Oestradiol and Progesterone Variability in Adolescent Females: Associations with Brain Structure and Mental Health Problems

ABSTRACT Objective Adolescent females are at increased risk for adverse mental health problems, and puberty is thought to be a critical factor. Pubertal onset involves substantial variability in oestradiol (E2) and progesterone (P4), yet the impact of these hormone dynamics remains unclear. We investigated whether within-individual E2 and P4 variability across one month relates to brain structure and mental health problems in adolescent females. Methods Participants were 147 females (11–17 years) from the community-based, cross-sectional Puberty and NeuroDevelopment in Adolescents (PANDA) study in Australia. Salivary E2 and P4 were collected weekly for one month, with variability indexed as within-subject standard deviation. Structural MRI was acquired on the final sampling day. Mental health problems were assessed via self- and parent-report. Linear regression and mediation analyses tested associations between hormone variability, brain structure, and mental health, adjusting for demographics. Results Greater P4 variability was associated with smaller left thalamus volume (Cohen’s d = −0.26, pFDR = 0.031). 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 in pre-menarchal adolescents (d = −0.192, p = 0.02). Weekly reductions in E2 predicted lower positive affect (d = 0.084, p = 0.048). Conclusion These findings indicate that hormone variability may meaningfully shape brain and behavioural development in adolescent girls differently from hormone-related transitions in adulthood. Larger, replicable, and longer-term studies are needed to confirm these patterns. Oestradiol and Progesterone Variability in Adolescent Females: Associations with Brain Structure and Mental Health Problems. Muskan Khetan 1, Ye Ella Tian 2, Nandita Vijayakumar 3,4, Sarah Whittle 1,4 Centre for Youth Mental Health, University of Melbourne, Australia Department of Psychiatry, University of Melbourne, Australia Murdoch Children’s Research Institute, Australia School of Psychology, Deakin University, Australia