Menopause, Pelvic Organ Prolapse
Conditions
Keywords
Pelvic organ prolapse, Menopause, Estrogen, Premarin
Brief summary
This is a study to determine how vaginal estrogen cream given for several weeks before pelvic reconstructive therapy will effect elastic fiber assembly in the muscularis layer of the vaginal wall. Postmenopausal women with at least Stage 2 pelvic organ prolapse will receive either estrogen vaginal cream or placebo cream 6-8 weeks prior to reconstructive surgery. At time of surgery, full thickness biopsies will be obtained from a standardized location at the top of vagina. The investigators will measure the thickness of the vaginal muscularis, elastic fiber number and morphology, and analyze if elastic fiber synthesis or degradation is affected by estrogen therapy. The results will provide important data to support a larger clinical trial to determine if preoperative and maintenance estrogen therapy alter long-term success rates of pelvic reconstructive surgery for pelvic organ prolapse.
Interventions
DRUGPremarin
OTHERPlacebo
Sponsors
American Urogynecologic Society Foundation Astellas Research Award
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Women, still with uterus, planning total hysterectomy as part of surgical repair for pelvic organ prolapse * Symptomatic anterior and/or apical vaginal prolapse greater than or equal to Stage 2 (i.e., bulge extends to at least 1 cm of the hymen or beyond) * Women between 1 and 10 years after menopause. Menopause is defined as one year of amenorrhea or surgical ovariectomy. * Age 40-70 years old * No estrogen replacement therapy in the last 1 month * Physically capable of daily application of vaginal cream
Exclusion criteria
* BMI \>35 * Prior surgical repair of prolapse involving the vaginal cuff. * Prior total hysterectomy * Premenopausal or postmenopausal \>10 years * Prior steroid hormone replacement therapy of duration \>1 month (oral or vaginal estrogen, testosterone or corticosteroids) * History of connective tissue disease (Ehlers-Danlos, Marfan, etc) * History of vaginal radiation * Contraindications for estrogen replacement therapy (current, or history of, spontaneous deep vein thrombosis, stroke, coronary artery disease, breast or endometrial cancer) * Concurrent use of steroid cream for treatment of Lichen sclerosis * Recent history (within last month) of vaginal infection or vaginitis * Current tobacco use
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Vaginal Wall Degradative Activity, Mucosa, MMP-9 | Time of surgery, i.e. after 6-8 weeks of intervention | Will assess zymograms for total matrix metalloprotease (MMP) 9 activity |
| hCOL3, (Per-Protocol) | Time of surgery, i.e. after 6-8 weeks of intervention | Data represent ratio of total mRNA relative to postmenopausal external control. |
| Lysyl Oxidase (LOX) (Per-Protocol) | Time of surgery, i.e. after 6-8 weeks of intervention | Data represent ratio of total mRNA relative to postmenopausal external control. |
| LOXL1 (Per-Protocol) | Time of surgery, i.e. after 6-8 weeks of intervention | Data represent ratio of total mRNA relative to postmenopausal external control. |
| Tropoelastin (Per-Protocol) | Time of surgery, i.e. after 6-8 weeks of intervention | Data represent ratio of total mRNA relative to postmenopausal external control. |
| TGFB1 (Per-Protocol) | Time of surgery, i.e. after 6-8 weeks of intervention | Data represent ratio of total mRNA relative to postmenopausal external control. |
| Vaginal Wall Composition: Epithelium (Intention to Treat) | Time of surgery, i.e. after 6-8 weeks of intervention | Will assess vaginal wall histology - thicknesses of epithelium |
| Vaginal Wall Composition: Epithelium (Per-Protocol) | Time of surgery, i.e. after 6-8 weeks of intervention | Will assess vaginal wall histology - thicknesses of epithelium |
| Vaginal Wall Composition: Muscularis (Intention to Treat) | Time of surgery, i.e. after 6-8 weeks of intervention | Will assess vaginal wall histology - thicknesses of muscularis |
| Vaginal Wall Composition: Muscularis (Per-Protocol) | Time of surgery, i.e. after 6-8 weeks of intervention | Will assess vaginal wall histology - thicknesses of muscularis |
| hCOL1A1, Per-Protocol | Time of surgery, i.e. after 6-8 weeks of intervention | Data represent ratio of total mRNA relative to postmenopausal external control. |
| Total Collagen Content in Vaginal Muscularis, (Per-Protocol) | Time of surgery, i.e. after 6-8 weeks of intervention | Will assess hydroxy-proline assays as index of amount of collagen |
| Vaginal Wall Degradative Activity, Muscularis, MMP-9 | Time of surgery, i.e. after 6-8 weeks of intervention | Will assess zymograms for total matrix metalloprotease (MMP) 9 activity |
| Vaginal Wall Composition: Lamina Propria (Intention to Treat) | Time of surgery, i.e. after 6-8 weeks of intervention | Will assess vaginal wall histology - thickness of lamina propria. |
| Vaginal Wall Composition: Lamina Propria (Per-Protocol) | Time of surgery, i.e. 6-8 weeks of intervention | Will assess vaginal wall histology - thickness of lamina propria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum Estrone Levels, Surgery | Time of surgery | — |
| Serum Estradiol Levels, Baseline | Baseline | — |
| Serum Estradiol Levels, Surgery | Time of surgery | — |
| Estimated Blood Loss | Time of surgery, i.e. after 6-8 weeks of intervention | Intraoperative estimated blood loss |
| Serum Estrone Levels, Baseline | Baseline | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Premarin Premarin cream 0.625mg/1gm. Applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery.
Premarin | 15 |
| Placebo Placebo cream, applied to vagina by applicator as 1gm nightly for 2 weeks then 1gm 2 nights per week for 4-6 weeks or until day of surgery.
Placebo | 15 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 2 | 2 |
| Overall Study | Protocol Violation | 4 | 1 |
Baseline characteristics
| Characteristic | Premarin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 55.1 years STANDARD_DEVIATION 5.4 | 58.9 years STANDARD_DEVIATION 5.1 | 57.2 years STANDARD_DEVIATION 5.5 |
| Body mass index | 29.2 kg/m^2 STANDARD_DEVIATION 5.4 | 31.7 kg/m^2 STANDARD_DEVIATION 4.1 | 30.5 kg/m^2 STANDARD_DEVIATION 4.9 |
| Parity | 3 deliveries | 4 deliveries | 4 deliveries |
| Race/Ethnicity, Customized Hispanic White | 7 participants | 10 participants | 17 participants |
| Race/Ethnicity, Customized Non-Hispanic Black | 1 participants | 3 participants | 4 participants |
| Race/Ethnicity, Customized Non-Hispanic White | 7 participants | 2 participants | 9 participants |
| Sex: Female, Male Female | 15 Participants | 15 Participants | 30 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 15 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 |
Outcome results
Primary
hCOL1A1, Per-Protocol
Data represent ratio of total mRNA relative to postmenopausal external control.
Time frame: Time of surgery, i.e. after 6-8 weeks of intervention
Population: Patients completing surgery with biopsy specimens available for analysis and who were adherent to study medication (per protocol)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Premarin | hCOL1A1, Per-Protocol | 2.19 ratio |
| Placebo | hCOL1A1, Per-Protocol | 0.37 ratio |
p-value: <0.001Wilcoxon (Mann-Whitney)
Primary
hCOL3, (Per-Protocol)
Data represent ratio of total mRNA relative to postmenopausal external control.
Time frame: Time of surgery, i.e. after 6-8 weeks of intervention
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Premarin | hCOL3, (Per-Protocol) | .92 ratio |
| Placebo | hCOL3, (Per-Protocol) | .37 ratio |
p-value: 0.05Wilcoxon (Mann-Whitney)
Primary
LOXL1 (Per-Protocol)
Data represent ratio of total mRNA relative to postmenopausal external control.
Time frame: Time of surgery, i.e. after 6-8 weeks of intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Premarin | LOXL1 (Per-Protocol) | .64 ratio | Standard Error 0.12 |
| Placebo | LOXL1 (Per-Protocol) | .69 ratio | Standard Error 0.14 |
p-value: 0.82t-test, 2 sided
Primary
Lysyl Oxidase (LOX) (Per-Protocol)
Data represent ratio of total mRNA relative to postmenopausal external control.
Time frame: Time of surgery, i.e. after 6-8 weeks of intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Premarin | Lysyl Oxidase (LOX) (Per-Protocol) | .74 ratio | Standard Error 0.14 |
| Placebo | Lysyl Oxidase (LOX) (Per-Protocol) | .51 ratio | Standard Error 0.09 |
p-value: 0.15t-test, 2 sided
Primary
TGFB1 (Per-Protocol)
Data represent ratio of total mRNA relative to postmenopausal external control.
Time frame: Time of surgery, i.e. after 6-8 weeks of intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Premarin | TGFB1 (Per-Protocol) | .61 ratio | Standard Error 0.13 |
| Placebo | TGFB1 (Per-Protocol) | .81 ratio | Standard Error 0.11 |
p-value: 0.25t-test, 2 sided
Primary
Total Collagen Content in Vaginal Muscularis, (Per-Protocol)
Will assess hydroxy-proline assays as index of amount of collagen
Time frame: Time of surgery, i.e. after 6-8 weeks of intervention
Population: Patients completing surgery with biopsy specimens available for analysis and who were adherent to study medication (per protocol)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Premarin | Total Collagen Content in Vaginal Muscularis, (Per-Protocol) | 302.6 mg collagen per mg muscularis wet weight | Standard Error 146.1 |
| Placebo | Total Collagen Content in Vaginal Muscularis, (Per-Protocol) | 94.86 mg collagen per mg muscularis wet weight | Standard Error 29.86 |
p-value: 0.1t-test, 2 sided
Primary
Tropoelastin (Per-Protocol)
Data represent ratio of total mRNA relative to postmenopausal external control.
Time frame: Time of surgery, i.e. after 6-8 weeks of intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Premarin | Tropoelastin (Per-Protocol) | .78 ratio | Standard Error 0.24 |
| Placebo | Tropoelastin (Per-Protocol) | .69 ratio | Standard Error 0.11 |
p-value: 0.7t-test, 2 sided
Primary
Vaginal Wall Composition: Epithelium (Intention to Treat)
Will assess vaginal wall histology - thicknesses of epithelium
Time frame: Time of surgery, i.e. after 6-8 weeks of intervention
Population: Patients completing surgery with biopsy specimens available for analysis (intention to treat)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Premarin | Vaginal Wall Composition: Epithelium (Intention to Treat) | 413.9 microns | Standard Error 63.7 |
| Placebo | Vaginal Wall Composition: Epithelium (Intention to Treat) | 314.1 microns | Standard Error 42.6 |
p-value: 0.21t-test, 2 sided
Primary
Vaginal Wall Composition: Epithelium (Per-Protocol)
Will assess vaginal wall histology - thicknesses of epithelium
Time frame: Time of surgery, i.e. after 6-8 weeks of intervention
Population: Patients completing surgery with biopsy specimens available for analysis and who were adherent to study medication (per protocol)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Premarin | Vaginal Wall Composition: Epithelium (Per-Protocol) | 550.5 microns | Standard Error 45.1 |
| Placebo | Vaginal Wall Composition: Epithelium (Per-Protocol) | 314.1 microns | Standard Error 42.6 |
p-value: 0.002t-test, 2 sided
Primary
Vaginal Wall Composition: Lamina Propria (Intention to Treat)
Will assess vaginal wall histology - thickness of lamina propria.
Time frame: Time of surgery, i.e. after 6-8 weeks of intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Premarin | Vaginal Wall Composition: Lamina Propria (Intention to Treat) | 1042.3 microns | Standard Error 169.8 |
| Placebo | Vaginal Wall Composition: Lamina Propria (Intention to Treat) | 895.1 microns | Standard Error 153.3 |
p-value: 0.53t-test, 2 sided
Primary
Vaginal Wall Composition: Lamina Propria (Per-Protocol)
Will assess vaginal wall histology - thickness of lamina propria
Time frame: Time of surgery, i.e. 6-8 weeks of intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Premarin | Vaginal Wall Composition: Lamina Propria (Per-Protocol) | 1133.4 microns | Standard Error 166.2 |
| Placebo | Vaginal Wall Composition: Lamina Propria (Per-Protocol) | 895.1 microns | Standard Error 153.3 |
p-value: 0.33t-test, 2 sided
Primary
Vaginal Wall Composition: Muscularis (Intention to Treat)
Will assess vaginal wall histology - thicknesses of muscularis
Time frame: Time of surgery, i.e. after 6-8 weeks of intervention
Population: Patients completing surgery with biopsy specimens available for analysis (intention to treat)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Premarin | Vaginal Wall Composition: Muscularis (Intention to Treat) | 5670.4 microns | Standard Error 2154.7 |
| Placebo | Vaginal Wall Composition: Muscularis (Intention to Treat) | 2807.1 microns | Standard Error 622.5 |
p-value: 0.22t-test, 2 sided
Primary
Vaginal Wall Composition: Muscularis (Per-Protocol)
Will assess vaginal wall histology - thicknesses of muscularis
Time frame: Time of surgery, i.e. after 6-8 weeks of intervention
Population: Patients completing surgery with biopsy specimens available for analysis and who were adherent to study medication (per protocol)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Premarin | Vaginal Wall Composition: Muscularis (Per-Protocol) | 7570.7 microns | Standard Error 3193.1 |
| Placebo | Vaginal Wall Composition: Muscularis (Per-Protocol) | 2807.1 microns | Standard Error 622.5 |
p-value: 0.088t-test, 2 sided
Primary
Vaginal Wall Degradative Activity, Mucosa, MMP-9
Will assess zymograms for total matrix metalloprotease (MMP) 9 activity
Time frame: Time of surgery, i.e. after 6-8 weeks of intervention
Population: All specimens with sufficient amount of tissue available for zymography analysis were used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Premarin | Vaginal Wall Degradative Activity, Mucosa, MMP-9 | 8.97 Relative Units/mg protein | Standard Error 1.77 |
| Placebo | Vaginal Wall Degradative Activity, Mucosa, MMP-9 | 56.73 Relative Units/mg protein | Standard Error 23.2 |
p-value: 0.06t-test, 2 sided
Primary
Vaginal Wall Degradative Activity, Muscularis, MMP-9
Will assess zymograms for total matrix metalloprotease (MMP) 9 activity
Time frame: Time of surgery, i.e. after 6-8 weeks of intervention
Population: All specimens with sufficient amount of tissue available for zymography analysis were used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Premarin | Vaginal Wall Degradative Activity, Muscularis, MMP-9 | 37.03 Relative Units/mg protein | Standard Error 15.06 |
| Placebo | Vaginal Wall Degradative Activity, Muscularis, MMP-9 | 132.34 Relative Units/mg protein | Standard Error 35.48 |
p-value: 0.02t-test, 2 sided
Secondary
Estimated Blood Loss
Intraoperative estimated blood loss
Time frame: Time of surgery, i.e. after 6-8 weeks of intervention
Population: In both study arms, 13 participants did undergo surgery and, therefore, had an estimated blood loss value available for analysis. However, one patient each from both study arms did not have biopsies taken (technical considerations/ intraoperative decision or conversion from total to supracervical hysterectomy without ability to collect biopsy).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Premarin | Estimated Blood Loss | 285 mL | Standard Deviation 134 |
| Placebo | Estimated Blood Loss | 285 mL | Standard Deviation 270 |
p-value: 1t-test, 2 sided
Secondary
Serum Estradiol Levels, Baseline
Time frame: Baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Premarin | Serum Estradiol Levels, Baseline | 11.1 pg/mL | Standard Error 3.7 |
| Placebo | Serum Estradiol Levels, Baseline | 8.4 pg/mL | Standard Error 1.6 |
p-value: 0.51t-test, 2 sided
Secondary
Serum Estradiol Levels, Surgery
Time frame: Time of surgery
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Premarin | Serum Estradiol Levels, Surgery | 7.8 pg/mL | Standard Error 1.3 |
| Placebo | Serum Estradiol Levels, Surgery | 11.6 pg/mL | Standard Error 2.7 |
p-value: 0.24t-test, 2 sided
Secondary
Serum Estrone Levels, Baseline
Time frame: Baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Premarin | Serum Estrone Levels, Baseline | 18.0 pg/mL | Standard Error 2.3 |
| Placebo | Serum Estrone Levels, Baseline | 18.5 pg/mL | Standard Error 3.9 |
p-value: 0.91t-test, 2 sided
Secondary
Serum Estrone Levels, Surgery
Time frame: Time of surgery
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Premarin | Serum Estrone Levels, Surgery | 22.8 pg/mL | Standard Error 3.5 |
| Placebo | Serum Estrone Levels, Surgery | 24.9 pg/mL | Standard Error 6.5 |
p-value: 0.78t-test, 2 sided