Mind the Knowledge Gap!
Male Bias in Medical Research
Hi Beautiful Friends!
To understand the poor consensus on menopause care, let’s look at the broader problem: the historical lack of medical research on women.
Good Ol’ Aristotle
While the basic assumption of male* physical superiority likely predates Ancient Greece, we start to see records of inaccurate information on female anatomy and physiology in writings from the poster boy of Western civilization himself. Surely, if we could sit down with Aristotle to share what we know today, we’d all have a good chuckle over some of his original explanations for the biological differences between the sexes. In the name of not killing the messenger, we should recognize that the society in which he lived bred these inexact and culturally biased hypotheses. He just happened to be the one to diligently pen them to paper.
In On the Generation of Animals, Aristotle calls the female a “mutilated male.” The famous philosopher describes the female body as “the inverse of the male body, with its genitalia ‘turn’d outside in.’” This description paints an interesting picture, and one quite different from the image of female genitalia found in my last newsletter about sexual health.
Another commonly held view was that women were merely smaller men. As more science reveals significant differences between men and women in biology and physiology, this idea is shifting but it prevailed for centuries and still impacts present day.
The view of woman as a “mutilated,” miniature man centered the male body while positioning the female one as diminutive and biologically defective. (Never mind the miraculous and essential role the female body holds in creating life and bringing it into this world.) Males have been the preferred and suitable human subjects of scientific study because, aside from the reproductive organs, all other organs and functions will operate the same for women as they do for men, right? Wrong. This false belief deterred real investigation of women’s bodies. Based on imagination rather than evidence, male bias created a feedback loop of ignorance and built a solid canon of medical misunderstanding around the female body.
A Bad Joke
In college, a male friend of mine joked that he could never trust something that bled for seven days and didn’t die. He got that joke from South Park where in context it doesn’t target the female but lands it as a ridicule of the misogynistic speaker. In comedy, context matters but that didn’t stop my friend (and many other South Park fans) from trying. Anyway, being of the literal mind, I remember having two thoughts. First, “well, it’s not exactly bleeding.” After all, menses is vastly different from the blood coursing through our veins or through the skin when injured. And second, math. I started to calculate all the days I had actually “bled” and “survived” because, as any menstruator past puberty knows, it’s far more than seven days. It’s also no joke. But I suppose it makes sense that without understanding the complex, orchestrated hormonal cycles that result in menstruation, people might fear it. And when we are scared of what we don’t understand, we joke.
Menstruation is the visible piece of the ovulatory-menstrual cycle, and as such it has been the focal point, while the other phases—follicular, ovulatory and luteal, which have equal if not more impact on a woman’s mood, cognition, energy, and sociability—have had inadequate emphasis.
Similarly, the cessation of menstruation has been the defining focal point of menopause. That very last bleed is an indication that a woman is no longer producing sex hormones at the level necessary to support ovulatory-menstrual cycles and reproduction. However, those hormone levels begin to change as early as age thirty-five. And estrogen, progesterone, and testosterone continue to decline even after the final menstrual period. A blip on a very long timeline, that final menstrual period cannot even be established as such until a full year has passed without a subsequent bleed. It’s for these reasons that I have a hard time with the word “menopause,” but more on that in a future post.
The widespread misconception from ancient times was that women absorbed too much moisture from their food and therefore needed to bleed monthly. (Menopause Manifesto, p. 13.) Also, the blood was viewed as toxic. Dr. Jen Gunter in her new book Blood on all things menstruation points out that even as late as 1974 there were multiple letters published in The Lancet, a prestigious medical journal, hypothesizing that the toxicity of menstrual blood could wilt flowers. (Blood, p. 11.) I mean, I kill plants all the time, but entirely without menses.
It seems to me that the monthly vaginal bleed, while frightening to some who lack knowledge and familiarity, is sort of beside the point. In fact, it’s after the point.
At the turn of the 20th century with the discovery of hormones, rather than taking newfound interest in the female body, researchers argued that the menstrual cycle and its complex, varied release of hormones introduced too many variables to make women good test subjects. Good grief! Women were both too similar and too different from men to make them worthy of scientific study! Still, at the most basic level of biomedical research, investigators mostly choose to study male cells and animals. (Doing Harm, p. 11.)
Thalidomide Nightmare
In the 1950s, the drug thalidomide was used widely in Europe and Canada to treat morning sickness during pregnancy. Tragically, the women who took this medicine gave birth to babies with severe deformities or experienced prenatal death.
Around the same time in Puerto Rico, a large scale trial for the first oral contraceptive Enovid was “marked by a lack of consent, a lack of full disclosure, a lack of true informed choice, and a lack of clinically relevant research regarding risk.” Out of 200 women in the first trial, three died and many reported terrible side effects such as nausea, dizziness, headaches, and blood clots, but those who complained were discounted as “unreliable historians.” More on this in a future post.
Eventually in 1977, the FDA issued a broad policy recommending the exclusion of women of childbearing potential (even those who used contraception, who were single, or whose husbands were vasectomized) from Phase I and early Phase II drug trials. The FDA itself would eventually refer to its own exclusion rule as “rigid and paternalistic” and acknowledge that it created a “paucity of information about the effects of drugs in women.” (Doing Harm, p. 33.) After all, women are not just smaller men. Beyond weight difference, there are a multitude of other factors such as percentage body fat, hormonal fluctuations, enzyme levels, and speed of metabolism that affect response to a drug. (Doing Harm, p. 43.)
A Few Steps Forward
Eventually, as a result of the feminist movement in the ‘70s, more women entered the medical field and began strongly advocating for the inclusion of women in research.
During the ‘80s, activists protested the exclusion of women from HIV drug trials, and a group of female scientists founded the Society for Women’s Health Research.
In 1985, the Reports of the Public Health Service Task Force on Women’s Health Issues pushed NIH and FDA to issue new guidelines for the inclusion of more women in studies.
By 1993, the FDA finally reversed its policy banning women from participating in studies, and to ensure NIH implementation of the new guidelines, Congress passed the Revitalization Act into law.
In 1991, the NIH hired the first (and to this day, only) female director, cardiologist Bernadine Healy. Healy was a strong proponent of hormone therapy. In her book, A New Prescription for Women's Health: Getting the Best Medical Care in a Man’s World, she details the demonstrated benefits of estrogen. She wrote:
“As I see it, women have a competitive health and survival edge before menopause. Women during their childbearing years are protected against many problems that affect men. I see no reason to relinquish that advantage after menopause - not if I can help it.” (A New Prescription for Women’s Health, p. 201.)
Healy then launched the Women’s Health Initiative (WHI), a set of clinical trials and an observational study that enrolled 161,000 postmenopausal women for a period of 15 years. (Doing Harm, p. 33.) The WHI was a randomized control study, the gold standard of evidence-based medicine. It was the biggest, most expensive study of women ever in history!
A Giant Step Back
Some of the intention behind the WHI was…
An attempt to make up for centuries of inadequacy in women’s medical research. Unfortunately, the flaws in design, the mining of the data, and the poor handling of the initial press release managed to set women’s health back by several decades. The fear-mongering was particularly damaging to the promotion of medical research on women.
In her 2023 book Eve: How the Female Body Drove 200 Million Years of Human Evolution, researcher Cat Bohannon details the reality and the consequences of the “male norm” or “male bias” in the biological sciences. She writes, “From 1996 to 2006, more than 79 percent of the animal studies published in the scientific journal Pain included only male subjects.” (Eve, p. 5.) Many prominent scientific journals suffered from the same problem. Likely because the 1993 Revitalization Act only mandated “the inclusion of women …. in studies with human subjects, and only Phase 3 research” or the final trials conducted more broadly after earlier, smaller studies have demonstrated safety. (Doing Harm, p. 34.) In 2014, the NIH finally introduced a policy to address the problem of male bias in preclinical research.
Even as late as 2000 nearly two-thirds of NIH studies “didn’t bother analyzing their data for sex differences.” (Eve, p. 9.) Bohannon explains that it takes more than ten years for a drug to go through testing and, if approved, make it to the shelf. That means 2004 would have been the first year that drugs approved for sale had been adequately tested on women. Unfortunately, drugs that came to market before the 1993 Revitalization Act are not required to go back and test again using women as subjects. (Eve, p. 10.) Thus, women are frequently guinea pigs prescribed medications that have never been tested on them.
What is the real impact?
Between 1997 and 2000, 8 out of the 10 prescription drugs that were taken off the market by the FDA due to severe adverse effects, caused greater health risks in women. Women are 50 to 75 percent more likely than men to react adversely to medication. (Doing Harm, p. 44.)
In the case of opioids such as Oxycontin, the crisis was and remains more challenging for women because they typically require a higher dose to receive the same pain-relieving effect, making them even more prone to addiction.
In 2013, 21 years after the sleep aid Ambien was first approved, the FDA finally issued new instructions for the administration for women in response to the fact that they take longer to clear the drug from their bloodstream. This drug had been prescribed at a dose twice that necessary for most women for over two decades.
General anesthesia had been widely used on both sexes before testing for specific sex differences in 1999.
Where are we now?
In 2001, a committee for the IOM (Institute of Medicine) compiled data in a report entitled Exploring Biological Contributions to Human Health- Does Sex Matter? The answer was a resounding yes—“Sex does matter” and in “ways that we did not expect…in ways that we have not begun to imagine.” The report went on to state that “sex differences of importance to health and human disease occur throughout the life span…from womb to tomb.” These differences need to be taken into account in the design and analysis phase of studies “in all areas and at all levels of biomedical and health-related research.” (Doing Harm, p. 44.)
A 2008 report Women’s Health: Progress, Pitfalls, and Promises by the same agency, revealed substantial progress on:
Breast cancer
Cardiovascular disease
Cervical cancer
and some progress on:
Depression
HIV/AIDS
Osteoporosis
In fact, breast cancer has made so many strides that 90% of those diagnosed today will survive.
Unfortunately, the report found that little progress had been made in the following areas:
Unintended pregnancy
Maternal mortality (US rates are much higher than other developed nations and significantly higher for women of colour compared to white women)
autoimmune disease
drug addiction
lung, ovarian, and endometrial cancer
nonmalignant gynecological disorders, including uterine fibroids, endometriosis, chronic pelvic pain, pelvic floor disorders, polycystic ovary syndrome, and sexually transmitted infections
Alzheimer’s disease
The report went on to acknowledge that it didn’t review all areas, some of which had “little research to discuss.” Menopause was on this list that also included:
Arthritis
Chronic fatigue syndrome
Chronic pain, colorectal cancer
Eating disorders
Fibromyalgia
Incontinence
IBS
Pregnancy-related issues
Melanoma
Mental illnesses other than depression
Migraine
Sexual dysfunction
Stress-related disorders
Thyroid disease
Type 2 diabetes
(Doing Harm, p. 47.)
In particular, endometriosis, a common and painful condition, remains significantly undervalued and underfunded.
Overall, progress is being made but the pace of progress is slow and stalling in some areas.
Mind the Gap
It’s clear that we suffer from a knowledge gap in women’s health as a result of an overwhelming male bias in medical research. This gap obviously hurts women, but it hurts men too because certain “women’s diseases” also affect men.
Decidedly, the gap has and continues to hurt women’s health more. Yet there are other gaps equally if not more damaging. The trust gap, which I’ll look at in my next blog post, works to reinforce the knowledge gap and to prevent women from getting the care they deserve. Have you ever had the experience of being dismissed in the doctor’s office? If so, you might have personal experience with both the knowledge gap and the trust gap. Trust goes both ways, as they say. Without it the relationship between women and medicine is a troubled one.
If you’d like to share any questions, thoughts, or personal experience with any sort of gap (subway, tooth, or what have you), I’d love to hear it. Please comment or send me a message!
*The research content for this Substack is riddled with binary terms such as woman/man and male/female. Though sex and gender have historically been reduced to binaries, in reality, nature is much more diverse and complicated. Remaining scientifically curious about the not-insignificant proportion of intersex humans, (those born with a combination of female and male biological traits), will deepen our understanding of hormone function in the human body. Unbaised scientific curiosity, honesty, and rigor leads naturally to inclusivity for all bodies and better health care for all.
Book References:
Eve: How the Female Body Drove 200 Million Years of Human Evolution by Cat Bohannon, 2023
Doing Harm: The Truth About How Bad Medicine and Lazy Science Leave Women Dismissed, Misdiagnosed and Sick by Maya Dusenbery, 2018
A New Prescription for Women's Health: Getting the Best Medical Care in a Man's World, by Bernadine Healy, 1995
Thanks for the well researched and entertaining article on a very important topic