Association of premature natural and surgical menopause with incidence of depression requiring hospitalization: a prospective cohort study.

Background: Premature menopause is associated with depression in postmenopausal women. However, current evidence ignores the differences between premature natural and surgical menopause, and there is a lack of exploration of the mechanisms underlying the association between premature menopause and depression.

Objective: To examine the association of premature natural and surgical menopause with incidence of depression requiring hospitalization, and to evaluate whether frailty and menopausal hormone therapy are significant factors contributing to a higher incidence of depression requiring hospitalization associated with premature natural and surgical menopause, in comparison to women who experience menopause after age 40.

Study Design: This cohort included 139,691 postmenopausal women from the UK Biobank, 44,734 of whom participated the 7-year online mental health survey. Reproductive histories were obtained at enrollment. Depression requiring hospitalization was identified based on electronic health records and the Patient Health Questionnaire-9. Cox proportional hazard models and Poisson regression models were fitted.

Results: During a median (interquartile range) follow-up of 12.53 (11.71-13.25) years, 7563 participants (5.41%) developed depression requiring hospitalization. In the fully adjusted model, compared with women who experienced menopause >40, the hazard ratios (95% confidence intervals) of those with premature natural and surgical menopause for depression requiring hospitalization were 1.27 (1.17-1.38) and 1.76 (1.43-2.16), respectively. Similar findings were observed in the association of premature natural (risk ratio=1.17, 95% confidence interval: 1.00-1.39) and surgical menopause (risk ratio=1.62, 95% confidence interval: 1.05-2.51) with depression as measured by the Patient Health Questionnaire-9 score. An inverse dose-response relationship was observed in the analysis of alternate age thresholds and depression requiring hospitalization. When premature natural menopause was compared with women who experienced menopause >40, the proportion of the mediating effect of frailty and menopausal hormone therapy on depression requiring hospitalization was 27.43% (9.53%-229.00%) and 65.15% (45.57%-136.00%), respectively. When premature surgical menopause was compared with women who experienced menopause >40, the proportion of the mediating effect of frailty and menopausal hormone therapy on depression requiring hospitalization was 8.30% (2.59%-34.00%), 42.90% (27.96%-81.00%), respectively.

Conclusion: Premature menopause, especially surgical premature menopause, is significantly associated with depression requiring hospitalization in women. Frailty and adjustment of hormone therapy strategies during menopause may be potential targets for intervention.