Researchers have long known that women are more likely to experience adverse drug reactions (ADR). Previous studies have attempted to quantify this, finding that women are 50-75% more likely to report adverse drug reactions as compared to men. Why this might be the case has remained uncertain, with a popular theory resting on the idea that body weight differs by sex – where, with a simple dosage adjustment, women’s drug reactions may be alleviated. However, a new study in mice has debunked the myth that female bodies are just scaled down versions of their male counterparts, instead suggesting there are several sex differences in traits that could help explain the unequal burden of drug reactions.

Previous research also shows that sex-specific physiological differences exist between men and women that determine how drugs are absorbed, distributed, metabolized and eliminated from the body. Therefore, body weight alone may not explain the female bias in drug reactions. To understand this further, the researchers adopted a method used in evolutionary biology known as allometry, investigating the relationship between a pre-clinical trait – such as fat mass, glucose and LDL cholesterol – and body size. Their findings were published in the journal Nature Communications.

“Our analyses showed sex differences in many traits that cannot be explained by body weight. For example, iron levels and body temperature, morphology traits such as stored fat, and heart rate variability,” said Dr. Laura Wilson, lead author of the study. The latest research highlights the gender bias that persists in biomedical research – a consequence of which is our limited knowledge on how women and people assigned female at birth experience disease. The authors also highlighted the need for sex-based data to advance care in an “equitable and effective manner.”

“Most biomedical research has been conducted on male cells or male animals,” Dr. Wilson said, adding that it is assumed that such pre-clinical research results will apply to all other bodies as well. “But we know men and women experience disease differently, including how diseases develop, the length and severity of symptoms and effectiveness of treatment options.”

Since most drugs available today received approval based on trials in male bodies, researchers previously suggested women might be overmedicated, resulting in adverse drug reactions. They advocated an evidence-based dose reduction to address this sex bias. The Food and Drug Administration (FDA) has already recommended dosage reductions for some drugs for women, while certain anti-fungal and antihypertensive drugs seem to show positive results when adjusted for weight, the authors noted in an article in The Conversation.

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As the authors noted in The Conversation, the findings revealed that the relationship between a trait and body weight varied considerably, suggesting that differences between males and females cannot be generalized. “We analysed over two million data points, capturing over 300 traits in mice, a preclinical disease model, and it’s clear females aren’t just smaller versions of males,” Dr. Wilson stated.

“Ignoring these differences in some cases, such as measures of blood cells, bone and organs, could result in missing a lot of the population variation for a particular trait: up to 32% for females and 46% for males. This complexity means we need to consider sex differences for drug dosing on a case-by-case basis,” they wrote. Dr. Wilson summed it up by adding that drug reactions are unlikely to be alleviated by adjusting the dosage for body weight.

When it comes to drug reactions, a lack of understanding on why they present with a sex bias may negatively affect the health of women. Researchers pointed out that many prescription drugs have been recalled as they pose a risk to women. Many women have also reported discontinuing medication due to adverse reactions. Meanwhile, there are several economic costs attached to drug reactions as well, including a higher rate of hospital admissions and longer hospital stays. Greater efforts to study sex-specific differences then may help prevent a significant number of these cases as well as the costs incurred.

Women have historically been left out of biomedical research, as documented by a range of studies. Over the years, directives have been issued to increase female participation. However, while comparatively more women are now being included in research, sex-based analysis of the outcomes remains abysmally low, as noted by a recent study.

“Given the significant sex differences from biology to behavior, excluding females means one cannot assume that any findings would apply to females… Moreover, it is possible that by doing a sex-based analysis, scientific breakthroughs could occur that could be important for all people by understanding how certain interventions vary by sex,” Vineet Arora, a professor of medicine, told STAT in 2020.

One such example of a sex difference that could have a major impact on health was highlighted by Dr. Wilson: “…[C]rushing chest pain is often cited as a primary symptom of heart attack. While this might be common for men, it’s a much less common symptom for women. Women are more likely to experience intense nausea.”

The authors of the recent study thus made a case for analyzing sex-based data in biomedical research that could better inform our understanding of disease timelines and devising effective, sex-specific treatments. As Dr. Wilson said, “Our study could help clarify the nature of the differences in responses to certain drugs and provide a path forward to reducing drug reactions.”