The Best Women’s Health Companies Will Add New Knowledge

It’s becoming evident that, in aggregate, women are having a different experience with the COVID-19 vaccine than men are. They report more side effects, more severe side effects, and account for the majority of adverse events that have been reported. The vaccine is still highly effective, and side effects are mostly mild and manageable, but still, women’s experience with it is different.

Since reading about this, I’ve been conducting an informal poll of friends and colleagues to see if they’ve noticed this difference. I usually get a squint and then nod: yeah, now that you mention it, that sounds right.

There have been similar reports for other vaccines and drugs. A 2020 study found 86 drugs that male and female bodies broke down differently. In most cases, women metabolized the drugs more slowly than men, leading to higher levels of exposure and higher rates of adverse side effects. All drugs were FDA approved and included antidepressants, cardiovascular and anti-seizure drugs, and analgesics.

Ambien is one of the most notable examples of the “drug dose gender gap.” It was approved in 1992 — well before clinical trials were required to report on safety and efficacy by gender. After approval, a series of accidents due to “sleepy driving,” primarily by women, caused researchers to investigate the drug’s differential effects. They found that after eight hours, a standard 10mg dose resulted in 15% of women and 3% of men having drug levels high enough to cause next-morning impairment. In 2013 — more than 20 years after its initial launch — the Ambien dosing guidance for women was updated.

Women aren’t “small men”

These examples illustrate the obvious: male and female biology is different. And it seems especially different during the reproductive years, when female hormone levels and fluctuations are uniquely high. Ironically though, it wasn’t until quite recently that this specific group of women was even permitted to enroll in clinical trials, much less be uniquely monitored. Until 1993, FDA guidance banned women of childbearing age from participating in early-phase clinical trials. They were considered vulnerable, and also riskier test subjects due to their hormone fluctuations. In 1993 (one year after Ambien’s approval), the FDA reversed its position and went further to recommend that trial participants be representative of the patient population that is likely to be prescribed the drug once it is approved. In 1998, the Agency issued a final rule specifying that new drug applications must present safety and efficacy data for important populations, including sex, age, and racial subgroups.

So, twenty years ago, researchers began to investigate the differential effects of approved drugs on women’s biology. Until then, women were more or less viewed as smaller versions of men. And even though we’re doing clinical trials differently today, the knowledge gaps that stem from this history persist.

Medical knowledge, like most bodies of knowledge, builds on itself. With fewer studies, fewer trial participants, and less knowledge early on, our understanding of the differential effects of medical conditions and their treatments on women is simply less mature.

Marked differences have been observed for:

• autoimmune disease (2x more prevalent in women)
• cardiovascular disease (more poorly controlled and higher mortality than in men)
• diabetes (more comorbidities in women)
• depression (prevalence is 1.7x for women)
• brain disorders (nearly ⅔ of Alzheimer’s patients are women)
• cancer, infectious disease, and even substance abuse disorders.

Yet despite these observations, we lack a cohesive understanding of what causes these differences and how prevention, diagnosis, and treatment should differ for women as a result. And to make things even more complicated, all this says nothing of our understanding of conditions that affect only women.

Many women-specific health conditions are poorly understood

Even within the women-specific medical field, too many conditions are understood anecdotally, rather than systematically. The connection between each woman’s experience and the broader condition that they share is too often missing. We have hypotheses instead of a sophisticated understanding of genes and biochemical pathways and environmental factors that create common symptoms. This results in part from our lack of data about what is actually going on in women’s bodies, especially related to hormone fluctuations during their reproductive years. And it’s compounded by inconsistent documentation of women’s experiences. Many still struggle to find providers who take their symptoms seriously, rather than dismissing them outright or explaining them as manifestations of an underlying psychological condition.

Take menopause, for example. We’re only just beginning to talk about it, even though every woman on the planet experiences it. Our understanding of why some women experience its symptoms earlier and more severely is limited, as is our ability to alleviate those symptoms through targeted therapies. A reproductive endocrinologist recently said to me, regarding menopause: “we’re simply in the dark ages.”

Miscarriage is another example. An estimated 10–20% of pregnancies end in miscarriage. Most studies offer a wide range because few countries actually track these statistics. And unless a woman experiences multiple sequential miscarriages, they’re usually not investigated for cause or contributing factors (though we do know that age and ethnicity correlate with miscarriage prevalence). What’s equally surprising is that despite how common miscarriage is, we’re shocked every time there’s an op-ed about the subject. It’s so under-discussed that it ends up being headline-worthy, despite its frequency.

Endometriosis, which affects one in ten women and is associated with extreme pain and infertility, was recently characterized by the New York Times as overlooked (as a “woman’s disease”), unimportant (because it doesn’t kill you), and taboo (because it relates to menstrual problems). Owing to all of these factors, our knowledge of what causes it, how to diagnose it, and how to treat it is woefully inadequate. Many women experience the symptoms of endometriosis for over a decade before finally arriving at a diagnosis. And even then, treatment options are limited.

Leaders in women’s health will add new knowledge

These are just a few examples. When it comes to the health of women, our knowledge gaps are wide and it’s time to start closing them. This has to begin, first and foremost, with an understanding of one of our key biological differences that made us undesirable clinical trial candidates for so long: our hormone fluctuations and the genes that control them. This topic merits its own dedicated piece, but suffice it to say that women’s hormone levels vary widely, and this is likely to impact a range of conditions that they experience, far beyond the obvious fertility implications.

Women have long been participants in and advocates for advancing their own health causes. We march and hashtag and phone bank to raise awareness: we share our personal stories with one another and sometimes more widely through digital platforms. But we owe it to ourselves and our mothers and daughters to go beyond campaigns — to collect the messy and mundane and sometimes unpleasant data about what actually happens in our bodies day to day.

This requires new tools to collect the data, starting with hormone data, on a daily basis. It requires platforms to share that data with physicians and researchers who can draw insights from it in aggregate. And finally, it requires incentives — perhaps starting with consumer pressure — to translate those insights into updated guidelines. It took 21 years for Ambien’s dosing to be modified for women, despite widely reported incidents of impaired driving. That’s simply unacceptable.

This is a call for entrepreneurs in pursuit of new knowledge in women’s health: who appreciate that women aren’t small men; who see women’s health as more than just reproductive health; and who are driven to do the hard work of collecting the data, making sense of it, and disseminating this knowledge widely.

If you’re building or starting a company in this area, say hi — sara@spero.vc