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Study Explores the Complex Relationship Between Menopausal Hormone Therapy and Brain Health

Recent research indicates that menopausal hormone therapy (MHT) can influence brain health, but outcomes may vary based on a woman’s surgical history, the duration of therapy, and her age at the last use of MHT.

This study, published on October 8 in a Reviewed Preprint in eLife, has garnered attention for its rigorous examination of the relationship between MHT and brain health among a substantial sample of women in the UK. The editors emphasize the critical need to better understand MHT’s effects on the brain in order to offer tailored medical assistance for women experiencing menopause.

Throughout a woman’s life, hormonal levels, particularly oestrogens and progesterone, fluctuate significantly, especially as menopause approaches. MHT is frequently prescribed to alleviate symptoms linked to these hormonal changes and has often been thought to offer protective benefits for the brain and mitigate the risk of Alzheimer’s disease, although findings in this area remain inconsistent.

Lead author Claudia Barth, who is part of the Division for Mental Health and Substance Abuse at Diakonhjemmet Hospital in Oslo, Norway, highlights, “Previous studies have shown mixed results regarding MHT and brain health, raising questions about how timing, formulation, and administration methods might affect MHT’s efficacy.” This investigation aimed to explore the relationships between various MHT parameters, different treatment strategies, genetic predispositions, and brain health metrics in women of middle to older age.

Utilizing the extensive data set from the UK Biobank—which includes anonymized genetic, lifestyle, and health information—the researchers examined nearly 20,000 women who had undergone MRI scans. These participants were classified based on their MHT usage status: current users, past users, and never users, with most being postmenopausal. The analysis focused on determining the ‘brain age gap’, which reflects the disparity between chronological age and brain age, in addition to other indicators of brain health.

The findings revealed some intriguing aspects. Women who had previously used MHT exhibited no significant distinctions in brain age when compared to those who had never used it. However, current MHT users displayed larger ‘brain age gaps’—indicating older brain ages relative to their chronological ages—compared to never-users. They also had smaller volumes in both the left and right hippocampi.

Additionally, the timing of MHT usage was crucial among past users, as those who ceased treatment at an older age after menopause experienced higher brain age gaps and reduced hippocampal volumes. The data also suggested that longer durations of MHT use correlated with similar outcomes.

Interestingly, current MHT users who had undergone surgeries to remove their womb and/or ovaries showed smaller brain age gaps compared to their counterparts without such surgical histories. The study found no significant differences in brain health effects based on attributes like dosage, active ingredients (synthetic versus bioidentical), or the delivery method (pill or patch).

The researchers investigated whether the known Alzheimer’s risk gene, APOE ɛ4, affected the relationship between MHT and brain health, but found no significant connections.

In reflecting on their findings, the authors commented that while some negative brain health indicators were linked to current MHT usage and advanced age at last use, the data does not support a broad neuroprotective role of MHT nor a tendency toward severe adverse outcomes for women’s brain health.

“Our findings indicate that there are subtle yet complex interactions between MHT use and brain health, underscoring the importance of a tailored approach to MHT administration,” Barth states. “Importantly, our analysis provides insights on population-level associations rather than guidance for individual health decisions regarding MHT.”

The authors further noted that current MHT users were generally younger than past and never-users, and a smaller percentage were postmenopausal (67% compared to 80%). This suggests that many current users may be experiencing perimenopause, a phase often accompanied by cognitive and mood-related symptoms. As such, the need for MHT could reflect evolving neurological changes during this transitional period.

Senior author Ann Marie de Lange, a Senior Research Fellow in the Department of Clinical Neurosciences at Lausanne University Hospital in Switzerland, concluded, “The impact of MHT on women’s brain health may fluctuate based on factors like timing, length of use, and surgical history. However, given the cross-sectional nature of our study, we cannot infer causality. Ongoing research into the long-term effects of MHT on brain health is essential for understanding individual risks and benefits. Women globally face significant choices regarding MHT utilization, yet the existing lack of comprehensive research hinders informed decision-making.”

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