Inflammation and insulin resistance partially mediate the relationship between age at menopause and depression in postmenopausal women: A cross-sectional study of NHANES 2005-2018

Objective: To evaluate depression in postmenopausal women and to explore the relationship between age at menopause, hormone therapy, and depression, while also identifying potential mediators that may explain these associations. Methods: This cross-sectional study analyzed data from National Health and Nutrition Examination Survey (NHANES) (2005-2020) for women older than 60 years who completed the Patient Health Questionnaire 9 (PHQ-9) depression questionnaire (n=7,027). Exposures included age at menopause and self-reported hormone therapy; the outcome was depression severity (PHQ-9 ≥10). Covariates included sociodemographics, body mass index, medical conditions, and biomarkers (C-reactive protein, homeostatic model assessment of insulin resistance). Survey-weighted logistic regression, Bayesian modeling, and causal mediation analysis were used. Missing data were handled with multiple imputation and inverse probability weighting. Analyses were conducted with R software, with P<0.05 considered significant. Results: In this NHANES sample of postmenopausal women older than 60 years, earlier age at menopause was associated with depression (P<0.0001). Hormone therapy did not show a significant association with depression (OR=0.58, 95% CI: 0.23-1.4), while higher education levels were protective (college degree: OR=0.89, 95% CI: 0.85-0.92, P<0.001). C-reactive protein and homeostatic model assessment of insulin resistance partially accounts for the statistical association between menopause and depression (P<0.0001). Conclusion: Age at menopause is inversely associated with depression in women older than 60 years. This relationship is statistically accounted for by the role of inflammation and insulin resistance. Self-reported hormone therapy is not associated with depression in postmenopausal women.