Sex and Gender Shape Health—Time for Science to Establish Clarity

Our biological sex - physical and physiological traits - and our gender - the roles and identities we take on throughout life - both influence our health. Yet research measuring sex and gender effects remains fragmented, constraining evidence-informed decision-making.
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The effects of sex and gender attributes on clinical outcomes: a systematic review - Biology of Sex Differences

Background Biological sex and sociocultural gender may influence changes in health status critical to clinical decision-making, yet scientific evidence of their effects on clinically relevant outcomes remain uncertain. We aimed to systematically review research on sex and gender effects on clinical outcomes and to assess the consistency and significance of associations between sex, gender, and clinical outcomes. Methods We searched Medline, Embase, PsycInfo, CINAHL, and Web of Science from each database’s inception to November 20, 2023, and included English language peer-reviewed research utilizing standardized measures of sex and gender attributes in adults to measure their association with clinically relevant outcomes. We performed a risk of bias assessment and certainty assessment using criteria set a priori. We created visualizations of results with links to study quality and sex and gender attributes, which facilitated certainty assessment. We reported results across sex and gender-related attributes and measures. Results Of the 12,964 unique records identified, 19 studies with a total of 643,093 participants (54% male) were included in data synthesis. Four studies measured attributes of sex (testosterone, sex-specific polygenic score), and 15 studies measured attributes of gender (gender identity, roles, and adherence to masculine norms). We observed great heterogeneity in the direction and significance of the associations, resulting in evidence of moderate certainty only for the association between testosterone level and depression, and erectile function. We regarded all other evidence as very low in certainty. Conclusion Research findings regarding the effects of sex and gender attributes on clinical outcomes is variable. However, results suggest that neither sex nor gender attributes should be ignored when investigating clinically relevant outcomes. To enhance certainty, future research should delve into sex and gender attributes concurrently, taking into account that clinical disorders are not evenly distributed across sexes and genders. This approach would provide needed evidence to drive precision medicine and person-centered care. PROSPERO CRD42023456917. Funding: Global Brain Health Institute, Alzheimer’s Association, and Alzheimer’s Society UK Pilot Award for Global Brain Health Leaders (GBHI ALZ UK-23–971123); Canada Research Chairs Program for Neurological Disorders and Brain Health (CRC-2021-00074).

Our research team from the University of Toronto and the KITE Toronto Rehabilitation Institute, Canada, synthesized evidence from 19 observational studies involving more than 643,000 adults. Unlike previous reviews that focused on binary sex or gender categories, we examined measurable attributes of sex - such as hormone levels and polygenic scores - as well as gender identity, roles, and adherence to masculine or feminine norms, across 34 health outcomes. Our goal was to identify which aspects of sex and gender matter for  clinical decision-making.

The evidence revealed clear sex-specific health effects. Testosterone, for instance,  was linked to sexual and reproductive health, mental well-being, and certain cancers. However, differences between total and bioavailable testosterone highlight the urgent need for greater precision in measuring hormonal effects on health.

Our results also highlighted the critical role of gender norms. Adherence to masculine norms and stress from role discrepancies were linked to depression, anxiety, and cardiovascular risk in men. Research on feminine gender norms remains limited, reflecting a persistent  androcentric bias in the evidence base. Addressing this gap is essential for advancing precision medicine and equitable health care.

Our results reinforce the importance of measuring attributes of sex and gender together. Health is shaped not only by physical and physiological traits but also by peoples' roles, norms, and social relationship. To make precision medicine effective for all, future scientific research must study sex and gender jointly, rather than treating them as separate or binary categories, recognizing the diversity of both biological traits and gender expression, and that health reflects the deeply interconnected effects of sex and gender.

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