2025/06/03 by Andrew McGovern, Kristen Montgomery, Liisa A.M. Galea · 1 voice
Health Professions · Medicine · Social Sciences · #Diversity and Career in Medicine #Obesity and Health Practices #Sex and Gender in Healthcare
paper · pdf · doi:10.1111/1471-0528.18239
openalex publication_date 2025/06/03 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/28
In an era where debates over the number of genders or sexes have sparked significant public discourse, why, if there has always been an acknowledgment of at least two genders or sexes, have we not fully committed to studying both in depth? Currently, medical research has seen an outstanding commitment to sex-specific medicine for males, which is then applied to females. Within this minimal binary framework, there remain sex-biased experiences and health nuances that remain neglected, underscoring a need to invest in understanding differences that occur within sexes and genders. The time has come to challenge the binary policies which still fail women and revolutionise our approach to health research by embracing human diversity, ensuring medical research is on a path towards all individuals receiving the personalised care they deserve. Sex differences in brain disorder prevalence are well documented. Many disorders more prevalent in males manifest earlier in life, whereas disorders more common in females tend to have a later onset. Sex-related variations in disease manifestation and progression occur across a broad spectrum of disorders, not limited to neurological conditions. A large-scale Danish study examining over 1300 distinct disorders reported that females, on average, received a diagnosis 2 years later than males for the same conditions [1]. This diagnostic delay can be attributable to biological and social factors, but a significant contributor to this discrepancy is the predominance of medical knowledge and diagnostic frameworks derived from research conducted primarily on male subjects and based on male experiences. This bias is reflected in the characterisation of symptoms observed in females as “atypical,” a term used in a wide range of disorders, including those with a higher prevalence in females (posttraumatic stress disorder, depression, anxiety), indicating a systemic bias in medical research and clinical practice. The implications of such terminology are far-reaching, influencing researchers, funding agencies, publishers and individuals experiencing these symptoms. Consider the case of late-onset sporadic Alzheimer's disease (AD). Both modifiable and non-modifiable risk factors contribute to AD, with sex influencing each of these factors. Two-thirds of Alzheimer's patients are female. Furthermore, approximately 50% of Alzheimer's patients carry one or two APOEe4 alleles, and sex differences in risk are observed—females with these alleles exhibit a higher risk than males with these alleles. A recently approved FDA drug, Lecanemab, targeting AD to mitigate cognitive decline, received widespread attention. However, the differential efficacy of this treatment received far less scrutiny. The drug demonstrated greater effectiveness in males but showed limited benefit in females [2]. Additionally, it was less effective in individuals carrying two APOE4 alleles—precisely the population with the highest susceptibility to AD. Although this drug represents progress for a specific subset of patients—this selective efficacy highlights the core principle of precision medicine: drugs whose design is optimal for subpopulations. Serious side effects associated with the drug further complicate its use. Recent research has explored the profile of individuals most likely to experience these adverse effects; however, the analysis did not stratify by sex or gender [3]. This omission is significant, as understanding sex-specific side effects is critical for informed clinical decision-making. If the drug is both less effective and associated with greater risks in females, this knowledge is essential to optimising treatment strategies and patient safety. Although the absence of sex- or gender-based analyses in the aforementioned study is concerning, it reflects a broader trend across scientific literature. A comprehensive analysis conducted in 2019 revealed that although 68% of studies in neuroscience and psychiatry journals included both male and female subjects, only 5% incorporated sex as a discovery variable [4], rather than either not using it as a variable in the analyses or using it as a covariate. This omission prevents a thorough evaluation of whether sex influences outcomes. Similarly, a study focused on neuroimaging research in psychiatry found that when sex was treated as a discovery variable, 72% of studies identified sex-based differences in outcomes [5]. Additional research has demonstrated that integrating sex as a discovery variable enhances statistical power, as shown in studies on schizophrenia and asthma [6, 7]. This evidence reinforces that males cannot serve as the default model in biomedical research, given the substantial differences in disease manifestation, prevalence and biology. All nucleated cells in the body, not just in the reproductive tract, carry compositions of the X and Y chromosomes, and varying hormonal transitions can significantly influence cells to impact health outcomes and disease risk throughout life [8]. This highlights foundational differences between the sexes to show that males alone can no longer serve as the best model for clinical translation of biomedical research. Analysing sex and gender alone offers only a partial understanding of women's health, as female-specific factors significantly shape health outcomes and disease risk. These include diverse experiences, such as pregnancy, menopause, use of hormonal contraceptives or menopausal hormone therapy, all of which exert distinct effects on health outcomes far beyond reproductive organs. Despite the profound impact of female-specific health factors, a substantial research gap persists. In neuroscience, studies conducted exclusively in males outnumber female-only studies by a factor of nine [4]. Moreover, less than 2% of neuroscience research over time has addressed critical questions related to women's health. Research into female-specific experiences provides critical insights into the development of brain disorders (Box 1). For example, studying the impact of pregnancy on brain health offers insights into both short- and long-term outcomes on brain health [9]. Although previous pregnancies are associated with signs of reduced brain ageing [10], other studies have linked pregnancy experience to an increased risk of Alzheimer's disease. Our group recently found that the impact of previous pregnancies on ageing biomarkers varies depending on an individual's genetic risk for Alzheimer's disease [9]. These findings underscore the complexity of reproductive history's influence on brain ageing and highlight the importance of considering both genetic and experiential factors in understanding women's brain health and disease susceptibility. Perinatal depression encompasses multiple subtypes. Research has identified distinct patterns, including depression onset restricted to pregnancy, early in the postpartum and/or in late postpartum [11]. Biomarker profiles undergo significant fluctuations across these stages; thus, recognising and delineating these subtypes is pivotal for advancing precision medicine approaches to perinatal depression. This illustrates that understanding health and disease requires more than binary comparisons between sexes; it necessitates examining the heterogeneity within sexes and genders, including consideration of sex-specific experiences. Diversity within biological and social categories must be appreciated to develop nuanced and effective medical interventions. Despite its critical importance, women's health research remains significantly underfunded in the United States, Canada and globally [12]. The consequences of this neglect are profound. The lack of sex- and gender-specific research leads to delayed diagnoses, representing missed opportunities for timely interventions, often critical for achieving optimal outcomes. Furthermore, insufficient investment slows the implementation of precision medicine, ultimately resulting in preventable mortality and broader societal costs. A 2024 report from the World Economic Forum underscores the economic impact of this disparity, estimating that appropriate investment in women's health research could save the global economy 1 trillion annually. This highlights not only the scientific and medical imperatives but also the substantial economic benefits of prioritising equitable research practices. To address this disparity we must first and foremost, increase investment in women's health research. However, in addition to funding, it is crucial to raise awareness about the ongoing underfunding, undervaluation and lack of focus on women's health research. Organisations such as the BioInnovation Institute and the American Association for the Advancement of Science (AAAS), which have sponsored and hosted events on this critical issue, deserve commendation for their efforts in highlighting these challenges. The evidence is clear: investing in women's health research is not just about equity—it is a scientific and economic imperative. By including the diversity within sexes and genders, we can unlock new discoveries that advance medicine for all. With a potential trillion-dollar impact on the global economy, the time for transformative change in medical research is now. Only through change in our approach can we ensure that medicine truly serves its purpose: improving health outcomes for every individual. L.A.M.G. conceived the outline of the commentary. L.A.M.G., K.M., and A.J.M. synthesised the initial draft of the manuscript. All authors reviewed and edited the final draft. All authors approved the submitted version. The authors have nothing to report. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.