Pushing towards acknowledging sex differences in physiology and treatment efficacy (repost)

This is a post from my archives, originally posted on August 2, 2010.

It is no surprise to many people that men and women are sometimes more susceptible to certain diseases than the other. By virtue of having differing anatomy, physiology, and gender expectations, we are going to be prone to different types of diseases, injuries, syndromes, and whatever-you-call-its. That being said, the majority of pathologies affect both men and women relatively equally. Despite that fact, rarely do clinical trials explore the difference in response to treatments based on sex. In 2008, Phyllis Greenberger wrote a letter to Science, Flaunting the Feminine Side of Research Studies, lamenting the fact that more studies didn't explore the effect of sex as a variable on treatment efficacy.

To appropriately evaluate the success of women's representation in clinical trials, we must focus on the inclusion of women (and men) in studies of conditions that affect both sexes. Discussions of raw counts of overall research participation and inclusion of single-sex studies hide the fact that women's inclusion still lags in some key areas [...] Moreover, studies that include similar numbers of men and women rarely analyze or report the results by sex. This hampers our ability to understand the differences between men and women and to use this knowledge to improve health care outcomes.

In response to this letter, Dr. Isis wrote a really excellent blog post detailing the complications involved in including women in cardiovascular clinical trials.

Does Dr. Isis limit her research model because she secretly hates women (especially those hotter than her) and does not want to cure them?  No, but she appreciates that the effects of estrogen on vascular function are hugely complex and temporally based.  This stuff is so complex that people spend their careers studying it and there are all sorts of fancy books devoted to the topic.  In the human studies Dr. Isis has been/is involved with, we have to be careful to study women in the context of their menstrual cycle. [...] I could not agree more with Ms. Greenberger that the inclusion of women in clinical research is vital to the understanding of our unique physiology and I applaud her for reminding us of this public health disparity.  However, except in phase III or IV clinical trials where sample sizes may be sufficiently huge to allow for the inclusion of secondary endpoints and the splitting of populations for secondary analyses without devastating one's statistical power, splitting the populations of smaller, mechanistic studies can result in meaningless findings.

There's no easy answer to this problem, especially in systems where the cycling of estrogen may be a confounding factor in treatment efficacy. Sex is not the only variable here, but also the levels of sex endocrines circulating through the system, which is dependent on each individual woman's place in her cycle at the time of treatment. Still, something has to be done, because not taking these variables into account can lead to a misleading conclusion about treatment efficacy.

In Differences in Efficacy and Safety of Pharmaceutical Treatments between Men and Women: An Umbrella Review, published this month in PLoS ONE, Gartlehner et al. explored drug class reviews by the Drug Effectiveness Review Project to "determine whether clinically relevant differences in efficacy and safety exist between men and women when treated with commonly prescribed medications."

[T]he exact differences between men and women at the genetic, cellular, or functional levels of the body are largely unknown. [...] Although differences in risks for and prognoses of several diseases have been well documented,, sex-based differences in responses to pharmaceutical treatments and accompanying risks of adverse events are less clear. Variations in absorption, distribution, metabolism, and excretion of pharmaceuticals between men and women have been investigated and demonstrated for various drugs. [...] The majority of these findings indicate differences on physiological, pharmacodynamic, or pharmacokinetic outcomes and are mostly attributed to hormonal fluctuations. Whether such findings translate into clinically relevant differences in efficacy and safety of pharmacological treatments remains undetermined.

Unsurprisingly, they could only find studies that explored the effect of sex on treatment efficacy on 23% of the medications listed in the drug class reviews. Of that subsection, most of the medications had no significant difference in treatment efficacy between men and women. One difference they did find was that women respond less favorably than men to a relatively new class of antiemetics (5-HT3 antagonists) used to treat nausea in chemotherapy patients.

During chemotherapy, serotonin is released by certain epithelial cells in the digestive tract. This serotonin goes back to the brain and stimulates the vagus nerve, which feeds to the medullary vomiting center. The medullary vomiting center is pretty cool, it's this little corner of your brain with the sole purpose of deciding whether or not you should be vomiting at any given time. The serotonin released in response to chemotherapy says to your brain, "Hey, you need to vomit now," and then you do. These 5-HT3 antagonists block the receptor for serotonin, so the message isn't received by the medullary vomiting center, and you get to keep your breakfast. (Interestingly, these drugs don't seem to work in response to motion sickness, just chemical stimulation.)

Unfortunately for women, there's pretty clear evidence that men are more likely to see a positive result from these antiemetics than women:

(Click to enlarge)

58% of men, compared to 45% of women, responded favorably to prophylactic treatment with this class of antiemetics prior to chemotherapy. The mechanism underlying why this happens is unknown, but this is clear evidence that even in systems that don't directly involve endocrine cycling, men and women can still display different responses to treatments. The authors also found that women are more likely to experience adverse effects from statin medications, and that men are more likely to experience sexual dysfunction from second-generation antidepressants than women. Bear in mind that these findings are based on less than 1/4th of the drug classes reviewed by the Drug Effectiveness Review Project, because the vast majority of studies didn't even consider sex differences as a variable in treatment efficacy! Incorporating the effect of sex and endocrine cycling can be problematic for an investigator, as Dr. Isis describes in her post linked above, but even still she realizes the importance of doing it anyway whenever possible. At the end of the day, men and women are different, physiologically speaking, and clinical trials that do not attempt to address this fact somewhere along the line of treatment development are doing us all a disservice.

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Greenberger, P. (2008). Flaunting the Feminine Side of Research Studies Science, 322 (5906), 1325-1326 DOI: 10.1126/science.322.5906.1325b

Gartlehner, G., Chapman, A., Strobelberger, M., & Thaler, K. (2010). Differences in Efficacy and Safety of Pharmaceutical Treatments between Men and Women: An Umbrella Review PLoS ONE, 5 (7) DOI: 10.1371/journal.pone.0011895