Biomed Analysis: Target sex differences in research
Diseases, and drugs used to treat them, behave differently in men and women. Drug development needs to account for this, says Priya Shetty.
That men and women are biologically distinct is obvious, but this is not limited to physical or hormonal differences. Sex is strongly linked both to how diseases manifest themselves — their symptoms and severity, for instance — and to how drugs interact with the body.
Sex differences clearly have implications for biomedical research, especially drug development. Over the past 10–15 years, major research funding institutions such as the US National Institutes of Health (NIH) have encouraged inclusion of these factors into research protocols, and more journals such as the Journal of the American Association of Cardiology are now asking authors to incorporate sex differences into their analysis.
But last December, a cross-disciplinary review  of scientific research papers showed that while some progress had been made, the pace has been sluggish, especially in translating the findings from clinical research to practice.
And the need to account for sex differences in research has growing relevance for developing countries, where an increasing number of clinical trials are taking place.
This month, geneticists discovered striking sex-linked metabolic differences between men and women , which could affect disease onset and progression. A person's metabolic profile informs gene expression patterns, which in turn affect chronic diseases that are rising rapidly in poor countries.
Women tend to be worst affected by research that doesn't distinguish between the sexes. Through incorrect dosing they have suffered serious side-effects more often than men both during clinical trials and when treated with approved drugs.
Dosing tends to be adjusted by body weight. But the percentage of fat in the body, which is naturally higher for women, also affects how it processes a drug. This is not taken into account in deciding standard doses, or in the information provided on product labels, so women can fare worse after treatment.
Understanding such differences is vital. For instance, in the 1990s, data showed that women under 55 years of age were twice as likely to die after a heart attack than men in the same age group; now, mortality is only slightly higher in women than in men.
This drop in women's mortality stemmed in part from doctors' growing awareness that they might not have the same response to drugs like statins. They realised that heart disease can manifest differently in men and women — they may have different risk profiles, symptoms, or treatment needs on admission to hospital.
The roots of this biomedical bias against women seem to start in basic research, the precursor of clinical trials. This type of research has usually used male animals, to avoid the complexities of the hormonal and reproductive systems of female animals, which would require larger sample sizes to achieve a comparable result.
Challenges in action
Research-funding agencies such as the US Food and Drug Administration (FDA) and the NIH have guidelines to ensure that researchers guard against this bias, and indeed actively try and redress it with targeted research.
But this is hardly an area of focus for biomedical researchers in the developing world, and WHO guidelines tend to focus on different gender issues (such as making trials culturally appropriate for women).
And even where guidelines exist, there are challenges in implementing them. For one thing, since the terms 'sex' (which is a biological definition) and 'gender' (social) are often incorrectly used interchangeably, many journals and institutions still think of this as a social science issue, particularly since the current focus on the issue stems from women's rights movements.
Few funders devote any cash to the hard science of underlying biological mechanisms that might explain why men and women respond differently to drugs.
And accounting for sex-specific differences in research protocols, and running the subsequent data through finely-grained analyses that are stratified according to sex, will inevitably lengthen a research project. This can use up precious resources and delay the sharing of potentially useful results.
Focus on women's health
It is now well established that major diseases such as diabetes, stroke, and several cancers, as well as Alzheimer's disease, depression and other mental illness, differ in how they manifest, and how they should be treated, in women.
All these diseases are now a significant strain on the health systems of developing countries, and public health scientists expect that this will only get worse in coming years. As countries and donors allocate resources to meet the challenge, they should note that research into chronic diseases will be incomplete if it ignores sex differences.
Personalised medicine, which promises to tailor treatment to people according to their genetic risk profiles and environmental factors, will also need to incorporate biological sex differences.
But the goal is not to provide nuanced disease diagnosis and management for the sake of it — treatment can always be improved, after all. It is to ensure that women's health is taken seriously.
Researchers must not shortcut around the issues of biological sex differences. Focusing only on implementing health programmes that suit women culturally is not enough. Medical research shouldn't keep pushing forward without addressing this fundamental flaw.
Journalist Priya Shetty specialises in developing world issues including health, climate change and human rights. She writes a blog, Science Safari, on these issues. She has worked as an editor at New Scientist, The Lancet and SciDev.Net.
 Oertelt-Prigione et al. Analysis of sex and gender-specific research reveals a common increase in publications and marked differences between disciplines. BMC Medicine doi:10.1186/1741-7015-8-70 (2010)
Discovery of sexual dimorphisms in metabolic and genetic biomarkers. PLoS Genetics doi:10.1371/journal.pgen.1002215 (2011)