Investigation of Microbiomes of Postmenopausal Women Looking for Outcomes and Response to Estrogen Therapy (IMPLORE)

IMPLORE Study: Investigation of Microbiomes of Postmenopausal Women Looking for Outcomes and Response to Estrogen Therapy

In this proposed pilot study, 16S ribosomal RNA (rRNA) gene sequencing will be used in the analysis of bacterial communities (microbiomes) in postmenopausal women with vulvovaginal atrophy (VVA) before and after eight weeks of vaginal estrogen use. The investigators plan to characterize the composition and dynamics of the microbiomes of the vagina, bladder, and rectum for quantitative and qualitative changes in the distribution of operational taxonomic units (OTUs) before and after eight weeks of local vaginal estrogen therapy. Although the vagina, bladder, and gut microbiomes have been increasingly independently studied, less is known about the interactions of the bacterial communities among the three environments as well as the dynamic relationship with menopausal status and vaginal estrogen therapy and the investigators seek to elucidate these relationships further.

Study Overview

• Status: Completed
• Conditions: Vaginal Atrophy; Female Urogenital Diseases; Postmenopausal Symptoms; Postmenopausal Atrophic Vaginitis; Genitourinary Disease
• Intervention / Treatment: Drug: Conjugated Estrogens Cream

Detailed Description

This is an open-label pilot study of vaginal estrogen therapy in postmenopausal participants with vulvovaginal atrophy. The investigators seek to evaluate the effects of vaginal estrogen therapy on the vaginal, urinary, and rectal bacterial communities (microbiomes) and assess the (i) quantitative change in relative abundance of Lactobacillus among the community composition of bacteria in the vagina, and (ii) to evaluate the vaginal maturation index (VMI), vaginal pH, and vaginal inflammatory biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF and correlate any notable changes with changes noted in the vaginal microbiome, and (iii and iv) observe for quantitative and qualitative changes in the distribution of operational taxonomic units (OTUs) among the bladder and rectal microbiomes. These changes will also be compared to the results yielded from the vaginal microbiome analysis. Additionally the investigators will assess for quantitative changes in the bladder and rectal inflammatory biomarkers (IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF) and correlate these findings with any notable changes in the bladder and rectal microbiomes. Furthermore, changes in these biomarkers will be compared with the data (inflammatory and microbial) yielded from vaginal sampling. Bio-specimens and patient questionnaires will be assessed at baseline and again after eight weeks of vaginal estrogen therapy.

20 participants will receive the intervention (vaginal estrogen therapy) for 8 weeks. 5 participants who meet the same inclusion/exclusion criteria will not receive the intervention and will be sampled at the same time points. The additional 5 participants are intended to serve as a control cohort to demonstrate stability of the microbiome over the study period. The 5 participants may be compared to the 20 participants receiving therapy but that is not part of the primary or secondary outcomes.

The investigators believe that examining the dynamic relationships of the genitourinary-rectal region is innovative and vital to validating the investigator's understanding and assumptions of the pathophysiology and treatment approaches of this disorder.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama At Birmingham

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Postmenopausal with vulvovaginal atrophy
• Age ≥55 years old and a screening vaginal pH of ≥5.
• Without menses for ≥12 months.
• No uterovaginal or vaginal vault prolapse beyond the hymen.
• No estrogen replacement within the last month (may come off current treatment, i.e. wash out, to join the study)

Exclusion Criteria:

• Patients with BMI >35kg/m2
• Any patients with infections requiring antibiotic or antifungal therapy during the study period.
• Study patients may not use any vaginal suppositories, douches, or vaginal hygiene wipes within the month preceding enrollment. For patients already on hormone therapy, will be allowed to undergo a "wash out" period of estrogen or progesterone products for one month prior to enrollment.
• Additional exclusions included patients with systemic conditions requiring immunosuppressive drugs, currently receiving chemotherapy, or history of pelvic radiation.
• Any patients with contraindications to vaginal estrogen therapy including: vaginal bleeding of unknown etiology; known, suspected, or history of breast cancer or estrogen-dependent neoplasia; active DVT, PE, or h/o these conditions; active arterial thromboembolic disease (ie. stroke or MI) or h/o of these; known liver disease or thrombophilic disorders.
• Current tobacco use.
• Allergy to Premarin® or its constituents.
• Concurrent use of steroid creams for other indications (ie. lichen sclerosis)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Conjugated Estrogens Cream; 0.625mg/1g cream, 1g applied vaginally nightly for 2 weeks then 2x/week for 8 weeks	Drug: Conjugated Estrogens Cream; 0.625mg/1g cream, 1g applied vaginally nightly for 2 weeks then 2x/week for 8 weeks; Other Names: Premarin Vaginal Cream
NO_INTERVENTION: Control Cohort; No intervention will be given.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantitative change in relative abundance of Lactobacillus among the community composition of bacteria in the vagina as measured by 16S ribosomal RNA (rRNA) gene sequencing.	The quantitative change in relative abundance of Lactobacillus among the community composition of bacteria in the vagina will be assessed from baseline to 8 weeks. The investigators hypothesize that a pre-specified statistically significant quantitative increase in the relative abundance of Lactobacillus will be seen among the participants that receive treatment.	Baseline, 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vaginal Maturation Index (VMI)	Change in the vaginal maturation index from baseline to 8 weeks	Baseline, 8 weeks
Vaginal pH	Change in the vaginal pH from baseline to 8 weeks	Baseline, 8 weeks
Vaginal inflammatory biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF	Change in the vaginal inflammatory biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF from baseline to 8 weeks	Baseline, 8 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantitative and qualitative changes in the distribution of operational taxonomic units (OTUs) in the bladder microbiome.	Quantitative and qualitative changes in the distribution of operational taxonomic units (OTUs) from baseline to 8 weeks.	Baseline, 8 weeks
Quantitative and qualitative changes in the distribution of operational taxonomic units (OTUs) in the rectal microbiome.	Quantitative and qualitative changes in the distribution of operational taxonomic units (OTUs) from baseline to 8 weeks.	Baseline, 8 weeks
Bladder inflammatory biomarkers (IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF)	Change in the concentration of bladder inflammatory biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF from baseline to 8 weeks	Baseline, 8 weeks
Rectal inflammatory biomarkers (IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF)	Change in the concentration of rectal inflammatory biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF from baseline to 8 weeks	Baseline, 8 weeks

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Investigators: Principal Investigator: Kyle P Norris, MD, University of Alabama At Birmingham

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 1, 2019
• Primary Completion (ACTUAL): January 14, 2021
• Study Completion (ACTUAL): January 14, 2021

Study Registration Dates

• First Submitted: June 11, 2019
• First Submitted That Met QC Criteria: June 20, 2019
• First Posted (ACTUAL): June 25, 2019

Study Record Updates

• Last Update Posted (ACTUAL): May 27, 2021
• Last Update Submitted That Met QC Criteria: May 26, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Inflammatory Response; Genitourinary Syndrome of Menopause; Vaginal Atrophy; Vaginal Microbiome; Microbial Colonization; Vaginal Estrogen Therapy; Urinary Microbiome; Rectal Microbiome; Conjugated Estrogen Cream
• Additional Relevant MeSH Terms: Pathological Conditions, Anatomical; Vaginal Diseases; Vaginitis; Atrophic Vaginitis; Atrophy; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Estrogens, Conjugated (USP)
• Other Study ID Numbers: IRB-300002968

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes