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.

Objective The relationship between depression and estrogen withdrawal remains controversial. The authors examined the effects of gonadotropin-releasing hormone agonist-induced ovarian suppression on mood, sleep, sexual function, and nighttime hot flushes. They focused on whether participating women experienced clinically significant depressive symptoms and whether specific symptoms associated with hypogonadism (nighttime hot flushes and disturbed sleep) increased susceptibility to depression. Method Participants were 72 healthy pre-menopausal women, ages 19–52 years, with no current or past axis I psychiatric diagnosis or gynecological or other medical illness. After 2 months of baseline screening, women received monthly injections of leuprolide acetate (3.75 mg) for 2–3 months. Outcomes were measured using the Beck Depression Inventory (BDI) and a daily rating scale measuring the severity of several affective and behavioral symptoms. Data were analyzed by repeated-measures analysis of variance using PROC MIXED (for mixed models). Results BDI scores ≥10 were reported in four of the 72 women (5.6%). Relative to baseline, induced hypogonadism was associated with significantly decreased sexual interest, disturbed sleep, and more severe nighttime hot flushes, but no significant change in any mood-related symptom score. Hot flush severity was significantly correlated with disturbed sleep. Conclusions These data demonstrate that clinically significant depressive symptoms were rare accompaniments of short-term estradiol withdrawal and induced hypogonadism in healthy premenopausal women. Additionally, neither nighttime hot flushes nor disturbed sleep were sufficient to cause depressive symptoms in hypogonadal women.

The small sample size notwithstanding, these data emphasize the potential behavioral relevance of ADT in humans, which may include contribution to the antidepressant effects of DHEA.