The Estrogen Impact on Overactive Bladder Syndrome: Female Pelvic Floor Microbiomes and Antimicrobial Peptides

NCT ID: NCT02524769

Last Updated: 2021-04-15

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

NA

Total Enrollment

27 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-12-31

Study Completion Date

2017-06-30

Brief Summary

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The medical field is beginning to adopt treatments that alter an individual's microbiome to improve patient health; however, this approach has not been adopted for treatment of lower urinary tract symptoms (LUTS). Here, the investigators propose the first step in development of such a therapy. If the investigators hypothesis is correct, the investigators could change the first line of treatment for hypoestrogenic women and develop future therapies that modulate bacteria in the bladder to improve not only LUTS but also treatment response. This could lead to the first treatment for lower urinary disorders that incorporates a person's individual microbiome.

Detailed Description

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Overactive bladder (OAB) syndrome is characterized by the symptom complex of urinary urgency, usually with associated frequency and nocturia, with or without urgency urinary incontinence in the absence of infection or other pathology. Vaginal estrogen, a well-documented treatment for OAB in hypoestrogenic women, has been shown to improve symptoms of frequency, urgency and urgency urinary incontinence (UUI). Several theories have been proposed to explain the mechanism underlying estrogen's effect on lower urinary tract symptoms (LUTS). Investigators propose that estrogen treatment influences bacterial communities (microbiomes) in the vagina and bladder and alters urothelial and vaginal (AMPs); thereby improving OAB symptoms in hypoestrogenic women.

Long-standing medical dogma has been replaced by clear evidence that a female urinary microbiome (FUM) exists.This suggests that the FUM is a factor in lower urinary tract symptoms (LUTS) and that FUM diversity contributes to LUTS and treatment response, like the vaginal microbiome and its contribution to vaginal symptoms.

In hypoestrogenic women, the vaginal microbiome shifts from low diversity communities, commonly dominated by Lactobacillus, to more diverse communities dominated by anaerobes; this change can be reversed with estrogen treatment. Since the FUM of women with OAB includes bacteria similar to those of the vaginal microbiome (e.g. Lactobacillus, Gardnerella, and diverse anaerobes), investigators reason the FUM would respond similarly to estrogen and become less diverse. While almost nothing is known about urinary/vaginal microbiome interplay, even less is known about immune response modulation in the bladder and vagina. However, estrogen reduces the subsequent urinary tract infection (UTI) rate in hypoestrogenic women affected by recurrent UTI, and estrogen induces urothelial antimicrobial peptide (AMP) expression. Since AMPs exhibit microbicidal activity, stimulate inflammation, and facilitate epithelial barrier homeostasis, estrogen may work through AMPs as mediators to optimize microbial equilibrium.

Conditions

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Overactive Bladder

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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conjugated estrogen

All patients in the study will receive 0.625 mg conjugated estrogen/gram to use 0.5 grams twice weekly with the applicator for 12 weeks.

Group Type OTHER

conjugated estrogen

Intervention Type DRUG

0.625 mg conjugated estrogen/gram and instructions to use 0.5 grams twice weekly with the applicator.

Interventions

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conjugated estrogen

0.625 mg conjugated estrogen/gram and instructions to use 0.5 grams twice weekly with the applicator.

Intervention Type DRUG

Other Intervention Names

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Vaginal estrogen Premarin Cream® 0.625 mg

Eligibility Criteria

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Inclusion Criteria

* Clinical diagnosis of Overactive bladder
* Clinical diagnosis of Postmenopausal:
* English language skills sufficient to complete questionnaires
* Clinical indication for vaginal estrogen use
* Not currently receiving vaginal estrogen therapy

Exclusion Criteria

* Currently on systemic hormone replacement therapy (HRT) Have been on HRT within the past three months
* Clinical diagnosis of estrogen dependent malignancies
* Allergy to local estrogen therapy
* Insufficient language skills to complete study questionnaires
* Women with active, urinary tract infection
* Received antibiotics within the past two weeks
* Clinical diagnosis of stage 3 or 4 pelvic organ prolapse
* Patient unwilling to use vaginal estrogen preparation
* Currently on anticholinergic medication Have received anticholinergic medication within the past three months
* Previously failed two medications for treatment of OAB Previously received intra-vesicle botulinum toxin injections Previously had posterior tibial nerve stimulation Previously had implantation of sacral neuromodulator
* Patients wishing to start anticholinergic medication at the initial encounter
* Undiagnosed abnormal genital bleeding
* Clinical diagnosis of deep vein thrombosis (DVT) Clinical diagnosis of pulmonary embolism (PE)
* Clinical diagnosis of arterial thromboembolic disease
* Clinical diagnosis of liver dysfunction or disease
* Clinical diagnosis of protein C, protein S or antithrombin or deficiency other known thrombophilic disorders
Minimum Eligible Age

55 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No

Sponsors

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Loyola University

OTHER

Sponsor Role lead

Responsible Party

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Elizabeth Mueller

M.D. PhD

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Cynthia Brincat, MD

Role: PRINCIPAL_INVESTIGATOR

Loyola University

Locations

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Loyola University Medical Center

Maywood, Illinois, United States

Site Status

Countries

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United States

References

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Pearce MM, Hilt EE, Rosenfeld AB, Zilliox MJ, Thomas-White K, Fok C, Kliethermes S, Schreckenberger PC, Brubaker L, Gai X, Wolfe AJ. The female urinary microbiome: a comparison of women with and without urgency urinary incontinence. mBio. 2014 Jul 8;5(4):e01283-14. doi: 10.1128/mBio.01283-14.

Reference Type BACKGROUND
PMID: 25006228 (View on PubMed)

Hilt EE, McKinley K, Pearce MM, Rosenfeld AB, Zilliox MJ, Mueller ER, Brubaker L, Gai X, Wolfe AJ, Schreckenberger PC. Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J Clin Microbiol. 2014 Mar;52(3):871-6. doi: 10.1128/JCM.02876-13. Epub 2013 Dec 26.

Reference Type BACKGROUND
PMID: 24371246 (View on PubMed)

Wolfe AJ, Toh E, Shibata N, Rong R, Kenton K, Fitzgerald M, Mueller ER, Schreckenberger P, Dong Q, Nelson DE, Brubaker L. Evidence of uncultivated bacteria in the adult female bladder. J Clin Microbiol. 2012 Apr;50(4):1376-83. doi: 10.1128/JCM.05852-11. Epub 2012 Jan 25.

Reference Type BACKGROUND
PMID: 22278835 (View on PubMed)

Khasriya R, Sathiananthamoorthy S, Ismail S, Kelsey M, Wilson M, Rohn JL, Malone-Lee J. Spectrum of bacterial colonization associated with urothelial cells from patients with chronic lower urinary tract symptoms. J Clin Microbiol. 2013 Jul;51(7):2054-62. doi: 10.1128/JCM.03314-12. Epub 2013 Apr 17.

Reference Type BACKGROUND
PMID: 23596238 (View on PubMed)

Fok CS, McKinley K, Mueller ER, Kenton K, Schreckenberger P, Wolfe A, Brubaker L. Day of surgery urine cultures identify urogynecologic patients at increased risk for postoperative urinary tract infection. J Urol. 2013 May;189(5):1721-4. doi: 10.1016/j.juro.2012.11.167. Epub 2012 Dec 3.

Reference Type BACKGROUND
PMID: 23219547 (View on PubMed)

Nelken RS, Ozel BZ, Leegant AR, Felix JC, Mishell DR Jr. Randomized trial of estradiol vaginal ring versus oral oxybutynin for the treatment of overactive bladder. Menopause. 2011 Sep;18(9):962-6. doi: 10.1097/gme.0b013e3182104977.

Reference Type BACKGROUND
PMID: 21532512 (View on PubMed)

Tseng LH, Wang AC, Chang YL, Soong YK, Lloyd LK, Ko YJ. 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(1):47-51. doi: 10.1002/nau.20583.

Reference Type BACKGROUND
PMID: 19089890 (View on PubMed)

Stewart WF, Van Rooyen JB, Cundiff GW, Abrams P, Herzog AR, Corey R, Hunt TL, Wein AJ. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003 May;20(6):327-36. doi: 10.1007/s00345-002-0301-4. Epub 2002 Nov 15.

Reference Type BACKGROUND
PMID: 12811491 (View on PubMed)

Eriksen PS, Rasmussen H. 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 Apr 21;44(2):137-44. doi: 10.1016/0028-2243(92)90059-8.

Reference Type BACKGROUND
PMID: 1587379 (View on PubMed)

Brading AF. A myogenic basis for the overactive bladder. Urology. 1997 Dec;50(6A Suppl):57-67; discussion 68-73. doi: 10.1016/s0090-4295(97)00591-8.

Reference Type BACKGROUND
PMID: 9426752 (View on PubMed)

Griebling TL, Liao Z, Smith PG. Systemic and topical hormone therapies reduce vaginal innervation density in postmenopausal women. Menopause. 2012 Jun;19(6):630-5. doi: 10.1097/gme.0b013e31823b8983.

Reference Type BACKGROUND
PMID: 22205148 (View on PubMed)

Brotman RM, Shardell MD, Gajer P, Fadrosh D, Chang K, Silver MI, Viscidi RP, Burke AE, Ravel J, Gravitt PE. Association between the vaginal microbiota, menopause status, and signs of vulvovaginal atrophy. Menopause. 2014 May;21(5):450-8. doi: 10.1097/GME.0b013e3182a4690b.

Reference Type BACKGROUND
PMID: 24080849 (View on PubMed)

Raz R. Urinary tract infection in postmenopausal women. Korean J Urol. 2011 Dec;52(12):801-8. doi: 10.4111/kju.2011.52.12.801. Epub 2011 Dec 20.

Reference Type BACKGROUND
PMID: 22216390 (View on PubMed)

Coyne K, Revicki D, Hunt T, Corey R, Stewart W, Bentkover J, Kurth H, Abrams P. Psychometric validation of an overactive bladder symptom and health-related quality of life questionnaire: the OAB-q. Qual Life Res. 2002 Sep;11(6):563-74. doi: 10.1023/a:1016370925601.

Reference Type BACKGROUND
PMID: 12206577 (View on PubMed)

Rahn DD, Ward RM, Sanses TV, Carberry C, Mamik MM, Meriwether KV, Olivera CK, Abed H, Balk EM, Murphy M; Society of Gynecologic Surgeons Systematic Review Group. Vaginal estrogen use in postmenopausal women with pelvic floor disorders: systematic review and practice guidelines. Int Urogynecol J. 2015 Jan;26(1):3-13. doi: 10.1007/s00192-014-2554-z. Epub 2014 Nov 13.

Reference Type BACKGROUND
PMID: 25392183 (View on PubMed)

Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SS, McCulle SL, Karlebach S, Gorle R, Russell J, Tacket CO, Brotman RM, Davis CC, Ault K, Peralta L, Forney LJ. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1(Suppl 1):4680-7. doi: 10.1073/pnas.1002611107. Epub 2010 Jun 3.

Reference Type BACKGROUND
PMID: 20534435 (View on PubMed)

Thomas-White K, Taege S, Limeira R, Brincat C, Joyce C, Hilt EE, Mac-Daniel L, Radek KA, Brubaker L, Mueller ER, Wolfe AJ. Vaginal estrogen therapy is associated with increased Lactobacillus in the urine of postmenopausal women with overactive bladder symptoms. Am J Obstet Gynecol. 2020 Nov;223(5):727.e1-727.e11. doi: 10.1016/j.ajog.2020.08.006. Epub 2020 Aug 11.

Reference Type DERIVED
PMID: 32791124 (View on PubMed)

Other Identifiers

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207152

Identifier Type: -

Identifier Source: org_study_id

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