Multiple studies have demonstrated that the menopausal transition is associated with a 2- to 4-fold increased risk for clinically significant depressive symptoms. There have been several studies suggesting that hormone therapy may improve depressive symptoms in women presenting with depression during this transition.  A recent study examined the efficacy of hormone replacement therapy in preventing the onset of depressive symptoms in a group of euthymic perimenopausal and early postmenopausal women.

This was a double-blind, placebo-controlled randomized trial where women aged 45 to 60 years were randomized to receive either 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 estradiol; an identical placebo pill was given to the women using the transdermal placebo.

The Center for Epidemiological Studies – Depression Scale (CES-D) was used to measure depressive symptoms at baseline and at 1, 2, 4, 6, 8, 10, and 12 months.  Clinically significant depressive symptoms were defined as a CES-D score of 16 or above.

Of the 172 participants, the mean age was 51 years.  By the end of the follow-up period, 43 women (25%) developed clinically significant depressive symptoms. Women receiving placebo were nearly twice as likely as those receiving hormone therapy to report clinically significant depressive symptoms (32.3% vs 17.3%; odds ratio [OR], 2.5) and overall had higher mean CES-D scores across the intervention period.  The beneficial effects of hormone therapy were observed in the women in the early menopause transition but not in women during the late menopause transition or among postmenopausal women.

Baseline estradiol levels, baseline vasomotor symptoms, history of depression, and history of abuse did not moderate treatment effects. However, the researchers found that stressful life events occurring during the 6 months prior to entry into the study moderated the effect of hormone treatment on mean CES-D score such that the mood benefits of hormone therapy increased with a greater number of stressful events.

Should All Perimenopausal Women Receive Hormone Replacement Therapy?

This is a well-done and carefully constructed study.  Obviously it needs to be replicated in other populations; however, this is the first study suggesting that hormone replacement therapy, if initintatiated early in the menopausal transition, would decrease the risk of depression by more than 50%. That’s a pretty impressive finding.  

In an editorial accompanying this report, Should Hormone Therapy Be Used to Prevent Depressive Symptoms During the Menopause Transition?, Joffe and colleagues makes some very important points regarding the use of hormone therapy to prevent depression  in this population. Although there is a robust reduction in risk, this sort of intervention would require that women initiate treatment with hormone therapy as they begin the menopausal transition and they would most likely take hormones for at least several years.  (The median duration of the perimenopause is 4 years.)

Given concerns of increased risk for venous thromboembolism, cardiovascular risk and breast cancer among hormone therapy users documented in large-scale studies including WHI and HERS, this preventative intervention may carry more risk than many women and their treaters would be willing to tolerate. Joffe and colleagues also note that the hormone regimen used in this suty, transdermal estradiol (0.1 mg/d) with oral micronized progesterone (200 mg/d for 12 days every three months, uses substantially higher doses of estradiol than is typically recommended and may confer additional risk.

The most acceptable and successful primary prevention strategies are those that carry low risk, such as using folic acid supplementation in pregnancy to decrease the risk of neural tube defects.  When an intervention carries more risk, for example using hormone therapy over a period of years, it would be important to identify a high risk population so that those who are at low risk for a particular outcomes are not unnecessarily exposed to the risks associated with the intervention.  

Previous studies have demonstrated that women with histories of major depression and those who experience more severe vasomotor symptoms may be more vulnerable to perimenopausal depression; however, this study observed that baseline vasomotor symptoms or history of depression did not moderate treatment effects.  However, the researchers found that stressful life events occurring during the 6 months prior to entry into the study moderated the effect of hormone treatment such that the mood benefits of hormone therapy increased with a greater number of stressful events.

While the findings of this study are quite interesting, the use of hormone therapy to prevent depression during the menopausal transition in women without identified risk factors requires more study.

Ruta Nonacs, MD PhD


Gordon JL, Rubinow DR, Eisenlohr-Moul TA, Xia K, Schmidt PJ, Girdler SS.  Efficacy of Transdermal Estradiol and Micronized Progesterone in the Prevention of Depressive Symptoms in the Menopause Transition: A Randomized Clinical Trial.  JAMA Psychiatry. 2018 Jan 10.


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