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

• Sponsor: University of Texas Southwestern Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01778985
• Collaborator: American Urogynecologic Society Foundation Astellas Research Award (Other)
• Enrollment: 30
• Location: 1
• Arms: 2
• Duration (Months): 4
• Patients Per Site Per Month: 7.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pelvic Organ Prolapse; Menopause	Drug: Premarin; Other: Placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Effect of Preoperative Estrogen Treatment on Connective Tissues of the Pelvic Floor
• Study Start Date: Dec 1, 2012
• Actual Primary Completion Date: Mar 1, 2013
• Actual Study Completion Date: Apr 1, 2013

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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

2. 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

3. 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

4. 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

5. 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.

6. 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

7. 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

8. 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.

9. 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

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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

Secondary Outcome Measures

1. Serum Estrone Levels, Baseline [Baseline]

2. Serum Estrone Levels, Surgery [Time of surgery]

3. Serum Estradiol Levels, Baseline [Baseline]

4. Serum Estradiol Levels, Surgery [Time of surgery]

5. Estimated Blood Loss [Time of surgery, i.e. after 6-8 weeks of intervention]

   Intraoperative estimated blood loss

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 70 Years
• Sexes Eligible for Study: Female
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390

Sponsors and Collaborators

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

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: David Rahn, MD, Assistant Professor, Dept. of Obstetrics & Gynecology, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT01778985
• Other Study ID Numbers: STU-042011-101
• First Posted: Jan 29, 2013
• Last Update Posted: Oct 2, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by David Rahn, MD, Assistant Professor, Dept. of Obstetrics & Gynecology, University of Texas Southwestern Medical Center: Pelvic organ prolapse; Menopause; Estrogen; Premarin
• Additional relevant MeSH terms: Prolapse; Pelvic Organ Prolapse; Estrogens; Estrogens, Conjugated (USP)

Study Results

Participant Flow

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	15	15
COMPLETED	8	12
NOT COMPLETED	7	3

Baseline Characteristics

Arm/Group Title	Premarin	Placebo	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	15	15	30
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.1 (5.4)	58.9 (5.1)	57.2 (5.5)
Sex: Female, Male (Count of Participants)
Female	15 100%	15 100%	30 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
Non-Hispanic White	7 46.7%	2 13.3%	9 30%
Non-Hispanic Black	1 6.7%	3 20%	4 13.3%
Hispanic White	7 46.7%	10 66.7%	17 56.7%
Parity (deliveries) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [deliveries]	3	4	4
Body mass index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	29.2 (5.4)	31.7 (4.1)	30.5 (4.9)

Outcome Measures

1. Primary Outcome

Title	Vaginal Wall Composition: Epithelium (Intention to Treat)
Description	Will assess vaginal wall histology - thicknesses of epithelium
Time Frame	Time of surgery, i.e. after 6-8 weeks of intervention

Outcome Measure Data

Analysis Population Description

Patients completing surgery with biopsy specimens available for analysis ("intention to treat")

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	12	12
Mean (Standard Error) [microns]	413.9 (63.7)	314.1 (42.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.21
	Comments
	Method	t-test, 2 sided
	Comments

2. Primary Outcome

Title	Vaginal Wall Composition: Epithelium (Per-Protocol)
Description	Will assess vaginal wall histology - thicknesses of epithelium
Time Frame	Time of surgery, i.e. after 6-8 weeks of intervention

Outcome Measure Data

Analysis Population Description

Patients completing surgery with biopsy specimens available for analysis and who were adherent to study medication ("per protocol")

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	8	12
Mean (Standard Error) [microns]	550.5 (45.1)	314.1 (42.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	t-test, 2 sided
	Comments

3. Primary Outcome

Title	Vaginal Wall Composition: Muscularis (Intention to Treat)
Description	Will assess vaginal wall histology - thicknesses of muscularis
Time Frame	Time of surgery, i.e. after 6-8 weeks of intervention

Outcome Measure Data

Analysis Population Description

Patients completing surgery with biopsy specimens available for analysis ("intention to treat")

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	12	12
Mean (Standard Error) [microns]	5670.4 (2154.7)	2807.1 (622.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.22
	Comments
	Method	t-test, 2 sided
	Comments

4. Primary Outcome

Title	Vaginal Wall Composition: Muscularis (Per-Protocol)
Description	Will assess vaginal wall histology - thicknesses of muscularis
Time Frame	Time of surgery, i.e. after 6-8 weeks of intervention

Outcome Measure Data

Analysis Population Description

Patients completing surgery with biopsy specimens available for analysis and who were adherent to study medication ("per protocol")

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	8	12
Mean (Standard Error) [microns]	7570.7 (3193.1)	2807.1 (622.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.088
	Comments
	Method	t-test, 2 sided
	Comments	t(18)=1.78, p=0.088

5. Primary Outcome

Title	hCOL1A1, Per-Protocol
Description	Data represent ratio of total mRNA relative to postmenopausal external control.
Time Frame	Time of surgery, i.e. after 6-8 weeks of intervention

Outcome Measure Data

Analysis Population Description

Patients completing surgery with biopsy specimens available for analysis and who were adherent to study medication ("per protocol")

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	8	12
Median (Inter-Quartile Range) [ratio]	2.19	0.37

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Serum Estrone Levels, Baseline
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	15	15
Mean (Standard Error) [pg/mL]	18.0 (2.3)	18.5 (3.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.91
	Comments	t(28)=0.11, p=0.91
	Method	t-test, 2 sided
	Comments

7. Primary Outcome

Title	Total Collagen Content in Vaginal Muscularis, (Per-Protocol)
Description	Will assess hydroxy-proline assays as index of amount of collagen
Time Frame	Time of surgery, i.e. after 6-8 weeks of intervention

Outcome Measure Data

Analysis Population Description

Patients completing surgery with biopsy specimens available for analysis and who were adherent to study medication ("per protocol")

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	8	12
Mean (Standard Error) [mg collagen per mg muscularis wet weight]	302.6 (146.1)	94.86 (29.86)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.10
	Comments	t(18)=1.69, p=.10
	Method	t-test, 2 sided
	Comments

8. Primary Outcome

Title	Vaginal Wall Degradative Activity, Muscularis, MMP-9
Description	Will assess zymograms for total matrix metalloprotease (MMP) 9 activity
Time Frame	Time of surgery, i.e. after 6-8 weeks of intervention

Outcome Measure Data

Analysis Population Description

All specimens with sufficient amount of tissue available for zymography analysis were used.

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	7	8
Mean (Standard Error) [Relative Units/mg protein]	37.03 (15.06)	132.34 (35.48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.020
	Comments	t(10)=2.76, p=0.020
	Method	t-test, 2 sided
	Comments

9. Secondary Outcome

Title	Serum Estrone Levels, Surgery
Time Frame	Time of surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	12	13
Mean (Standard Error) [pg/mL]	22.8 (3.5)	24.9 (6.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments	t(23)=0.28, p=0.78
	Method	t-test, 2 sided
	Comments

10. Secondary Outcome

Title	Serum Estradiol Levels, Baseline
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	15	15
Mean (Standard Error) [pg/mL]	11.1 (3.7)	8.4 (1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.51
	Comments	t(28)=0.67, p=0.51
	Method	t-test, 2 sided
	Comments

11. Secondary Outcome

Title	Serum Estradiol Levels, Surgery
Time Frame	Time of surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	12	13
Mean (Standard Error) [pg/mL]	7.8 (1.3)	11.6 (2.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.24
	Comments	t(23)=1.23, p=0.24
	Method	t-test, 2 sided
	Comments

12. Primary Outcome

Title	Vaginal Wall Composition: Lamina Propria (Intention to Treat)
Description	Will assess vaginal wall histology - thickness of lamina propria.
Time Frame	Time of surgery, i.e. after 6-8 weeks of intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	12	12
Mean (Standard Error) [microns]	1042.3 (169.8)	895.1 (153.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.53
	Comments
	Method	t-test, 2 sided
	Comments

13. Primary Outcome

Title	Vaginal Wall Composition: Lamina Propria (Per-Protocol)
Description	Will assess vaginal wall histology - thickness of lamina propria
Time Frame	Time of surgery, i.e. 6-8 weeks of intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	8	12
Mean (Standard Error) [microns]	1133.4 (166.2)	895.1 (153.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.33
	Comments
	Method	t-test, 2 sided
	Comments

14. Primary Outcome

Title	hCOL3, (Per-Protocol)
Description	Data represent ratio of total mRNA relative to postmenopausal external control.
Time Frame	Time of surgery, i.e. after 6-8 weeks of intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	8	12
Median (Inter-Quartile Range) [ratio]	.92	.37

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

15. Primary Outcome

Title	Lysyl Oxidase (LOX) (Per-Protocol)
Description	Data represent ratio of total mRNA relative to postmenopausal external control.
Time Frame	Time of surgery, i.e. after 6-8 weeks of intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	8	12
Mean (Standard Error) [ratio]	.74 (.14)	.51 (.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.15
	Comments
	Method	t-test, 2 sided
	Comments

16. Primary Outcome

Title	LOXL1 (Per-Protocol)
Description	Data represent ratio of total mRNA relative to postmenopausal external control.
Time Frame	Time of surgery, i.e. after 6-8 weeks of intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	8	12
Mean (Standard Error) [ratio]	.64 (.12)	.69 (.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.82
	Comments
	Method	t-test, 2 sided
	Comments

17. Primary Outcome

Title	Tropoelastin (Per-Protocol)
Description	Data represent ratio of total mRNA relative to postmenopausal external control.
Time Frame	Time of surgery, i.e. after 6-8 weeks of intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	8	12
Mean (Standard Error) [ratio]	.78 (.24)	.69 (.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.70
	Comments
	Method	t-test, 2 sided
	Comments

18. Primary Outcome

Title	TGFB1 (Per-Protocol)
Description	Data represent ratio of total mRNA relative to postmenopausal external control.
Time Frame	Time of surgery, i.e. after 6-8 weeks of intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	8	12
Mean (Standard Error) [ratio]	.61 (.13)	.81 (.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.25
	Comments
	Method	t-test, 2 sided
	Comments

19. Primary Outcome

Title	Vaginal Wall Degradative Activity, Mucosa, MMP-9
Description	Will assess zymograms for total matrix metalloprotease (MMP) 9 activity
Time Frame	Time of surgery, i.e. after 6-8 weeks of intervention

Outcome Measure Data

Analysis Population Description

All specimens with sufficient amount of tissue available for zymography analysis were used.

Arm/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	7	8
Mean (Standard Error) [Relative Units/mg protein]	8.97 (1.77)	56.73 (23.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments
	Method	t-test, 2 sided
	Comments

20. Secondary Outcome

Title	Estimated Blood Loss
Description	Intraoperative estimated blood loss
Time Frame	Time of surgery, i.e. after 6-8 weeks of intervention

Outcome Measure Data

Analysis Population Description

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/Group Title	Premarin	Placebo
Arm/Group Description	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	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
Measure Participants	13	13
Mean (Standard Deviation) [mL]	285 (134)	285 (270)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Premarin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	6 - 8 weeks of preoperative use of vaginal estrogen (vs placebo) cream
Arm/Group Title	Premarin		Placebo
Arm/Group Description	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		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
All Cause Mortality
	Premarin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Premarin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Premarin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/15 (20%)		0/15 (0%)
Reproductive system and breast disorders
Vulvovaginal pain	2/15 (13.3%)	2	0/15 (0%)	2
Annoyance with cream use	1/15 (6.7%)	1	0/15 (0%)	1

Limitations/Caveats

4 patients nonadherent to study protocol in the Premarin arm.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.