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

Phase 4

Completed

• Conditions: Postmenopausal Symptoms; Vaginal Atrophy; Female Urogenital Diseases; Postmenopausal Atrophic Vaginitis; Genitourinary Disease
• Interventions: Drug: Conjugated Estrogens Cream

• Registration Number: NCT03996603
• Lead Sponsor: University of Alabama at Birmingham

Brief Summary

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.

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 (IL - Interleukin, TNF - tumor necrosis factor, MCP - monocyte chemoattractant protein, GM - granulocyte macrophage, CSF - colony stimulating factor) 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 Timeline

• Study First Submitted: 2019-06-11
• Study First Submitted QC: 2019-06-20
• Study First Posted: 2019-06-25
• Study Start: 2019-08-01
• Primary Completion: 2021-01-14
• Study Completion: 2021-01-14
• Results First Submitted: 2022-01-19
• Status Verified: 2024-04
• Results First Submitted QC: 2024-04-10
• Last Update Submitted: 2024-04-10
• Results First Posted: 2024-05-07
• Last Update Posted: 2024-05-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 25

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)

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Conjugated Estrogens Cream	Conjugated Estrogens Cream	0.625mg/1g cream, 1g applied vaginally nightly for 2 weeks then 2x/week for 8 weeks

Primary Outcome Measures

Name	Time	Method
Quantitative Change in Relative Abundance of Lactobacillus Among the Community Composition of Bacteria in the Vagina	Baseline, 8 weeks	The relative abundance of the Lactobacillus genus, as measured by 16S ribosomal RNA (rRNA) gene sequencing, is the proportion of Lactobacillus genus among the total vaginal microbiome. After analysis of the gene sequencing, the total yield of bacteria at the genus level equals 1.; 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.

Secondary Outcome Measures

Name	Time	Method
Change in Vaginal pH	Baseline, 8 weeks	Change in the vaginal pH from baseline to 8 weeks
Change in Vaginal Maturation Index (VMI)	Baseline, 8 weeks	The maturation value (MV) is calculated with the following formula: MV = % surface cells + (0.5 × % intermediate cells).; The outcome data is reported as the delta change from baseline to 8 weeks.; The data for the primary outcome has been entered using the "measure type - NUMBER" because the outcome is a delta or change in the vaginal maturation index.
Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF	Baseline, 8 weeks	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

Trial Locations

Locations (1)

University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States