Can estrogen improve vaginal health for postmenopausal women?

From the Fredricks lab, Vaccine and Infectious Disease and Clinical Research Divisions

Between 27 and 84% of postmenopausal women experience moderate to severe vaginal discomfort. This common discomfort can be remedied with local application of lubricants, moisturizers, or estrogen (estradiol) treatment. Although several treatment options have produced similar relief of vaginal discomfort, the Fredricks lab and investigators of the Menopause Strategies: Finding Lasting Answers for Symptoms and Health Trials (MsFLASH) Network at Fred Hutchinson Cancer Center sought to determine if topical moisturizer or local estrogen treatments differed in their benefits to vaginal health by assessing vaginal pH, metabolite levels, microbiota abundance and diversity. Their findings were published recently in JAMA Network Open as a secondary analysis of a randomized clinical trial.

Why do some women get vaginal discomfort also known as genitourinary syndrome of menopause (GSM)? Following the onset of menopause, women have decreased estrogen production which results in reduced glycogen synthesis from cells lining the vagina. In the presence of estrogen, glycogen-rich vaginal fluid promotes lactobacilli expansion in the vagina. This group of bacteria are shown to produce antimicrobial and anti-inflammatory factors and metabolize glycogen-derived polymers into lactic acid. The production of lactic acid functions to lower the pH in the vagina to a “healthy” acidic state. Therefore, high abundance of lactobacilli is thought to promote a “healthy” vaginal microenvironment. Low estrogen can also result in thinner vaginal tissues that are dry and fragile, features often present with vaginal discomfort. For these reasons, treatments of GSM have focused on restoring a low pH, adding moisture, and increasing estrogen levels in the vagina to remedy discomfort.

Clinical trials have addressed the ability of lubricants, moisturizers, and estrogen treatments to relieve vaginal discomfort in postmenopausal women, but there is a limited understanding of how these methods alter vaginal microbiota and metabolites in the vaginal fluid. Study of the vaginal microbiome is a growing field of research, spurred by the connection between vaginal microbiota abundance or diversity with disease and genital inflammation. As researchers continue to investigate changes in the vaginal microbiome and identify key factors that define a “healthy” vagina, these findings inform on “best treatment” approaches for common symptoms such as GSM and reducing susceptibility to vaginal inflammation and genitourinary-related diseases.

A clinical trial was completed to determine if vaginal moisturizer or estradiol vaginal tablet reduced vaginal symptoms as compared to a double placebo group (vaginal placebo gel and placebo pill). Consistent with other studies, the three treatment categories similarly reduced GSM. Using the data collected from this clinical trial, the Fredricks lab and MsFLASH network investigators conducted a secondary analysis to address a gap in knowledge, how interventions for GSM may change the vaginal microenvironment. Specifically, the authors posed the question, “What are the effects of estradiol or vaginal moisturizer on the vaginal microbiota, metabolome and pH after 12-week treatment in postmenopausal women?” First author, Dr. Sujatha Srinivasan further commented that “changes (or lack thereof) in the vaginal microenvironment may have implications beyond symptoms, and might be linked to risk for cervical cancer, genital infections or other outcomes - though our study did not evaluate those associations.”

Treatment of postmenopausal women with moderate to severe GSM using vaginal estradiol tablets for 12 weeks increased “healthy” Lactobacillus and Bifidobacterium abundance as compared to placebo and vaginal moisturizer treatments.
Treatment of postmenopausal women with moderate to severe GSM using vaginal estradiol tablets for 12 weeks increased “healthy” Lactobacillus and Bifidobacterium abundance as compared to placebo and vaginal moisturizer treatments. Image taken from original article.

From this secondary analysis, the researchers discovered that the women treated with the vaginal estradiol tablet had increased lactobacilli and bifidobacteria as compared to the moisturizer and placebo groups. As mentioned previously, elevated lactobacilli in vaginal microenvironments correlates with positive vaginal health outcomes. Additionally, changes in the metabolome, including an increase of lactic acid, were only observed in the vaginal estradiol tablet group as compared to the moisturizer and placebo groups. Metabolites present in the vaginal fluid are affected by the vaginal microbiota and thus changes to the microbiota likely affected changes in the vaginal metabolome. This was illustrated by increases in lactic acid which is a metabolite produced by lactobacilli and bifidobacteria. Lastly, all three categories of treatments reduced the pH of the vagina after 12 weeks of treatment. Interestingly, “this study demonstrated that a decrease in vaginal pH alone was insufficient to change the vaginal microbiota. While the changes with estrogen [treatment] were somewhat expected, the observation that low-pH vaginal products don’t change the vaginal microbiota is contrary to some expectations and suggests that “low pH” products may not be as helpful as their marketing claims,” commented Dr. Srinivasan.

The current view of a healthy vaginal microenvironment for postmenopausal women is characterized by three vaginal features: high lactobacilli abundance, elevated lactic acid metabolite levels, and a low (acidic) pH. “Such a microenvironment is typically associated with low inflammation” but “at this time, we don’t have specific information as to how this is beneficial to postmenopausal women,” stated Dr. Srinivasan. However, Dr. Srinivasan proposed a hopeful connection between using vaginal estradiol tablets to treat GSM and promoting vaginal “health” prior to genitourinary-related disease development. These studies, pave the way for future “investigation into the benefits of a Lactobacillus-dominant microbiota in postmenopausal women,” concluded Dr. Srinivasan.

The spotlighted research was funded by the National Institutes of Health.

UW/Fred Hutch Cancer Consortium members Michael Wu, Susan Reed, Katherine Guthrie, Daniel Raftery, and David Fredricks contributed to this work.

Srinivasan S, Hua X, Wu MC, Proll S, Valint DJ, Reed SD, Guthrie KA, LaCroix AZ, Larson JC, Pepin R, Bhasin S, Raftery D, Fredricks DN, Mitchell CM. 2022. Impact of Topical Interventions on the Vaginal Microbiota and Metabolome in Postmenopausal Women: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 5(3):e225032.