Analysis of nearly 125,000 UK Biobank participants reveals menopause correlates with measurable shrinkage in gray matter volumes within the medial temporal lobe and anterior cingulate cortex—brain regions essential for memory formation and emotional regulation. Women using hormone replacement therapy showed the most pronounced volume reductions, alongside higher rates of anxiety, depression, and sleep disturbances compared to untreated postmenopausal women. This counterintuitive finding likely reflects selection bias, as women prescribed HRT typically already exhibited more severe menopausal symptoms and pre-existing mental health challenges. The research adds compelling neuroanatomical evidence to emerging concerns about menopause's impact on brain health, complementing previous studies linking estrogen decline to cognitive changes and mood disorders. While the cross-sectional design cannot establish causation, the scale and specificity of regional brain changes suggest menopause represents a critical neurological transition requiring closer clinical attention. For the millions of women navigating menopause, these findings underscore the importance of comprehensive mental health monitoring during this period, regardless of HRT status. The apparent ineffectiveness of hormone therapy in preserving brain structure challenges current treatment paradigms and highlights the need for alternative neuroprotective strategies during this vulnerable life stage.