Linking Oestradiol (E2) Timing and Tempo, Brain Development, and Mental Health in Adolescent Females

Khetan, M.; Vijayakumar, N.; Tian, Y. E.; Whittle, S.

doi:10.1101/2025.04.23.650187

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bioRxiv · 10.1101/2025.04.23.650187

Linking Oestradiol (E2) Timing and Tempo, Brain Development, and Mental Health in Adolescent Females

Khetan, M.·Vijayakumar, N.·Tian, Y. E.·Whittle, S.

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Abstract

Background: Earlier timing and faster tempo of puberty have been associated with altered brain development and increased mental health symptoms in adolescents, particularly females. However, the role of oestradiol (E2) in these associations is unclear. Methods: Using longitudinal data from the US-based Adolescent Brain Cognitive Development Study SM (ABCD Study (R), we investigated whether, in females (N ~ 3k), E2 timing (at age 10) and tempo (rate of change from age 10 to 12) were prospectively associated with mental health symptoms at age 13 via structural brain development from age 10 to 12. Linear mixed-effects models and Bayesian mediation models were fitted to investigate the aims of the study. Results: Findings showed that E2 timing was not associated with mental health symptoms. However, earlier E2 timing was associated with a greater reduction in total cortical volume, total surface area, and surface area in the superior and middle temporal cortex over time. Further, a faster E2 tempo was associated with an increase in mental health symptoms, and this association was mediated by a faster reduction in total cortical volume and total surface area over time. Conclusion: Findings suggest that earlier E2 timing and faster E2 tempo contribute to accelerated development of gray matter structure in adolescent females, and for E2 tempo, such associated brain changes may partly contribute to increased mental health risk.

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Khetan, M., Vijayakumar, N., Tian, Y. E., Whittle, S.. 2025-04-23. Linking Oestradiol (E2) Timing and Tempo, Brain Development, and Mental Health in Adolescent Females. https://doi.org/10.1101/2025.04.23.650187

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