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

• ClinicalTrials.gov Identifier: NCT02524769
• Recruitment Status: Completed
• First Posted: August 17, 2015
• Results First Posted: April 15, 2021
• Last Update Posted: April 15, 2021
• Sponsor: Loyola University
• Information provided by (Responsible Party): Elizabeth Mueller, Loyola University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Overactive Bladder	Drug: conjugated estrogen	Not Applicable

Detailed Description:

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Long-standing medical dogma has been replaced by clear evidence that a female urinary microbiome (FUM) exists.This suggests that the FUM is a factor in lower urinary tract symptoms (LUTS) and that FUM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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Estrogen Impact on Overactive Bladder Syndrome: Female Pelvic Floor Microbiomes and Antimicrobial Peptides
• Study Start Date: December 2015
• Actual Primary Completion Date: November 2016
• Actual Study Completion Date: June 2017

Arms and Interventions

Arm	Intervention/treatment
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.	Drug: conjugated estrogen; 0.625 mg conjugated estrogen/gram and instructions to use 0.5 grams twice weekly with the applicator.; Other Name: Vaginal estrogen Premarin Cream® 0.625 mg

Outcome Measures

Primary Outcome Measures :

1. Change in the Relative Abundance of Lactobacillus [ Time Frame: 0, 12 weeks ]
   The relative abundance of Lactobacillus to total microbes per sample was measured before and after treatment. The within-participant change in relative abundance of Lactobacillus was calculated subtracting pre-treatment from post-treatment.

Secondary Outcome Measures :

1. Change in OAB Symptoms [ Time Frame: 0, 12 weeks ]
   OAB symptoms are measured using the Overactive Bladder Questionnaire (OAB-q). The OAB-q symptom score ranges from 0-100 with higher scores indicating greater symptom severity. A change score is calculated as the post-treatment score minus the pre-treatment score.
2. OAB Symptoms Associated With Relative Abundance of Lactobacillus [ Time Frame: 0, 12 weeks ]
   The investigators will determine whether change in OAB symptoms using the OAB-q before and after treatment is associated with the change in participants' relative abundance of Lactobacillus before and after treatment. The OAB-q symptom score ranges from 0-100 with higher scores indicating greater symptom severity.
3. Change in Urothelial Antimicrobial Peptide (AMP) Levels [ Time Frame: 0, 12 weeks ]
   The investigators will compare participants' AMP levels before and after treatment. AMP activity level is measured as bacterial growth inhibition in square millimeters normalized to the total peptide bond concentration. Change is calculated as the post-treatment AMP level minus the pre-treatment AMP level.
4. Change in OAB Symptoms Associated With Change in AMP Levels [ Time Frame: 0, 12 weeks ]
   The investigators will determine whether any change in OAB symptoms using the OAB-q before and after treatment is associated with the change in participants' AMP levels before and after treatment. AMP activity level is measured as bacterial growth inhibition in square millimeters normalized to the total peptide bond concentration. The OAB-q symptom score ranges from 0-100 with higher scores indicating greater symptom severity.

Eligibility Criteria

• Ages Eligible for Study: 55 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Illinois

Loyola University Medical Center

Maywood, Illinois, United States, 60153

Sponsors and Collaborators

Loyola University

Investigators

• Principal Investigator: Cynthia Brincat, MD; Loyola University

More Information

Publications:

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Elizabeth Mueller, M.D. PhD, Loyola University
• ClinicalTrials.gov Identifier: NCT02524769
• Other Study ID Numbers: 207152
• First Posted: August 17, 2015
• Results First Posted: April 15, 2021
• Last Update Posted: April 15, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Elizabeth Mueller, Loyola University:

Urge Urinary Incontinence; Urinary Incontinence

Additional relevant MeSH terms:

Urinary Bladder, Overactive; Urinary Bladder Diseases; Urologic Diseases; Lower Urinary Tract Symptoms; Urological Manifestations; Estrogens; Estrogens, Conjugated (USP); Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs