When Were Women Included in Medical Studies?

Women were formally required to be included in federally funded clinical research in the United States beginning in 1993, when Congress passed the NIH Revitalization Act. But that single date hides a more tangled history. For most of the twentieth century, women of childbearing age were actively barred from drug trials by federal policy, and even after the legal mandate, progress in actually enrolling women, analyzing data by sex, and changing how drugs are prescribed has been uneven at best.

How Women Came to Be Excluded

The roots of the exclusion trace to two drug disasters. Thalidomide, prescribed for morning sickness in the late 1950s and early 1960s, caused severe birth defects in thousands of children worldwide. Then, through the 1970s, it became clear that diethylstilbestrol (DES), a synthetic estrogen given to pregnant women to prevent miscarriage, was causing a rare vaginal cancer in their daughters decades later. Together, these events created what researchers have called a “protectionist ethic” around women in research. The fetus appeared vulnerable both immediately and across generations, and the response was to keep women away from experimental drugs entirely.¹

That aversion was codified in 1977, when the FDA issued a guideline recommending that women of childbearing potential be excluded from early-phase drug trials. The intent was to protect unborn children from unknown drug effects. The practical result was that for the next sixteen years, the default research subject for almost every non-reproductive medical condition was male. Diseases that affected both sexes equally, or even predominantly women, were studied in men’s bodies and the findings were applied to everyone.

The Policy Turning Points

The reversal came in stages. In 1993, the FDA formally lifted its 1977 restriction, publishing new guidance encouraging (though not requiring) the inclusion of women in clinical trials and calling for analysis of drug data by sex. That same year, Congress passed the NIH Revitalization Act, which went further: it required NIH-funded researchers to enroll women and racial and ethnic minorities in clinical trials, including women of childbearing age, and explicitly forbade using cost as a justification for excluding them.²

A second major shift came in 2015–2016, when the NIH announced that researchers seeking federal funding would also need to account for sex as a biological variable in preclinical research, meaning animal and cell-based studies. The policy, which took effect for grant applications submitted on or after January 25, 2016, required investigators to design experiments that could detect sex differences in vertebrate animals and human subjects, or to justify why studying only one sex was scientifically appropriate.³ Before that policy, the vast majority of animal studies in fields from neuroscience to immunology defaulted to male subjects without explanation.

Internationally, the picture has been less structured. The European Medicines Agency historically lacked explicit regulatory policies mandating either the inclusion of women in drug-authorization trials or the routine analysis of results by sex, lagging behind the U.S. framework.⁴

Why It Matters That Women Were Left Out

The exclusion was not just an equity issue. It was a safety issue. Women and men metabolize drugs differently in ways that change how well a medication works, how long it stays in the body, and how likely it is to cause side effects. Women tend to have slower gastric emptying, higher body fat, and lower kidney filtration rates than men. Certain liver enzymes that break down drugs are more active in women, while others are more active in men. These differences alter how much of a drug actually reaches the bloodstream and how quickly the body clears it.⁵

The consequences are not abstract. A large analysis of FDA-approved drugs found that for the vast majority of medications examined, women had higher blood concentrations and longer elimination times than men. Among drugs with identifiable side effects, the direction of those blood-level differences correctly predicted which sex would experience more adverse reactions about 88% of the time. Nearly all drugs with higher blood levels in women were associated with more side effects in women than in men.⁶

Some drugs also simply work differently. Ibuprofen, for instance, appears to be more effective in men, while opioids and certain sedatives are more effective in women. Despite this evidence, most prescribing guidelines remain sex-neutral, and clinician awareness of these differences in routine practice has been described as inadequate.⁷

The Zolpidem Wake-Up Call

The sleep medication zolpidem (sold as Ambien) became one of the most visible examples of what happens when sex differences go unaccounted for. Women clear zolpidem from their bodies roughly a third more slowly than men, leading to higher morning blood levels and greater next-day impairment, including drowsy driving.⁸ In 2013, the FDA took the unusual step of recommending that the starting dose for women be cut in half. The drug had been on the market for over two decades before that change was made. It is worth noting that the sex difference in clearance was not some hidden biochemical subtlety. It was a direct consequence of the metabolic differences that had been documented for years but largely ignored in dosing decisions.

Pain Research and the Male-Only Problem

Pain is one of the starkest examples of why studying only one sex produces misleading results. Research in mice has shown that the immune cells responsible for chronic pain are fundamentally different between males and females. In male mice, cells called microglia in the spinal cord drive pain hypersensitivity. In female mice, microglia are not required at all; instead, a different branch of the immune system, likely T cells, takes over.⁹ The researchers concluded bluntly that male mice cannot serve as proxies for females in pain research.

More recent work has identified additional sex-specific mechanisms. A signaling molecule called CGRP plays a role in pain in females but not males, and the hormone prolactin and its receptor contribute to pain sensitization in a female-specific way.¹⁰ These are not minor tweaks to the same pathway. They represent entirely different biological machinery. Decades of pain drug development based on male-only animal studies may have produced treatments optimized for only half the population.

The Variability Myth That Kept Female Animals Out of Labs

For years, one of the most common justifications for excluding female animals from experiments was the claim that the estrous cycle (the rodent equivalent of the menstrual cycle) made female data too “noisy.” Researchers argued that hormonal fluctuations introduced extra variability that would require larger, more expensive studies to account for. This belief was remarkably persistent despite thin supporting evidence.

Recent studies have directly tested the assumption and found it wanting. One study of continuous body temperature and activity recordings in mice found that males actually displayed higher variability than females across multiple timescales. Accounting for the estrous cycle reduced measurement variability in females by only about 3% for body temperature and 1% for activity, confirming that cycles contributed a small but structured amount of variance, not the chaos researchers feared.¹¹ Another study of food intake in mice found no significant sex difference in variability across any testing condition, and in one paradigm, males were actually more variable than females, the opposite of the traditional claim.¹²

Research on sleep architecture in female mice similarly found that the estrous cycle had less influence on sleep patterns than the genetic background of the mouse strain, and what effects there were depended on genotype.¹³ In other words, the “variability problem” that was used for decades to justify excluding females was largely a myth. Male mice were at least as variable, and often more so.

Cardiovascular Disease and the Persistent Gap

Heart disease is the leading cause of death in women in most high-income countries, yet women remain underrepresented in the trials that shape how it is treated. An analysis of cardiovascular clinical trials found that women were underrepresented relative to the disease population in about 62% of trials, and there was no improvement over time in the proportion of trials with adequate representation.¹⁴ The underrepresentation spans drug trials, acute coronary syndrome research, heart failure studies, and trials of interventional procedures and devices.¹⁵

This gap is particularly concerning because heart disease does not behave the same way in women and men. Women are more likely to have diffuse, non-obstructive coronary artery disease rather than the localized blockages that are the classic textbook presentation. Their coronary arteries tend to be smaller, so less plaque buildup is needed to restrict blood flow. Plaque itself differs in composition. Extrapolating findings from male-dominated trials to women may lead not just to less effective treatment but to active harm.¹⁶

Enrollment Is Not the Same as Analysis

Even when women are enrolled in trials, that does not guarantee the data will be analyzed or reported by sex. A review of randomized controlled trials involving women veterans between 2008 and 2018 found that only a quarter of trials that included both men and women reported their results broken down by sex. Most of those that did were published in 2015 or later, suggesting the practice is relatively new even among researchers who enroll mixed-sex populations.¹⁷ In cardiovascular research specifically, sex-specific outcomes for both efficacy and safety are still not systematically presented in the most influential trials.¹⁸

This means a trial could enroll a perfectly representative mix of men and women and still produce results that are effectively sex-blind. If you do not separate the data and look, you cannot find differences even when they exist. The NIH’s mandates address enrollment but have been slower to enforce rigorous reporting standards.

Who Funds the Research Shapes Who Gets Studied

The funding source of a clinical trial turns out to be a meaningful predictor of whether women are adequately represented. A study analyzing over 1,400 high-impact clinical research papers found that industry-funded trials, which made up about 44% of the total, enrolled significantly more men (roughly 61%) than women (roughly 39%). NIH-funded trials, by contrast, enrolled slightly more women than men.¹⁹ The NIH’s inclusion mandates appear to work for the research it funds. But most clinical trials globally are funded by pharmaceutical and device companies, which are not subject to the same legal requirements. The gap between publicly funded and privately funded research on sex representation has practical consequences for the drugs and devices that eventually reach the market.

Pregnant and Lactating Women Remain a Blind Spot

Even as the inclusion of women in general has improved, one group remains almost categorically excluded: pregnant and lactating women. The protectionist impulse that started with thalidomide and DES has been remarkably durable for this population. Randomized trials routinely exclude them, and the result is that most medications taken during pregnancy have little or no controlled safety data. Evidence about drug effects during pregnancy instead accumulates slowly and haphazardly from clinical observations after drugs are already in use.²⁰

The COVID-19 pandemic made this problem visible. A review of international trial registries found that pregnant women were broadly excluded from COVID-19 treatment and vaccine trials, even as the pandemic created urgent clinical need. The authors argued that while “ethical” concerns about fetal exposure are routinely cited, the habitual exclusion of pregnant women from research is itself unethical, because it forces them to make health decisions with almost no evidence to guide them.²¹

Barriers That Compound for Women of Color

Policy mandates can require that women be included, but they cannot by themselves address the structural barriers that make participation harder for some women than others. A systematic review examining why African American women specifically do not participate in clinical research identified several recurring themes across studies. In more than half the studies reviewed, participants cited mistrust in the medical and scientific community, concern about the safety of study procedures or medications, and fear of experimentation or randomization. Half also cited limited understanding of and access to information about trials. Financial and logistical burdens, including time commitments, transportation, and inadequate compensation, were mentioned in about 44% of studies.²²

These barriers are not incidental. Medical mistrust among African American communities has deep historical roots, and it intersects with present-day disparities in health care access, insurance coverage, and geographic proximity to research centers. Mandating diverse enrollment without addressing these underlying issues produces compliance on paper without meaningful participation in practice.

The Male Default in Medical Textbooks

The exclusion of women from research has a downstream counterpart in medical education. Anatomy textbooks, the foundational visual reference for every medical student, disproportionately depict male bodies. A study analyzing over 5,000 images from eleven commonly used anatomy atlases and textbooks published between 2015 and 2020 found that about 62% of images that could be categorized by sex depicted males, while about 38% depicted females. The male bias persisted across all body regions, including images showing characteristics not specific to either sex.²³

Earlier analyses of specific textbooks found the same pattern. Female anatomy was typically shown only in sex-specific sections (breasts, reproductive organs), while male anatomy served as the default for surface anatomy, musculoskeletal illustrations, and clinical cases. When female clinical cases did appear, they tended toward conditions that society stereotypically associates with women, like varicose veins or osteoporosis, even though those conditions affect men as well.²⁴ The visual bias extends beyond sex to stereotypical emotional expressions and limited representation of different ages, ethnicities, and body types.²⁵

When future doctors spend years learning from images that treat the male body as the norm, it reinforces the same assumption that shaped research policy for decades: that male biology is universal and female biology is a specialized variation. The research gap and the education gap feed each other.

The Male Default in Published Research Today

Even in top-tier journals with explicit policies requiring authors to report whether both sexes were included, the male default persists in practice. An analysis of publications in Nature found that while male-only and female-only studies occurred at roughly similar rates, they were framed very differently. Female-only studies were overwhelmingly concentrated in sex-specific conditions like pregnancy or ovarian biology. Male-only studies, by contrast, dominated research on traits and conditions that affect both sexes. Male biology is still treated as broadly generalizable, while female biology is positioned as specialized or context-dependent.²⁶

That framing asymmetry matters because it means the inclusion mandates, while they have increased the raw number of women enrolled in studies, have not fully overturned the deeper conceptual habit of treating male data as the default from which female data deviates. Policies changed the rules. Changing the assumptions is a slower project, and by most measures, it is still underway.