Because women appear to be at increased risk for new onset and recurrent depression as they transition into the menopause, it has been hypothesized that declining ovarian function — or estrogen “withdrawal” — may trigger depressive symptoms in some women.  While this is a very reasonable and totally plausible hypothesis, no studies have formally tested the estrogen withdrawal hypothesis of perimenopausal depression (PMD).

This study included asymptomatic postmenopausal women who had a history of perimenopausal depression previously responsive to hormone therapy and asymptomatic postmenopausal women with no history of depression. Both groups of women were first treated with 3 weeks of transdermal estradiol (100 µg/day). The they were randomized to receive continue estradiol (100 µg/day; n=27) or matched placebo skin patches (n=29) for an additional 3 weeks under double-blind conditions.

None of the women reported depressive symptoms during the open-label treatment with estradiol.  However, women with a history of PMD switched from estradiol to placebo experienced a significant increase in depression symptom severity.  Women with a history of PMD who continued estradiol therapy and all women in the control group remained asymptomatic.

This small, but very elegant, study indicates that for a subset of vulnerable women, the normal changes in ovarian estradiol levels that occur during the menopausal transition can trigger an abnormal behavioral state.  While we know that estrogen levels modulate neurotransmitter systems involved in mood regulation, we do not precisely understand why some women are more vulnerable to hormonal changes than others.  It is hypothesized that women who have had depressive symptoms associated with other reproductive hormone shifts, such as postpartum depression or PMS, may be more susceptible to menopausal mood symptoms.  In addition, this study suggests that women with a history of PMD should be alert to the risk of recurrent depression when they attempt to discontinue hormone therapy.

Ruta Nonacs, MD PhD

Schmidt PJ, Ben Dor R, Martinez PE, Guerrieri GM, Harsh VL, Thompson K, Koziol DE, Nieman LK, Rubinow DR.  Effects of Estradiol Withdrawal on Mood in Women With Past Perimenopausal Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2015 Jul 1;72(7):714-26.

Soares CN, Zitek B.  Reproductive hormone sensitivity and risk for depression across the female life cycle: a continuum of vulnerability?  J Psychiatry Neurosci. 2008 Jul;33(4):331-43.

Soares CN.  Mood disorders in midlife women: understanding the critical window and its clinical implications.  Menopause. 2014 Feb;21(2):198-206.


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