Hormone therapy linked to subtly rising depressive symptoms in older women

Older women who use hormone therapy after menopause may experience slightly greater increases in depressive symptoms over time than men of the same age, according to a longitudinal study of cognitively unimpaired adults from the Harvard Aging Brain Study and affiliated studies. The work is presented as an early, peer-reviewed accepted version of the article.

The study followed 585 participants with an average age of 71.6 years, of whom 58.3 percent were women. Among the women, 42 percent reported current or past use of post-menopausal hormone therapy, a common treatment for menopause-related symptoms including vasomotor complaints and depressive symptoms. At baseline, 7 percent of women self-reported mild to moderate depressive symptoms on the Geriatric Depression Scale, with scores between 11 and 19. The researchers used linear mixed-effect models to track how depression scores changed over time in relation to hormone therapy use.

Female hormone therapy users reported significantly greater depressive symptoms over time relative to age-matched men, with a model estimate of 0.11 (95 percent CI reported as -0.22 to -0.01; p = 0.03), an association that held even after adjusting for a history of depressive episodes. However, the same comparison between female users and female non-users did not reach statistical significance (estimate -0.10; 95 percent CI -0.21 to 0.01; p = 0.07). In the overall group, the authors conclude, female users and non-users did not differ in how their depression scores changed, and the contrast with men should be interpreted with that caveat in mind.

The most striking finding concerned brain imaging markers. White matter hyperintensity volume moderated the relationship between hormone therapy and changing depressive symptoms: in the setting of high white matter hyperintensity volume, female users reported greater depressive symptoms over time relative to men (estimate -0.09; 95 percent CI -0.18 to -0.01; p = 0.03), but not relative to female non-users (estimate -0.06; 95 percent CI -0.15 to 0.04; p = 0.28).

The authors emphasise that the findings underscore the importance of investigating menopausal treatment factors that may affect depressive symptoms in older women, and of understanding their relationship with white matter lesions. As an observational analysis of self-reported hormone therapy use in a cognitively unimpaired, largely older sample, the study cannot establish that hormone therapy causes worsening mood, and the reported differences were subtle. Further work will be needed to clarify whether white matter health identifies a subgroup of women for whom menopausal hormone treatment carries different mood-related trajectories in later life.

Subject of Research: Longitudinal associations between post-menopausal hormone therapy use and changes in depressive symptoms in cognitively unimpaired older women

Article Title: Longitudinal associations of hormone therapy and depressive symptoms in cognitively unimpaired older women

Article References: Lopez Garcia, K. A., Klinger, H. M., Munro, C. E., Properzi, M. J., Chhatwal, J. P., Yang, H.-S., Donovan, N. J., Shirzadi, Z., Schultz, A. P., Yau, W.-Y. W., Johnson, K. A., Sperling, R. A., Gatchel, J., Buckley, R. F., & Coughlan, G. T. (2026). Longitudinal associations of hormone therapy and depressive symptoms in cognitively unimpaired older women. BMC Medicine. https://doi.org/10.1186/s12916-026-05311-y

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05311-y

Keywords: hormone therapy, depressive symptoms, menopause, older women, white matter hyperintensities, Geriatric Depression Scale, Harvard Aging Brain Study, longitudinal study, Alzheimer's disease risk factors, brain imaging, APOE ε4, BMC Medicine