The role of estradiol fluctuation in the pathophysiology of perimenopausal depression: A hypothesis paper

Abstract

The menopause transition, which constitutes the five or so years surrounding the final menstrual period, has been established as a time of increased risk for depressive symptoms. While mounting research suggests that exposure to more extreme and fluctuating levels of estradiol (E2) plays a role, it remains unclear which specific trigger is most strongly implicated in the development of depressive mood: acute E2 withdrawal or extreme increases in E2. The current review summarises the literature supporting the role of each, considering research pertaining to perimenopausal depression as well as other reproductive mood disorders in which ovarian hormone change is believed to play a key role, namely premenstrual dysphoric disorder and postpartum depression. Taking together the available research pertaining to the various reproductive mood disorders, we propose that women may exhibit one of four E2 sensitivity profiles, each of which may have important implications for the expected timing and severity of depressive mood during the menopause transition: the E2-increase sensitive profile, developing depressive mood in response to elevations in E2, the E2-decrease sensitive profile, for whom E2 withdrawal triggers negative mood, the E2-change sensitive profile, characterised by mood sensitivity to E2 change in either direction, and the E2 insensitive profile for whom changes in E2 have negligible psychological effects. The evidence supporting the existence of such profiles are summarised, potential biological mechanisms are briefly highlighted, and implications for future research are discussed.