Sex and gender in neurodevelopmental conditions

Abstract

Health-related conditions often differ qualitatively or quantitatively between individuals of different birth-assigned sexes and gender identities, and/or with different gendered experiences, requiring tailored care. Studying the moderating and mediating effects of sex-related and gender-related factors on impairment, disability, wellbeing and health is of paramount importance especially for neurodivergent individuals, who are diagnosed with neurodevelopmental conditions with uneven sex/gender distributions. Researchers have become aware of the myriad influences that sex-related and gender-related variables have on the manifestations of neurodevelopmental conditions, and contemporary work has begun to investigate the mechanisms through which these effects are mediated. Here we describe topical concepts of sex and gender science, summarize current knowledge, and discuss research and clinical challenges related to autism, attention-deficit/hyperactivity disorder and other neurodevelopmental conditions. We consider sex and gender in the context of epidemiology, behavioural phenotypes, neurobiology, genetics, endocrinology and neighbouring disciplines. The available evidence supports the view that sex and gender are important contributors to the biological and behavioural variability in neurodevelopmental conditions. Methodological caveats such as frequent conflation of sex and gender constructs, inappropriate measurement of these constructs and under-representation of specific demographic groups (for example, female and gender minority individuals and people with intellectual disabilities) limit the translational potential of research so far. Future research and clinical implementation should integrate sex and gender into next-generation diagnostics, mechanistic investigations and support practices.

Fig. 1 |. Why are sex and gender important for neurodevelopmental conditions?

Sex-related biological attributes (blue) and, to a lesser extent, gender-related sociocultural factors (green) serve specific roles in moderating and mediating the sex-differential likelihood of the emergence of neurodevelopmental conditions^,,,, presumably explaining the male preponderance in prevalence, sex-moderated and sex-specific aetiological factors, and converging mechanisms of neurodivergent development and sex differentiation (such as overlapping downstream molecular pathways and neuroendocrine–immune mechanisms). Sex-related biological and gender socialization mechanisms also converge with mechanisms shaping the lifespan development of neurodivergent individuals^,. Sex-related and gender-related attributes also influence how neurodevelopmental conditions are diagnosed and how multilevel phenotypic presentations vary among individuals^,. Specifically, these attributes moderate or mediate the behavioural and cognitive manifestations of neurodevelopmental and co-occurring health conditions, account for developmental heterogeneity, shape (and are shaped by) brain development and neurodivergent biology, and impact how and when neurodevelopmental conditions are recognized and diagnosed (especially owing to implicit and explicit gender biases, gender role expectations and gendered stereotypes of neurodivergent presentations). Findings and reflections then drive the nosological evolution and the operationalization of the diagnostic criteria for neurodevelopmental conditions iteratively. Ultimately, new knowledge generated by sex-informed and gender-informed research will have a clinical impact in reducing recognition and diagnostic biases, and in enabling the development and evaluation of sex-specific and tailored biological interventions based on sex-informed neurodivergent biology, and the design and implementation of gender-aware and gender-informed care and support for neurodivergent individuals of all sexes and genders.

Fig. 2 |. Simplified schema of the influences of sex-related and gender-related attributes on brain development.

Visualization of different levels at which sex-related and gender-related attributes influence brain development, interacting with environmental factors. Sex-related attributes can influence brain development before or shortly after birth and throughout life, whereas the influence of gender-related attributes occurs after birth and throughout the lifespan. SRY encodes sex-determining region Y protein, which stimulates male gonadal development and fetal testosterone production. NLGN4Y encodes neuroligin-4 and is a candidate autism gene. F, females; M, males; SCA, sex chromosome aneuploidies; XCI, X chromosome inactivation; ↑, factor increases the likelihood of developing and/or presenting neurodevelopmental conditions; ↓, factor decreases the likelihood of developing and/or presenting neurodevelopmental conditions. ^aSee Fig. 1 for more examples of sex-related and gender-related attributes.