Male Contraception Begs for a Paradigm Shift

Aaron Hamlin
5 min readNov 28, 2016

Researchers recently published a phase-two male contraceptive trial. There are three phases before the FDA decides whether to approve a drug, so getting this far was a major accomplishment based on decades of research.

The downside is that the trial went poorly. An independent safety committee ended it early. But we can use this lesson to guide us to a better route — non-hormonal approaches.

This trial’s particular regimen used synthetic testosterone and progestin injections every eight weeks to stop sperm production. Stopping sperm production is slow. The drug took six months to work in 96% of men — that is, to get their sperm count below one million per milliliter. And even then, eight of the 266 men who entered the efficacy phase didn’t return to a normal sperm count after one year. One man’s sperm count didn’t return even after four years.

Among those who responded to the drug, the annual pregnancy rate was about 2%. Considering this 2% pregnancy rate was under perfect use, the typical-use (real world) annual pregnancy rate would be higher. Typical-use pregnancy rates are always much higher than perfect-use whenever contraceptive effectiveness relies on the user, like having to remember a pill. In this case, the user has to monitor his sperm count and regularly return to the doctor for injections.

To get this real-world figure, we can extrapolate from the female injectable counterpart, Depo-Provera, which has a 0.2% perfect-use and 6% typical-use annual pregnancy rate. Estimating, we can put the typical-use annual pregnancy rate for this male injectable around 10 to 20%. The importance of a contraceptive to have a very low typical-use pregnancy rate is clear when you consider the need to avoid unintended pregnancies over many years.

From the 320 men in the study’s suppression phase, researchers attributed two serious adverse psychiatric events to the drug. One man became severely depressed and another man attempted suicide. Additionally, there was a completed suicide, though the researchers considered it due to the participant’s reported inability to cope with academic pressures and not the drug treatment.

The safety committee halted the study reasoning that the side effects were more prevalent than expected, particularly “depression and other mood changes” Most depression cases were moderate to severe. Other common side effects included muscular pain (16%) and acne (45%). Unfortunately, this study didn’t have a control group for comparison.

This isn’t the first lesson we’ve seen on side effects with hormonal male contraception. In a double-blind, placebo-controlled 2008 study with about 300 treated men, it again took many months to halt sperm production, some men didn’t respond to the drug, and there was one man who attempted suicide.

Since there wasn’t a control group for the current study, it’s hard to confidently connect which events were attributable to the drug. But when you look at the two trials together, the severity of psychiatric side effects is a warning sign, especially two suicide attempts and one suicide among about 600 healthy men.

There’s already been some inappropriate backlash on this study. For example, Daily Show comedian Michelle Wolf made it seem like the men themselves somehow ordered the study be stopped. Then USA Today continued in the same vain saying that men “can’t handle side effects that women face daily”.

To be clear, every drug has side effects. Those side effects, for instance, are the top reasons for discontinuation for both Depo-Provera and the Pill. While sometimes exasperating, most of those risks aren’t actually fatal. Even in the worst case scenario with smokers aged 35–44, the annual attributable risk of death for those using oral contraceptives is less than one in 5,000.

In this study, however, there was an actual suicide and an attempted suicide within a sample of just over a few hundred in only a year. That’s on top of the issues already mentioned. We may partly be seeing these more severe side effects simply because it takes a higher hormonal dosage to stop sperm production than to stop ovulation.

Perhaps most intriguing is that over 80% of the men who finished this trial were still willing to use the drug — even after learning why the trial was stopped. That says something. Men desperately want a new male contraceptive!

Recognizing that demand, there are strategies moving forward.

First, some researchers are exploring daily hormonal dosing. This spreads out the dosage and avoids the peak-and-valley-shaped hormonal levels from injectables. That daily dosing might alleviate some side effects and potentially fix the sperm count recovery issue. Still, that doesn’t address the nonresponder issue, the need for repeated semen analysis, or three-to-six month wait before the drug works.

Alternatively, other researchers are using new biotech methods to identify non-hormonal approaches. At Male Contraception Initiative, we strongly prefer this second option. There’s no need to play the game of which sex can put up with the worse side effects.

Here, you can target functions like sperm motility or the sperm’s ability to fertilize an egg. These convenient approaches act on mature (or nearly mature) sperm — which means you don’t have to wait for months to get them to work. Other non-hormonal approaches include relaxing specific muscles in the vas deferens to stop ejaculation while allowing orgasm. There are also novel approaches for blocking sperm passage.

The takeaway here isn’t to reduce funding for male contraceptive research. Rather, the takeaway is that it’s time to focus on a new paradigm — non-hormonal male contraceptives. And if you want them available down the road, then the time to fund them is now, because drug development — hormonal or not — takes a long time.

Originally published at on November 28, 2016.