Menopause represents a major psychosocial and biological transition for women, characterized by the cessation of ovarian hormone production and symptoms such as fatigue, sleep disturbances, anxiety, and memory difficulties. Research indicates that there is a connection between menopause and elevated risk of mood disorders and changes in brain structure, specifically in regions related to memory and emotional regulation. Hormone replacement therapy (HRT) is commonly used to alleviate menopausal symptoms, although its effects on mental health and cognition remain debated. Some studies report the benefits of HRT, while others indicate potential risks like increased anxiety and depression.
The aim of this study was to assess how menopause and HRT use are linked with mental health, sleep, cognition, and brain structure in a large population-based cohort. The study compared pre-menopausal women, post-menopausal women who had never used HRT, and post-menopausal women who had used HRT, focusing on measures of depression, anxiety, sleep quality, cognitive performance, and gray matter volume in key brain regions.
Data were collected from the UK Biobank, which includes 124,780 women (mean age = 53.7 ± 8.1 years) after exclusion of participants with dementia, hysterectomy, very early menopause, or incomplete data. The sample included 49,772 pre-menopausal women (mean age = 45.9 years), 52,252 post-menopausal women not using HRT (mean age = 58.2 years), and 22,756 post-menopausal women using HRT (mean age = 60.4 years). Mental health results involved GP and psychiatrist visits for anxiety or depression, self-reported symptom scales (modified patient health questionnaire-4 [PHQ-4] and generalized anxiety disorder [GAD] measures), antidepressant/anxiolytic use, and International Classification of Diseases, 10th Revision (ICD-10) diagnoses. Sleep measures involved insomnia, tiredness, and sleep duration. Cognitive performance was evaluated using reaction time, prospective memory, and digit-span tasks. About 10,873 women underwent magnetic resonance imaging (MRI) scan, and gray matter volumes of the hippocampus, entorhinal cortex (EC), and anterior cingulate cortex (ACC) were extracted. Statistical analyses used linear and generalized linear models adjusted for age, education, income, body mass index (BMI), smoking status, time since menopause, HRT duration, and relevant clinical covariates.
Post-menopausal women showed worse mental health results than pre-menopausal women in many measures. The likelihood of GP visits for nerves, anxiety, or depression differed significantly between groups (F(2,124,762) = 263, p < 0.0001), with both post-menopausal groups reporting increased levels compared to pre-menopausal women, and the HRT group reporting the highest levels. Similar group differences were observed for psychiatrist visits (F(2,124,762) = 84.7, p < 0.001). Modified PHQ-4 scores showed a strong group effect (F(2,118,281) = 748, p < 0.0001) with higher depressive symptoms in post-menopausal groups, specifically in HRT users. Anxiety scores followed the same pattern. ICD-10 diagnoses of anxiety were significantly more common in post-menopausal women on HRT (χ² = 27.2, p < .00001).
Sleep disturbances were more prevalent after menopause. Insomnia showed a robust group effect (F(2,124,762) = 803, p < 0.0001) with increased levels in both post-menopausal groups. Tiredness was highest in the HRT group F(2,124,761) = 153, p < 0.0001). Sleep duration decreased in post-menopausal women regardless of HRT use (F(2,124,761) = 224, p < 0.0001). Cognitive performance was largely preserved, although reaction time differed modestly by group (F(2,124,259) = 4600, p < 0.0001), with slower responses in post-menopausal women not using HRT compared with pre-menopausal women.
Neuroimaging analyses revealed significant gray matter reductions after menopause. Hippocampal volume differed by group (F(2,9,218) = 88.1, p <0.0001), with reductions observed in both post-menopausal groups and greatest in HRT users. Similar patterns were found in the EC (F(2,9,214) = 9.82, p < 0.0001) and ACC (F(2,9,214) = 70.4, p < 0.0001).
In conclusion, this study highlights that menopause adversely affects mental health, sleep quality, and gray matter volume in brain regions associated with memory and emotion, while cognitive performance remains largely stable. Post-menopausal women using HRT showed higher anxiety, depression, and brain volume reductions, potentially reflecting pre-existing vulnerabilities rather than direct effects of HRT. These findings underscore the complex interactions between menopause and HRT and highlight the importance of assessing mental health prior to therapy, emphasizing the need for personalized support for women during menopause.
Reference: Zuhlsdorff K, Langley C, Bethlehem R, et al. Emotional and cognitive effects of menopause and hormone replacement therapy. Psychol Med. 2026;56:e24. doi:10.1017/S0033291725102845
