Investigation of the Effect of the Female Urinary Microbiome on Incontinence (FUM)

August 30, 2021 updated by: Alan J. Wolfe, Loyola University
This purpose of this study is to understand the types of bacteria that are in the bladder and vagina in patients with overactive bladder (OAB) symptoms and understand if the types of bacteria change when with the use of estrogen in the vagina. The investigators are also trying to understand how estrogen influences the body's ability to make substances called peptides that can kill bacteria.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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. OAB affects approximately 31% of women over the age of 65. 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). The 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Long-standing medical dogma has been replaced by clear evidence that a female urinary microbiome (FUM) exists. The investigators recently reported that the FUM in women without OAB is less diverse than the FUM of women with OAB. The investigators soon will report that FUM status stratifies women with OAB into treatment response groups and women with less diverse FUMs are more likely to respond to anti-cholinergic OAB therapy (Thomas-White et al., in preparation). 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), the investigators reason the FUM would respond similarly to estrogen and become less diverse. Although transvaginal medications likely alter nearby bacterial niches (e.g. the bladder), no study has reported the urinary microbiomic response to vaginal estrogen.

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.

The investigators hypothesize that, following estrogen treatment of hypoestrogenic women with OAB, symptom improvement will be associated with 1) reduced FUM diversity, 2) alteration of other FUM characteristics and 3) increased AMP levels. The investigators propose two specific aims:

Aim 1: To compare pelvic floor microbiome (PFM) diversity and AMP levels before and after estrogen treatment in hypoestrogenic women with OAB symptoms.

Aim 2: Determine if FUM characteristics correlate with OAB symptoms.

Study Type

Interventional

Enrollment (Actual)

35

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Illinois
      • Maywood, Illinois, United States, 60153
        • Loyola University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Women who present with symptoms of OAB, defined as a condition characterized by urgency, with or without urgency incontinence, usually with frequency and nocturia in the absence of obvious pathology or infection [9], with atrophic vaginitis.
  • Postmenopausal by history (i.e., defined as twelve months or greater since last menstrual period), surgical menopause with removal of bilateral ovaries, or age over 55 with a previous hysterectomy (without removal of bilateral ovaries).
  • English language skills sufficient to complete questionnaires
  • Clinical indication for vaginal estrogen use (i.e., hypoestrogenic findings on physical examination)
  • Patients not currently receiving vaginal estrogen therapy

Exclusion Criteria:

  • Patients currently on systemic hormone replacement therapy (HRT) or who have been on HRT within the past three months
  • Patients with current diagnosis or history of estrogen dependent malignancies (e.g., breast or endometrial malignancies)
  • Contraindication or allergy to estrogen therapy
  • Insufficient English language skills to complete study questionnaires
  • Women with active, standard culture positive urinary tract infection at baseline assessment, or those with a urine dip positive for leukocytes and nitrates on straight catheterized sample.
  • Patients who have received antibiotics within the past two weeks
  • Patients with stage 3 or 4 pelvic organ prolapse based on the pelvic organ prolapse quantitation system (POP-q)
  • Patients unwilling to use vaginal estrogen preparation
  • Patients currently on anticholinergic medications or who have received anticholinergic medications within the past three months
  • Patients who have previously failed two medications for treatment of OAB or have previously received more advanced treatment for OAB including intra-vesicle botulinum toxin injections, posterior tibial nerve stimulation, or implantation of a sacral neuromodulator
  • Patients wishing to start anticholinergic medication at the initial encounter
  • Undiagnosed abnormal genital bleeding
  • Active deep vein thrombosis (DVT), pulmonary embolism (PE), or a history of these conditions
  • Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions
  • Known liver dysfunction or disease
  • Known protein C, protein S, or antithrombin deficiency or other known thrombophilic disorders

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Estrogen Arm
The intervention for this study is an estrogen cream (i.e., Premarin Cream®). Women in this study will receive this estrogen cream and apply it to their vagina twice weekly for 12 weeks
Drug: Estrogen Cream
Participants are provided a vaginal estrogen cream (i.e., Premarin Cream® 0.625 mg conjugated estrogen/gram) and instructed to use 0.5 grams with an applicator twice weekly for 12 weeks.
Other Names:
  • Premarin Cream®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
0, 12 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
0, 12 weeks
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.
0, 12 weeks
Change in Urothelial Antimicrobial Peptide (AMP) Levels
Time Frame: 0, 12 weeks
The investigators will compare participants' AMP activity levels before and after treatment. AMP activity level is measured as the diffusion of AMPs in bacterial agar from the center of the well to which the patient's purified biological sample is applied. The diffusion of AMPs in the agar results in the killing of bacteria and a clearing around the well. This clearing of bacterial growth is measured in square millimeters and then normalized to the total peptide concentration. Change is calculated as the post-treatment AMP activity level minus the pre-treatment AMP activity level.
0, 12 weeks
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.
0, 12 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Loyola University

Collaborators

Kimberly-Clark Corporation

Investigators

  • Principal Investigator: Alan Wolfe, PhD, Loyola University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2016

Primary Completion (Actual)

March 1, 2018

Study Completion (Actual)

May 1, 2018

Study Registration Dates

First Submitted

July 10, 2016

First Submitted That Met QC Criteria

July 13, 2016

First Posted (Estimate)

July 18, 2016

Study Record Updates

Last Update Posted (Actual)

September 23, 2021

Last Update Submitted That Met QC Criteria

August 30, 2021

Last Verified

November 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 207777

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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