A study suggests that menopausal hormone therapy (MHT) may have moderate effects on brain health, but this depends on a woman’s history of surgical interventions, duration of treatment and age at last use. The study, published as a peer-reviewed preprint in eLife, was described by the editors as an important investigation that uses a robust model of brain ageing to examine the links between hormone therapy and brain health in a large population of women in the UK. The paper addresses a topic that the editors believe is of great importance as MHT and its effects on the brain need to be better understood in order to provide effective and personalized medical support to menopausal women.
Link Between Hormone Therapy and Brain Age
Concentrations of ovarian hormones such as estrogens and progesterone fluctuate throughout a woman’s life, particularly in the years leading up to menopause when ovarian function declines. Hormone replacement therapy is often prescribed to minimize the symptoms of these fluctuations during menopause and is widely believed to protect the brain and reduce the risk of Alzheimer’s disease. However, the evidence for this is contradictory.
“The mixed results of previous studies on MHT and brain health raise the question of whether a combination of timing, formulation and route of administration could play a crucial role in the effectiveness of MHT,” explains lead author Claudia Barth, a researcher in the Department of Mental Health and Substance Abuse at Diakonhjemmet Hospital in Oslo, Norway. “In this study, the researchers investigated the associations between MHT variables, different MHT regimens, genetic factors and brain measurements in middle-aged to older women.
The researchers used data from the UK Biobank, which contains anonymized genetic, lifestyle and health-related information as well as biological samples. They analyzed data from nearly 20,000 women who had undergone MRI brain scans and were either currently receiving, had previously received or had never received hormone therapy, most of whom reported being past the menopause. They examined MRI images of the brain to determine the “brain age gap” – the difference between chronological and brain age – as well as other indicators of brain health. According to the team, the results were puzzling. In women who had received hormone therapy in the past, there was no significant difference in brain age compared to non-users. But in women currently receiving MHT, the difference between brain age and actual age was greater on average than in women who had never undergone hormone therapy. This suggests that their brains were older than their actual chronological age. They also had smaller brain volumes in the left and right hippocampus. In addition, for former patients, the age at which they last received MHT made a difference. Those who were older at the time of their last post-menopausal therapy had a larger gap between brain age and actual age, as well as a smaller hippocampal volume. Similar results were found in women who received MHT over a longer period of time.
Women on MHT who had undergone surgery to remove their uterus and/or both ovaries had a smaller deviation in brain age than women on MHT without the same surgical history. And unexpectedly, there was no difference in MHT-related variables such as dose or active ingredients, regardless of whether they were synthetic or bioidentical, or whether they were taken as a tablet or patch. The researchers also investigated whether a known risk gene for Alzheimer’s disease, known as APOE ɛ4, influenced the effect of MHT on indicators of brain health, and again found no association. In reviewing the results, the authors noted that while some minor adverse brain health characteristics were associated with current MHT therapy and older age of women at last therapy, the results did not demonstrate a general neuroprotective effect of hormone therapy, nor did they demonstrate serious adverse effects on the female brain.
Long-Term Effects of Hormone Therapy Need to be Further Investigated
According to the researchers, the results point to subtle but complex relationships between hormone therapy and brain health, and underline the need for a personalized approach to hormone therapy. Importantly, they say, these analyses provide a comprehensive overview of population-based associations, and are not intended to inform individual-level decisions regarding the benefits and risks of using hormone therapy during menopause. The authors add that the current MHT patients were significantly younger than previous as well as non-users, and a smaller proportion of them were postmenopausal (67% versus 80%), suggesting that a greater proportion of these women may have been in perimenopause, which is often associated with neurological symptoms such as cognitive decline and mood swings. The need for hormone therapy could therefore be an indicator of neurological changes during this transition, which then stabilize later in life, the authors say.
According to the researchers, these results suggest that the effect of MHT on female brain health may vary depending on factors such as timing, duration of therapy and surgical history. However, this study is a cross-sectional study and the researchers cannot establish causality. Future studies examining the long-term effects of hormone therapy on brain health are of immense importance to understand individual risk profiles and benefits.