SHAPE: Sex Hormones and Atherosclerosis Prevention in Perimenopausal Women

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT00608062
• Collaborator: National Institute on Aging (NIA) (NIH)
• Enrollment: 155
• Location: 1
• Arms: 8
• Duration (Months): 67.8
• Patients Per Site Per Month: 2.3

Study Details

Study Description

Brief Summary

The purpose of this study is to find out why women's arteries stiffen as they go through menopause, and how this is affected by estrogen loss. We believe that arteries stiffen with the loss of estrogen because of "oxidative stress," the production of molecules that can damage cells and tissues in the body, and because the arteries lose their ability to expand, or dilate.

Condition or Disease	Intervention/Treatment	Phase
Arterial Stiffening; Aging; Menopause	Drug: GnRHant - Ganirelix acetate; Drug: Transdermal estradiol patch; Drug: Transdermal placebo patch	N/A

Detailed Description

As women get older and go through menopause, estradiol levels decrease. Also with aging, the arteries that are located around the heart get stiffer. Over time this increase in arterial stiffness can lead to a number of health problems such as high blood pressure and heart disease. In this study we want to find out if a short-term drop in estrogen levels in premenopausal and perimenopausal women can cause arteries to become stiffer, and why this happens. Additionally, in postmenopausal women, we want to find out if a short-term increase in estrogen levels causes their arteries to become more flexible (less stiff).

Arterial health (i.e., stiffness) will be examined in premenopausal, perimenopausal and postmenopausal women before and after they are given a drug called Ganirelix™ (for 7 days), which will markedly lower their reproductive hormones. After the first 4 days of taking Ganirelix™, the women will be randomly placed into 1 of 2 treatment groups to take either estrogen (0.075 mg/d skin patch) replacement or placebo for the rest of the Ganirelix treatment. This is to increase estrogen levels back to the normal level. After having the patch on for 4 days, arterial health will be examined again.

Pre-specified Outcome Measures were divided into unit-of-measurement specific Outcome Measure tables for the purposes of results reporting to ClinicalTrials.gov

Study Design

• Study Type: Interventional
• Actual Enrollment: 155 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• Official Title: Biological Mechanisms of Arterial Stiffening With Age and Estrogen Deficiency
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Oct 25, 2012
• Actual Study Completion Date: Oct 25, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pre1 Premenopausal - GnRHant plus estradiol	Drug: GnRHant - Ganirelix acetate; 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7; Other Names: Ganirelix ; Drug: Transdermal estradiol patch; 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)
Placebo Comparator: Pre2 Premenopausal - GnRHant plus placebo	Drug: GnRHant - Ganirelix acetate; 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7; Other Names: Ganirelix ; Drug: Transdermal placebo patch; Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)
Experimental: Peri1 Perimenopausal (early) - GnRHant plus estradiol	Drug: GnRHant - Ganirelix acetate; 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7; Other Names: Ganirelix ; Drug: Transdermal estradiol patch; 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)
Placebo Comparator: Peri2 Perimenopausal (early) - GnRHant plus placebo	Drug: GnRHant - Ganirelix acetate; 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7; Other Names: Ganirelix ; Drug: Transdermal placebo patch; Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)
Experimental: Peri3 Perimenopausal (late) - GnRHant plus estradiol	Drug: GnRHant - Ganirelix acetate; 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7; Other Names: Ganirelix ; Drug: Transdermal estradiol patch; 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)
Placebo Comparator: Peri4 Perimenopausal (late) - GnRHant plus placebo	Drug: GnRHant - Ganirelix acetate; 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7; Other Names: Ganirelix ; Drug: Transdermal placebo patch; Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)
Experimental: Post1 Postmenopausal - GnRHant plus estradiol	Drug: GnRHant - Ganirelix acetate; 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7; Other Names: Ganirelix ; Drug: Transdermal estradiol patch; 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)
Placebo Comparator: Post2 Postmenopausal - GnRHant plus placebo	Drug: GnRHant - Ganirelix acetate; 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7; Other Names: Ganirelix ; Drug: Transdermal placebo patch; Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)

Outcome Measures

Primary Outcome Measures

1. Arterial Stiffness (Carotid Artery Compliance) During Saline [Baseline, day 4 of GnRHant and day 7 of GnRHant and estradiol or placebo treatment]

   Carotid artery compliance measured by carotid artery ultrasound and brachial artery blood pressure

2. Endothelial Function [Baseline, day 4 of GnRHant and Day 7 of GnRHant and estradiol or placebo treatment]

   Brachial artery flow-mediated dilation (FMD) assessed by ultrasound. This other outcome measure was originally specified as "Secondary" in error and has been updated to "Primary" to be consistent with the protocol.

Other Outcome Measures

1. Supine Brachial Blood Pressures [Baseline, day 4 of GnRHant and day 7 of GnRHant and estradiol or placebo treatment]

2. Estradiol [Baseline, day 4 of GnRHant and day 7 of GnRHant and estradiol or placebo treatment]

   This other outcome measure was originally specified as "Secondary" in error and has been updated to "Other, Pre-specified" to be consistent with the protocol. Serum estradiol for clinical characteristics and to detect changes in estradiol levels with the interventions.

3. Progesterone [Baseline, Day 4 GnRHant, Day 7 GnRHant+Add-back]

   This other outcome measure was originally specified as "Secondary" in error and has been updated to "Other, Pre-specified" to be consistent with the protocol. Serum progesterone was measured for clinical characteristics and to determine changes in sex hormones.

4. Total Antioxidant Status (TAS) [Baseline, Day 4 GnRHant, Day 7 GnRHant+Add-back]

   This other outcome measure was originally specified as "Secondary" in error and has been updated to "Other, Pre-specified" to be consistent with the protocol. TAS is an antioxidant and is a biomarker of oxidative stress.

5. Endothelin-1 (ET-1) [Baseline, Day 4 GnRHant, Day 7 GnRHant+Add-back]

   This other outcome measure was originally specified as "Secondary" in error and has been updated to "Other, Pre-specified" to be consistent with the protocol.

6. Plasma Norepinephrine [Baseline, Day 4 GnRHant, Day 7 GnRHant+Add-back]

   This other outcome measure was originally specified as "Secondary" in error and has been updated to "Other, Pre-specified" to be consistent with the protocol.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy women of all races and ethnic backgrounds in one of the following groups:

• Premenopausal: 18-49 years, regular menstrual cycles with no change in observed cycle length (21-35 days)

• Perimenopausal: 40-55 years, categorized as either early (at least 2 cycles with cycle length changes of at least 7 days) or late (more than 3 months of amenorrhea) transition

• Postmenopausal: 45-70 years, more than 12 months of amenorrhea as defined by the menopausal staging system (STRAW); additionally, postmenopausal women will be categorized into early and late stages as defined by the STRAW definition, specifically, women who are less than 5 years postmenopause will be considered early, and women more than 6 years will be categorized as late

• All postmenopausal women will have undergone natural menopause

• No oral contraceptive or Hormone Replacement Therapy (HRT) use for at least 6 months

• Resting blood pressure less than 140/90 mmHg

• Plasma glucose concentrations less than 110 mg/dl under fasting conditions

• Sedentary or recreationally active (less than 3 days of vigorous aerobic exercise)

• No use of medications that might influence cardiovascular function

• Nonsmokers

• No use of vitamin supplements or willing to stop use for duration of the study

Exclusion Criteria:

• History of or active estrogen-dependent neoplasms, acute liver or gallbladder disease, vaginal bleeding, venous thromboembolism, hypertriglyceridemia, and cardiovascular disease

• Known allergy to transdermal patch or GnRHant

• Other contraindications to HRT and GnRHant

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Anschutz Medical Center, Clinical Translational Research Center and Exercise Research Laboratory	Aurora	Colorado	United States	80045

Sponsors and Collaborators

• University of Colorado, Denver
• National Institute on Aging (NIA)

Investigators

• Principal Investigator: Kerrie L Moreau, PhD, University of Colorado, Denver

Study Documents (Full-Text)

None provided.

More Information

Publications

• Eskurza I, Monahan KD, Robinson JA, Seals DR. Effect of acute and chronic ascorbic acid on flow-mediated dilatation with sedentary and physically active human ageing. J Physiol. 2004 Apr 1;556(Pt 1):315-24. Epub 2004 Jan 30. Erratum in: J Physiol. 2004 May 1;556(Pt 3):1014.
• Gavin KM, Jankowski C, Kohrt WM, Stauffer BL, Seals DR, Moreau KL. Hysterectomy is associated with large artery stiffening in estrogen-deficient postmenopausal women. Menopause. 2012 Sep;19(9):1000-7. doi: 10.1097/gme.0b013e31825040f9.
• Ihionkhan CE, Chambliss KL, Gibson LL, Hahner LD, Mendelsohn ME, Shaul PW. Estrogen causes dynamic alterations in endothelial estrogen receptor expression. Circ Res. 2002 Nov 1;91(9):814-20.
• Moreau KL, Donato AJ, Seals DR, DeSouza CA, Tanaka H. Regular exercise, hormone replacement therapy and the age-related decline in carotid arterial compliance in healthy women. Cardiovasc Res. 2003 Mar;57(3):861-8.
• Moreau KL, Gavin KM, Plum AE, Seals DR. Ascorbic acid selectively improves large elastic artery compliance in postmenopausal women. Hypertension. 2005 Jun;45(6):1107-12. Epub 2005 May 2.
• Moreau KL, Meditz A, Deane KD, Kohrt WM. Tetrahydrobiopterin improves endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women. Am J Physiol Heart Circ Physiol. 2012 Mar 1;302(5):H1211-8. doi: 10.1152/ajpheart.01065.2011. Epub 2012 Jan 13.
• Virdis A, Ghiadoni L, Pinto S, Lombardo M, Petraglia F, Gennazzani A, Buralli S, Taddei S, Salvetti A. Mechanisms responsible for endothelial dysfunction associated with acute estrogen deprivation in normotensive women. Circulation. 2000 May 16;101(19):2258-63.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT00608062
• Other Study ID Numbers: 06-0537; R01AG027678
• First Posted: Feb 6, 2008
• Last Update Posted: Dec 24, 2020
• Last Verified: Dec 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by University of Colorado, Denver: endothelial function; women; female; estrogen deficiency; sex hormones; adiposity; oxidative stress; antioxidants
• Additional relevant MeSH terms: Estradiol; Ganirelix

Study Results

Participant Flow

Recruitment Details	Participants were recruited from the Denver metro area between March 2007 and March 2012. The first participant was enrolled on March 6, 2007 and the last participant was enrolled in March 2012.
Pre-assignment Detail	A total of 155 women consented to participate. During screening, 33 women did not qualify (12 premenopausal, 14 perimenopausal [11 early- and 3 late], and 7 postmenopausal). Twenty-three withdrew from participation before baseline testing and 7 women withdrew from participation after baseline testing but prior to randomization.

Arm/Group Title	Pre1	Pre2	Peri1	Peri2	Post1	Post2
Arm/Group Description	Premenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Premenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal (early and late combined) - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal (early and late combined) - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)
Period Title: Overall Study
STARTED	12	12	19	21	13	15
COMPLETED	12	12	19	21	13	15
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Pre1	Pre2	Peri1	Peri2	Post1	Post2	Total
Arm/Group Description	Premenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Premenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Total of all reporting groups
Overall Participants	12	12	17	21	12	13	87
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	12 100%	12 100%	17 100%	21 100%	12 100%	11 84.6%	85 97.7%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	2 15.4%	2 2.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32 (8)	33 (7)	49 (3)	50 (4)	56 (5)	60 (6)	47 (11)
Sex: Female, Male (Count of Participants)
Female	12 100%	12 100%	17 100%	21 100%	12 100%	13 100%	87 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	12 100%	12 100%	17 100%	21 100%	12 100%	13 100%	87 100%
Body Mass (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	66.8 (15.6)	64.2 (11.0)	65.6 (8.1)	68.7 (11.9)	70.5 (14.7)	69.7 (9.3)	67.6 (11.7)
Body Mass Index (BMI) (kg/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m2]	23.8 (5.6)	24.4 (5.3)	24.1 (3.2)	25.2 (3.9)	26.7 (5.9)	26.5 (2.7)	25.1 (4.4)
Systolic Blood Pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	109 (8)	110 (7)	113 (14)	115 (11)	117 (14)	120 (14)	114 (12)
Diastolic Blood Pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	70 (7)	72 (5)	71 (9)	73 (6)	73 (8)	74 (10)	72 (8)
VO2peak (ml/kg/min) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ml/kg/min]	35.3 (6.0)	31.0 (5.5)	27.7 (4.0)	27.5 (5.8)	24.8 (3.9)	24.1 (2.9)	28.2 (5.9)
Glucose (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	4.7 (0.3)	4.6 (0.6)	4.5 (0.3)	4.7 (0.5)	5.0 (0.7)	4.6 (0.6)	4.7 (0.5)
Insulin (pmol/L) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [pmol/L]	38	42	28	28	28	31	35
Total Cholesterol (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	3.7 (0.7)	4.0 (0.9)	4.5 (0.9)	4.2 (0.6)	4.7 (0.9)	4.7 (0.9)	4.3 (0.9)
Low-density Lipoprotein (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	2.3 (0.5)	2.2 (0.7)	2.7 (1.0)	2.4 (0.5)	2.9 (0.8)	2.8 (0.9)	2.6 (0.8)
High-density Lipoprotein (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	1.1 (0.1)	1.3 (0.2)	1.3 (0.2)	1.3 (0.3)	1.3 (0.3)	1.3 (0.3)	1.3 (0.3)

Outcome Measures

1. Primary Outcome

Title	Arterial Stiffness (Carotid Artery Compliance) During Saline
Description	Carotid artery compliance measured by carotid artery ultrasound and brachial artery blood pressure
Time Frame	Baseline, day 4 of GnRHant and day 7 of GnRHant and estradiol or placebo treatment

Outcome Measure Data

Analysis Population Description

Early and late perimenopausal were collapsed into 1 perimenopausal group

Arm/Group Title	Pre1	Pre2	Peri1	Peri2	Post1	Post2
Arm/Group Description	Premenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Premenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal (early and late combined) - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal (early and late combined) - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)
Measure Participants	12	12	19	21	13	15
Baseline	1.31 (0.27)	1.34 (0.18)	0.90 (0.27)	1.02 (0.33)	0.89 (0.25)	0.74 (0.23)
GnRHant alone	1.27 (0.27)	1.19 (0.34)	0.89 (0.27)	0.94 (0.29)	0.85 (0.24)	0.79 (0.22)
GnRHant + Add-Back	1.29 (0.26)	1.14 (0.38)	0.98 (0.27)	0.94 (0.27)	0.92 (0.27)	0.80 (0.19)

2. Primary Outcome

Title	Endothelial Function
Description	Brachial artery flow-mediated dilation (FMD) assessed by ultrasound. This other outcome measure was originally specified as "Secondary" in error and has been updated to "Primary" to be consistent with the protocol.
Time Frame	Baseline, day 4 of GnRHant and Day 7 of GnRHant and estradiol or placebo treatment

Outcome Measure Data

Analysis Population Description

Numbers for some groups are reduced because of poor ultrasound image quality.

Arm/Group Title	Pre1	Pre2	Peri1	Peri2	Post1	Post2
Arm/Group Description	Premenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Premenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)
Measure Participants	12	12	17	21	12	13
Baseline	9.8 (2.5)	11.3 (2.5)	7.7 (2.6)	6.1 (2.7)	5.4 (1.7)	5.3 (2.2)
Day 4 of GnRHant alone	7.1 (2.3)	8.9 (2.7)	5.8 (2)	6.6 (2)	4.9 (1.5)	4.9 (1.4)
Day 7 of GnRHant plus treatment	10.6 (3.3)	7.8 (3.0)	9.6 (3.3)	6.1 (2.7)	8.4 (2.4)	4.2 (1.7)
Acute Vitamin C Infusion Day 7	8.4 (3.1)	11.2 (4.8)	9.3 (3.4)	11.2 (3.6)	7.8 (3.4)	6.7 (2.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pre1, Pre2, Peri1, Peri2, Post1, Post2
	Comments
	Type of Statistical Test	Other
	Comments	Repeated measurements of FMD were modeled using a general linear mixed model with maximum likelihood estimation. An unstructured covariance structure allowing for heterogeneity in the parameter estimate for each level of menopause stage was chosen for the model based on using AIC to compare various covariance structures.
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Mixed Models Analysis
	Comments

3. Other Pre-specified Outcome

Title	Supine Brachial Blood Pressures
Time Frame	Baseline, day 4 of GnRHant and day 7 of GnRHant and estradiol or placebo treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pre1	Pre2	Peri1	Peri2	Post1	Post2
Arm/Group Description	Premenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Premenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)
Measure Participants	12	12	17	21	12	13
Baseline	102 (10)	108 (9)	111 (13)	109 (15)	117 (10)	123 (13)
Day 4 of GnRHant alone	107 (7)	111 (13)	112 (12)	108 (13)	116 (9)	115 (8)
Day 7 of GnRHant plus treatment	103 (10)	110 (14)	108 (13)	109 (16)	112 (10)	111 (8)

4. Other Pre-specified Outcome

Title	Estradiol
Description	This other outcome measure was originally specified as "Secondary" in error and has been updated to "Other, Pre-specified" to be consistent with the protocol. Serum estradiol for clinical characteristics and to detect changes in estradiol levels with the interventions.
Time Frame	Baseline, day 4 of GnRHant and day 7 of GnRHant and estradiol or placebo treatment

Outcome Measure Data

Analysis Population Description

Data are for subsample of women who completed FMD with useuable data

Arm/Group Title	Pre1	Pre2	Peri1	Peri2	Post1	Post2
Arm/Group Description	Premenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Premenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)
Measure Participants	12	12	17	21	12	13
Baseline	229	270	360	147	39	37
GnRHant alone	147	127	92	99	37	37
GnRhant+Add-back	202	134	187	106	165	37

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pre1, Pre2, Peri1, Peri2, Post1, Post2
	Comments
	Type of Statistical Test	Other
	Comments	Similar analyses as primary outcome
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Mixed Models Analysis
	Comments

5. Other Pre-specified Outcome

Title	Progesterone
Description	This other outcome measure was originally specified as "Secondary" in error and has been updated to "Other, Pre-specified" to be consistent with the protocol. Serum progesterone was measured for clinical characteristics and to determine changes in sex hormones.
Time Frame	Baseline, Day 4 GnRHant, Day 7 GnRHant+Add-back

Outcome Measure Data

Analysis Population Description

Data presented are from those women who had FMD with usable images

Arm/Group Title	Pre1	Pre2	Peri1	Peri2	Post1	Post2
Arm/Group Description	Premenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Premenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)
Measure Participants	12	12	17	21	12	13
Baseline	1.8	2.1	1.1	1.3	1.1	0.9
GnRHant alone	1.3	1.7	1.0	1.0	1.0	0.6
GnRhant+Add-back	1.0	1.0	0.8	1.6	1.0	0.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pre1, Pre2, Peri1, Peri2, Post1, Post2
	Comments
	Type of Statistical Test	Other
	Comments	same analysis as primary outcome
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Mixed Models Analysis
	Comments

6. Other Pre-specified Outcome

Title	Total Antioxidant Status (TAS)
Description	This other outcome measure was originally specified as "Secondary" in error and has been updated to "Other, Pre-specified" to be consistent with the protocol. TAS is an antioxidant and is a biomarker of oxidative stress.
Time Frame	Baseline, Day 4 GnRHant, Day 7 GnRHant+Add-back

Outcome Measure Data

Analysis Population Description

Data are presented from participants that completed the endothelial function testing and who had usable images.

Arm/Group Title	Pre1	Pre2	Peri1	Peri2	Post1	Post2
Arm/Group Description	Premenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Premenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)
Measure Participants	12	12	17	21	12	13
Baseline	1.4 (0.2)	1.4 (0.2)	1.3 (0.2)	1.3 (0.1)	1.3 (0.2)	1.3 (0.2)
GnRHant alone	1.4 (0.2)	1.5 (0.1)	1.3 (0.2)	1.3 (0.2)	1.3 (0.1)	1.4 (0.3)
GnRhant+Add-back	1.4 (0.1)	1.4 (0.1)	1.3 (0.1)	1.3 (0.1)	1.3 (0.2)	1.3 (0.2)

7. Other Pre-specified Outcome

Title	Endothelin-1 (ET-1)
Description	This other outcome measure was originally specified as "Secondary" in error and has been updated to "Other, Pre-specified" to be consistent with the protocol.
Time Frame	Baseline, Day 4 GnRHant, Day 7 GnRHant+Add-back

Outcome Measure Data

Analysis Population Description

Data are presented from women who completed endothelial function testing and whom had usable images

Arm/Group Title	Pre1	Pre2	Peri1	Peri2	Post1	Post2
Arm/Group Description	Premenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Premenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)
Measure Participants	12	12	17	21	12	13
Baseline	5.2 (1.5)	5.2 (0.9)	5.9 (1.3)	6.2 (1.6)	6.2 (1.4)	6.4 (1.1)
GnRHant alone	5.5 (1.7)	5.5 (0.9)	6.0 (1.8)	5.9 (0.9)	6.5 (2.1)	6.5 (0.9)
GnRhant+Add-back	6.0 (1.1)	5.0 (0.7)	5.9 (1.6)	5.7 (1.9)	6.0 (1.8)	6.4 (0.9)

8. Other Pre-specified Outcome

Title	Plasma Norepinephrine
Description	This other outcome measure was originally specified as "Secondary" in error and has been updated to "Other, Pre-specified" to be consistent with the protocol.
Time Frame	Baseline, Day 4 GnRHant, Day 7 GnRHant+Add-back

Outcome Measure Data

Analysis Population Description

Data are presented from women who completed endothelial function testing and whom had useable images.

Arm/Group Title	Pre1	Pre2	Peri1	Peri2	Post1	Post2
Arm/Group Description	Premenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Premenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Perimenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)	Postmenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)
Measure Participants	12	12	17	21	12	13
Baseline	161	184	227	247	231	242
GnRHant alone	144	156	235	233	280	217
GnRhant+Add-back	146	217	231	217	204	221

Adverse Events

Adverse Event Reporting Description	Participants were asked at each vascular visit to complete a symptom questionnaire. These data were reviewed immediately by the PI and the study physician. Further, these data were summarized for the Safety Officer annually.
Arm/Group Title	Pre1		Pre2		Peri1		Peri2		Post1		Post2
Arm/Group Description	Premenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)		Premenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)		Perimenopausal (early and late combined) - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)		Perimenopausal (early and late combined) - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)		Postmenopausal - GnRHant plus estradiol GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal estradiol patch: 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)		Postmenopausal - GnRHant plus placebo GnRHant - Ganirelix acetate: 1 subcutaneous injection at 0.5 mg then daily injections of 0.25 mg for 6 days (total of 7 days of injections); testing will occur on injection day 4 and day 7 Transdermal placebo patch: Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)
All Cause Mortality
	Pre1		Pre2		Peri1		Peri2		Post1		Post2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)		0/19 (0%)		0/21 (0%)		0/13 (0%)		0/15 (0%)
Serious Adverse Events
	Pre1		Pre2		Peri1		Peri2		Post1		Post2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)		0/19 (0%)		0/21 (0%)		0/13 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Pre1		Pre2		Peri1		Peri2		Post1		Post2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/12 (66.7%)		4/12 (33.3%)		9/19 (47.4%)		8/21 (38.1%)		5/13 (38.5%)		4/15 (26.7%)
Gastrointestinal disorders
Bloating	2/12 (16.7%)	2	1/12 (8.3%)	1	4/19 (21.1%)	4	2/21 (9.5%)	2	2/13 (15.4%)	2	1/15 (6.7%)	1
Nausea	2/12 (16.7%)	2	1/12 (8.3%)	1	2/19 (10.5%)	2	1/21 (4.8%)	1	0/13 (0%)	0	0/15 (0%)	0
Injury, poisoning and procedural complications
Cardiovascular/neurology	0/12 (0%)	0	0/12 (0%)	0	0/19 (0%)	0	1/21 (4.8%)	1	0/13 (0%)	0	1/15 (6.7%)	1
Musculoskeletal and connective tissue disorders
Joint Pain	1/12 (8.3%)	1	1/12 (8.3%)	1	1/19 (5.3%)	1	3/21 (14.3%)	3	0/13 (0%)	0	0/15 (0%)	0
Reproductive system and breast disorders
Breast tenderness	0/12 (0%)	0	0/12 (0%)	0	1/19 (5.3%)	1	1/21 (4.8%)	1	0/13 (0%)	0	0/15 (0%)	0
Vaginal bleeding	4/12 (33.3%)	4	2/12 (16.7%)	2	1/19 (5.3%)	1	1/21 (4.8%)	1	0/13 (0%)	0	0/15 (0%)	0
Other urogenital	1/12 (8.3%)	1	0/12 (0%)	0	2/19 (10.5%)	2	1/21 (4.8%)	1	2/13 (15.4%)	2	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders
Injection site reaction	1/12 (8.3%)	1	1/12 (8.3%)	1	0/19 (0%)	0	3/21 (14.3%)	3	1/13 (7.7%)	1	2/15 (13.3%)	2
Patch irritation	6/12 (50%)	6	2/12 (16.7%)	2	3/19 (15.8%)	3	2/21 (9.5%)	2	2/13 (15.4%)	2	2/15 (13.3%)	2

Limitations/Caveats

Budget cuts lead to: 1) endothelial cell protein expression outcome not analyzed and deleted; 2) small numbers of early and late perimenopausal groups, thus, it was collapsed into 1 peri group. Ultrasound image quality also lead to small numbers.

More Information

Certain Agreements

Principal Investigators are NOT 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.