1. JAMA Psychiatry. 2018 Feb 1;75(2):149-157. doi: 10.1001/jamapsychiatry.2017.3998.

Efficacy of Transdermal Estradiol and Micronized Progesterone in the Prevention
of Depressive Symptoms in the Menopause Transition: A Randomized Clinical Trial.

Gordon JL(1), Rubinow DR(2), Eisenlohr-Moul TA(2), Xia K(2), Schmidt PJ(3),
Girdler SS(2).

Author information: 
(1)Department of Psychology, University of Regina, Regina, Saskatchewan, Canada.
(2)Department of Psychiatry, University of North Carolina at Chapel Hill.
(3)Section on Behavioral Endocrinology, National Institute of Mental Health,
Department of Health and Human Services, Bethesda, Maryland.

Importance: The menopause transition and early postmenopausal period are
associated with a 2- to 4-fold increased risk for clinically significant
depressive symptoms. Although a few studies suggest that hormone therapy can
effectively manage existing depression during this time, to our knowledge, there 
have been no studies testing whether hormone therapy can prevent the onset of
perimenopausal and early postmenopausal depressive symptoms.
Objective: To examine the efficacy of transdermal estradiol plus intermittent
micronized progesterone (TE+IMP) in preventing depressive symptom onset among
initially euthymic perimenopausal and early postmenopausal women. A secondary aim
was to identify baseline characteristics predicting TE+IMP's beneficial mood
Design, Setting, and Participants: Double-blind, placebo-controlled randomized
trial at the University of North Carolina at Chapel Hill from October 2010 to
February 2016. Participants included euthymic perimenopausal and early
postmenopausal women from the community, aged 45 to 60 years.
Interventions: Transdermal estradiol (0.1 mg/d) or transdermal placebo for 12
months. Oral micronized progesterone (200 mg/d for 12 days) was also given every 
3 months to women receiving active TE, and identical placebo pills were given to 
women receiving placebo.
Main Outcome Measures: Scores on the Center for Epidemiological
Studies-Depression Scale (CES-D), assessed at baseline and months 1, 2, 4, 6, 8, 
10, and 12 after randomization, and the incidence of clinically significant
depressive symptoms, defined as a CES-D score of at least 16.
Results: Of 172 participants, 130 were white (76%), and 70 were African American 
(19%), with a mean household income of $50 000 to $79 999. The mean age was 51
years, and 43 developed clinically significant depressive symptoms. Women
assigned to placebo were more likely than those assigned to TE+IMP to score at
least 16 on the CES-D at least once during the intervention phase (32.3% vs
17.3%; odds ratio [OR], 2.5; 95% CI, 1.1-5.7; P = .03) and had a higher mean
CES-D score across the intervention period (P = .03). Baseline reproductive stage
moderated the effect of treatment (β, -1.97; SEM, 0.80; P for the
interaction = .03) such that mood benefits of TE+IMP vs placebo were evident
among women in the early menopause transition (β, -4.2; SEM, 1.2; P < .001) but
not the late menopause transition (β, -0.9; SEM, 0.3; P = .23) or among
postmenopausal women (β, -0.3; SEM, 1.1; P = .92). Stressful life events in the 6
months preceding enrollment also moderated the effect of treatment on mean CES-D 
score such that the mood benefits of TE+IMP increased with a greater number of
events (β, 1.22; SEM, 0.40; P = .003). Baseline estradiol levels, baseline
vasomotor symptoms, history of depression, and history of abuse did not moderate 
treatment effects.
Conclusions: Twelve months of TE+IMP were more effective than placebo in
preventing the development of clinically significant depressive symptoms among
initially euthymic perimenopausal and early postmenopausal women.
Trial Registration: clinicaltrials.gov Identifier: NCT01308814.

DOI: 10.1001/jamapsychiatry.2017.3998 
PMCID: PMC5838629
PMID: 29322164