Effects of Estradiol Withdrawal on Mood in Women With Past Perimenopausal Depression: A Randomized Clinical Trial

Abstract

Importance: Perimenopause is accompanied by an increased risk of new and recurrent depression. The coincidence of declining ovarian function with the onset of depression led to the inference that "withdrawal" from physiologic estradiol levels underpinned depression in perimenopause. To our knowledge, this is the first controlled systematic study to directly test the estrogen withdrawal theory of perimenopausal depression (PMD).

Objective: To examine the role of estradiol withdrawal in PMD.

Design, setting, and participants: Initial open-label treatment with estradiol followed by randomized, double-blind, placebo-controlled, parallel-design evaluation of continued estradiol treatment was evaluated at an outpatient research facility at the National Institutes of Health Clinical Center. An intent-to-treat analysis was performed between October 2003 and July 2012. Participants included asymptomatic postmenopausal women with past PMD responsive to hormone therapy (n = 26) and asymptomatic postmenopausal women with no history of depression (n = 30) matched for age, body mass index, and reproductive status who served as controls. Data were analyzed between November 2012 and October 2013 by repeated-measures analysis of variance.

Interventions: After 3 weeks of open-label administration of transdermal estradiol (100 µg/d), participants were randomized to a parallel design to receive either estradiol (100 µg/d; 27 participants) or matched placebo skin patches (29 participants) for 3 additional weeks under double-blind conditions.

Main outcomes and measures: Center for Epidemiologic Studies-Depression Scale and 17-item Hamilton Depression Rating Scale (completed by raters blind to diagnosis and randomization status), self-administered visual analog symptom ratings, and blood hormone levels obtained at weekly clinic visits.

Results: None of the women reported depressive symptoms during open-label use of estradiol. Women with past PMD who were crossed over from estradiol to placebo experienced a significant increase in depression symptom severity demonstrated using the Center for Epidemiologic Studies-Depression Scale and 17-item Hamilton Depression Rating Scale, with mean (SD) scores increasing from estradiol (ie, 2.4 [2.0] and 3.0 [2.5]) to placebo (8.8 [4.9] and 6.6 [4.5], respectively [P = .0004 for both]). Women with past PMD who continued estradiol therapy and all women in the control group remained asymptomatic. Women in both groups had similar hot-flush severity and plasma estradiol levels during use of placebo.

Conclusions and relevance: In women with past PMD that was previously responsive to hormone therapy, the recurrence of depressive symptoms during blinded hormone withdrawal suggests that normal changes in ovarian estradiol secretion can trigger an abnormal behavioral state in these susceptible women. Women with a history of PMD should be alert to the risk of recurrent depression when discontinuing hormone therapy.

Trial registration: clinicaltrials.gov Identifier: NCT00060736.

Conflict of interest statement

Conflict of Interest Disclosures: This work was written as part of the official duties of Peter J. Schmidt, MD, asa government employee.

Figures

Figure 1.. CONSORT Diagram

All women were postmenopausal; therefore, endogenous estradiol production did not contribute to the changes in reproductive hormones that were observed. Twenty-three women with past perimenopausal depression (PMD) and 16 control women were receiving hormone therapy before starting the study.

Figure 2.. Estradiol Withdrawal Precipitation of Depressive Symptoms

Women with past perimenopausal depression (PMD) randomized to placebo (but not those randomized to estradiol and control women randomized to either estradiol or placebo) had significantly increased (ie, more symptomatic) Center for Epidemiologic Studies-Depression Scale (CES-D) scores compared with scores during the open-label administration of estradiol. In addition, CES-D scores in women with PMD during use of placebo were significantly increased compared with the scores of both control women randomized to placebo and those with past PMD randomized to estradiol. The dosage of estradiol used throughout the study was 100 μg/d. Data markers indicate the arithmetic mean; error bars, SE.