One hundred and twenty years ago, Archibald Garrod (now lauded as the father of precision medicine1) wrote, “Just as no two individuals of a species are absolutely identical in bodily structure neither are their chemical processes carried out on exactly the same lines”2.
We now understand that genetic variations underlie the physiological differences that Garrod observed between individuals, and that this variability is due to differences in only a fraction of our genes. Human males are, genetically, 99.9% the same regardless of race, and the same degree of variability is present between human females. The genetic similarity between men and women though, is 98.5%, meaning the difference between the sexes is 15 times greater than the difference between individuals of the same sex. As comically pointed out by MIT Professor of Biology, David Page3, who has championed the need for consideration of sex in all aspects of medicine, that’s the same as the genetic difference between male humans and chimpanzees.
Unfortunately, Garrod’s extrapolation of biological variability progressed only so far as to liken humans to vegetables and other animals, and to speculate on variability between ‘the several races of mankind’. Garrod was aware of sex differences in vulnerability to diseases but thought ‘the influence of sex is much less obvious’ than the differences between children and adults2.
More than half of human diseases (based on the International Classification of Disease-10 or Global Burden of Disease classifications) have age-adjusted incidence rates that are different between men and women4. Sex and gender affect disease pathogenesis, manifestation, progression, diagnosis and treatment responses for heart disease, cancer, chronic lung disease, stroke, Alzheimer’s disease, diabetes, chronic kidney disease, chronic liver disease, depression, COVID-19 and more5.
Differences in biology
The fundamental genetic difference between men and women — the XX or XY genotype — is responsible for much more than sex determination, secondary sex characteristics and reproduction.
The Y chromosome has genes that are homologous to some on the X chromosome but they are expressed differently in tissues throughout the body, and have different functional consequences5. Imprinting of the X chromosomes and X chromosome inactivation in females during development means they carry maternal and paternal imprints and have more variability in expression of genes on their X chromosomes. The other 22 pairs of chromosomes (the autosomes) are also imprinted in sex-specific ways. So, from the time of conception, there are differences in gene expression between males and females that persist throughout life5.
Endogenous and environmental factors (e.g. hormones and pollutants, respectively) alter gene expression in sexually dimorphic ways5. These cause sex differences in bodily structure and function and create distinctly different biological systems in males and females, which influence susceptibility to disease across the lifespan5. Sex differences in endocrine function are accompanied by differences in the function of the immune system, aging and neurological function, metabolism and numerous other cells and systems.
Females are more likely than males to have adverse drug reactions, in part owing to sex differences in body composition, drug metabolism and drug excretion that can cause differences in the effects of medicines6.
Not all differences in health and disease between men and women can be accounted for entirely by biological differences between the sexes. Gender (the socially constructed norms that determine roles, behaviours and relationships) has effects on health and disease that can be distinct from sex (the biological characteristics of males and females). Gender influences behaviours that may affect susceptibility to disease (e.g. smoking), access to healthcare, the provision of care by health practitioners and institutions, or an individual’s behaviour in response to symptoms, diagnosis or treatment7. Unlike the binary classification of sex, gender is fluid and is a continuum of coexisting masculine and feminine traits.
Sexism in medicine is bad for everyone
A failure of sexual equality in medical research, which has traditionally seen medications trialled exclusively in men, with results then extrapolated to women, is a major contributing factor to differences in health outcomes8. Sex bias in medicine is generally considered to disadvantage women over men, but this is not always the case.
The relative rarity of breast cancer in men has seen it treated as analogous to breast cancer in women, with treatment deduced from evidence collected largely from studies of women. However, recent evidence shows breast cancer in men to be a disease that is distinct, and with worse outcomes, from that in women8. The perception of breast cancer as a ‘women’s disease’ has stigmatised breast cancer in men9, which may contribute to men’s later presentation in the course of the disease10 and worse outcomes.
It is only relatively recently that we have begun to appreciate that depression in men may manifest differently than it does in women and that sex differences in prevalence are an artefact of inaccurate diagnostic instruments11. This too is a consequence of medicine’s sexist past.
“Viewing the patient through a sex and gender lens is the first step towards personalising care”12. We need to move past sex and gender biases and their restrictions on our ability to diagnose and treat disease, and embrace sex and gender as critical and fundamental determinants of health and disease.
1 Perlman & Govindaraju, 2016. Archibald E. Garrod: the father of precision medicine. Genetics in Medicine
2 Garrod, 1902. The incidence of alkaptonuria: a study in chemical individuality. The Lancet
4 Westergaard et al., 2019. Population-wide analysis of differences in disease progression patterns in men and women. Nature Communications
5 Mauvais-Jarvis et al., 2020. Sex and gender: modifiers of health, disease, and medicine. The Lancet
6 Askhi & Johar Kaid, 2019. Sexual Dimorphism in Drug Metabolism and Pharmacokinetics, Current Drug Metabolism
7 Bartz et al., 2020. Clinical Advances in Sex- and Gender-Informed Medicine to Improve the Health of All. JAMA Internal Medicine
8 Sabih et al., 2021. Management of Male Breast Cancer: The Journey so Far and Future Directions. World Journal of Oncology
9 Midding et al., 2018. Men With a “Woman’s Disease”: Stigmatization of Male Breast Cancer Patients—A Mixed Methods Analysis. American Journal of Men's Health
10 Fox et al., 2022. Male breast cancer: an update. Virchows Archiv
11 Martin et al., 2013. The Experience of Symptoms of Depression in Men vs Women. JAMA Psychiatry
12 Miller et al., 2015. Sex Differences Research, Precision Medicine, and the Future of Women's Health. Journal of Women's Health