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Summary

Recently Srinivasan et al. [1] published the results of a post-hoc pre-specified secondary analysis of a 12-week multicenter randomized clinical trial (RCT) of postmenopausal women with moderate to severe genitourinary symptoms in order to compare modifications in the diversity and composition of the vaginal microbiota, metabolome, and pH among women using 10 μg of a vaginal estradiol tablet or a low pH moisturizer gel vs a low pH placebo. A total of 144 women (mean age, 61 ± 4 years) were included in this sub-analysis. The research group found that after 12 weeks of treatment, the microbiota was significantly dominated with Lactobacillus and Bifidobacterium communities among 36 women (80%) in the estradiol group, compared to 16 women (36%) using the moisturizer and 13 women (26%) using placebo (p < 0.001). The composition of vaginal fluid metabolites also varied among women in the estradiol group with significant changes in 90 of 171 measured metabolites (53%; p < 0.001), including an increase in lactate. The 12-week pH among women in the estradiol group was lower as compared to the placebo group (median [interquartile, IQR] pH, 5 [4.5-6.0] vs 6 [5.5-7.0]; p = 0.005) but not for the moisturizer group compared to the placebo group (median [IQR] pH, 6 [5.5-6.5]; p = 0.28). There was a decrease in pH from baseline to 12-weeks within the moisturizer group (median [IQR] pH, 7 [6.0-7.5] vs 6 [5.5-6.5]; p < 0.001) and the placebo group (median [IQR] pH, 7 [7.0-7.5] vs 6 [5.5-7.0]; p < 0.001) groups. Remarkably, women with high-diversity bacterial communities at baseline exhibited greater median change in pH compared with women with low-diversity communities (median [IQR] change, −1 [−2 to −0.5] vs −0.3 [−1.1 to 0], p = 0.007). The investigators concluded that the use of vaginal estradiol tablets resulted in significant variations in the vaginal microbiota and metabolome with a lowering in pH, mainly in women with high-diversity bacterial communities at baseline. Low pH moisturizer or placebo did not significantly impact the vaginal microbiota or metabolome despite lowering vaginal pH. Estradiol use may offer additional genitourinary health benefits to postmenopausal women.

Commentary

Postmenopausal women complaining with the genitourinary symptoms are often prescribed vaginal estradiol or moisturizers to improve their discomfort, but data regarding the effects of these therapies on the local microenvironment are still inconclusive. Regarding the effects of estradiol or vaginal moisturizers on the vaginal microbiota, metabolome, and pH after 12-weeks of treatment in postmenopausal women is still a matter of debate.

The MsFLASH Vaginal Health Trial was a multicenter, double-blind RCT of vaginal estradiol tablets 10 μg  (plus placebo gel) or vaginal moisturizing gel (plus placebo tablet) vs dual placebo in 302 postmenopausal women with moderate to severe vulvovaginal discomfort [2]. In this secondary analysis of 144 postmenopausal participants (of the original 302) with moderate to severe vulvovaginal symptoms, the authors [1] demonstrated that women using vaginal 10 μg estradiol tablets presented larger changes in the vaginal microbiota and metabolome compared to those using a vaginal moisturizer or placebo despite a decrease in pH within each intervention group. It is interesting to point out that although participants in all treatment groups had significant decreases in vaginal pH over 12 weeks, those in the estradiol group had the largest decrease, associated with changes in the composition of the vaginal microbiota and metabolites. The effect of estradiol was greatest in women with a high-diversity vaginal microbial community, high pH, and low vaginal maturation index at study entry and was not associated with changes in serum levels of estrogen. Several intervention trials studying postmenopausal women with vaginal complaints measure clinician-driven metrics, such as visual appearance on examination, pH, or vaginal epithelial cell maturation [3,4]. In a meta-analysis of randomized trials, vaginal estradiol was associated with significant improvement in these findings to a greater extent than placebo, but not necessarily correlated to women’s report of symptoms [5]. This in-depth analysis demonstrates the same discrepancy, reporting that estradiol was associated with significant, profound changes in microbiota, small molecule metabolites, and pH of the vagina but did not confer a significantly greater symptom benefit compared to placebo [2]. The placebo gel had high lubricity, which likely conferred the symptom benefit without microbiota and metabolite changes in the vaginal microenvironment. These findings demonstrated that a relevant drop in vaginal pH with interventions does not necessarily turn out in the same biological result in all patients. Indeed, the decrease only in vaginal pH seems not to be sufficient to modify the microbiota in women who are experiencing genitourinary symptoms in the postmenopausal period. Moreover, the metabolites in the vaginal fluid did not shift significantly with low-pH treatments, even among women with high-diversity vaginal microbial community, thus suggesting that lowering pH alone may not change microbial or host metabolic paths. Women with a high-diversity of microbiota at enrollment had more modifications in diversity of the microbial community with the administration of vaginal estrogen. Interestingly, vaginal estrogen administration, seems to be involved in the additional reduction of pH even among women with a low-diversity microbial community, suggesting that estradiol integration enables an increase in the metabolic activity of Lactobacilli and Bifidobacteria that represent the most important lactic acid-producers. Furthermore, even among women who started the treatment showing high-diversity microbial communities, there was no significant difference in symptom improvement among treatment groups, demonstrating an absence of causal relation between microbiota and the relevance of postmenopausal vaginal discomfort. It is plausible that the microbial and metabolic modifications determined by estradiol therapy may be a factor in contributing to overall well-being in some way not detected and reported by questionnaires.  It is interesting to point out that women before menopause show higher relative levels of vaginal Lactobacilli that are associated with lower expression of proinflammatory cytokines and chemokines [6], even if data are still inconclusive regarding the difference in vaginal fluid immune markers between pre- and postmenopausal women, as well as the impact of the vaginal microbiota or metabolites on this difference [7,8]. A RCT on the administration of vaginal probiotic in postmenopausal women demonstrated short-term reduction in proinflammatory gene pathways that increased Lactobacilli [9]. These findings suggested that the increase of vaginal Lactobacilli in women experiencing postmenopausal vaginal symptoms may enhance vaginal heath regardless of the effectiveness on related symptoms. Indeed, the MsFLASH Vaginal Health Trial demonstrated that although the biological effects of estrogen on the vaginal microenvironment may not be linked to symptom improvement, they may reflect an important change in vaginal mucosal characteristics not observed with products that simply lower pH.

In conclusion, these data corroborated the general hypothesis that treatment of genitourinary symptoms of the menopause with topical estradiol changes the vaginal microenvironment in ways that may promote genitourinary health regardless of the impact on symptoms thus becoming an area of future investigation in the era of precision medicine.

Andrea Giannini, MD
Department of Clinical and Experimental Medicine
University of Pisa, Pisa Italy

 

References

  1. Srinivasan S, Hua X, Wu MC, et al. Impact of Topical Interventions on the Vaginal Microbiota and Metabolome in Postmenopausal Women: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2022;5(3):e225032.
    https://pubmed.ncbi.nlm.nih.gov/35353163/
  2. Mitchell CM, Reed SD, Diem S, et al. Efficacy of vaginal estradiol or vaginal moisturizer vs placebo for treating postmenopausal vulvovaginal symptoms: a randomized clinical trial. JAMA Intern Med. 2018;178(5):681-690.
    https://pubmed.ncbi.nlm.nih.gov/29554173/
  3. Christmas MM, Song B, Bell RJ, Iliodromiti S, Mitchell C, Hickey M; International COMMA (Core Outcomes in Menopause) Consortium. Variation in outcome reporting and measurement tools in clinical trials of treatments for genitourinary symptoms in peri- and postmenopausal women: a systematic review. 2020;27(9):1070-1080.
    https://pubmed.ncbi.nlm.nih.gov/32852462/
  4. Lima SMRR, Honorato JV. Critical analysis of methods for assessing genitourinary syndrome of menopause used in clinical trials. 2019;26(12):1436-1442.
    https://pubmed.ncbi.nlm.nih.gov/31644509/
  5. Biehl C, Plotsker O, Mirkin S. A systematic review of the efficacy and safety of vaginal estrogen products for the treatment of genitourinary syndrome of menopause. 2019;26(4):431-453.
    https://pubmed.ncbi.nlm.nih.gov/30363010/
  6. Anahtar MN, Byrne EH, Doherty KE, et al. Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract. 2015;42(5):965-976.
    https://pubmed.ncbi.nlm.nih.gov/25992865/
  7. Chappell CA, Isaacs CE, Xu W, et al. The effect of menopause on the innate antiviral activity of cervicovaginal lavage. Am J Obstet Gynecol. 2015;213(2):204.e1-204.e6.
    https://pubmed.ncbi.nlm.nih.gov/25818668/
  8. Murphy K, Keller MJ, Anastos K, et al. Impact of reproductive aging on the vaginal microbiome and soluble immune mediators in women living with and at-risk for HIV infection. PLoS One. 2019;14(4):e0216049.
    https://pubmed.ncbi.nlm.nih.gov/31026271/
  9. Bisanz JE, Enos MK, Mwanga JR, Changalucha J, Burton JP, Gloor GB, Reid G. Randomized open-label pilot study of the influence of probiotics and the gut microbiome on toxic metal levels in Tanzanian pregnant women and school children. mBio. 2014;5(5):e01580-e14.
    https://pubmed.ncbi.nlm.nih.gov/25293764/

 


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