Increasing dysregulation of ovarian hormones, including varying levels of estradiol and low levels of progesterone, is associated with greater depressive symptom burden during perimenopause than the presence of vasomotor symptoms (VMS), a study in the Journal of Clinical Endocrinology and Metabolism suggests.

A total of 50 unmedicated women between the ages of 35 and 56 years (mean age, 48.4 ± 3.9 years) with mild-to-moderate depressive symptoms were enrolled at the Massachusetts General Hospital and Brigham and Women’s Hospital. The mean Montgomery-Åsberg Depression Rating Scale (MADRS) score was 15.5 ± 5.3. The investigators assessed each patient’s depressive symptoms, estradiol and progesterone serum levels, and VMS frequency each week for a total of 8 weeks.

The daily subjective VMS were assessed with a self-reported diary, whereas liquid chromatography-mass spectrometry and chemiluminescence immunoassays were used to measure serum levels of estradiol and progesterone, respectively. The severity of depressive symptoms was measured with the 10-item MADRS, which included a score range between 0 and 60. Scores on the MADRS between 7 and 19 as well as 20 to 30 identify mild and moderate depression, respectively.

Continue Reading

At baseline, the median follicle-stimulating hormone level was 24.8 (interquartile range [IQR], 6.9–54.4) IU/L, and the median estradiol level was 83.0 (IQR, 41.0–148.0) pg/ml. Approximately 87.5% of participants reported VMS at baseline. Additionally, 87.3% of patients reported depressive symptoms that were subthreshold for a current major depressive episode. The MADRS scores remained in the mild-to-moderate range at most assessments during the study.

Estradiol exceeded the detectable threshold ≥1 time during the study in 90% of patients, and 93% of patients had detectable estradiol levels during each study visit. In an analysis adjusted for higher body mass index, lifetime depression history, and stressful life events, higher levels of depressive symptoms were associated with greater variability in estradiol (β=0.11; 95% CI, 0.04-0.18; P =.002) and the absence of progesterone levels that was consistent with ovulation (β=-2.68; 95% CI, −4.10 to −1.27; P <.001). The frequency of VMS was not associated with high depressive symptoms.

Limitations of the study included its observational nature and the performance of hormone assessments only once per week, which could have missed all ovulatory cycles.

The researchers noted that “the highly variable and unpredictable reproductive hormone dynamics during the perimenopause explain, at least in part, the variability in depressive symptoms even within an individual.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Joffe H, de Wit A, Coborn J, et al. Impact of estradiol variability and progesterone on mood in perimenopausal women with depressive symptoms. J Clin Endocrinol Metab. 2020;105(3):e642-e650.