Caroline M Mitchell1, Nanxun Ma2, Alissa J Mitchell3, Michael C Wu2, D J Valint4, Sean Proll4, Susan D Reed5, Katherine A Guthrie2, Andrea Z Lacroix6, Joseph C Larson2, Robert Pepin7, Daniel Raftery8, David N Fredricks9, Sujatha Srinivasan4. 1. Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, MA. Electronic address: caroline.mitchell@mgh.harvard.edu. 2. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA. 3. Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, MA. 4. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA. 5. Department of Obstetrics and Gynecology, University of Washington, Seattle WA. 6. Herbert Wertheim School of Public Health, University of California, San Diego CA. 7. Department of Anesthesiology and Pain Medicine, University of Washington, Seattle WA. 8. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Anesthesiology and Pain Medicine, University of Washington, Seattle WA. 9. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Medicine, University of Washington, University of Washington, Seattle WA.
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.
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.
Authors: Catherine A Chappell; Charles E Isaacs; Weimin Xu; Leslie A Meyn; Kevin Uranker; Charlene S Dezzutti; Bernard J Moncla; Sharon L Hillier Journal: Am J Obstet Gynecol Date: 2015-03-25 Impact factor: 8.661
Authors: Caroline M Mitchell; Sujatha Srinivasan; Anna Plantinga; Michael C Wu; Susan D Reed; Katherine A Guthrie; Andrea Z LaCroix; Tina Fiedler; Matthew Munch; Congzhou Liu; Noah G Hoffman; Ian A Blair; Katherine Newton; Ellen W Freeman; Hadine Joffe; Lee Cohen; David N Fredricks Journal: Menopause Date: 2018-05 Impact factor: 2.953
Authors: Caroline M Mitchell; Susan D Reed; Susan Diem; Joseph C Larson; Katherine M Newton; Kristine E Ensrud; Andrea Z LaCroix; Bette Caan; Katherine A Guthrie Journal: JAMA Intern Med Date: 2018-05-01 Impact factor: 21.873
Authors: Caroline M Mitchell; Sujatha Srinivasan; Xiang Zhan; Michael C Wu; Susan D Reed; Katherine A Guthrie; Andrea Z LaCroix; Tina Fiedler; Matthew Munch; Congzhou Liu; Noah G Hoffman; Ian A Blair; Katherine Newton; Ellen W Freeman; Hadine Joffe; Lee Cohen; David N Fredricks Journal: Menopause Date: 2017-10 Impact factor: 3.310
Authors: Jonathan L Golob; Steven A Pergam; Sujatha Srinivasan; Tina L Fiedler; Congzhou Liu; Kristina Garcia; Marco Mielcarek; Daisy Ko; Sarah Aker; Sara Marquis; Tillie Loeffelholz; Anna Plantinga; Michael C Wu; Kevin Celustka; Alex Morrison; Maresa Woodfield; David N Fredricks Journal: Clin Infect Dis Date: 2017-11-29 Impact factor: 9.079