The effects of sex and gender attributes on clinical outcomes: A systematic review

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 among the sexes. 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).