Women Are Overmedicated Due to Male-Dominated Studies, Scientists Say
Despite women purchasing and consuming more medications than men, most clinical drug research trials predominantly utilize male subjects.
As a result, women tend to be overmedicated and experience significantly more adverse drug reactions (ADRs) than men, according to researchers at the University of California Berkeley and the University of Chicago.
In the study, published in Biology of Sex Differences in 2020, scientists combed through data from about 5,000 medical research journal articles. They found evidence of a dosage sex bias in 86 medications approved by the U.S. Food and Drug Administration (FDA), including but not limited to antidepressants, anti-convulsant and heart medications, sleep aids, and analgesics.
The researchers found the differences in pharmacokinetics (PK)—or drug absorption, distribution, metabolism and excretion between sexes—were strongly linked to different rates of ADRs. Of the 86 drugs assessed, 76 had higher PK values in women, meaning women metabolized and excreted them more slowly, increasing their overall exposure.
PK values vary from one individual to another, but there are notable sex-based differences that remain consistent even when the dosage is altered for body weight.
"Absorption is a compound's ability to pass through barriers such as the intestinal or nasal lining, the lungs or skin. Distribution is how the drug is distributed throughout the body and its propensity to accumulate in any given tissue," explained Sharon Ayd, Ph.D., chief executive officer at Ayd BioPharma Consulting Group, LLC. "Metabolism is how the body breaks down the drug, usually by the liver. Excretion is the rate and process by which the drug and metabolites exit the body."
PK values vary from one individual to another, but there are notable sex-based differences that remain consistent even when the dosage is altered for body weight. These differences can be found in cis women and trans and nonbinary individuals assigned female at birth.
Researchers analyzed the 59 drugs with clinically identifiable side effects and found higher PK values correlated to substantially higher rates of adverse effects in 96 percent of them. Women were more than twice as likely to experience ADRs than men overall. And those side effects were worse in women more than 90 percent of the time, despite all subjects receiving the same dose. ADRs ranged from headache and fatigue to depression and seizures.
"From 1977 to 2003, most drugs removed from the market or included in top class-action lawsuits were resultant of adverse side effects experienced by women," said Gail Trauco, R.N., BSN-OCN.
History of sex-based exclusion in clinical research
These findings aren't a revelation. Medical professionals have long known women are more prone to ADRs than men, even with dosages adjusted for body weight. But until the early '90s, clinical drug trials rarely involved female subjects.
"This goes way back in time to when men's physiology was supposed to represent the norms and women, who are full of complicating factors like monthly hormonal fluctuations, are only represented in reproductive biology matters," said Sandra El Hajj, a health professional specializing in preventive global health and commissioner of health, environment and health policies at United Nations Association of Lebanon. "This leaves a group of people unrepresented, leading to a big question about whether or not women are receiving optimal health treatment."
The concern about how menstrual-related hormonal fluctuations could skew data has led researchers to exclude female subjects even in animal-based studies.
Researchers have historically been apprehensive about exposing women to drugs that may cause fertility issues or congenital disabilities. This fear intensified after the disastrous effects of thalidomide, a sedative and morning sickness medication used in the 1950s and '60s, which caused thousands of congenital disabilities in Europe. The FDA barred thalidomide from use in the U.S. and simultaneously banned women of "childbearing potential" from early clinical trials.
The concern about how menstrual-related hormonal fluctuations could skew data has led researchers to exclude female subjects even in animal-based studies.
"This risk was greatly overestimated and resulted in the development of drugs without evidence of safety and effectiveness in women," said Aaron Emmel, Pharm.D., MHA, BCPS, founder and director of educational programs at PharmacyTechScholar.com.
In 1993, the National Institutes of Health (NIH) passed the NIH Revitalization Act, which mandated phase III clinical trials include men and women, and later established the Office of Research on Women's Health.
Nonetheless, thousands of drugs approved before 1993 remain on the market. And, while gender equality in research improved—especially in phase III trials, where the medicine is evaluated in comparison to previous treatments—many studies still underrepresent women or do not analyze or publish sex-based data.
"Even though more and more women are being included in drug trials, very few researchers analyze the data for sex differences. That's why we rarely see a drug offer different dosages on account of sex, even though that should be the most obvious consequence of engaging with gendered data sets," said Daniel Boyer, M.D., of the Farr Institute.
"The danger of this is best illustrated by the DIG study on the effects of digitalis on mortality," he continued. "When data were analyzed without regard for gendered differences in interaction, the results were conclusive that digitalis didn't reduce mortality, but reduced hospitalization frequency. When the results were evaluated for gendered differences, it was revealed that mortality rates in men actually decreased, but increased in women."
The gender gap remains especially pronounced in trial phases I and II, Emmel and Trauco said, where researchers gather a substantial amount of information regarding a drug's efficacy, safety and dosage.
"What we have wound up with, with many drugs, is a one-size-fits-all dosing approach, where the same dose and frequency is given to a patient regardless of their sex. We see the same thing regarding other important demographic factors, such as height and weight, body composition, age, and other health-related factors," Emmel said. "It is quite possible that for many drugs on the market with a single recommended adult dose, the optimal dose may vary substantially for a patient based on their sex and/or the other factors mentioned."
In 2016, the NIH took another step to mitigate gender bias by requiring grant applicants to recruit men and women for studies, yet the issue is far from resolved.
Perhaps unsurprisingly, COVID-19 clinical studies, for the most part, have not done much better in rectifying the research gender gap.
"COVID-19 clinical studies followed the same pattern of using predominantly male subjects. Women typically have stronger immune responses than men, but this also translates to more common and more severe reactions to vaccines than men," Boyer explained. "Of the many COVID-19 studies out in scientific journals by late December 2020, only 4 percent planned to test sex variables in their data. The fact that there wasn't any direct approach to test COVID impact and the effects of the treatment on women of different descriptions exposed women to unnecessary risk. We may have been lucky with COVID vaccines because they don't seem to affect women negatively, but that may not always be the case."
Why women and men process drugs differently
Genetic, hormonal and physical variations impact how men and women process drugs differently.
"Research has shown a significant difference in the activity of drug-metabolizing enzymes produced by the liver between sexes," Emmel said. "These enzymes metabolize many drugs, so this may play a major role in the differences of side effects observed between women and men. Female hormones impact enzyme activity, so contraceptives, pregnancy and menopause further compound this."
Women are more likely than men to take two or more medications simultaneously as well, increasing the risk of drug interactions. Oral contraceptives, for instance, frequently interact with other medicines, according to Emmel.
Also, because women tend to have more fat deposits than men, Boyer said it's important to consider sex and body composition when evaluating medications like opioids, which are stored in fat cells. Ayd added that antipsychotics, antidepressants and anti-anxiety medications fall in this category, too.
"The fact that women typically weigh less than men should also influence dosage requirements, but drugs are rarely tested with weight variations in mind," Boyer said.
"Digestion is yet another difference between men and women. Women produce lesser gastric acid and thus digest food slower than men," Ayd explained. "Therefore, medicines like antifungal ketoconazole that need an acidic environment may not be very effective in women."'
Genetic, hormonal and physical variations impact how men and women process drugs differently.
Emmel said any drug might affect people differently based on sex. Likewise, all medications carry some risk of side effects.
An oft-cited example of the perils of insufficient sex-based clinical research is zolpidem, brand-name Ambien. The popular sleep aid was on the market for several years before officials noted its disproportionate adverse effects on women and cut the recommended dose for women in half. Ambien remains in women's bloodstreams for longer and, in excessive amounts, can lead to intense drowsiness and significant cognitive impairment related to its sedative properties. An overdose can be fatal.
"Another example is acetaminophen: A recent study suggested that liver toxicity is more common in women, and those events tend to be much more severe than in men," Emmel said.
Boyer noted hypertension, which affects more women than men, kidney disease and disorders, and myocardial infarction are a few conditions that would benefit from more sex-specific treatment research.
Ayd suggested it would likewise be tremendously beneficial to utilize more female subjects in clinical trials for drugs used for women's health issues, including hormone replacement therapy, cancers of the female reproductive system, methotrexate, and certain antidepressants.
To mitigate the implications of gender disparity in clinical research, Irving Zucker and Brian J. Prendergast, authors of the UC Berkeley and University of Chicago study, advise the FDA to label drugs known to affect sexes differently. They also suggest doctors prescribe a lower dose of various such medications for people assigned female at birth.
"Drugs bring in billions in revenue, and women are prescribed more drugs than men, making them the dominant economic block for pharmaceuticals," Boyer said. "For the amount of money they bring pharmaceutical companies, I'd say the extra work the involvement of female subjects would necessitate is a small price to pay to keep the biggest client demographic safe."
