Baby Blues: Setbacks in Developing Male Contraceptives


Amused, I clicked the hashtag and learned that a clinical trial for TU NET-EN, an injectable male contraceptive, had been cancelled due to “intolerable side effects.” As I looked around the Internet that day, I saw that the hashtag reflected widespread outrage among women: we have had to stomach the unpleasant side effects of hormonal contraceptives for decades, and now an entire study is down the tubes because men can’t handle a little bit of acne?

I was a little frustrated but mostly curious.. Was this outrage really justified, or were the side effects in the cancelled study actually worse than those in studies of female contraceptives? As a scientist-in-training, I was concerned with the lack of rigor in the way the study was discussed online. It’s easy for a hashtag to go unquestioned and unanalyzed, especially when it meshes well with what we might already think. And as a feminist, I wanted to make sure that poorly conveyed arguments didn’t hurt the overall cause, as is often the case.

To determine whether or not the hashtag was justified, I tried to approach the issue like a scientist: how bad were the side effects, and how prevalent? How are side effects assessed in female contraceptive trials? And why doesn’t a male contraceptive exist yet? I decided to compare the male contraceptive study with a 2010 study on Natazia, the most recently FDA-approved oral contraceptive for women, to see if the cancellation of the male contraceptive study was really due to male fragility, or if the side effects were actually more extreme than in trials of female contraceptives.

Before settling on Natazia, I thought a lot about which study to compare to the TU NET-EN study. Should I use the very early experiments done during the invention of the birth control pill?  Because female oral contraceptives have more than fifty years of refinement compared to male birth control, an early female contraceptive might be more directly comparable. However, the dramatic changes in research ethics and social mores over time deterred me from comparing this way. For example, societal factors like the stigma of taking birth control influence the dropout rate of any study, and to compare women in the 1950s and men in 2016 ignores the giant shift in public opinion toward contraception in the intervening years. Instead, the Natazia study offered comparable contemporary ethics and social norms, and it answered the question of what kind of side effects women are expected to deal with in this day and age.

The male contraceptive study recruited 320 healthy men aged 18-45 years who were in stable, monogamous relationships and who had normal sperm production and function. TU NET-EN was designed to reversibly suppress sperm production, and it was administered by injection of two hormones, a progestogen and an androgen. Progestogens and androgens are two major classes of sex hormones that help differentiate male and female characteristics during development. Men have higher levels of androgens, and women have higher levels of progestogens and estrogens, but both sexes have all three types of hormones. Previous studies of male contraceptives that contain only androgens have shown them to be effective, but with potential long-term adverse effects. Progestogen was added to reduce those effects. Study participants received injections of these two hormones every eight weeks for up to 26 weeks.

The treatment showed some promise, with 95% of men showing at least a 15-fold decrease in sperm count after treatment. It was far from perfect, though: some men had rebounds in sperm count; some did not have suppression in sperm count with treatment; and four pregnancies occurred over the course of the study in partners of men whose sperm counts had been sufficiently suppressed, raising the question of whether reducing sperm count is a reliable approach to preventing pregnancy. For those of you keeping track at home, that’s a 1.5% rate of pregnancy (4 pregnancies out of 266 couples), marginally worse than the female birth control pill (0.99%).

So here we have a male contraceptive that is slightly less effective than existing methods. In addition to the lower efficacy, the side effects are also concerning. Nearly 50% of the men reported acne, though only one case qualified as severe. However, 16.9% of participants reported emotional disorder thought to be related to treatment. Symptoms like headache and weight gain rang in around 5% and 3%, respectively. Of the 20 men who dropped out of the study, six cited changes in mood as their reason for discontinuing. Researchers speculated that low testosterone levels after treatment could explain some of the effects on mood and suggested that an altered injection schedule might reduce these side effects. However, all but three of the cases of mood disorder came from the same research center, which suggests the effect might be location-specific 

Despite the negative effects, 80% of the male participants and 78% of their female partners were satisfied with the treatment at the end of the study. However, to the researchers’ chagrin, two independent safety committees, the Data Safety and Monitoring Committee and the Research Project Review Panel of the World Health Organization Department of Reproductive Health deemed the study too dangerous to continue. 29% of the adverse events experienced by participants were classified as “definitely related” to treatment, a number too high for the study to be continued. A second concern was from the small number of men in the study who did not recover normal sperm count even 52 weeks after the last injection. One man did not recover within four years of his last injection.

Male Contraceptive Natazia
Rate of pregnancy 1.5% 0.99%
Side effect prevalence 50% 11.5%
Drop out rate 7.5% 10.3%

Concerns about side effects and long-term adverse health effects have always surrounded female oral contraceptives, and it seems, at least anecdotally, that most women have experienced some adverse side effects from oral contraceptives. I’ve heard from plenty of women who have stopped or switched their birth control because of weight gain, acne, or moodiness. But what do studies looking at female contraceptives look like compared to this canceled study?

I looked at one of the two clinical trials included in the FDA’s Clinical Review of the new combined oral contraceptive, Natazia, to compare its efficacy and side effects with TU NET-EN. Natazia, like other combined oral contraceptives, uses one type of estrogen and one type of progestogen to suppress ovulation and thicken cervical mucus. 1377 healthy female volunteers between the ages of 18 and 50 took one pill per day for 20 months. Over the course of the study there were nine pregnancies in almost two years, a 0.99% failure rate, lower than that of the male contraceptive study. As far as preventing pregnancy goes, Natazia appears more effective than the injected male contraceptive.

In addition to being more effective at preventing pregnancy, Natazia also produced fewer side effects than TU NET-EN. The most commonly reported side effect was the common cold, which is highly unlikely to be related to treatment. This was followed by headache, with 11.5% of participants reporting headaches or migraine. Nearly 300 of the women dropped out of the study before completion, and half of those dropped out because of symptoms like acne and headache. To determine if these side effects are due to Natazia treatment, a second study focusing more on side effects found small increases (less than 6%) in acne, weight gain, and irregular bleeding in women receiving the drug versus those receiving a placebo. This suggests that some of the side effects reported are indeed related to Natazia itself. But taken as a whole, side effects appear much less common for Natazia than for the male contraceptive.

The study on Natazia’s side effects is not without caveats, though. Because combined oral contraceptives are known to increase the risk of blood clot, women at risk for vascular disease were excluded from the study, along with women diagnosed with depression and women with a BMI over 30. Without these women in the study, the reports of dangerous side effects will be much lower. However, their exclusion is reasonable, since doctors do not prescribe combined oral contraceptives to women with these conditions. And since no reports of mood were taken into account in the study on Natazia, though they figured prominently in the TU NET-EN study, it’s unclear whether the researchers failed to ask about mood or instead if no volunteers reported mood changes.

I compared these two studies to try to determine whether men were really being let off easier in terms of side effects than women when it comes to contraceptive research, and at least in these two studies alone, it seems that men and women are in fact treated similarly in the research, and drugs that are safe and effective move forward, while those that have questionable safety are sent back for more testing.

However, there is plenty of historical evidence that dramatic side effects have not stopped previous studies of female contraceptives the way they stopped this study of male contraceptives. Preliminary studies of the first birth control pill by Dr. Gregory Pincus in the 1950s had nearly 50% drop-out rates, and over the years, severe side effects of oral contraceptives and other methods of birth control have become obvious after drug approval.

There are multiple reasons these early studies continued in spite of the reported side effects. When the FDA first approved the original birth control for contraceptive use, the organization had different priorities compared to today. Fake medicine was prevalent, and patients were being ripped off by quack doctors. To curtail fraud, the FDA’s main function was to determine the efficacy of proposed drugs, but it paid less attention to their safety. Even so, safety concerns were raised in the approval process for the first birth control pill because it would be the first drug prescribed to healthy individuals. It took five long months of interviewing doctors who were prescribing the pill about its potential long-term effects before the FDA finally approved the drug for use as a contraceptive.

The continuation of trials for female contraceptives even in the face of adverse effects is also likely related to the fact that the risk conferred by these contraceptives was so much smaller than the risks conferred by pregnancy: preeclampsia, diabetes, hypertension, and heart attacks, to name a few. While it is certainly true that women should receive the safest drugs possible regardless of the effects of not taking it, the line of reasoning that the side effects of birth control are preferable to the risks of pregnancy has certainly shaped the history of approval for oral contraceptives for women. And herein may lie the answer to why no male contraceptives exist yet. The risk of unintended pregnancy doesn’t loom quite so large over men, and it’s much more difficult to argue in our patriarchal society that healthy men should experience side effects when they face no health risk by not taking a contraceptive. But this is not a very good excuse: if we extend this argument, it’s almost impossible that a male contraceptive will ever be approved by the FDA. Instead, we have to reframe the argument so that both men and women take on some of the health burden of preventing pregnancy as well as pregnancy-related side effects. It may help to invoke Margaret Sanger’s rhetoric here. She so desperately wanted a birth control pill so that women could take charge of their sexual lives and decide for themselves whether or not to become pregnant. She saw birth control not as a burden but as a tool and as an opportunity. Why shouldn’t men have their own opportunity to decide whether or not they want to have a child?

Scientifically, there may be another reason birth control for men has been delayed. In the 1950s, Dr. Pincus and his colleagues realized that women naturally suppress ovulation during pregnancy, so they modeled their drugs on the natural process. In men, there is no equivalent change in fertility to exploit in the same way. Pincus did in fact attempt to create a male contraceptive around the same time as he created the Pill, but as we can see, the search continues today.

The (admittedly imperfect) comparison of these two studies suggests that male and female contraceptives are in fact currently held to similar standards. It’s disappointing that the female study did not take mood into account when quantifying side effects, but overall, the percentage of women facing adverse side effects was considerably smaller than the percentage of men. Clearly the hashtag wasn’t capturing the scientific reality of the study but instead reflected the cultural norms that will continue to plague the search for a male birth control until they are addressed: the general lack of concern with women’s emotional well-being and the need to reframe the responsibilities, risks, and rights of birth control to include men too. Currently, the Affordable Care Act requires insurers to cover contraceptives – but not vasectomies – evidence that policymakers still consider birth control solely a women’s issue. On the scientific front however, TU NET-EN researchers seem optimistic about pressing onward with different doses and injection schedules in a future trial.  What’s more, the men involved were willing to take on some of the burdens of preventing pregnancy, which bodes well for societal acceptance of male contraceptives. Still, it’s only with concerted efforts both in science and in public perception that we can really have #birthcontrolforall.

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