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Contraception

New study doesn’t show men are wimps about contraception side effects, low vasectomy rate might

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?

Excellent example of a terrible headline

The Study

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

  1. A significant percentage of adverse events came from one study center
  2. None of the men appeared to have been formally screened for depression beforehand.
  3. “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
  4. 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.

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  • 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.

Discussion

58 thoughts on “New study doesn’t show men are wimps about contraception side effects, low vasectomy rate might

  1. Thanks for clearing this up. I was waiting for someone who actually knows about medicine and medical trials to comment on this – the many articles on it weren’t helpful in that regard. Thank you for being informative!🙂

    Posted by Andrew Davis (@Swahili_Jones) | November 1, 2016, 7:52 pm
  2. Weren’t all those contraceptive failures due to not using a backup method until it had attained full effectiveness?

    Posted by Loren Pechtel | November 1, 2016, 7:59 pm
  3. I just don’t understand men not having vasectomies. I had mine in 1976 right before our third child was born. We knew we were finished and never even discussed tubal ligation. I was actually working as an ICU nurse in the US Navy and had the procedure done about 2 hours before my shift ended. Went home for the weekend with 4 percodan and a couple of ice packs and layed on the sofa all weekend.

    Best decision I ever made. My wife of nearly 49 years has never complained about it.

    Posted by rekster | November 1, 2016, 10:04 pm
    • Agreed completely, especially with the “Best decision I ever made.” I waited until our second (and last) child was born safely and healthy, and that’s when I had mine.

      I did it in the morning. It took about an hour, and then I sat at home on an ice pack for the afternoon, and the next day was back going, so it didn’t even take a weekend (although I was a little sore for a couple of days)

      Posted by The Bofa on the Sofa | November 29, 2016, 7:50 am
  4. (An aside: suicide in the UK is no longer illegal. Groups who work with those at risk of suicide say that the term ‘commit’ should no longer be used; they see it as stigmatising and unhelpful.)

    Posted by korhomme | November 1, 2016, 11:32 pm
  5. Reblogged this on things I've read or intend to.

    Posted by donesoverydone | November 2, 2016, 10:00 am
  6. I wonder how much of this is related to the abysmal state of sexual health education. My partner had some pretty crazy ideas about what a vasectomy would mean for him. Once I cleared those up, he was happy to have the procedure done.

    Posted by thevexedmuddler | November 2, 2016, 11:01 am
  7. I had a vasectomy, and would do it again. But I would go to a doctor who performs them on a regular basis, rather than someone who does them infrequently. I had discomfort walking for 6 months afterward, and it was about 2 years before I could sleep on my right side without discomfort, due to the way the incisions were made. It was still worth it for the safety compared to the options available to my wife.

    Posted by BlankRelief | November 2, 2016, 11:59 am
  8. I just learned yesterday that my sister’s insurance covers a tubal ligation 100% but a vasectomy only partially. That made the decision for their family, especially since it was a “While you’re in there…” kind of situation.

    Posted by Pragmatist | November 2, 2016, 12:09 pm
  9. I’m curious about how your response might change considering that the severity of acne and other side effects was apparently measured and reported in table 2 of the paper. It looks like of the 771 adverse events attributable to the birth control, 698 were “mild,” 65 were “moderate” and 8 were “severe.” (Specifically for acne, there was 1 case reported as “severe.”)

    Above you say, “For example and perspective, a study comparing the birth control patch with the pill found a serious adverse event rate of 2%.” With only 8 severe AEs out of 771, wouldn’t this study indicate a serious adverse event rate of only 1.04%?

    Posted by K | November 2, 2016, 12:10 pm
    • Thanks for your article, it is an excellent review of the issue. I have found the coverage of the case severely lacking, as the problem was not “men are wimps” but “review panel cancel study”. Finding an article that discuses the case and includes comparisons to other birth control methods studies has been a ray of hope.
      However, I want to emphasize K’s comment. Only 8 of the 771 side effects where considered “severe”. Even considering that 8 of 320 men had severe side effects this only makes 2.5%, which is comparable with female methods and pretty good for a phase 2 trial.
      I hope that further studies are more careful measuring the emotional effects like depression. It is a topic that is sadly ignored in a lot of cases.

      Posted by Mariana Esther Martinez-Sanchez | November 9, 2016, 7:36 am
  10. Dear god, thank you for this article. Please get this published or something similar in the more mainstream media outlets. The misandrist clickbait articles about this and the comments on them are becoming ridiculous.

    Posted by BrothaDarkness | November 2, 2016, 1:02 pm
    • Misandry isn’t a real thing, but thanks for playing “I Want to Be a Victim, Too! Pity Me!”

      Posted by Cere | November 2, 2016, 6:41 pm
      • What kind of comments and articles do you think this blog post is responding too? Go look at the comment section of any article about this. it’s filled with comments attacking all men such as “lol proof that men are weak, such babies, suck it up” without good justification. sounds like misandry to me. i’ll think of all of this BS next time i hear the men need feminism because we’ve been socialized to not show emotions…….

        Posted by LordSnizzleShanks | November 2, 2016, 8:56 pm
  11. I agree with the issues with the study – but for clarification – the rate of SAEs was only about 1%… there were 3 related SAEs. 99% were considered minor or moderate.

    Posted by Jessie | November 2, 2016, 1:18 pm
    • I think it depends how you define severe.
      Might someone want to know how many of the 45% of men who got acne had severe cystic acne and what percentage had a minor breakout?
      And an emotional disorder? What is that? And how can you saw a suicide was unrelated to a drug that can exacerbate depression?

      However, for me the biggest issue is this gross imbalance of side effect reporting. Someone wasn’t trained correctly, someone was recruiting inappropriate candidates, or someone was over calling or under calling side effects/adverse events. It is not ethical to expose anyone to a clinical trial of any kind when that is happening.

      Posted by Dr. Jen Gunter | November 2, 2016, 1:36 pm
      • Adverse events and their severity ratings can be defined in a manual. If the manual does not include the list of side effects, then there will at least be a manual explaining how to rate the severity of any side effect. I’m not sure what system they used since this is an international study, but in the US we use the CTCAE (for cancer), so the rating of an SAE is only slightly subjective.

        Also, they don’t say what diagnostic manual they are using – so yeah it’s very vague what an emotional disorder is! I completely agree, especially since they have depression as a separate AE.

        I also agree that there is likely some confounding factors involving the Indonesia site. Idk if it warrants every site to be closed – or just that one.

        The DR/PI decides whether or not an event is related to the Investigational Drug, and the monitoring boards confirm. It’s not out of the realm of possibility – but they did have a participant overdose on acetaminophen, and reported that event as related to the ID, so I’m inclined to think the suicide is unrelated.

        They did have a 20% drop out rate, but there are female BC studies with a 30% or higher (44%) drop out rate due to side effects. And this study had lots of AEs, but since they were minor (91%) I’m surprised it was shut down. Female patch studies have had mild to moderate site pain and the studies continued. Many published studies do not list the actual number of AEs (bc they finished and this information is not necessary to publish) so it’s difficult to compare.

        I would think the sperm count issue would be the major cause for concern.

        But I agree with the authors that this warrants further study. The rate of SAEs is only at 1% in this study (less than the 2% of female BC). I think it’s important for readers to understand that there is a difference between SAEs and AEs when comparing studies. BUT I agree the rate of AEs is too high and the regimen needs to be modified. I just don’t want people to write off the study because they read there were more side effects than with female BC when the drop out rates of female BC studies due to side effects have been even higher and the studies have continued.

        Posted by Jessie | November 3, 2016, 7:09 am
      • I agree however, when you read the study it says that the acne breakouts were minimal in the India male group so one has to wonder why? And that means that the acne could be related to other factors.

        I believe the suicide was suggested by the family that the man was going through excess stress from his job. So in essence you cannot decide whether it was exposure to the drugs or not.

        Posted by Lakemom | November 7, 2016, 10:28 am
  12. Serious question though… I’ve seen some crazy stories about PVPS (Post Vasectomy Pain Syndrome) and that it is underreported/not understood/not well studied. So is there any good data or studies on this or is it still just a shrug/ we don’t really know what happens?

    Posted by Spamalot | November 2, 2016, 6:30 pm
  13. The rate of vasectomies in the US appears to be related to cost, and the availability to women of free or low cost tubal ligations. Apparently, a third of Canadian men and half of New Zealand men have had vasectomies.

    Posted by Andy Mcguiness | November 2, 2016, 7:27 pm
    • I wondered somewhat about how many women had their tubal ligation done as part of a C sections vs laparoscopically. Far as I know as part of a c-section it’s fairly trivial. Though have read it comes with a lot more paperwork/patient interaction for the surgeon.

      I did some reading, apparently vasectomies aren’t included under the Affordable Care Act contraception mandate. Which is kinda crazy considering the cost differential, not to mention tubal ligation sucks a hella lot more than a vasectomy.

      Posted by Gibbon1 | November 3, 2016, 2:39 am
  14. “These side effect rate is pretty high with this new study of men when compared with contraception studies for women,” OB-GYN and blogger Jen Gunter wrote. “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%.” Remember that in the study, nearly half of the men got acne.

    Acne, mood swings, pain at the injection site, and other minor AEs were high, but the serious AE rate was <1-3%, depending on how you count the one instance of depression, one of suicide (which was deemed likely not related I think), and 8 mostly temporary declines in fertility. That is on par with what has been observed in studies on women.

    Posted by B.M. | November 3, 2016, 9:13 am
  15. Is it standard to call any change in libido, whether up or down, an adverse event? Because I’m not quite seeing why an *increase* in libido is called that unless it reaches really unpleasant proportions.

    Posted by Irene | November 3, 2016, 10:26 am
  16. yeah, I’ll just get a vasectomy from any one of the zero doctors who will give one to a young man, because “it might cause me permanent, irreversible infertility” despite me repeatedly stating I do not and will never want children

    Posted by jim | November 4, 2016, 7:45 pm
  17. “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.”

    These are two very different statistics and aren’t comparable. The 2.8% refers to the number of the men who developed depression during the trial, none of the cases could be definitively linked to the treatment and we aren’t given a number from a control group to compare. The 0.5% (or 1 in 200) statistic refers to the difference between the percentage of women who started taking anti-depressants after being prescribed the pill (2.2%) versus those who started anti-depressants but were not given the pill (1.7%). These stats refer to all the women covered in the study, not just adolescents (for whom the difference was more marked).

    It’s also important to note that we don’t actually know what the actual rate of depression was, as a diagnosis does not always mean a prescription. We also don’t know what the effect was on women who had suffered depression in the past as they were not included in the study. I say this because I started the contraceptive pill recently and had a sudden and severe bout of depression. This would have been reported as an adverse event in a drug trial, but it would not have been included in the Danish study.

    Anyway, my point is that I don’t think the contraceptive pill is particularly safe, especially for those who are at risk of depression. I’d like to see how it would fare in a drug trial today.

    Posted by Felicity | November 5, 2016, 12:01 pm
  18. And for anyone who is interested, this is the Health review of the study results from a Health journalist quality review organization. There was not control group to this study which is important to note.

    http://www.healthnewsreview.org/news-release-review/study-limitations-didnt-make-it-into-otherwise-strong-release-on-male-birth-control-shot/

    Posted by Lakemom | November 7, 2016, 10:52 am
  19. Hi, I find your article very informative. Now, what I’m seeing quite frequently from women is the claim that men were specially cared on these studies, that these levels of risk are even greater on women’s contraceptives and that doesn’t discontinued their research. I find that, in general information around the internet, that’s not true. But I need some comprehensive data on that. Can you help me?

    Thanks in advance.

    Posted by Alan Flamer | November 8, 2016, 5:48 am

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