This article is more than 5 years old. Information may no longer be current.

Estradiol withdrawal may induce recurrent perimenopausal depression

Changes in ovarian estradiol secretion may lead to abnormal behavior among postmenopausal women with past perimenopausal depression who previously received hormone therapy, according to results from a randomized, double-blind, placebo-controlled trial.

“Depression risk increases in perimenopause, and depression is cited as a primary reason for resuming menopausal hormone therapy,” study researcher Peter J. Schmidt, MD, of the NIMH Section on Behavioral Endocrinology, and colleagues wrote. “The role of estradiol — either declining levels or low levels — in the precipitation of perimenopausal depression is unknown, largely owing to the associational and indirect nature of the evidence linking ovarian function and depression.”

To determine associations between declining ovarian function, or estradiol withdrawal, and depression during perimenopause, researchers evaluated 26 asymptomatic postmenopausal women with past perimenopausal depression (PMD) that were responsive to hormone therapy and 30 asymptomatic postmenopausal women with no history of depression, aged 45 to 65 years. All women received transdermal estradiol for 3 weeks, and then were randomly assigned to receive either estradiol (n = 12 with past PMD, 15 controls) or matched placebo skin patches (n = 15 with past PMD, 15 controls) for an additional 3 weeks.

Women with past PMD who received placebo had increases in depression severity ratings (P < .001), Beck Depression Inventory scores (P = .05) and visual analog symptom scores for depression, social isolation, early morning wakening and lack of motivation compared with their scores following baseline estradiol treatment.

Women with past PMD who received continued estradiol and controls remained asymptomatic and did not experience significant changes in depression symptom severity between initial and continued treatment.

While receiving placebo, women with past PMD had higher Center for Epidemiologic Studies-Depression Scale scores compared with women with past PMD who continued estradiol (P < .001) and controls who received placebo (P < .001). Hamilton Depression Rating Scale scores and Beck Depression Inventory scores were also significantly higher among women with past PMD receiving placebo.

“Although women with past PMD had a recurrence of depressive symptoms during estradiol withdrawal, control women had no perturbations of mood during the same hormonal manipulation. These observations, in the context of similar plasma reproductive hormone levels, suggest that normal changes in ovarian estradiol secretion can trigger abnormal behavioral state in susceptible women,” Schmidt and colleagues wrote.

In an accompanying editorial, Paul Newhouse, MD, and Kimberly Albert, BS, of Vanderbilt University, “propose that changing levels of estradiol may directly modify the activity of dorsal and ventral emotional regulation nodes and circuits, modifying the cognitive and emotional consequences of life stress…but the impact of this effect may be determined by the preexisting emotional state and the presence or absence of concurrent psychosocial stress.” – by Amanda Oldt

Disclosure: The researchers report no relevant financial disclosures.