Impact of Estradiol Variability and Progesterone on Mood in Perimenopausal Women With Depressive Symptoms

Context: Women are at increased risk for depressive symptoms during the menopause transition. Changes in estradiol secretion and presence of vasomotor symptoms (VMS) contribute to perimenopausal depressive symptoms, but links with progesterone have not been investigated. Objective: To determine whether estradiol variability, ovulatory levels of progesterone, and VMS burden are independently associated with perimenopausal depressive symptomatology. Design and Intervention: Depressive symptoms, serum levels of estradiol and progesterone, and VMS frequency were assessed weekly in an 8-week observational study. Association of mood with estradiol variability, ovulatory levels of progesterone, and VMS frequency were estimated using generalized estimating equation models. Setting: Academic medical center. Patients: Fifty unmedicated perimenopausal women with mild-to-moderate depressive symptoms (mean Montgomery-Asberg Depression Rating Scale [MADRS] score 15.5 +/- 5.3). Main Outcome Measure: Depressive symptoms (MADRS score). Results: During the study, 90.0% of participants had varying estradiol levels, 51.1% had ovulatory progesterone levels, and 90% had VMS. Greater estradiol variability and absence of progesterone levels consistent with ovulation, but not VMS frequency, are associated with higher levels of depressive symptoms (beta = 0.11 [95% confidence interval (95% CI), 0.04 to 0.18; P = 0.001]; beta = -2.62 [95% CI, -4.52 to -0.71; P = 0.007], respectively), after accounting for higher body mass index, lifetime history of depression, and stressful life events. Conclusions: Increasing dysregulation of ovarian hormones, but not VMS, associates with more depressive symptom burden during perimenopause. These results suggest that perimenopausal mood instability is driven by the underlying hormonal dysregulation of the menopause transition involving changes in both estradiol and progesterone.