Sex-specific hormonal trajectories reveal an early neuroendocrine vulnerability window preceding menopausal depressive symptoms.

Abstract

Depressive symptoms show marked sex differences in prevalence and symptom profiles, with sex hormones thought to play a key role. However, systematic evaluations of age-related hormone variation across the adult lifespan remain limited. We analyzed data from 8421 adults (4204 males and 4217 females) drawn from the National Health and Nutrition Examination Survey (NHANES) collected between 2013 and 2016. Estradiol and testosterone levels, along with depressive symptoms assessed using the Patient Health Questionnaire-9 (PHQ-9), were included in the analysis. Participants were stratified by decade-based age groups, and group means were plotted to characterize age-related hormone levels and depressive symptom severity. Differences between groups were examined using independent t-tests and one-way ANOVA with Bonferroni correction. Decade-based age stratification was used because it reflects major endocrine transition stages across adulthood. Compared to the non-depressed group, both male and female participants aged 28-57 showed altered hormone trajectories. Notably, in females, estradiol levels began to abnormally elevate in the 28-37 age range and were associated with depressive symptom severity in the 38-57 age range among the depressed group. Within the PHQ-9 item-level analysis, depressed females exhibited significantly higher fatigue and lower insomnia scores compared to depressed males (p < .05). In the non-depressed groups, males scored significantly lower on all depressive symptoms except for psychomotor changes and self-harm or suicidal ideation compared to females (all p < .05). Estradiol showed a clear midlife inflection with pronounced instability emerging between ages 28 and 47. Our findings reveal sex- and age-specific trajectories of hormones and depressive symptoms across adulthood, with early estradiol variation emerging in female and externalizing features predominating in males at distinct life stages. These previously underrecognized patterns suggest an early neuroendocrine sensitive window, underscoring the need for mechanism-focused longitudinal studies and highlighting opportunities for earlier, sex-tailored clinical strategies.