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Science Spotlight

Investigating the mechanisms of genitourinary syndrome of menopause

From the Fredricks lab, Vaccine and Infectious Disease Division, and Massachusetts General Hospital

Genitourinary syndrome of menopause (GSM), characterized by urogenital dryness, pain, and discomfort, affects half of all postmenopausal women, causing sexual dysfunction and decreased quality of life. Currently, the pathophysiological mechanisms behind this condition are unknown. Menopause is accompanied by a drop in circulating estrogen, leading earlier studies to posit that GSM may be related to estrogen loss. To test this hypothesis, a previously published study led by Dr. Caroline Mitchell (Massachusetts General Hospital)— the Menopause Strategies: Finding Lasting Answers for Symptoms and Health (MsFLASH) Vaginal Health Trial—evaluated the use of topical estradiol (a form of estrogen) treatment for GSM in postmenopausal women with moderate to severe vulvovaginal symptoms. Symptoms improved in most trial participants, but were not significantly more improved in those receiving estradiol treatment versus placebo, suggesting other unknown mechanisms are responsible for GSM symptoms.

Drs. Caroline Mitchell and Sujatha Srinivasan (Fredricks lab, Vaccine and Infectious Disease Division) hypothesized that if GSM is not caused by a lack of estrogen, factors such as the vaginal microbiome and mucosal inflammation could be driving the GSM symptoms. To test this, they conducted a nested sub-study in the American Journal of Obstetrics and Gynecology using vaginal swab samples from MsFLASH. The analysis compared a subsample of 20 participants from each arm who experienced the greatest MBS improvement over the 12-week study period vs. 20 with the least improvement, classified as “responders” and “non-responders,” respectively. Mitchell and colleagues evaluated the diversity of vaginal microbiota and the presence of vaginal mucosal immune inflammation markers between responders and non-responders. “Having a microbiota with high abundance of lactobacilli has beneficial reproductive and sexual health outcomes for premenopausal women including lower risk for preterm birth and acquisition of sexually transmitted diseases. Only 20 to 40% of postmenopausal women have vaginal microbiotas dominated by Lactobacillus species. We hypothesized that the vaginal microbiota and inflammatory markers (decreased Lactobacillus abundance and increased inflammation) contribute to GSM,” explained Dr. Srinivasan.

Figure Legend: Association between bacterial communities and vaginal fluid metabolites with responder status. Beta-diversity plots showing that the vaginal microbiota (A) and vaginal fluid metabolites (B) was similar between responders and non-responders throughout the treatment trial of 12 weeks. Each dot represents the bacterial community (A) or vaginal fluid metabolome (B) in a single participant and data are shown across 3 time points; baseline, week 4 and week 12. There was also no significant difference in the proportion of women with Lactobacillus dominance between responders and non-responders at any visit (C). Responders are women with ≥2-point decrease in most bothersome symptom severity (MBS), while non-responders include women with ≤1-point decrease in MBS across 12 weeks.
Figure Legend: Association between bacterial communities and vaginal fluid metabolites with responder status. Beta-diversity plots showing that the vaginal microbiota (A) and vaginal fluid metabolites (B) was similar between responders and non-responders throughout the treatment trial of 12 weeks. Each dot represents the bacterial community (A) or vaginal fluid metabolome (B) in a single participant and data are shown across 3 time points; baseline, week 4 and week 12. There was also no significant difference in the proportion of women with Lactobacillus dominance between responders and non-responders at any visit (C). Responders are women with ≥2-point decrease in most bothersome symptom severity (MBS), while non-responders include women with ≤1-point decrease in MBS across 12 weeks. Figure created by Sean Proll from the Fredricks Lab

The authors compared vaginal microbiota, vaginal fluid metabolites and/or soluble mucosal immune markers between responders and non-responders. Surprisingly, they “found no association between change in symptom severity and the vaginal microbiota, Lactobacillus dominance, vaginal fluid metabolites, or soluble immune markers.” Dr. Srinivasan said. “However, we noted that more women using estradiol had Lactobacillus-dominant bacterial communities and lower pH than women using moisturizer or placebo at 12 weeks,” Dr. Srinivasan explained. These results suggest that although a change in symptom severity is not correlated with vaginal microbiota or soluble markers of immune inflammation, treatment with estradiol correlates with lower vaginal microbial diversity and lower pH, both proxies for better vaginal health outcomes.  

Although this study did not find a correlation between symptom severity and vaginal microbiota or immune inflammation, the results have larger implications for understanding the relationship between superficial features of the vaginal environment and GSM symptoms. “For clinicians, the takeaway from the study is that while topical estradiol can change the composition of the postmenopausal vaginal microbiota from a diverse community to Lactobacillus dominance, these changes may not alter symptom severity,” Dr. Mitchell said. Going forward, Dr. Mitchell said that this work “highlights the need for additional studies to evaluate other contributing pathways that may be associated with GSM.”    

Mitchell CM, Nanxun M, Mitchell AJ, Wu MC, Valint DJ, Proll S, Reed SD, Guthrie KA, Lacroix AZ, Larson JC, Pepin RP, Raftery D, Fredricks DN, Srinivasan S. Association between postmenopausal vulvovaginal discomfort, vaginal microbiota, and mucosal inflammation. Am J Obstet Gynecol. 2021 Mar 4;S0002-9378(21)00151-4. doi: 10.1016/j.ajog.2021.02.034.

This work was supported by the National Institutes of Health and the National Institute on Aging.

UW/Fred Hutch Cancer Consortium members Michael Wu, Katherine Guthrie, Susan D. Reed, Daniel Raftery and David N. Fredricks were key contributors to this work.