Clinical trial NCT03996603: Investigation of Microbiomes of Postmenopausal Women Looking for Outcomes and Response to Estrogen Therapy
Official title: IMPLORE Study: Investigation of Microbiomes of Postmenopausal Women Looking for Outcomes and Response to Estrogen Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Female Urogenital Diseases
Vaginal Atrophy
Postmenopausal Atrophic Vaginitis
Genitourinary Disease
Postmenopausal Symptoms
Keywords: Genitourinary Syndrome of Menopause
Vaginal Atrophy
Vaginal Estrogen Therapy
Inflammatory Response
Microbial Colonization
Urinary Microbiome
Vaginal Microbiome
Rectal Microbiome
Conjugated Estrogen Cream
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
First posted: 2019-06-25
Enrollment: 25
Sex: FEMALE
Minimum age (years): 55
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Quantitative Change in Relative Abundance of Lactobacillus Among the Community Composition of Bacteria in the Vagina
timeFrame: Baseline, 8 weeks
Secondary outcomes:
measure: Change in Vaginal Maturation Index (VMI)
timeFrame: Baseline, 8 weeks
measure: Change in Vaginal pH
timeFrame: Baseline, 8 weeks
measure: Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF
timeFrame: Baseline, 8 weeks
Other outcomes:
measure: Quantitative and Qualitative Changes in the Distribution of Operational Taxonomic Units (OTUs) in the Bladder Microbiome.
timeFrame: Baseline, 8 weeks
measure: Quantitative and Qualitative Changes in the Distribution of Operational Taxonomic Units (OTUs) in the Rectal Microbiome.
timeFrame: Baseline, 8 weeks
measure: Bladder Inflammatory Biomarkers (IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF)
timeFrame: Baseline, 8 weeks
measure: Rectal Inflammatory Biomarkers (IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF)
timeFrame: Baseline, 8 weeks
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
Study officials:
affiliation: University of Alabama at Birmingham
name: Kyle P Norris, MD
role: PRINCIPAL_INVESTIGATOR
References: