Women are not just small men – more pre-clinical research needed on sex-specific drug dosages

New research has revealed a range of factors for why women’s bodies respond differently to drugs prescribed by their doctors, and it’s not just the fact that they are a different weight to men.

The research might help alleviate some of the overdosing which affects women more than men.

Men and women experience disease differently, but we know less about how women experience it – and how to effectively treat it – than we do for men.

Historically, biomedical research has overrepresented male cells, male animal models and male participants, while underrepresenting female subjects. Generalising data to women, without considering physiological differences between sexes, has sometimes had disastrous effects.

For example, women are 50-75% more likely to experience adverse reactions to prescription drugs than men. Previously, much of this reaction was thought to be due to differences in body weight – but new research published in Nature Communications – has found that it’s much more complicated than that.

The study of mice, which are one of the most common animal models for investigating human disease, found that females aren’t just smaller versions of males.

Read more: Gender imbalance in drug testing.

“Our study uncovers the ways in which males and females can vary across many pre-clinical traits, indicating that biomedical research needs to focus more closely on measuring how and in what ways the sexes differ,” first author Dr Laura Wilson, Head of Biological Anthropology at the Australian National University, told Cosmos.

“Particularly, when a relationship between sex and drug dose is uncovered, our data suggest dose-response is likely to be different for males and females.”

“The methods in our study could help clarify the nature of these differences and provide a path forward to reducing drug reactions.”

The problem of gender bias in biomedical research is much more widely acknowledged now; in 2019 the Sex and Gender Sensitive Research Call to Action Group published an article urging Australia to align with other nations and implement sex and gender analysis in health and medical research.

Scientists know that cardiovascular symptoms in women aren’t equivalent to men’s and shouldn’t be treated as such and that the neuroimmunology of the female brain is different from males.

“Drug reactions in women are sometimes said to be due to sex differences in body weight rather than differences in how the drug works in the body,” explains Wilson.

“Therefore, it’s thought that if drug doses are adjusted according to body weight, women will often receive lower doses than they do now – which may alleviate adverse reactions.”

But these new findings suggest that this may not always be the case.

The group collated data from the International Mouse Phenotyping Centre and ran meta-analytical models on these data – more than 2 million data points.

“We asked the question of whether all the differences between males and females in preclinical traits can be explained by body weight,” says Wilson.

Wilson and her team analysed 363 preclinical traits; physiology traits such as iron levels , LDL cholesterol, and body temperature; morphology traits such as lean mass and fat mass, and heart traits such as heart rate variability.

Graphical abstract showing different drug dosages
Graphical abstract of the study illustrating how physiological traits can influence the required dose of drugs in different sexes. Credit: Szymon Drobniak

“We found the relationship between a trait and body weight varied considerably across all the traits we examined, meaning that the differences between males and females could not be generalised: females weren’t simply smaller versions of males.

That means that these physiological traits don’t scale proportionally to weight difference, so the reduction in female traits may be greater than what you would expect from body size. As a consequence, when administering medicine, the actual dose required may be less than what’s calculated by using just body mass, potentially resulting in overdosing.

“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,” adds Wilson.

“This complexity means we need to consider sex differences for drug dosing on a case-by-case basis.”

Since many drugs are withdrawn from the market due to risks of adverse drug responses in women, determining sex-specific drug dose–response curves is a viable way of reducing their occurrence.

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