| Title: | Menopausal hormone therapy and the female brain: Leveraging neuroimaging and prescription registry data from the UK Biobank cohort |
| Journal: | eLife |
| Published: | 29 May 2025 |
| DOI: | https://doi.org/10.7554/elife.99538.3 |
Publication 15167
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
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 younger gray matter brain age relative to MHT users without such history. We found no associations by APOE ε4 status and with other MHT variables. 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). </p>
Ovarian hormones, including oestrogens and progesterone, fluctuate throughout each menstrual cycle, during and after pregnancy, and in the years leading up to menopause when ovarian function begins to decline. During these transitional years, up to 80% of women will experience symptoms such as hot flashes and night sweats, which are believed to stem from the brain. Menopausal hormone therapy (MHT) often contains low doses of estrogens with or without progesterone and is commonly prescribed to minimize menopausal symptoms. MHT is believed to protect the brain and reduce the risk of Alzheimer's disease; however, the evidence supporting this claim is conflicting. Furthermore, additional research is necessary to evaluate the risks and benefits of MHT on brain health. It remains unclear whether other factors, including a genetic predisposition to Alzheimer's disease, the age at which MHT begins, the formulation, and the route of administration (e.g., pills or a transdermal patch), affect the impact of MHT on the brain. Addressing these questions is crucial to inform clinical decision-making regarding the prescription of MHT and to subsequently enhance women's brain health during and beyond the menopause transition. Barth et al. analyzed brain imaging data as well as data about lifestyle and demographic factors and histories of gynecological surgeries, of over 20,000 current, past, and never users of MHT from the UK Biobank cohort. As a proxy for brain health, they calculated the so-called 'brain age gap', which refers to the difference between a person's actual chronological age and their estimated brain age calculated from brain imaging data using machine learning; e.g., if someone's chronological age is 50 years and their predicted brain age is 45, the brain age gap is -5 years. A negative brain age gap indicates a 'younger-looking' brain, while a positive brain age gap suggests a brain that appears 'older'. Barth et al. further looked at the volume of the hippocampus, a brain region important for memory, learning and emotion regulation. They found that women who were current MHT users had an 'older looking brain' than women who had never taken MHT. The volume of the hippocampus was also smaller. In past users, the age at which MHT was last taken also made a difference. Those who were older at the time of their last use after menopause had an "older looking" brain and lower hippocampal volumes. Similar results were found for women who took MHT for longer. However, women on MHT who had undergone surgery to remove their womb and/or both ovaries had a 'younger looking brain' than women on MHT without similar surgical histories. Interestingly, factors such as a genetic risk for Alzheimer's disease, differences in formulations, or methods of administration did not appear to affect brain health in this study. The findings of Barth et al. suggest that MHT does not have a general neuroprotective effect, nor does it lead to severe adverse effects on brain health. Instead, the impact of MHT on the brain may be influenced by various factors, including age, duration of use, and past surgical history. However, since the study is cross-sectional, meaning it was conducted at a single point in time, direct causality cannot be established. Future research examining the long-term impact of MHT on brain health is crucial for understanding individual risk profiles and benefits. Women around the world are faced with critical decisions regarding MHT use, yet the current lack of comprehensive research leaves them without the necessary evidence to make informed choices.</p>
6 Authors
- Claudia Barth
- Liisa AM Galea
- Emily G Jacobs
- Bonnie H Lee
- Lars T Westlye
- Ann-Marie G de Lange
1 Application
| Application ID | Title |
|---|---|
| 27412 | Boosting the power of GWAS using novel statistical tools |
Enabling scientific discoveries that improve human health