Association between postmenopausal vulvovaginal discomfort, vaginal microbiota, and mucosal inflammation

Abstract

Background: Half of all postmenopausal women report symptoms of vulvar, vaginal, or urinary discomfort with substantial impact on sexual function and quality of life; underlying mechanisms leading to symptoms are poorly understood.

Objective: To examine the possibility that the vaginal microbiota and/or mucosal immune response contributes to the severity of bothersome vaginal symptoms, we conducted a substudy of samples from a randomized trial of vaginal treatment for genitourinary syndrome of menopause to compare these features between women whose symptoms improved and women whose symptoms did not improve.

Study design: This is a secondary analysis of samples collected in a 12-week randomized trial of treatment with vaginal estradiol or moisturizer vs placebo for moderate-severe postmenopausal symptoms of vaginal discomfort. We randomly selected 20 women in each arm with ≥2-point decrease in most bothersome symptom severity (responders) and 20 matched controls with ≤1-point decrease (nonresponders). At 0, 4, and 12 weeks, we characterized vaginal microbiota (16S ribosomal RNA gene sequencing), vaginal fluid metabolites (broad-based metabolomic profiling), vaginal fluid-soluble immune markers (Meso Scale Discovery), pH, and vaginal maturation index. We compared responders with nonresponders at baseline and across all visits using linear mixed models to evaluate associations with microbiota, metabolites, and immune markers, incorporating visit and participant-specific random effects while controlling for treatment arm.

Results: Here, the mean age of women was 61 years (n=120), and most women (92%) were White. At enrollment, no significant differences were observed between responders and nonresponders in age, most bothersome symptom type or severity, microbiota composition or diversity, Lactobacillus dominance, metabolome, or immune markers. There was a significant decrease in diversity of the vaginal microbiota in both responders and nonresponders (P<.001) over 12 weeks. Although this change did not differ by responder status, diversity was associated with treatment arm: more women in the estradiol arm (63%) had Lactobacillus-dominant, lower diversity bacterial communities than women in the moisturizer (35%) or dual placebo (23%) arms (P=.001) at 12 weeks. The metabolome, vaginal maturation index, and measured immune markers were not associated with responder status over the 12 weeks but varied by treatment arm.

Conclusion: Postmenopausal vaginal symptom severity was not significantly associated with vaginal microbiota or mucosal inflammatory markers in this small study. Women receiving vaginal estradiol experienced greater abundance of lactobacilli and lower vaginal pH at end of treatment.

Trial registration: ClinicalTrials.gov NCT02516202.

Keywords: genitourinary syndrome of menopause; menopause; vaginal estradiol; vaginal microbiome; vaginal moisturizer.

Conflict of interest statement

Disclosure statement: Dr. Mitchell reports receiving grant funding from Merck, and has served as a consultant to Scynexis, Inc. Dr. Reed receives research funding from Bayer. Dr. Fredricks receives royalties from BD. Dr. Srinivasan has received speaking honoraria from Lupin Inc. The remaining authors report no conflicts of interest.

Copyright © 2021 Elsevier Inc. All rights reserved.

Figures

Figure 1.

Bacterial composition of vaginal fluid from responders and non-responders at baseline evaluated by 16S rRNA sequencing. Relative abundance of the top 30 taxa shown from enrollment vaginal 16S rRNA sequencing. Bacterial taxa less than 1% abundance were categorized in the “other” group. Responders (n = 60) were defined as women who had a ≥2-point decrease in most bothersome symptom (MBS) severity over 12 weeks of treatment and non-responders (n = 60) were defined as women who had

Figure 2.

(A) Beta diversity represented by Principle Coordinate Analysis plots. Each dot represents the bacterial community in a single participant and data is shown across three timepoints; baseline, week 4 and week 12. Axes are the coordinates of maximal variability in the multivariate data with PC1 and PC2 explaining 16.81% and 9.87% of the variation, respectively. The bacterial community was similar between responders (n=58 and 58 at weeks 4 and 12, respectively) and non-responders throughout the trial (n=60 and 59 at weeks 4 and 12). (B) Responders had a higher median Shannon index (α -diversity) at enrollment compared to non-responders (p = 03). (C) There was no statistically significant difference in the proportion of women with Lactobacillus dominance between responders and non-responders at any visit. (D) The Shannon index decreased significantly throughout the trial, especially in the estrogen and moisturizer arms, but was not associated with responder status. Responders were defined as women who had a ≥2-point decrease in most bothersome symptom (MBS) severity over 12 weeks of treatment and non-responders were defined as women who had <1-point decrease.

Figure 3.

Regression coefficients +/− standard error of linear mixed models evaluating associations (negative or positive) of the concentration of soluble vaginal immune markers at all time points with vulvovaginal symptom severity. A negative correlation means that with higher symptom severity, marker concentration is lower.