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Impact of estradiol variability and progesterone on mood in perimenopausal women with depressive symptoms

Joffe H1,2,3de Wit A1,4Coborn J1,2Crawford S5Freeman M3Wiley A1Athappilly G1Kim S1Sullivan KA1Cohen LS3Hall JE6.

J Clin Endocrinol Metab. 2019 Nov 6. pii: dgz181. doi: 10.1210/clinem/dgz181. [Epub ahead of print]





To determine whether estradiol variability, ovulatory levels of progesterone, and VMS burden are independently associated with perimenopausal depressive symptomatology.


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.


Academic medical center.


Fifty unmedicated perimenopausal women with mild-to-moderate depressive symptoms (mean Montgomery-Åsberg Depression Rating Scale [MADRS] score 15.5 ± 5.3).


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 (β= 0.11, 95% confidence interval [95%CI] [0.04 to 0.18, p=0.001]; β= -2.62 [95%CI -4.52 to -0.71, p=0.007], respectively), after accounting for higher BMI, lifetime history of depression, and stressful life events.


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.