Background
Previous work has shown that the vaginal microbiome decreases in Lactobacillus predominance and becomes more diverse after menopause. It has also been shown that
estrogen therapy restores Lactobacillus dominance in the vagina and that topical estrogen is associated with overactive bladder
symptom improvement. We now know that the bladder contains a unique microbiome and
that increased bladder microbiome diversity is associated with overactive bladder.
However, there is no understanding of how quickly each pelvic floor microbiome responds
to estrogen or if those changes are associated with symptom improvement.
Objective
This study aimed to determine if estrogen treatment of postmenopausal women with overactive
bladder decreases urobiome diversity.
Study Design
We analyzed data from postmenopausal participants in 2 trials (NCT02524769 and NCT02835846) who chose vaginal estrogen as the primary overactive bladder treatment and used
0.5 g of conjugated estrogen (Premarin cream; Pfizer, New York City, NY) twice weekly
for 12 weeks. Baseline and 12-week follow-up data included the Overactive Bladder
questionnaire, and participants provided urine samples via catheter, vaginal swabs,
perineal swabs, and voided urine samples. Microbes were detected by an enhanced culture
protocol. Linear mixed models were used to estimate microbiome changes over time.
Urinary antimicrobial peptide activity was assessed by a bacterial growth inhibition
assay and correlated with relative abundance of members of the urobiome.
Results
In this study, 12 weeks of estrogen treatment resulted in decreased microbial diversity
within the vagina (Shannon, P=.047; Richness, P=.043) but not in the other niches. A significant increase in Lactobacillus was detected in the bladder (P=.037) but not in the vagina (P=.33), perineum (P=.56), or voided urine (P=.28). The change in Lactobacillus levels in the bladder was associated with modest changes in urgency incontinence
symptoms (P=.02). The relative abundance of the genus Corynebacterium correlated positively with urinary antimicrobial peptide activity after estrogen
treatment.
Conclusion
Estrogen therapy may change the microbiome of different pelvic floor niches. The vagina
begins to decrease in diversity, and the bladder experiences a significant increase
in Lactobacillus levels; the latter is correlated with a modest improvement in the symptom severity
subscale of the Overactive Bladder questionnaire.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic and PersonalCorporate R&D ProfessionalsOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to American Journal of Obstetrics & GynecologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Association between the vaginal microbiota, menopause status, and signs of vulvovaginal atrophy.Menopause. 2014; 21: 450-458
- Vaginal microbiome of reproductive-age women.Proc Natl Acad Sci USA. 2011; 108: 4680-4687
- Vaginal microbial diversity among postmenopausal women with and without hormone replacement therapy.Can J Microbiol. 2005; 51: 777-781
- Effects of low dose estrogen therapy on the vaginal microbiomes of women with atrophic vaginitis.Sci Rep. 2016; 6: 24380
- A systematic review of the effects of estrogens for symptoms suggestive of overactive bladder.Acta Obstet Gynecol Scand. 2004; 83: 892-897
- An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction.Neurourol Urodyn. 2010; 29: 4-20
- Systemic and topical hormone therapies reduce vaginal innervation density in postmenopausal women.Menopause. 2012; 19: 630-635
- A promising protein responsible for overactive bladder in ovariectomized mice.Taiwan J Obstet Gynecol. 2017; 56: 196-203
- Estrogen supports urothelial defense mechanisms.Sci Transl Med. 2013; 5: 190ra80
- The female urinary microbiome: a comparison of women with and without urgency urinary incontinence.mBio. 2014; 5 (e01283–14)
- Incontinence medication response relates to the female urinary microbiota.Int Urogynecol J. 2016; 27: 723-733
- Interplay between bladder microbiota and urinary antimicrobial peptides: mechanisms for human urinary tract infection risk and symptom severity.PLoS One. 2014; 9: e114185
- Cutaneous burn injury modulates urinary antimicrobial peptide responses and the urinary microbiome.Crit Care Med. 2017; 45: e543-e551
- Ribonuclease 7 shields the kidney and bladder from invasive uropathogenic Escherichia coli infection.J Am Soc Nephrol. 2019; 30: 1385-1397
- Estrogenic action on innate defense mechanisms in the urinary tract.Maturitas. 2014; 77: 32-36
- Culturing of female bladder bacteria reveals an interconnected urogenital microbiota.Nat Commun. 2018; 9: 1557
- Prevalence and incidence of urinary incontinence in community-dwelling populations.J Am Geriatr Soc. 1990; 38: 273-281
- Psychometric validation of an overactive bladder symptom and health-related quality of life questionnaire: the OAB-q.Qual Life Res. 2002; 11: 563-574
- The standardization of terminology of female pelvic organ prolapse and pelvic floor dysfunction.Am J Obstet Gynecol. 1996; 175: 10-17
- Vaginal estrogen use in postmenopausal women with pelvic floor disorders: systematic review and practice guidelines.Int Urogynecol J. 2015; 26: 3-13
- Randomized comparison of tolterodine with vaginal estrogen cream versus tolterodine alone for the treatment of postmenopausal women with overactive bladder syndrome.Neurourol Urodyn. 2009; 28: 47-51
- Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder.J Clin Microbiol. 2014; 52: 871-876
- RStudio: integrated development for R.(Available at:)http://www.rstudio.com/(Accessed June 6, 2020)Date: 2015
- Amphipathic alpha helical antimicrobial peptides.Eur J Biochem. 2001; 268: 5589-5600
- Why the product labeling for low-dose vaginal estrogen should be changed.Menopause. 2014; 21: 911-916
- Determining the importance of change in the overactive bladder questionnaire.J Urol. 2006; 176 (discussion 632): 627-632
- vegan: community ecology package [Computer program].(Available at:)https://CRAN.R-project.org/package=vegan(Accessed June 6, 2020)Date: 2019
- cowplot: streamlined plot theme and plot annotations for ‘ggplot2’ [Computer program].(Available at:) (Accessed June 6, 2020)
- ggplotify: convert plot to ‘grob’ or ‘ggplot’ object [Computer program].(Available at:) (Accessed June 6, 2020)
- ggplot2: elegant graphics for data analysis [Computer program].(Available at:)https://ggplot2.tidyverse.org(Accessed June 6, 2020)Date: 2016
Benness C, Wise B, Cutner A, Cardozo L. Does low dose vaginal estradiol improve frequency and urgency in postmenopausal women? [abstract]. Proceedings of the American urogynecology society meeting. Cambridge: Massachusetts; 1992: 13th annual.
- Low-dose 17 beta-estradiol vaginal tablets in the treatment of atrophic vaginitis: a double-blind placebo controlled study.Eur J Obstet Gynecol Reprod Biol. 1992; 44: 137-144
- Randomized trial of estradiol vaginal ring versus oral oxybutynin for the treatment of overactive bladder.Menopause. 2011; 18: 962-966
- Vaginal oestradiol for the treatment of lower urinary tract symptoms in postmenopausal women--a double-blind placebo-controlled study.J Obstet Gynaecol. 2001; 21: 383-385
- Novel insight into the vaginal microflora in postmenopausal women under hormone replacement therapy as analyzed by PCR-denaturing gradient gel electrophoresis.Eur J Obstet Gynecol Reprod Biol. 2004; 117: 76-81
- Ecological resilience—in theory and application.Annu Rev Ecol Syst. 2000; 31: 425-439
- Exploratory comparison of vaginal glycogen and Lactobacillus levels in premenopausal and postmenopausal women.Menopause. 2015; 22: 702-709
- Corynebacterium urealyticum: a comprehensive review of an understated organism.Infect Drug Resist. 2015; 8: 129-145
- One-year treatment persistence with local estrogen therapy in postmenopausal women diagnosed as having vaginal atrophy.Menopause. 2015; 22: 1197-1203
- ImageJ2: ImageJ for the next generation of scientific image data.BMC Bioinformatics. 2017; 18: 529
Article Info
Publication History
Published online: August 10, 2020
Accepted:
August 6,
2020
Received in revised form:
July 23,
2020
Received:
January 30,
2020
Footnotes
K.T.W. reports being a member of the advisory board of Live UTI Free. K.A.R. reports receiving research support from Kimberly-Clark Corporation . L.B. reports receiving editorial stipends from the Journal of the American Medical Association, Female Pelvic Medicine and Reconstructive Surgery, and UpToDate. E.R.M. reports receiving research support from Astellas Scientific and Medical Affairs Inc, being a member of the advisory board of the Boston Scientific Corporation , receiving royalties from UpToDate, and performing legal review for Bulter-Snow and Ethicon . A.J.W. reports receiving research support from Astellas Scientific and Medical Affairs Inc and Kimberly-Clark Corporation. S.T., C.B., C.J., E.E.H., and L.M.D. report no conflict of interest.
This study has been registered on ClinicalTrials.gov with clinical trial identification numbers NCT02524769 (https://clinicaltrials.gov/ct2/show/NCT02524769) and NCT02835846 (https://clinicaltrials.gov/ct2/show/NCT02835846).
This study was funded by the Loyola Urogynecology Division Research Fund, an investigator-initiated grant from the Kimberly-Clark Corporation, by 2 National Institutes of Health awards given to A.J.W. and L.B. (R56DK104718 and R01 DK104718), and by the Arthur J. Schmitt Dissertation Fellowship. The funders had no input in the design, execution, or interpretation of the study.
Cite this article as: Thomas-White K, Taege S, Limeira R, et al. Vaginal estrogen therapy is associated with increased Lactobacillus in the urine of postmenopausal women with overactive bladder symptoms. Am J Obstet Gynecol 2020;223:727.e1-11.
Identification
Copyright
© 2020 Elsevier Inc. All rights reserved.
