Increased estradiol and improved sleep, but not hot flashes, predict enhanced mood during the menopausal transition

Abstract

Background: The antidepressant effect of estrogen in women undergoing the menopause transition is hypothesized to be mediated by central nervous system effects of increasing estradiol on mood or through a pathway involving suppression of hot flashes and associated sleep disturbance. Estrogen therapy (ET) and the hypnotic agent zolpidem were selected as interventions in a three-arm, double-blind, placebo-controlled trial to distinguish the effects of estradiol, sleep, and hot flashes on depression.

Methods: Women with depressive disorders, hot flashes, and sleep disturbance were randomly assigned to transdermal 17β-estradiol 0.05 mg/d, zolpidem 10 mg/d, or placebo for 8 wk. Changes in serum estradiol, perceived sleep quality, objectively measured sleep, and hot flashes were examined as predictors of depression improvement [Montgomery-Åsberg Depression Rating Scale (MADRS)] using multivariate linear regression.

Results: Seventy-two peri/postmenopausal women with depression disorders were randomized to 17β-estradiol (n = 27), zolpidem (n = 31), or placebo (n = 14). There was no significant difference between groups in depression improvement (overall MADRS decrease 11.8 ± 8.6). Increasing estradiol (P = 0.009) and improved sleep quality (P < 0.001) predicted improved mood in adjusted models but reduced hot flashes (P = 0.99) did not. Post hoc subgroup analyses revealed that the therapeutic effect of increasing estradiol levels on mood was seen in perimenopausal (P = 0.009), but not postmenopausal, women.

Conclusions: For women with menopause-associated depression, improvement in depression is predicted by improved sleep, and among perimenopausal women, by increasing estradiol levels. These results suggest that changes in estradiol and sleep quality, rather than hot flashes, mediate depression during the menopause transition. Therapies targeting insomnia may be valuable in treating menopause-associated depression.

Fig. 1.

Study participation by treatment assignment.

Fig. 2.

Mean (±sd) changes in depression symptoms on the MADRS by treatment assignment. Change in depression symptoms did not differ between treatment groups (P = 0.12).

Fig. 3.

Correlations between improvement in depression (change in MADRS score) and change in serum estradiol level (A), change in perceived sleep quality (B), and change in subjectively measured hot flashes (C) across all study subjects. All change values represent the difference of baseline subtracted from study end.

Fig. 4.

Correlations between improvement in depression (change in MADRS score) and change in serum estradiol levels (A) and between change in MADRS score and in perceived sleep quality (B) separated by perimenopausal (□) and postmenopausal (▾) status. All change values represent the difference of baseline subtracted from study end.