Depression in the menopause transition: cortisol circadian rhythms and sleep impairment as mechanisms of risk

Award: $38,400

The menopause transition (MT) is a vitally important, yet understudied, period of time in women’s health. Women in the MT experience significant hormonal changes (e.g., estrogen), are at a 2-4-fold increased risk for developing significant depressive symptoms, and report substantial changes in sleep health. In this project, we will examine the role of hormone variability on sleep impairment as a potential mechanism for the development of depression.

Need/Problem: The menopause transition (MT) is a critical time period in women’s health, characterized by changes in reproductive hormones (changes in estrogen), a 2-4-fold increase risk for major depression (MDD), and the emergence of significant sleep impairment. To date, experimentally controlled sleep science research in women’s health is scant.

Grant Summary: This research utilizes a randomized-control trial design to study relationships among sleep health (measured via self-report, cortisol circadian rhythms, and wrist actigraphy) and depression in the menopause transition. 

Goals and Projected Outcomes: The goal of this project is to increase our understanding of changes in women’s health during midlife. This research will provide mechanistic insight into the impact of estrogen variability on depression, cortisol circadian rhythms, and sleep impairment and form the scientific premise for a biobehavioral model to advance our understanding of mechanisms contributing to vulnerability to affective state change associated with hormonal flux.

Paul Geiger, Ph.D.

Grant Details: Women in the menopause transition (MT) are 2-4 times more likely to develop major depression compared with pre- and post-menopausal women. Prior work from our group found that greater estrogen (E2) variability predicted the emergence of clinically significant levels of depressive symptoms for women in the MT, especially in those who had more recent stressful life events. However, the mechanisms by which E2 variability increases risk for depression remains unknown. Sleep impairment (trouble falling asleep, staying asleep, waking early) is experienced by up to 60% of women in the MT, and is a contributing causal factor of depression. It was commonly believed that vasomotor symptoms (VMS) fully explained sleep problems in the MT. However, some women reporting VMS do not report sleep impairment, and some women without VMS do report sleep impairment. An alternative, though not mutually exclusive possibility, is that sleep, similar to depression, may be disrupted by E2 variability and be a mechanism of risk for depression in the MT.

Framed within a diathesis-stress model of disease, the primary objective of this research is to determine the role of estrogen variability in cortisol rhythm dysregulation and sleep impairment as mechanisms of risk for the severity of depressive symptomatology in the MT. The rationale for examining E2 variability as a diathesis for sleep problems is twofold. First, sensitivity to hormonal flux during specific reproductive events has been shown to have detrimental effects on sleep, and second, estrogen is a powerful modulator of cortisol (HPA-axis), each of which are particularly impaired in individuals experiencing stressful life events. The central hypothesis of the proposed research is that the relationship between greater E2 variability and depressive symptoms are mediated by cortisol rhythm dysregulation and sleep impairment, particularly in women experiencing stressful life events. The secondary hypothesis is that stabilization of E2 variability (with transdermal estradiol; TE) will improve cortisol circadian rhythm and, consequently, sleep and depressive symptoms.  It is acknowledged that sleep impairment and depression are inextricably linked, yet directional causality is difficult to determine. Exploratory analyses will utilize the current study’s design to examine the temporal ordering of effects between changes in depression and changes in sleep in response to TE. By examining temporal effects on sleep and depression in response to TE, we may obtain clues into the causative direction between sleep and depression in women in the MT.