The Impact of Estradiol Dynamics During the Menopause Transition on Depression Risk: A Narrative Review of...

The menopausal transition (MT) is linked to the development of burdensome symptoms that have substantial adverse impacts on women. Depression risk specifically stands out given its association with adverse impacts on quality of life, higher health care utilization, and reduced occupational functioning. Explorations into the pathophysiology of depression risk during MT have focused largely on the role of estrogen dynamics, specifically estradiol (E2), the most neuroactive form of estrogen, and whether changes in E2 across MT impact brain health. In this narrative review, we describe how E2 dynamics across MT modulate neurobiological processes to confer risk for depressive symptoms and perimenopausal-onset major depressive episode (PO-MDE). First, we examine changing E2 dynamics characteristic of MT and what is known about their clinical impacts on brain health, focusing on patterns of E2 release that underlie PO-MDE, as well as how supplementary E2 treatment informs our understanding of E2's role in the pathogenesis of this illness. Next, we explore potential mechanisms by which E2 dynamics may impact neurobiological processes to confer risk for depression. This is accomplished through examination of E2's neuromodulatory activity on the following domains: 1) neurotransmitter signaling, 2) neuroimmune function, 3) brain glucose metabolism, and 4) synaptogenesis. We also consider how findings may inform treatment and potential future directions in research.