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In this conceptual review, the authors propose a novel mechanistic candidate in the etiology of depression with onset in the menopause transition (“perimenopausal depression”) involving alterations in stress-responsive pathways, induced by ovarian hormone fluctuation.

The relevant literature in perimenopausal depression, including prevalence, predictors, and treatment with estrogen therapy, was reviewed. Subsequently, the growing evidence from animal models and clinical research in other reproductive mood disorders was synthesized to describe a heuristic model of perimenopausal depression development.

The rate of major depressive disorder and clinically meaningful elevations in depressive symptoms increases two- to threefold during the menopause transition. While the mechanisms by which ovarian hormone fluctuation might impact mood are poorly understood, growing …