Menopause is linked to higher rates of anxiety, depression, and sleep disruption, along with subtle losses of gray matter in brain regions involved in emotion and memory, and hormone replacement therapy (HRT) does not appear to fully offset these effects, even in otherwise healthy women.
Results from a large UK Biobank cohort study of nearly 125,000 women showed postmenopausal participants had worse mental health and sleep outcomes and small but measurable differences in the brain structure compared with premenopausal women. However, HRT was not associated with clear improvements in these outcomes, underscoring its limited role in addressing menopausal mental health symptoms.
“To our knowledge, this is the first study to investigate the effects of menopause and HRT on mental health, cognition, and brain structure in a very large sample of women,” lead author Katharina Zuhlsdorff, PhD, at the University of Cambridge, Cambridge, England, and colleagues wrote.
The study was published online on January 27 in Psychological Medicine.
Mixed Findings
Menopause is a natural hormonal transition that starts in midlife and is marked by decreased estrogen and progesterone. Many women report mood disturbances, anxiety, sleep problems, and cognitive complaints during this period. HRT is commonly used to alleviate these symptoms, but its effects on mental health, cognition, and brain structure remain unclear.
Prior studies have reported mixed findings, with some suggesting HRT has a protective effect on mood and cognition, whereas others indicate an increased risk for anxiety, depression, or dementia.
The investigators highlighted that large-scale systematic analyses are needed to clarify how menopause and HRT affected women’s psychological well-being, cognitive performance, and brain structure.
They noted that “only few large-scale studies…have investigated how mental health measures are impacted,” emphasizing the need to examine these outcomes in a population-based sample.
To better understand these associations, they analyzed data from the UK Biobank — population-based cohort that included 124,780 women with information on menopausal status, psychological symptoms, cognitive performance, and HRT use. The average age of menopause onset was 49.45 years.
Participants were categorized as premenopausal (n = 49,800), postmenopausal without HRT (n = 52,300), and postmenopausal with HRT (n = 22,800). A subset of 10,873 women also had structural MRI data, which allowed the investigators to examine gray matter volumes in regions involved in memory and emotional regulation, including the hippocampus, entorhinal cortex, medial temporal lobe (MTL), and anterior cingulate cortex (ACC).
Psychological symptoms were assessed via self-reported measures of anxiety and depression, using modified Patient Health Questionnaire and the Generalized Anxiety Disorder scale, along with sleep duration and fatigue.
Cognitive performance was evaluated through reaction time, digit span, and prospective memory tasks.
Key Findings
Compared with premenopausal women, postmenopausal women were more likely to report anxiety, depression, and insomnia (P < .0001 for all). Sleep duration was shorter and fatigue scores were higher in both postmenopausal groups (P < .0001).
Women who had used HRT reported the highest prevalence of psychological symptoms, though differences between HRT users and nonusers were modest (P < .0001).
Cognitive differences were generally small but detectable. Postmenopausal women had slower reaction times and slightly lower prospective memory scores than premenopausal women (P < .0001). The investigators did not find any notable cognitive benefit from HRT use.
“As we age, our reaction times tend to get slower — it’s just a part of the natural aging process, and it happens to both women and men. You can imagine being asked a question at a quiz — while you might still arrive at the correct answer as your younger self, younger people would no doubt get there much faster. Menopause seems to accelerate this process, but HRT appears to put the brakes on, slowing the aging process slightly,” Zuhlsdorff said in a statement.
In the MRI analyses, lower gray matter volumes were found in the hippocampus, entorhinal cortex, MTL, and ACC among postmenopausal women (P < .0001 for all). Women who used HRT had the smallest volumes in these regions, even after adjusting for age, education, lifestyle factors, and comorbidities (P < .0001).
Exploratory analyses suggested that women who initiated HRT later or had higher baseline anxiety or depression scores tended to have lower gray matter volumes (P ≤ .027), indicating that preexisting psychological factors may contribute to these structural differences.
Although the study excluded participants diagnosed with dementia, prior research suggests that HRT could be associated with an increased risk, especially with long-term use, the investigators noted.
Case-control and cohort studies from Denmark and Taiwan, as well as randomized trials, have reported a higher risk for dementia in women using estrogen plus progestin therapy, with depression potentially contributing to this risk.
In the current study, participants with an ICD10 diagnosis of dementia were excluded and there appeared to be no effect of menopause or HRT on memory, but slower reaction times were observed in postmenopausal women not on HRT.
The findings highlighted the importance of closely monitoring the cognitive health of women who are considering or taking HRT.
Need for Longitudinal Studies
Commenting on the study findings, Ciara McCabe, professor of neuroscience, psychopharmacology and mental health at the University of Reading in Reading, England, noted that while previous research has suggested a link between HRT and depression, this study indicates that HRT is more often prescribed to women who already have higher levels of depression and anxiety, challenging the idea that HRT directly causes depression.
“Longitudinal studies are still needed that track mood and brain changes over time to properly assess if HRT can improve anxiety and depression,” McCabe said in a statement from the UK nonprofit Science Media Centre.
“The effect of HRT on brain health in menopause continues to be a topic of debate, and old clinical trials like the Women’s Health Initiative have failed to answer this question. Either way, this is an important complication that millions of women experience in the UK, so deserves close attention in the future,” she added.
The study was funded by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) and the NIHR Applied Research Centre. Zuhlsdorff reported being funded by the Angharad Dodds John Bursary, Downing College, University of Cambridge, and The Foulkes Foundation Fellowship. McCabe reported having no relevant financial relationships.
https://www.medscape.com/viewarticle/menopause-mood-and-brain-structure-hrt-may-not-fully-offset-2026a100038m
