drugs that block the receptor) are in fact already on the market, for things like anxiety, blood pressure, prostate issues and panic attacks. All that would be needed, the scientists say, is a blocker for P2X1-purinoceptors. The resulting pill could combine antagonists for P2X1-purinoceptors and alpha 1a-adrenergic receptor antagonists, stopping sperm transport and keeping men infertile … until they stopped taking it.
No hormonal side effects, one drug already exists, and it’s reversible? This could be the male contraceptive we’ve been waiting for. The fact that the mice were healthy without both receptors, and didn’t have major blood pressure problems suggests that it might be doable. But it’s also possible that the two drugs combined could have some side effects. For example, alpha 1a-adrenergic receptors are also present and important in fat tissue and the gastrointestinal tract. And would effective doses for a contraceptive in humans really not affect blood pressure? P2X1-purinoceptors are also important in regulating blood pressure, so would combined drugs in humans amplify blood pressure side effects?
It’s also important to realize that these mice were born and raised without these receptors. This means they were able to adapt to function without them. That’s great for the mice, but humans would obviously not want these receptors knocked out entirely. They would want to take a pill that stops sperm transport and then reverses. It’s possible that the human body might respond very differently to a sudden blockade of P2X1-purinoceptors and alpha 1a-adrenergic receptors than a mouse that has lacked them for its entire life.
So this male contraceptive may have a long way to go before humans begin popping them. Still, I’m sure many men will be relieved to know that the possibility is out there for a contraceptive that keeps their vigorous thrusting intact.
The male mouse in this video may be an infertile double knockout (that is, researchers have shut down the genes for receptors that control sperm ejaculation), but he's still shows lots of interest in the ladies.
Credit: C. White et al/PNAS 2013