Rethinking: Sex Matters

Each week, after I inject myself with anti-TNF alpha, a biologic treatment for rheumatoid arthritis, I get a rash. I get inflammation.

I also get irritated.

Adverse reactions to biologics are more commonly reported by female patients. A rheumatologist mentioned this after I gave a talk at MIT recently on sex differences related to vaccination and infectious disease. Then she asked me, “Has anybody ever looked into that?”

Well. Wouldn’t you think so?

In fact, people might assume that researchers who test drugs and companies that make medicines take sex differences into account. After all, we are accustomed to lots of things being sex-specific. There’s clothing created for females and bicycles built for females. There are replacement knees designed to accommodate not only females’ size but also gait and weight distribution. Females, unsurprisingly, are different than males.

Still, almost no one is paying attention to the fact that sex matters on a cellular level. Femaleness and maleness are more than the sum of an individual’s genitalia. The difference is manifest in our molecules—the very enzymes that metabolize the drugs we take, for instance. Mounting evidence from my lab and others around the globe reveals differences in men’s and women’s responses to pathogens as well as therapies, no matter whether we’re looking at Zika, malaria, flu, lupus or heart disease. The mere fact that 80 percent of all autoimmune disease patients are women should be a red flag that women’s immune systems respond differently than men’s.

It’s time to rethink biological sex differences on a very fundamental level. We need to design research studies from the outset to compare the sexes by making an a priori hypothesis that males and females will be different.

What we’ve done to date, largely, is go back into the scientific literature after studies are complete and analyze the data in a way so that sex differences reveal themselves. That’s not ideal, and purists reject this method despite a growing list of post-hoc observations of sex differences in responses to treatments for diseases.

The Government Accountability Office reported in 2015 that while more women than men today enroll in clinical trials, the NIH is not doing a good job at ensuring comparison between the sexes in the trials that they fund.

It was only in the early 1990s that Congress started to make noise about the NIH needing to enroll as many women as men in clinical trials, that women needed to be equally represented. A quarter century later, more women than men are enrolled—that’s progress!—but nobody bothers to compare data.

In fact, not a single vaccine is sex-specific. The HPV vaccine, a beautiful preventive measure, is an interesting example. It’s the only one I can think of where dosage and schedule all are based on trials for girls. And once we realized the vaccine could protect boys too, we simply applied data collected from girls to boys.

But now data about the HPV vaccine show a higher antibody response in girls than in boys. You might ask: If the response in boys is high enough to protect them, who cares?

More and more of us do, in fact. The dogma—that sex doesn’t matter—is changing. Arturo Casadevall, editor-in-chief of the journal mBio, invited me and my colleagues, including Bill Moss, to write about the RTS,S malaria vaccine and increased mortality in girls.

We challenged WHO statements that said increased mortality in girls was “largely due to the low female mortality in the control arm” and “could be due to chance.” We argued that “further clinical studies should explore whether girls need lower doses of the RTS,S/AS01 vaccine or should receive the vaccine with or separately from other vaccines or at different ages than boys.”

If you survey the old data for measles and polio vaccination, you’ll see similar trends: Females suffered mortality at higher rates with those vaccines too. So at what point do we stop saying, ‘Well, with malaria it was all due to chance’? Was it all due to chance with measles? With the oral polio vaccine?

This isn’t just about vaccines. It’s also about drugs that are widely prescribed for common disorders. For example: Women metabolize zolpidem, the active ingredient in sleep medications, more slowly than men. That 2012 discovery came after two decades of women overdosing on a drug known to significantly impair driving—on the advice of their doctors. In 2010, for instance, women experienced more than two-thirds of all 64,000 zolpidem-related emergencies. In January 2013, the FDA warned that the recommended dose for women should be halved, a change now incorporated in the drug directions. As far as I know, it’s the first sex-specific dosage labeling for a widely prescribed drug.

There needs to be more of that. Despite studies showing that in women, a half dose of the flu vaccine is as effective as a full dose and may cause fewer adverse reactions, the FDA still recommends that men and women receive the same full dose annually. I’m not a physician, but I value the concerns of patients about this. For them, and for myself, there should be sex-specific recommendations. But we’re never going to get those until we embark on studies with an a priori hypothesis reflecting that sex matters and until studies are designed appropriately to look at sex differences.