There has been a lot of discussion recently about a new hormonal contraception study for men that was halted early due to adverse events. Two of the side effects that led to early termination were acne and mood disorders leading many to wonder, what gives? Can’t men hack hormones—or are researchers biased and letting men get off easy?
Headlines proclaimed that the study was called off because men can't handle the kind of hormonal effects women deal with every day they're on birth control. But it's not that simple at all.
The study was a phase 2 trial of a combination of an injectable testosterone and norethisterone (a progestin and a hormone in many birth control pills) for men. The goal was to see if the drug suppressed sperm, prevented pregnancy, was safe, and if the men who used it found the side effect profile acceptable. There was no placebo arm as placebo arms in contraception studies are unethical for obvious reasons.
In total, 320 men enrolled and 266 completed enough of the study to produce data on how well the product worked. The good news is that the drug combination was very successful and almost 96 percent of men has suppressed sperm. There were four pregnancies, for a pregnancy rate of 1.57/100 users. The Pearl Index was calculated as 2.18 pregnancies per 100 person years (basically if 100 people use the method, 2.18 will get pregnant over that year). The Pearl Index is 1.5-2 for the birth control pill. Other good news is that more than 75 percent of men said they were satisfied with the method and would use it again.
The study was halted early as one of two independent safety panels took issue with the high rate of side effects. This wasn’t the researchers saying, “Oh these poor men.” This was an independent review board. The adverse events that raised concerns were: acne (45 percent), increased libido (38 percent), “emotional disorder” (16.9 percent), injection site pain (23.1 percent), and myalgias, or muscle pain (16.3 percent). One man committed suicide—which somehow the researchers said wasn’t related to the drug because his family said he was stressed at work—and one other attempted suicide.
How bad is it? Well, to assess that you have to compare study with study. You can’t compare the findings of a phase 2 trial with the echo chamber of personal experience that is the Internet, or an op-ed column.
The side effect rate is pretty high with this new study of men when compared with contraception studies for women. For example and perspective, a study comparing the birth control patch with the Pill found a serious adverse event rate of 2 percent. The Pill reduces acne for 70 perent of women, and in studies with the Mirena IUD, the rate of acne is 6.8 percent, a fraction of what was observed in the male contraception trial.
As for the depression outcomes, let's look at that recently reported study on depression with the birth control Pill. It has some good points, but also lots of issues—the most glaring being no control group (i.e. no copper IUD users). But let’s say for argument’s sake the study is accurate depression-wise, which would mean the birth control pill accounted for one additional case of depression per 200 adolescent users (or 0.5 percent). In the male contraception study 2.8 percent of users developed depression, so much higher.
However, for the most accurate comparison we need prospective studies of women using birth control pills and those have not clearly demonstrated a link between depression and the Pill. That doesn’t discount personal experiences. Might there be a subset of women prone to depression with hormones? Might it be multifactorial so several events must be in place for the Pill to trigger depression? Sure, but we don’t have those answers yet.
As an aside, to anyone telling women not to use the pill because it’s possible that an additional 0.5 percent of adolescents could develop depression, I assume you are also telling women these same women that they should certainly not get pregnant as 15 percent of women develop postpartum depression.
There are four significant issues with the study:
- A significant percentage of adverse events came from one study center.
- None of the men appeared to have been formally screened for depression beforehand.
- “Emotional disorders” weren’t defined in the paper (perhaps they were in the study). I’m a doctor and I don’t know what that means.
- For five men it took more than 52 weeks (but less than 74 weeks) for spermatogenesis to recover. One man still had no return of adequate sperm for fertility at 4 years.
Based on the above I think scientifically it was reasonable to stop the study. Was it to spare men possible excessive side effects, a possible increased risk of suicide, and ill-defined emotional issues at one study site? Sure, that’s ethics. It doesn’t mean the study was a failure, it means the side effect/adverse event profile was higher than expected and not distributed evenly among study centers and a group of reviewers wondered, "What’s up with this? Perhaps we should figure it out.” (It is curious to me that the delay in return to normal fertility wasn’t part of what prompted the independent review board to suggest, although likely they didn’t have that information at the time of the safety review.)
The biggest head scratcher for me is what was up with this one site? I also think if there are these early concerns about possible depression, further studies should formally screen men for depression. Maybe it is was the drug and maybe men with depression were more likely to self-select for the study. I think grading the severity of acne might also be important.
A) That's not why the study was stopped and B) women drop out of contraception studies all the time, too, and it doesn’t mean they are wimps. Here’s a quote from a prospective study looking at the Pill and Depo Provera and side effects and depression: “We observed that experiencing adverse symptoms may lead to method discontinuation.”
The dose of hormones was effective and that’s great, but the press and many people have forgotten this for catchy and misleading headlines. Ending studies early for safety happens. The conclusion isn’t men can’t handle hormones it means better screening may be needed before and during the next study for both depression and anxiety and maybe more uniform training among study centers.
Forget the study. We already have plenty of data on how women bear the burden of contraception when a similar option is available to both in the coupleship. Only 5 percent of American men have had a vasectomy, yet 15 percent of American women have had a tubal ligation. Almost weekly I discuss contraception with a woman who is having issues with multiple methods. She and her partner have finished childbearing and yet she can’t get him to make an appointment to discuss vasectomy. She just rolls her eyes. She’s given up asking. She assumed the not insignificant risk of pregnancy—usually more than once—and yet she cannot get her partner to assume the insignificant risk of a vasectomy. What exactly does that say? Yeah, I know this is not all men, but it’s a lot. And this, quite frankly, is bullshit. The numbers should be reversed.
Vasectomy only applies to those who have finished childbearing, it is about as adverse event free as contraception can be, and yet we still can’t get all eligible men to have one. This is what makes me depressed about male hormonal contraception, because it is unlikely that there will ever be a contraceptive as easy and as safe as vasectomy.
We need more research into reversible male contraceptives and hopefully what was learned from this study will be helpful; however, looking at vasectomy rates I’m pretty pessimistic about the majority of men choosing it as an option. Here’s hoping I’m proven wrong.
This post originally appeared on drjengunter.wordpress.com. It is edited and republished with permission.
