While progress has been made in the past two decades, medical research still routinely fails to consider the impact of sex and gender. Animal-based studies often exclude females, results are not disaggregated by sex, and researchers frequently don’t enrol enough adult women in later stage clinical trials.
However, a comprehensive new study of over 50,000 mice – which are the primary model for most genetic and clinical studies – has now shown that biological differences between the sexes are starker and more pervasive than we ever could have imagined.
An international research group analysed the differences between males and females for hundreds of characteristics, including weight, cholesterol levels, and blood chemistry. “They looked at a ridiculous number of phenotypic traits,” said Professor Judith Mank, a co-author of the study and Chair of Evolutionary and Comparative Biology at UCL. “Each gene was knocked out and then screened for its effect on males and females.”
“There were several cases of women getting up in the morning acting like ‘Ambien zombies’ – even driving under the influence of the drug”
The results were striking. “The study showed quite beautifully that we can’t always predict where there will be differences and in what regions and what genes. For example, the viscosity of the eye showed major differences – I would not have expected it, even doing what I do,” said Mank. “If we really can’t predict what traits show sex differences, can we really predict which drugs will have different effects in men and women?”
The vast majority of pre-clinical trials are done on male mice; according to a 2009 analysis, male animals outnumbered females 5.5 to 1 in neuroscience, 5 to 1 in pharmacology, and 3.7 to 1 in physiology. And, unsurprisingly, this inequality in research has serious consequences.
“There have been drugs that reached the market based on testing primarily in either human males or male mice that have had adverse effects in women and have had to have the dosage revised – or, in some cases, be pulled from the market,” said Mank.
“Ambien is a great example. When it reached the market, it became very clear that women were metabolising it differently, independent of body size differences.” The recommended dose for women had to be halved after there were several cases of women getting up in the morning acting like “Ambien zombies”, some even driving under its influence, which led to cases of homicide.
In fact, women are 50% more likely to develop an adverse drug reaction than men. Between 1997 and 2001, 8 of the 10 prescription drugs that were pulled from the market in the US posed greater health risks for women. The flu vaccine uses twice the dosage the average woman needs.
“With incomplete information it’s difficult for science to progress”
The issue of male bias in medical research has long been an issue the US has led on. Back in 1993, Congress made it a legal requirement that women and minorities be included in any government-funded health research. Women now account for roughly half of all participants in National Institutes of Health (NIH)-supported clinical research.
But, with growing recognition that it’s not just clinical human trials but pre-clinical animal ones that are failing women, the NIH has had to go even further.
“It’s clear in many different areas that not accounting for sex leads to incomplete information, and with incomplete information, it’s difficult for science to progress,” said Dr. Chyren Hunter, Associate Director at the Office of Research on Women’s Health (ORWH), part of the NIH.
“In many research fields, there’s data that says that when you are not aware that there might be sex differences in the treatment, in the disease process, in basic biological processes, then your result can’t be generalised,” she said.
“If we really can’t predict what traits show sex differences, can we really predict which drugs will have different effects in men and women?”
In 2016, it enacted a new Policy on Sex as a Biological Variable, which is unique for any government in the world. Now, all research funded by the NIH must show it is sensitive to sex differences, even at the pre-clinical level.
“We would like all of our researchers to consider, fully, whether it is appropriate to study one sex, and if not, they should think about disaggregating their data to be fully transparent about the vertebrate animals and humans that they’re studying,” said Hunter.
These new rules will undoubtedly have a huge impact. The NIH is the largest supporter of biomedical research in the world, with the budget coming from US taxpayers to the tune of over $30 billion.
However, research funded by private foundations or companies is not covered by the policy. In 2014, industry funded six times as many clinical trials as the NIH, highlighting the need for other additional solutions.
“When the gender diversity of researchers increases, the likelihood of there being a result that pays attention to gender and sex analysis also increases”
One alternative policy route could be found in the emerging data on the links between sex-sensitivity of medical research and the profile of the scientific workforce. A new study that samples more than 1.5 million medical research papers has shown there to be a strong correlation between medical studies’ sensitivity to sex and the number of women researchers and authors on the team.
“When the gender diversity of researchers increases, the likelihood of there being a result that pays attention to gender and sex analysis also increases,” said Matthias Nielsen, Assistant Professor at Aarhus University, and co-author of the study.
Yet, while gender diversity correlates with more sex-sensitive results, women in science are marginalised, making up just 35% of all medical research authors Nielsen’s team surveyed.
“How we populate our scientific organisations matters for the type of knowledge we produce”
“The research demonstrates that how we populate our scientific organisations matters for the type of knowledge we produce,” said Nielsen.
The NIH is starting to step up to these concerns, tackling women’s underrepresentation at the top of the biomedical profession alongside its policies around inclusive research. “Our Working Group on Women in Biomedical Careers is an umbrella for looking at career opportunities and development for women of colour, understudied women, and generally advancing women both internally in the NIH and externally,” said Hunter.
“We also have a training program dedicated to building infrastructure in women’s health. More than 50% of the individuals who are in that training program are women,” she added.
Programs like these that aim to help women push forward their medical research careers could have a powerful impact that extends far beyond government-funded research. However, Nielsen is quick to point out that correlation between more diverse teams and more sensitive research does not signal simple causation.
“They’re mutually supportive,” said Nielsen. “We need to think about the link between gender diversity in the scientific workforce on the one hand and gender and sex-based analysis on the other as a symbiotic relationship. It may also be the case that as the medical field becomes more attentive to issues of gender and sex analysis, it may attract more women researchers into interesting positions and into authorship of papers.”
(Picture Credit: Flickr/Asian Development Bank)