Effect of Preoperative Estrogen Treatment on Connective Tissues of the Pelvic Floor (PET)

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.

Study Overview

• Status: Completed
• Conditions: Pelvic Organ Prolapse; Menopause
• Intervention / Treatment: Other: Placebo; Drug: Premarin

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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.	Drug: Premarin; Other Names: Conjugated equine estrogen
PLACEBO_COMPARATOR: 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.	Other: Placebo; Other Names: Placebo cream

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: American Urogynecologic Society Foundation Astellas Research Award

Publications and helpful links

General Publications

• Rahn DD, Good MM, Roshanravan SM, Shi H, Schaffer JI, Singh RJ, Word RA. Effects of preoperative local estrogen in postmenopausal women with prolapse: a randomized trial. J Clin Endocrinol Metab. 2014 Oct;99(10):3728-36. doi: 10.1210/jc.2014-1216. Epub 2014 Jun 20.

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (ACTUAL): March 1, 2013
• Study Completion (ACTUAL): April 1, 2013

Study Registration Dates

• First Submitted: January 23, 2013
• First Submitted That Met QC Criteria: January 25, 2013
• First Posted (ESTIMATE): January 29, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): October 2, 2014
• Last Update Submitted That Met QC Criteria: September 18, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: Menopause; Pelvic organ prolapse; Estrogen; Premarin
• Additional Relevant MeSH Terms: Pathological Conditions, Anatomical; Prolapse; Pelvic Organ Prolapse; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Estrogens, Conjugated (USP)
• Other Study ID Numbers: STU-042011-101