Female Urogenital Diseases, Genitourinary Disease, Postmenopausal Atrophic Vaginitis, Postmenopausal Symptoms, Vaginal Atrophy
Conditions
Keywords
Genitourinary Syndrome of Menopause, Vaginal Atrophy, Vaginal Estrogen Therapy, Inflammatory Response, Microbial Colonization, Urinary Microbiome, Vaginal Microbiome, Rectal Microbiome, Conjugated Estrogen Cream
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.
Interventions
0.625mg/1g cream, 1g applied vaginally nightly for 2 weeks then 2x/week for 8 weeks
Sponsors
University of Alabama at Birmingham
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
55 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Change in Vaginal pH | Baseline, 8 weeks | Change in the vaginal pH from baseline to 8 weeks |
| 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Quantitative and Qualitative Changes in the Distribution of Operational Taxonomic Units (OTUs) in the Bladder Microbiome. | Baseline, 8 weeks | Quantitative and qualitative changes in the distribution of operational taxonomic units (OTUs) from baseline to 8 weeks. |
| Quantitative and Qualitative Changes in the Distribution of Operational Taxonomic Units (OTUs) in the Rectal Microbiome. | Baseline, 8 weeks | Quantitative and qualitative changes in the distribution of operational taxonomic units (OTUs) from baseline to 8 weeks. |
| Bladder Inflammatory Biomarkers (IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF) | Baseline, 8 weeks | 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 |
| Rectal Inflammatory Biomarkers (IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF) | Baseline, 8 weeks | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Conjugated Estrogens Cream 0.625mg/1g cream, 1g applied vaginally nightly for 2 weeks then 2x/week for 8 weeks
Conjugated Estrogens Cream: 0.625mg/1g cream, 1g applied vaginally nightly for 2 weeks then 2x/week for 8 weeks | 20 |
| Control Cohort No intervention will be given. | 5 |
| Total | 25 |
Baseline characteristics
| Characteristic | Conjugated Estrogens Cream | Total | Control Cohort |
|---|---|---|---|
| Age, Continuous | 65.5 years | 66 years | 71 years |
| Body Mass Index | 27.3 kg/m^2 | 27.3 kg/m^2 | 30.9 kg/m^2 |
| Currently on OAB/UUI Medication(s) | 3 Participants | 5 Participants | 2 Participants |
| Currently Sexually Active | 12 Participants | 14 Participants | 2 Participants |
| Diabetes Mellitus | 4 Participants | 4 Participants | 0 Participants |
| Hysterectomy | 10 Participants | 12 Participants | 2 Participants |
| Parity | 2 births | 2 births | 2 births |
| Prior Prolapse Surgery | 2 Participants | 4 Participants | 2 Participants |
| Prior SUI Surgery | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 7 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 17 Participants | 3 Participants |
| Recurrent UTIs | 2 Participants | 2 Participants | 0 Participants |
| Region of Enrollment United States | 20 Participants | 25 Participants | 5 Participants |
| Sex: Female, Male Female | 20 Participants | 25 Participants | 5 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Spontaneous Vaginal Delivery | 2 deliveries | 2 deliveries | 1 deliveries |
| Vaginal Maturation Index | 37.5 units on a scale | 40 units on a scale | 40 units on a scale |
| Vaginal pH | 6.8 pH | 7 pH | 7 pH |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 5 |
| other Total, other adverse events | 0 / 20 | 0 / 5 |
| serious Total, serious adverse events | 0 / 20 | 0 / 5 |
Outcome results
Primary
Quantitative Change in Relative Abundance of Lactobacillus Among the Community Composition of Bacteria in the Vagina
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.
Time frame: Baseline, 8 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Conjugated Estrogens Cream | Quantitative Change in Relative Abundance of Lactobacillus Among the Community Composition of Bacteria in the Vagina | Baseline | 0.07 Relative abundance |
| Conjugated Estrogens Cream | Quantitative Change in Relative Abundance of Lactobacillus Among the Community Composition of Bacteria in the Vagina | 8 weeks | 0.12 Relative abundance |
| Control Cohort | Quantitative Change in Relative Abundance of Lactobacillus Among the Community Composition of Bacteria in the Vagina | Baseline | 0.09 Relative abundance |
| Control Cohort | Quantitative Change in Relative Abundance of Lactobacillus Among the Community Composition of Bacteria in the Vagina | 8 weeks | 0.04 Relative abundance |
Secondary
Change in Vaginal Maturation Index (VMI)
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.
Time frame: Baseline, 8 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Conjugated Estrogens Cream | Change in Vaginal Maturation Index (VMI) | Baseline | 35 Change in vaginal maturation index value |
| Conjugated Estrogens Cream | Change in Vaginal Maturation Index (VMI) | 8 weeks | 60 Change in vaginal maturation index value |
| Control Cohort | Change in Vaginal Maturation Index (VMI) | Baseline | 42.5 Change in vaginal maturation index value |
| Control Cohort | Change in Vaginal Maturation Index (VMI) | 8 weeks | 47.5 Change in vaginal maturation index value |
Secondary
Change in Vaginal pH
Change in the vaginal pH from baseline to 8 weeks
Time frame: Baseline, 8 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Conjugated Estrogens Cream | Change in Vaginal pH | Baseline | 7.25 Vaginal pH |
| Conjugated Estrogens Cream | Change in Vaginal pH | 8 weeks | 5 Vaginal pH |
| Control Cohort | Change in Vaginal pH | Baseline | 7 Vaginal pH |
| Control Cohort | Change in Vaginal pH | 8 weeks | 7 Vaginal pH |
Secondary
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
Time frame: Baseline, 8 weeks
Population: Only one specimen resulted in a value for IL-10 post-treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Conjugated Estrogens Cream | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | IL-1b 8 WEEKS | 10.8 pg/mg |
| Conjugated Estrogens Cream | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | IL-10 BASELINE | 22.5 pg/mg |
| Conjugated Estrogens Cream | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | IL-10 8 WEEKS | 640.7 pg/mg |
| Conjugated Estrogens Cream | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | IL-4 8 WEEKS | 2.1 pg/mg |
| Conjugated Estrogens Cream | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | TNF-a BASELINE | 9.3 pg/mg |
| Conjugated Estrogens Cream | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | IL-1b BASELINE | 44.4 pg/mg |
| Conjugated Estrogens Cream | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | TNF-a 8 WEEKS | 7.1 pg/mg |
| Conjugated Estrogens Cream | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | IL-8 BASELINE | 3158.2 pg/mg |
| Conjugated Estrogens Cream | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | MCP-1 BASELINE | 102.5 pg/mg |
| Conjugated Estrogens Cream | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | IL-4 BASELINE | 10.0 pg/mg |
| Conjugated Estrogens Cream | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | MCP-1 8 WEEKS | 6.7 pg/mg |
| Conjugated Estrogens Cream | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | IL-8 8 WEEKS | 757.5 pg/mg |
| Control Cohort | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | MCP-1 8 WEEKS | 59.0 pg/mg |
| Control Cohort | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | IL-1b BASELINE | 132.9 pg/mg |
| Control Cohort | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | IL-1b 8 WEEKS | 373.6 pg/mg |
| Control Cohort | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | IL-4 BASELINE | 18.1 pg/mg |
| Control Cohort | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | IL-4 8 WEEKS | 11.1 pg/mg |
| Control Cohort | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | IL-8 BASELINE | 3724.3 pg/mg |
| Control Cohort | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | IL-8 8 WEEKS | 7941.0 pg/mg |
| Control Cohort | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | IL-10 8 WEEKS | 7.0 pg/mg |
| Control Cohort | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | TNF-a BASELINE | 11.6 pg/mg |
| Control Cohort | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | TNF-a 8 WEEKS | 12.0 pg/mg |
| Control Cohort | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | MCP-1 BASELINE | 29.1 pg/mg |
| Control Cohort | Vaginal Inflammatory Biomarkers: IL-1B, IL-4, IL-6, IL-8, IL-10, TNF-a, MCP-1, GM-CSF | IL-10 BASELINE | 12.7 pg/mg |
Other Pre-specified
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
Time frame: Baseline, 8 weeks
Population: This data was never collected.
Other Pre-specified
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.
Time frame: Baseline, 8 weeks
Population: There was only one participant and there was no range.
Other Pre-specified
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.
Time frame: Baseline, 8 weeks
Population: This data was never collected.
Other Pre-specified
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
Time frame: Baseline, 8 weeks
Population: This data was never collected.