Hormone Therapy May Head Off Menopausal Depression

Megan Brooks

January 11, 2018

Hormone therapy can prevent the onset of symptoms of depression during the menopause transition, according to results of a randomized controlled trial.

During a 12-month period, fewer women who used transdermal estradiol (multiple brands) plus intermittent micronized progesterone (multiple brands) (TE+IMP) developed symptoms of depression than those who received matching placebo. Women who had experienced more recent stressful life events showed greater benefit in mood from receiving hormone therapy, as did those in the earlier phase of the menopause transition.

The study was published online January 10 in JAMA Psychiatry.

50% Risk Reduction

The risk for clinically significant symptoms of depression increases twofold to fourfold during the menopause transition and early postmenopausal period. Some studies have suggested that hormone therapy can help to manage existing depression, but it is unclear whether it can prevent the onset of symptoms of depression in women who do noth have a history of such symptoms.

This study provides "some of the first evidence that we can prevent depressive symptoms with a transdermal estradiol regimen," Susan Girdler, PhD, from the Department of Psychiatry, University of North Carolina, Chapel Hill, said in a JAMA Psychiatry podcast.

The study included 172 nondepressed perimenopausal or early postmenopausal women aged 45 to 60 years (mean age, 51). They were randomly assigned to TE (0.1 mg/d) plus IMP (200 mg/d for 12 days) or matching placebo for 12 months.

Scores on the Center for Epidemiological Studies–Depression Scale (CES-D) were assessed at baseline and at regular intervals throughout the study period. The main outcome was clinically significant symptoms of depression, defined as a CES-D score of at least 16.

During the study period, 43 women (25%) developed clinically significant depression. "That would be consistent with what you would expect," Dr Girdler said. However, the risk was "cut in half" in women who received hormone therapy, she noted.

Twenty-eight (32.3%) women who received placebo scored at least 16 on the CES-D at least once during the 12-month study period, compared with 15 (17.3%) women taking hormone therapy (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.1 - 5.7; P = .03). In addition, for women who took placebo, the average CES-D score was higher throughout the intervention period (P = .03).

"Importantly," write the researchers, "these results were significant despite statistically adjusting for change in vasomotor symptom bother, suggesting that TE+IMP has direct prophylactic mood benefits that are independent from its beneficial effects on menopausal symptoms, as previously observed in women with major depressive disorder treated with TE+IMP."

The greatest benefit of TE+IMP in preventing the onset of symptoms of depression occurred in women who had experienced a greater number of recent life stressors and women in the early menopause transition.

"The findings need to be confirmed in further research, and if they are, I think it really speaks to this whole idea of precision medicine," Dr Girdler said. "I don't think the take-home message from our study should be that all women who are medically eligible for estrogen replacement therapy should necessarily be put on it to prophylactically prevent the development of depression."

Rather, she said, the results suggest it may be worthwhile to conduct a "very simple clinical interview" to assess current bleeding patterns to help determine where a woman is in the menopause transition and to uncover any recent life stressors. Such information might help guide treatment decisions.

More Research Needed

The authors of an accompanying editorial commend the researchers for "investigating the efficacy of a biologically rational strategy to prevent depressive symptoms in women at increased risk owing to reproductive stage using a randomized clinical trial design."

The authors also make "an important novel observation that recent stressful life events (reported by 59% of participants) moderate the preventative benefit of HT [hormone therapy] for depressive symptoms," note Hadine Joffe, MD, of Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, and colleagues.

"This finding suggests that chronic stress, hypothalamic-pituitary-adrenal axis perturbation, sleep disruption, inflammatory cytokines, or other factors triggered by stressful life experiences may interact with the central nervous system effects of HT to stabilize mood," they write.

Current guidance is to consider hormone therapy for the treatment of bothersome hot flashes in women within 10 years of the onset of menopause but not for preventive indications. Dr Joffe and colleagues agree with the authors' conclusion that more information is needed before hormone therapy should be considered for the prevention of symptoms of depression.

"While results of this randomized clinical trial are provocative and illustrate the potential role of gonadal steroids in the regulation of mood, they do not support a change in clinical guidance for the use of HT in women traversing menopause," they conclude.

The study was supported by the National Institutes of Health. The authors have disclosed no relevant financial relationships. Dr Joffe has received research funding from Merck and SAGE and is a consultant to NeRRe, Mitsubishi-Tanabe, Merck, and SAGE.

JAMA Psychiatry. Published online January 10, 2018. Full text, Editorial

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