Ovarian Hormone Fluctuation, Neurosteroids, and HPA Axis Dysregulation in Perimenopausal Depression: A Novel Heuristic Model

Objective: 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. Method: 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. Results: 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 evidence from basic and clinical research suggests that fluctuations in ovarian hormones and derived neurosteroids result in alterations in regulation of the HPA axis by gamma-aminobutyric acid (GABA). The authors' heuristic model suggests that for some women,, failure of the GABA(A) receptor to regulate overall GABA-ergic tone in the face of shifting levels of these neurosteroids may induce HPA axis dysfunction, thereby increasing sensitivity to stress and generating greater vulnerability to depression. Conclusions: The proposed model provides a basis for understanding the mechanisms by which the changing hormonal environment of the menopause transition may interact with the psychosocial environment of midlife to contribute to perimenopausal depression risk. Future research investigating this model may inform the development of novel pharmacological treatments for perimenopausal depression and related disorders, such as postpartum depression and premenstrual dysphoric disorder.