Abstract Changes in estrogen levels in women have been associated with increased risk for age-related neurodegenerative diseases, including Alzheimer’s disease, but the impact of exogenous estrogen exposure on the brain is poorly understood. Oral contraceptives (OC) and hormone therapy (HT) and are both common sources of exogenous estrogen for women in reproductive and post-menopausal years, respectively. Here we examined the association of exogenous sex hormone exposure with the brain’s white matter (WM) aging trajectories in postmenopausal women using and not using OC and HT (HT users: n=3,033, non-users n=5,093; OC users: n=6,964; non-users n=1,156), while also investigating multiple dMRI models. Cross-sectional brain dMRI data was analyzed from the UK Biobank using conventional diffusion tensor imaging (DTI), the tensor distribution function (TDF), and neurite orientation dispersion and density imaging (NODDI). Mean skeletonized diffusivity measures were extracted across the whole brain, and fractional polynomial regressions were used to characterize age-related trajectories for WM microstructural measures. Advanced dMRI model NODDI revealed a steeper WM aging trajectory in HT users relative to non-users, and for those using unopposed estrogens relative to combined estrogens treatment. By contrast, no interaction was detected between OC status and age effects on the diffusivity measures we examined. Exogenous sex hormone exposure may negatively impact WM microstructure aging in postmenopausal women. We also present normative reference curves for white matter microarchitectural parameters in women, to help identify individuals with microstructural anomalies.

Exogenous Sex Hormone Effects on Brain Microstructure in Women: A diffusion MRI Study in the UK Biobank