Effect of Preoperative Estrogen Treatment on Connective Tissues of the Pelvic Floor

Study Overview
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Brief Summary
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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.

Official Title
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Effect of Preoperative Estrogen Treatment on Connective Tissues of the Pelvic Floor

Conditions
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Pelvic Organ Prolapse, Menopause

Intervention / Treatment
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* Drug: Premarin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Premarin<br>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. | Drug: Premarin<br> <br> * Other names: Conjugated equine estrogen;|
| Placebo Comparator: Placebo<br>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. | Other: Placebo<br> <br> * Other names: Placebo cream;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vaginal Wall Composition: Epithelium (Intention to Treat) | Will assess vaginal wall histology - thicknesses of epithelium | Time of surgery, i.e. after 6-8 weeks of intervention | 
| Vaginal Wall Composition: Epithelium (Per-Protocol) | Will assess vaginal wall histology - thicknesses of epithelium | Time of surgery, i.e. after 6-8 weeks of intervention | 
| Vaginal Wall Composition: Muscularis (Intention to Treat) | Will assess vaginal wall histology - thicknesses of muscularis | Time of surgery, i.e. after 6-8 weeks of intervention | 
| Vaginal Wall Composition: Muscularis (Per-Protocol) | Will assess vaginal wall histology - thicknesses of muscularis | Time of surgery, i.e. after 6-8 weeks of intervention | 
| hCOL1A1, Per-Protocol | Data represent ratio of total mRNA relative to postmenopausal external control. | Time of surgery, i.e. after 6-8 weeks of intervention | 
| Total Collagen Content in Vaginal Muscularis, (Per-Protocol) | Will assess hydroxy-proline assays as index of amount of collagen | Time of surgery, i.e. after 6-8 weeks of intervention | 
| Vaginal Wall Degradative Activity, Muscularis, MMP-9 | Will assess zymograms for total matrix metalloprotease (MMP) 9 activity | Time of surgery, i.e. after 6-8 weeks of intervention | 
| Vaginal Wall Composition: Lamina Propria (Intention to Treat) | Will assess vaginal wall histology - thickness of lamina propria. | Time of surgery, i.e. after 6-8 weeks of intervention | 
| Vaginal Wall Composition: Lamina Propria (Per-Protocol) | Will assess vaginal wall histology - thickness of lamina propria | Time of surgery, i.e. 6-8 weeks of intervention | 
| hCOL3, (Per-Protocol) | Data represent ratio of total mRNA relative to postmenopausal external control. | Time of surgery, i.e. after 6-8 weeks of intervention | 
| Lysyl Oxidase (LOX) (Per-Protocol) | Data represent ratio of total mRNA relative to postmenopausal external control. | Time of surgery, i.e. after 6-8 weeks of intervention | 
| LOXL1 (Per-Protocol) | Data represent ratio of total mRNA relative to postmenopausal external control. | Time of surgery, i.e. after 6-8 weeks of intervention | 
| Tropoelastin (Per-Protocol) | Data represent ratio of total mRNA relative to postmenopausal external control. | Time of surgery, i.e. after 6-8 weeks of intervention | 
| TGFB1 (Per-Protocol) | Data represent ratio of total mRNA relative to postmenopausal external control. | Time of surgery, i.e. after 6-8 weeks of intervention | 
| Vaginal Wall Degradative Activity, Mucosa, MMP-9 | Will assess zymograms for total matrix metalloprotease (MMP) 9 activity | Time of surgery, i.e. after 6-8 weeks of intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Estrone Levels, Baseline |  | Baseline | 
| Serum Estrone Levels, Surgery |  | Time of surgery | 
| Serum Estradiol Levels, Baseline |  | Baseline | 
| Serum Estradiol Levels, Surgery |  | Time of surgery | 
| Estimated Blood Loss | Intraoperative estimated blood loss | Time of surgery, i.e. after 6-8 weeks of intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pelvic organ prolapse, Menopause, Estrogen, Premarin