Oestradiol and progesterone variability in adolescent females: Associations with brain structure and mental health problems

Adolescent females are at increased risk for mental health problems, and differences in pubertal hormone dynamics may help explain this vulnerability. During puberty, oestradiol (E2) and progesterone (P4) fluctuate substantially as endocrine patterns stabilise, yet little is known about how hormone variability relates to brain structure and emotional functioning during adolescence. We investigated within-individual variability in E2 and P4, measured weekly, and its relation to brain structure and mental health. Participants were 145 females (11-17 years) from the Puberty and NeuroDevelopment in Adolescents (PANDA) study in Australia. Salivary E2 and P4 were collected weekly for five weeks, with variability indexed as within-subject standard deviation. Structural MRI was acquired on the final sampling day. Mental health, including anxiety, depressive symptoms, and emotional dysregulation, was assessed using self- and parent-report measures. Linear regression and mediation analyses tested associations between hormone variability, brain structure, and mental health. Greater P4 variability was associated with smaller left thalamus volume (Cohen's d = -0.26, pFDR = 0.031). After removing an influential observation using Cook's distance, higher E2 variability was associated with fewer anxiety (d = -0.170, pFDR = 0.043) and depressive symptoms (d = -0.179, pFDR = 0.036), lower emotion dysregulation (d = -0.179, pFDR = 0.036), and smaller right hippocampus volume, particularly among premenarchal adolescents compared to postmenarchal adolescents (d = -0.192, p = 0.02). These findings indicate that hormone variability may shape brain and affective functioning in adolescent girls differently from hormone-related transitions in adulthood. Larger, replicable, and longer-term studies are needed to confirm these patterns.