Traumatic Brain Injury Associated with Altered Corpus Callosum Microstructure in Females: Exploring the Roles of Menopause Timing and Hormone Therapy in UK Biobank

Abstract Background Traumatic brain injury (TBI) has lasting effects on white matter, yet sex-specific factors such as menopause timing and hormone replacement therapy (HRT) may modulate these outcomes in females. Objectives To investigate how TBI, menopause timing, HRT use, and reproductive history relate to corpus callosum white matter microstructure in female UK Biobank participants. Design Cross-sectional analysis of UK Biobank diffusion MRI data using propensity score matching to compare females with TBI to controls. Methods We analyzed diffusion MRI data from females with and without TBI. Corpus callosum fractional anisotropy (FA), mean diffusivity (MD), and isotropic volume fraction (ISOVF) were assessed. TBI effects were examined across pre- and post-menopausal groups, accounting for HRT use, duration, and reproductive factors. Results Females with TBI (n=363) exhibited widespread corpus callosum alterations compared to propensity-matched controls (n=10,128), with reduced FA across all regions (genu: β=-0.006, FDR p=0.027; body: β=-0.006, FDR p=0.002; splenium: β=-0.004, FDR p=0.009) and elevated MD in anterior regions (genu: FDR p=0.001; body: FDR p=0.002). TBI sustained before menopause was associated with significantly lower splenium FA (β=-0.010, p=0.031) and higher body MD (β=0.000019, p=0.021) compared with TBI sustained after menopause and controls. HRT use did not modify TBI-related alterations in primary analyses. However, among HRT users (n=3,108), a significant TBI×duration interaction emerged for genu MD (β=2.00×10 −6 , p=0.0295), indicating that the effect of HRT duration on white matter microstructure differed between TBI cases and healthy females. Reproductive factors (parity, reproductive lifespan) independently predicted some white matter measures but did not confound TBI, menopause timing, or HRT associations. Conclusions TBI-related white matter changes in females are influenced by menopause timing and hormonal exposure, with HRT effects dependent on duration and injury context. These findings highlight the importance of sex- and hormone-specific approaches in TBI research and the need for longitudinal studies to clarify mechanisms and potential interventions.