Some months ago the issue of gender bias in medical research came up on the comment board. It was certainly an issue I’d occasionally read about. But I’m also a proponent of lifestyle design and intervention. I don’t spend as much time as others on the nitty-gritty of medical treatment for good reason, but the conversation got me thinking. Maybe it was time for an article after all….
And, so, the questions started coming. How does gender figure into medicine, and what exactly is gender bias in this context? How does it operate? How has it been measured? What consequences are there? How much should it influence our trust in medical literature and subsequent recommendations—the validity of findings, the efficacy of treatment, the safety of drug prescriptions? And, finally, what if any progress are we making or can we count on in the near future?
That Was Then, This Is Now: The Beginnings of Gender Bias
Bias is a form of systematic error that influences scientific investigations and distorts the findings. Bias will always be present in some form during a study, but the goal is to minimize it to the point where the results can still be trusted. Gender bias, then, refers to errors that arise due to differences between male and female participants or target subjects.
Way back when, gender bias was rife in the medical community. Up until the late 19th century, women were commonly diagnosed with “hysteria,” a (very convenient) condition to imply emotional instability was at the core of any complaints, particularly when related to the female reproductive organs. Thus, where medical practitioners were faced with female patients they couldn’t (or couldn’t be bothered to) diagnose, it was accepted practice to chalk it up to her mental state. Surprisingly, this medical mindset remained entrenched up until at least the 1970s, where a 1972 textbook titled Gynecology and Obstetrics, Current Diagnosis and Treatment suggested that nausea during pregnancy was the result of resentment and ambivalence towards childbearing.
In response, legislation was passed in the same decade to prevent gender discrimination in research in an attempt to ensure studies included box sexes and thereby maintained “equality.” Despite this, the emotional and cultural misconceptions that had skewed female-related medical research and treatment for centuries remained very much entrenched, while women were still regularly left out of trials for fears of pregnancy-related complications…despite the fact that drugs were still being administered to pregnant and breastfeeding women.
Then in 1994, there came the big break that gender-aware researchers had been hoping for. The U.S. National Institutes of Health (NIH) issued a guideline for the study of gender differences in clinical trials to ensure those drugs were suitable for both sexes.
The guideline addressed the exclusion of women from trials based on unfounded safety reasons, forcing researchers to consider the fact that men and women can have very different responses to the same drug. As a result, an estimated 80% of prescription drugs were withdrawn from the US market due to newly uncovered women’s health issues.
These days, there’s more women than men enrolled in clinical trials. Nonetheless, to some extent gender bias continues to underpin many aspects of medical research.
An Issue of Equality and Inequality
So, what are the different forms of gender bias still prevalent in today’s medical research realm? Let’s dig in here….
A Swedish study conducted from 1997 to 1999 sought to uncover the reasons behind why researchers excluded women from clinical trials. Based on 26 different case studies, they determined that the reasons behind these exclusions were:
lack of knowledge regarding the physiology and metabolism of women of childbearing age
a continuing desire to base repeat studies on former (male) study populations, and
tight research budgets that enabled inclusion of men but not women
Today, the almost universal inclusion of women in clinical trials might give the impression that things have improved markedly, but there’s plenty of problems still operating under the radar. A 2017 meta-analysis of 2,742 case reports showed a “statistically significant gender bias against female case reports,” while the Society for Women’s Health notes that the richest charities aren’t pushing for the inclusion of more women in medical research and that only 3% of grant proposals measured sex differences.
Ultimately, these biases exist due to polarizing assumptions of equality and inequality. On the one hand, researchers have long entertained the assumption that men and women suffer from the same symptoms and similar disease risk factors. Many clinical trials on men carry the assumption that the findings can be equally applied to women.
Despite this, those trials that compare the effects of drugs and treatments between men and women continue to highlight marked differences in the way women metabolize drugs and respond to treatments. Thus, the assumption of equality puts women at risk, not only reducing disease treatment efficacy but also risking exposure to unforeseen adverse side effects.
There’s also the valid point that men and women (as a whole) differ in environmentally and culturally influenced risk behaviors and exposures, and perhaps in their varied perception of symptoms. These are all valid concerns when it comes to clinical trials, but the biomedical model that governs most medical and clinical research tends to brush over this consideration—men and women are simply biological entities separated by hormonal and muscular variations.
At the other end of the spectrum, assumed inequalities occur when physicians consider women’s complaints to be less severe than men’s, due to the cultural notions of male stoicism and the fact that men have a lower average life expectancy and higher rates of mortality. This is reinforced by more frequent research into male-centric chronic diseases, which solidifies the notion that men are more “at risk.” This assumption contradicts the fact that women have higher rates of non-fatal chronic conditions which seriously impact their quality of life, particularly during those “additional” years when they’ve statistically outlived their male counterparts.
Consequences of Systemic Assumptions
The repercussions of this long-standing sex bias in the research realm are sneaky but far-reaching. For starters, larger proportions of women are diagnosed as having “non-specific symptoms and signs,” perhaps reflecting a disease classification system more suited to men than women. These same women might actually be suffering from a fully identifiable illness, but practitioners fail to diagnose it, due at least in part to traditionally male-based diagnostic criteria or to female-centric complaints that aren’t highlighted or even understood by historically (predominantly) male-based research. As a result, many women may receive no or improper treatment of their unidentified disease, something that can be frustrating at best and downright dangerous at worst.
Next, despite the fact that primary healthcare is used more by women than men, research indicates that short-stay and emergency hospital services may be more accessible to men. In one study of patients with the same ultimate diagnosis, women waited longer in emergency rooms and were admitted less often.
Then there’s the issue of incorrect drug dosages arising from insufficient trials on women. Eight of the ten prescription drugs that were withdrawn since 1997 posed greater health risks for women than men. Half of those drugs were withdrawn not because more women took them than men, but because their effects on women weren’t well known prior to FDA approval. For example, antihistamines Seldane and Hismanal and gastroprokinetic Propulsid “can in some circumstances prolong the interval between the heart muscle’s contractions and induce…a potentially fatal cardiac arrhythmia. Women have a higher incremental risk of suffering an arrhythmia after taking these drugs than do men probably because (1) the interval between heart muscle contractions is naturally longer for women than for men and (2) male sex hormones moderate the heart muscle’s sensitivity to these drugs.”
At a less morbid level, the FDA recently reduced female doses of Ambien, a common sleeping aid by half. Ambien and similar products had been on market shelves for years, but it wasn’t until the FDA completed tests on a new sleeping aid, Intermezzo, that they realized women metabolized the active ingredient much more slowly than men. Up until that point, it was assumed that women had the same response to the drug as men, and therefore that the recommended dosages should also be the same.
Because of lingering research bias, I’d say women probably have ample (more) reason to be more skeptical of pharmaceutical recommendations.
Gender Bias In Literature and Practice
Coronary Heart Disease
Despite the fact that coronary heart disease is very much a disease of both genders, its role in female mortality rates is arguably under-appreciated. Women with coronary heart disease tend to have worse outcomes than their male counterparts, and they generally receive less evidence-based treatment than men with CHD.
A 2014 study that examined access to care for 1123 admitted patients exhibiting coronary symptoms found that men were more likely to receive faster care compared to women. Researchers also observed that, when women were anxious, doctors tended to underplay the severity of their condition, while anxious men were still admitted quickly. Even more interestingly, both men and women with “feminine character traits” were less likely to receive timely care than those with masculine traits.
Statins and NSAIDs
In a review of 27 trials of statin use for CHD and 25 trials of NSAIDs for osteoarthritic pain, the two drugs showed a huge difference in inclusion of women. While NSAID trials reflected the population in which they were used, only 16% of women were included in trials despite 45% of statin users being female.
These statistics become even more alarming when we consider the fact that women are often more at risk of adverse side effects from statin use than men. Elderly women, for example, face a higher risk of developing muscular disorders following statin use, while postmenopausal women are at an increased risk of developing diabetes mellitus from statin use.
This is where things really get interesting. Many specialists now theorize that the high rate of adverse drug reactions in women may stem from biomedical research at its earliest stages—animal trials.
While over half of NIH-funded clinical research participants are women these days, the same progression in recognizing gender bias has not been reflected in animal research. Women have more strokes than men, but only 38% of animal studies on stroke used females. Many thyroid illnesses are up to ten times more prevalent in women, yet only 52% of animal trials used females. And studies that use mice and other rodents to test new drugs typically use only males, despite there being marked differences between the way men and women absorb and process drugs.
There’s plenty more where that came from. A 2011 review of gender bias in research on animals in 10 biological fields found that male bias was present in eight disciplines and most prominent in neuroscience, where male studies outnumber female by 5.5 to 1. According to researchers, in recent years male bias in human studies has declined while increasing in animal studies, and this doesn’t bode well for the safe development of drugs and disease treatments further down the line. This preponderance of males in animal research unfortunately runs the risk of obscuring key gender differences in clinical studies, preventing reproducibility in human studies, and is especially concerning given women experience higher rates of adverse drug reactions than do men.
Some Final Thoughts…
Clearly, there’s much that still needs to be addressed regarding gender inequalities in the medical research world, but we’ve thankfully come a long way from the days of “hysteria.” Women can now participate in phase one, two and three clinical trials, and the NIH continues to roll out legislation and training to ensure researchers don’t overlook or underplay the importance of including women in their trials. And in the animal research sector, the NIH has now enacted policies requiring a balance of genders in all future trial applications, unless sex-specific inclusion is unwarranted.
Unfortunately, however, many aren’t sure the solution is as simple as requiring equal gender representation in every study. As this opinion piece points out, “modifying experiments to include both males and females costs money and requires a duplication of time and effort—time that researchers might not have to spare or that might be better spent conducting other research—that is rarely practical or scientifically warranted.” The question appears to be one of practical resources, but I’ll admit something in me isn’t fully comfortable with this answer. A lot hinges on the definition of “unwarranted.”
Can we effectively prioritize funding for research where analyzing differences between the sexes promises to provide substantiated benefit—and opening the conversation more for defining that “benefit”? We’ll see. Providing the necessary funding for female or mixed-gender studies should at least ensure that scientists no longer have reason to exclude women from trials. And mandating disclosure when a study uses only male or female animals in the title should improve transparency and assist drug and treatment approval processes.
Thanks for reading folks. What say you? Are there issues and/or solutions you’d add to the mix? I’d love to hear your thoughts.
Mark Sisson is the founder of Mark’s Daily Apple, godfather to the Primal food and lifestyle movement, and the New York Times bestselling author of The Keto Reset Diet. His latest book is Keto for Life, where he discusses how he combines the keto diet with a Primal lifestyle for optimal health and longevity. Mark is the author of numerous other books as well, including The Primal Blueprint, which was credited with turbocharging the growth of the primal/paleo movement back in 2009. After spending three decades researching and educating folks on why food is the key component to achieving and maintaining optimal wellness, Mark launched Primal Kitchen, a real-food company that creates Primal/paleo, keto, and Whole30-friendly kitchen staples.