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/adverse events 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?
A phase 2 trial of a combination of an injectable testosterone and norethisterone (a progestin and a hormone similar to what is 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.
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% of men has suppressed sperm. There were 4 pregnancies for a pregnancy rate of 1.57/100 users. The Pearl Index was calculated as 2.18 pregnancies per 100 person years (basically 100 people use the method and 2.18 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% of men said they were satisfied with the method and would use it again.
The Bad News
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%), increased libido (38%), “emotional disorder” (16.9%), injection site pain (23.1%) and myalgias (or muscle pain, 16.3%). 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 attempted suicide.
Comparing Like With Like
You can’t compare the findings of a phase 2 trial with the echo chamber of personal experience that is the Internet. You have to compare study with study, not a study with an op-ed column. These 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%. The pill reduces acne for 70% of women and in studies with the Mirena IUD the rate of acne is 6.8%.
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. In the male contraception study 2.8% 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, anyone telling women not to use the pill because it’s possible that an additional 0.5% of adolescents could develop depression I assume you are also telling women these same women that they should certainly not get pregnant as 15% of women develop post partum depression.
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 5 men it took > 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 be formally screening men for depression. Maybe it is was 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.
As for the 20 men who dropped out because of side effects? That’s A) 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.
The study doesn’t say men are wimping out, our low vasectomy rate does
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% of American men have had a vasectomy yet 15% 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’d 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.
While vasectomy only applies to those 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.
- An earlier version of this post incorrectly stated both review boards recommended terminating early, it was one. The information about those who dropped out has also been included. I have also updated the post with the number of men with delayed/failure to return to normal fertility.