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Older age at menopause, longer reproductive period associated with lower depression risk

Longer exposure to endogenous estrogens, as indicated by older age at menopause and longer reproductive period, was associated with lower risk for depression later in life among postmenopausal women.

“Sex discrepancies have been described in the epidemiologic studies of depression, with a doubled lifetime risk of major depression among women compared with men; this disparity is more profound during women’s reproductive years,” Marios K. Georgakis, MD, of the National and Kapodistrian University of Athens, Greece, and colleagues wrote. “Intense fluctuations of ovarian hormones observed premenstrually, during pregnancy and postpartum, and perimenopausally have been associated with depression and have been proposed as the reason for this female preponderance during the specified time windows. Estrogens are thought to exert neuroprotective actions via receptors that have been recognized in the brain.”

To assess associations between age at menopause and duration of reproductive period with risk for depression among postmenopausal women with naturally occurring menopause, researchers conducted a meta-analysis of 14 studies (n = 67,714).

Depression in postmenopausal women was inversely associated with increasing age (OR = 0.98; 95% CI, 0.96-0.99) and duration of reproductive period (OR = 0.98; 95% CI, 0.96-0.99).

Menopause at age 40 years and older was associated with a 50% decreased risk for depression, compared with premature menopause.

Analysis of studies on severe depression indicated a 5% decrease in risk for severe depression with increasing age at menopause, in 2-year increments.

Sensitivity analysis of studies that controlled for past depression indicated similar results for age at menopause.

Heterogeneity and publication bias was not evident in the main analyses, according to researchers.

“Results of this study provide a novel paradigm for understanding the potential impact of central nervous system exposure to female reproductive hormones and depression. The implication is that prior and cumulative exposure to hormones has a sustained impact on the brain, increasing vulnerability to depression years after these exposures,” Hadine Joffe, MD, MSc, of Brigham and Women’s Hospital, Boston, and Joyce T. Bromberger, PhD, of the University of Pittsburgh, Pennsylvania, wrote in an accompanying editorial. “This meta-analysis is a commendable effort to expand thinking about the role of lifetime exposure to reproductive hormones in the occurrence of postmenopausal depression and to shift our research focus to explore a new paradigm. The literature in this area would benefit from prospective studies that investigate the incidence of diagnostically confirmed depression episodes during and after the menopausal transition.” – by Amanda Oldt

Disclosure: Georgakis and colleagues report no relevant financial disclosures. Joffe reports receiving research funding from Merck and Cephalon/Teva and serving as a consultant/advisor to Mitsubishi-Tanabe, Merck, and Noven.