March 20, 2023

Will Transdermal Estradiol and Micronized Progesterone Prevent Peri-menopausal
Depressive Symptoms?

By Anish Patel

Executive Director’s Note:  The perimenopausal transition can be a challenging time for women who may experience clinical depression, among other symptoms. Thankfully, research continues to emerge with new therapeutic avenues to address these common concerns. Summarizing a research review by Gordon et al, former FACTS elective student Anish Patel teaches us about the application of transdermal estradiol combined with micronized progesterone to address depressive symptoms in this population. At the time of publication in 2018, this research was the first to study the prophylactic benefits of this bioidentical hormone therapy to prevent depressive symptoms, and the study outcomes offer encouraging news for both medical professionals and the women they serve.

Introduction

The perimenopausal period signifies an important change in a woman’s life, as it denotes the transitional time associated with menopause. Menopause refers to the time frame where a woman’s periods stop; it is facilitated through changes in the menstrual cycle and associated with various physical and emotional symptoms. This time frame can last up to ten years and is characterized by decreased production of estrogen and other hormones.

The perimenopausal and early postmenopausal periods are associated with a 2- to 4-fold increased risk for clinically significant depressive symptoms.[1] Depression is now the number one cause of disease-related disability among women around the world. [2] [3] Furthermore, the prevalence of depression is at least twice as high in women as in men,[2] which shows a need to recognize symptoms faster and provide tools to support women through these changes.

“The perimenopausal and early postmenopausal periods are associated with a 2- to 4-fold increased risk for clinically significant depressive symptoms.”

One avenue for therapeutic intervention in this time frame was reviewed in the 2018 study by Gordon et al.[1] This double-blind, placebo-controlled randomized clinical trial included 172 perimenopausal and early post-menopausal women ranging from ages 45 to 60 and followed them for six years. The study aimed to assess whether a 12-month therapeutic intervention of transdermal estradiol and intermittent micronized progesterone was more effective than placebo to prevent the development of depressive symptoms during this period of change. The researchers collected socioeconomic data along with baseline parameters such as vasomotor symptoms, a positive history of major depression, history of physical or sexual abuse, and the presence of life stressors within the previous six months to assess a variety of scenarios that could arise when considering this therapy.

Methodology

Using the Stages of Reproductive Aging Workshop criteria, the researchers found 172 women ages 45 to 60 years who were medically healthy and in the perimenopausal or early postmenopausal stages. These patients self-referred in response to advertisements posted in the community of Chapel Hill, NC and on social media. The women were euthymic (a state of living without mood disorder) on study enrollment according to the Structured Clinical Interview section of the DSM-IV. The final demographics revealed that 130 participants were Caucasian (76%) and 70 were African-American (19%) with a mean household income of $50K to $80K. The mean age of participants was 51 years of age.

The study used a randomized, double-blind, placebo-controlled design in which the 172 women were either assigned treatment with patches of 0.1mg of 17β-estradiol or placebo patches. Additionally, 200mg/day of oral micronized progesterone was given to the treatment group for 12 days every 2 to 3 months, while identical schedules of placebo pills were implemented for the placebo group. The team then followed up at months 1, 2, 4, 6, 8, 10, and 12. To reduce confounding bias of progesterone on the effects of estradiol, no visits occurred while women were taking progesterone.

The team assessed depressive symptoms at each visit using the Center for Epidemiological Studies-Depression Scale (CES-D). Additionally, vasomotor symptom bother was measured via the Vasomotor Subscale of the Greene Climacteric Scale. Baseline serum estradiol levels were measured at the enrollment session. Stressful life events during the 6 months prior to this baseline assessment were measured using the Life Events Survey interview, modified to include moderate to severely stressful events.

The researchers used an intention-to-treat analysis, with a CES-D score of 16 or greater being considered clinically significant depressive symptoms. The team analyzed the data via SAS, version 9.2 and used logistic regression to examine the effect of treatment on the risk of developing a CES-D score of at least 16.

Results

Out of 172 women who entered the trial, the participants randomized to therapy vs. placebo did not differ significantly in terms of any baseline demographics or psychosocial variables. By the last visit at 12 months, 12 women (17%) assigned to the placebo group were in early perimenopause, 34 (49%) were in late perimenopause, and 22 (32%) were early postmenopausal. Out of the 172 participants, 43 (25%) obtained a score of at least 16 on the CES-D once during the study. Women assigned to the placebo group were more likely than those in the treatment group to score 16 or higher on the CES-D at least once during the intervention phase (OR 2.5, CI 1.1-5.7, p=.03). They also exhibited a significantly higher mean CES-D score across the 12-month intervention than participants in the therapy group.

Effect moderators such as reproductive stage, stressful life events, and adverse events were also studied. The researchers found that mood benefits of therapy vs. placebo were evident in women in the early menopause transition phase (β -4.2, SEM 1.2, p= <.001) but not as prevalent in the late menopause transition (β -0.9, SEM 0.3, p= .23) or among postmenopausal women (β -0.3, SEM 1.1, p= .92). Regarding the CES-D score, a significant interaction was noted between treatment and total number of stressful life events in the 6 months preceding enrollment in the study. Specifically, women with a higher number of stressful life events benefited more from treatment than the placebo group. Finally, those in the treatment group were more prone to have vaginal bleeding, including spotting (64% vs. 34%, p= <0.01), mild or moderate bleeding (80% vs. 44%, p=<0.01), heavy bleeding (37% vs. 13%, p=<0.01), and prolonged bleeding (15% vs. 1%, P=<0.01).

“Women with a higher number of stressful life events benefited more from treatment than the placebo group.”

Discussion

This groundbreaking research has major implications in women’s health and fertility awareness. The study shows that the incidence of clinical depression is common in perimenopausal and early postmenopausal women. The results bring light to the possibility of finding therapeutic avenues for an important time in a woman’s life in which she is experiencing considerable changes. Discovering ways to reduce the significant association with clinical depression during this stage would enable women to feel more in control of their lives during this transition. The authors note that, to their knowledge, this is the first study to test the prophylactic mood benefits of hormone therapy during and around menopause, making this research unique. The study explores ways to treat clinical depressive symptoms associated with this transition state, yet goes beyond this important outcome to also assess whether clinically depressive symptoms can, in fact, be prevented with hormonal interventions.

The authors bring up the Women’s Health Initiative study and related concerns about the possibility of hormone therapy leading to increased risks of breast cancer, cardiovascular events, and other adverse events. However, subsequent research has shown that transdermal estradiol combined with intermittent micronized progesterone is safe for women in the perimenopausal and postmenopausal stages when given at the lowest dose for the shortest amount of time to treat menopausal symptoms. The authors add that the American Society for Reproductive Medicine, the Endocrine Society, and others agree that hormone therapy is indicated to treat menopausal symptoms in younger women who are within ten years of menopause.[1]

Regarding baseline predictors of mood benefit, the study found that hormone therapy could be more beneficial for women in the early menopause transition and in women reporting more baseline stressful events. Interestingly, baseline vasomotor symptoms, a history of major depression or a history of physical or sexual abuse were not associated with a response to this therapy. This could imply these therapeutic benefits may be available to anyone in the menopause transition phase regardless of the presence or absence of these baseline characteristics. The known association of an increased risk of bleeding with this therapy is important to consider. This treatment regimen may be more beneficial for patients without an increased risk of bleeding. A thorough clinical exam and history are vital to identify patients who may benefit most from this therapy.

“The study found that hormone therapy could be more beneficial for women in the early menopause transition and in women reporting more baseline stressful events … [regardless of] baseline vasomotor symptoms, a history of major depression or a history of physical or sexual abuse.”

This study opens a window toward expanding our knowledge of different therapeutic options to combat a common problem during the menopause transition phase. Although this pilot study only assessed 172 patients, a larger trial could further explore the association between baseline characteristics and impact of therapy. This study was an important first step to understand how hormonal changes that affect the hypothalamic-pituitary axis impact not only physical symptoms but also emotional and psychological symptoms. Clinicians can use these foundational building blocks and develop more ways to support patients as they navigate a natural stage of life.

[1] 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;75(2):149-157. doi:10.1001/jamapsychiatry.2017.3998.

[2] Kessler RC. Epidemiology of Women and Depression. J Affect Disord. 2003 Mar;74(1):5-13. doi: 10.1016/s0165-0327(02)00426-3. PMID: 12646294.

[3] Murray, C.J. and Lopez, A.D. (1998) Alternative Projections of Mortality and Disability by Cause 1990-2020: Global Burden of Disease Study. The Lancet, 349, 1498-1504.
http://dx.doi.org/10.1016/S0140-6736(96)07492-2.

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