Sexual dimorphism in anxiety is programmed in-utero by sex-steroids: Proof of concept using a disease-model and stress responses to COVID pandemic.

Sex differences in the psychological impact of the COVID-19 pandemic have been consistently reported, showing disproportionally high rates of anxiety/distress in women relative to men. The mechanisms underlying this sexual dimorphism remain unclear. The present study queries the potential protective role of early hyperandrogenism on brain development. A natural model of sex-steroids abnormality, classic congenital adrenal hyperplasia (CAH), was used to test this question. CAH is characterized by adrenal androgen overproduction in utero (prenatal) through the neonatal critical developmental period. An online survey collected information on subjective responses to the COVID-19 pandemic. Matched on demographic variables, 60 adults carrying a diagnosis of classic CAH and 240 adults from the general population (non-CAH) were compared on levels of anxiety/distress in the first year of the COVID-19 pandemic (May 2020-April 2021). Structural Equation Modeling was used to test the modulation by CAH status of Sex effects on anxiety/distress. Results revealed lower levels of anxiety/distress in the female CAH group compared to the other 3 groups (male CAH, female non-CAH, and male non-CAH). This finding suggests that pre-neonatal hyperandrogenism might impact the development of neural circuits underlying anxiety processes, in a way that enhances resilience to chronic stress.