Summary: Menopausal hormone therapy (MHT) shows complex, context-dependent associations with brain health. In a large UK Biobank study, current MHT users exhibited slightly older brain age estimates and reduced hippocampal volumes compared with women who never used MHT, while past users did not differ significantly from never-users. The findings suggest that age at last use, duration of MHT, and prior gynecological surgery influence these associations.

Women who stopped MHT at an older age or who used it for longer periods tended to have larger brain age gaps. Overall, the results point to the need for individualized decisions about MHT that take into account timing, duration, and surgical history when assessing brain health.

Key Facts:

MHT’s relationship with brain health varies by age, treatment duration, and surgical history.
Current MHT users had modestly higher brain age gaps and smaller hippocampal volumes than never-users.
Personalized MHT decisions are needed because effects on the brain are subtle and complex.

Source: eLife

Overview: This study evaluates how menopausal hormone therapy (MHT) relates to brain structure and estimated brain age across a large sample of middle- to older-aged women in the UK Biobank. The analysis focuses on brain age gap measures derived from MRI, hippocampal volumes, white matter hyperintensities, and how these measures vary with MHT use, timing, duration, formulation, and prior surgical history.

This shows a woman looking at brain scans. — Women who were current MHT users had, on average, higher grey- and white-matter brain age gaps—indicating brains that appeared older than chronological age—than women who had never taken MHT. Credit: Neuroscience News

Ovarian hormones such as estrogens and progesterone change across a woman’s life and fluctuate markedly during the transition to menopause. MHT is commonly prescribed to ease menopausal symptoms and has been proposed to protect cognitive function and reduce Alzheimer’s disease risk, but prior research has produced mixed results.

Lead author Claudia Barth and colleagues note that inconsistencies across past studies raise questions about whether factors like timing of initiation, treatment duration, formulation, and route of administration alter MHT’s impact on the brain. This study aimed to examine these variables together with genetic risk (APOE ε4) and detailed neuroimaging measures.

Researchers analyzed data from the UK Biobank, a resource containing de-identified genetic, lifestyle, clinical, and imaging information. The sample included 19,846 women who had MRI brain scans and reported current, past, or no use of MHT; most participants were postmenopausal. The investigators derived tissue-specific brain age gap (BAG) estimates for gray matter (GM) and white matter (WM) from T1-, T2- and diffusion-weighted images and measured hippocampal and white matter hyperintensity (WMH) volumes.

Main findings showed that current MHT users had modestly higher GM and WM brain age gaps—indicating their brains appeared older than their chronological age—and smaller left and right hippocampal volumes compared with women who had never used MHT. In contrast, past MHT users did not differ significantly from never-users on these measures.

Among past users, two variables stood out: age at last MHT use and total duration of use. Women who were older when they stopped MHT after menopause, and those who used MHT for longer periods, tended to have larger brain age gaps, increased WMH volumes, and smaller hippocampi. Interestingly, women on MHT who had undergone hysterectomy with or without bilateral oophorectomy showed lower GM brain age gaps compared with MHT users who had not had these surgeries.

The investigators examined whether MHT formulation, active ingredient, dose, or route of administration (oral versus transdermal) explained these differences and found no robust associations after correction for multiple comparisons. They also tested for interactions with APOE ε4, the major genetic risk factor for Alzheimer’s disease, but found no evidence that APOE ε4 status modified the associations between MHT and the imaging measures.

The authors emphasize that effects were generally modest—for example, the largest group difference corresponded to roughly nine months of brain-age difference—and that cross-sectional data cannot establish causality. They also observed that current MHT users in the sample were, on average, younger and less often postmenopausal than past and never-users, suggesting a higher proportion of perimenopausal symptomatic women among current users. This raises the possibility that MHT use could correlate with transient neurological symptoms during the menopausal transition that later stabilize.

In summary, this population-level study indicates subtle and nuanced relationships between menopausal hormone therapy and brain health outcomes such as brain age gap and hippocampal volume. The findings suggest that timing of discontinuation, cumulative exposure, and prior gynecological surgery influence these associations, while formulation, dose, and APOE ε4 status appear less decisive in this dataset.

The researchers conclude that future longitudinal studies are essential to determine whether observed associations reflect causal effects of MHT, the underlying menopausal transition, or selection factors related to who receives MHT. Such work will be important for developing individualized, evidence-based guidance on MHT use that considers potential benefits and risks for brain health.

About this HRT and brain health research news

Author: Emily Packer
Source: eLife
Contact: Emily Packer – eLife
Image: The image is credited to Neuroscience News

Original Research: Open access. “Menopausal hormone therapy and the female brain: leveraging neuroimaging and prescription registry data from the UK Biobank cohort” by Claudia Barth et al., eLife

Abstract

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

Background and Objectives

Menopausal hormone therapy (MHT) is often assumed to be neuroprotective, yet empirical findings have been inconsistent. This study provides a comprehensive evaluation of MHT use and brain characteristics in middle- to older-aged women from the UK Biobank. It integrates prescription information, APOE ε4 genotype, and MRI-derived measures including tissue-specific gray and white matter brain age gap (BAG), hippocampal volumes, and white matter hyperintensity (WMH) volumes.

Methods

The analysis included 19,846 women with magnetic resonance imaging data: current-users (n = 1,153; mean age 60.1 ± 6.8 years), past-users (n = 6,681; mean age 67.5 ± 6.2 years), and never-users (n = 12,012; mean age 61.6 ± 7.1 years). For a sub-sample of 538 participants, primary care prescription records were available. Brain measures were derived from T1-, T2- and diffusion-weighted images. Regression models tested associations between brain measures and MHT variables such as user status, age at initiation, dosage and duration, formulation, route of administration, type (bioidentical vs synthetic), and active ingredient. The study also compared MHT users with and without a history of hysterectomy and/or bilateral oophorectomy and examined interactions with APOE ε4 status.

Results

Compared with never-users, current MHT users showed significantly higher GM and WM BAG—indicating older-appearing brain tissue—and smaller left and right hippocampal volumes; past users did not differ significantly from never-users. Effect sizes were modest, with the largest group difference equivalent to approximately 0.77 years (about nine months) for GM BAG. No significant associations were found between age at MHT initiation and the imaging measures. However, longer duration of use and older age at last use after menopause were associated with higher GM and WM BAG, larger WMH volume, and smaller hippocampal volumes. MHT users who had a hysterectomy with or without bilateral oophorectomy showed lower GM BAG than MHT users without this surgical history. Although carriers of two APOE ε4 alleles had smaller hippocampal volumes compared to non-carriers, there were no interactions between APOE ε4 and MHT variables. In the prescription sub-sample, detailed MHT variables were not significantly associated with brain measures after multiple-comparisons correction.

Discussion

These results indicate that population-level associations between MHT use and female brain health may depend on duration of use and past surgical history. The study underscores the importance of longitudinal research to determine causal relationships and to clarify how menopause-related neurological changes and MHT use interact. Improved evidence is needed to inform individualized, precision-based guidance on MHT and brain health.