Menopausal hormone therapy and the female brain: Leveraging neuroimaging and prescription registry data from the UK Biobank cohort.

Background: Menopausal hormone therapy (MHT) is generally thought to be neuroprotective, yet results have been inconsistent. Here, we present a comprehensive study of MHT use and brain characteristics in females from the UK Biobank. Methods: 19,846 females with magnetic resonance imaging data were included. Detailed MHT prescription data from primary care records was available for 538. We tested for associations between the brain measures (i.e. gray/white matter brain age, hippocampal volumes, white matter hyperintensity volumes) and MHT user status, age at first and last use, duration of use, formulation, route of administration, dosage, type, and active ingredient. We further tested for the effects of a history of hysterectomy ± bilateral oophorectomy among MHT users and examined associations by APOE ε4 status. Results: Current MHT users, not past users, showed older gray and white matter brain age, with a difference of up to 9 mo, and smaller hippocampal volumes compared to never-users. Longer duration of use and older age at last use post-menopause was associated with older gray and white matter brain age, larger white matter hyperintensity volume, and smaller hippocampal volumes. MHT users with a history of hysterectomy ± bilateral oophorectomy showed Conclusions: Our results indicate that population-level associations between MHT use and female brain health might vary depending on duration of use and past surgical history. Funding: The authors received funding from the Research Council of Norway (LTW: 223273, 249795, 273345, 298646, 300768), the South-Eastern Norway Regional Health Authority (CB: 2023037, 2022103; LTW: 2018076, 2019101), the European Research Council under the European Union's Horizon 2020 research and innovation program (LTW: 802998), the Swiss National Science Foundation (AMGdL: PZ00P3_193658), the Canadian Institutes for Health Research (LAMG: PJT-173554), the Treliving Family Chair in Women's Mental Health at the Centre for Addiction and Mental Health (LAMG), womenmind at the Centre for Addiction and Mental Health (LAMG, BHL), the Ann S. Bowers Women's Brain Health Initiative (EGJ), and the National Institutes of Health (EGJ: AG063843).