Arterial Stiffening, Aging, Menopause
Conditions
Keywords
endothelial function, women, female, estrogen deficiency, sex hormones, adiposity, oxidative stress, antioxidants
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.
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
Interventions
DRUGGnRHant - 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
0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)
Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)
Sponsors
National Institute on Aging (NIA)
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 70 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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
| Measure | Time frame | Description |
|---|---|---|
| Supine Brachial Blood Pressures | Baseline, day 4 of GnRHant and day 7 of GnRHant and estradiol or placebo treatment | — |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Pre1 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) | 12 |
| Pre2 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) | 12 |
| Peri1 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) | 17 |
| Peri2 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) | 21 |
| Post1 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) | 12 |
| Post2 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) | 13 |
| Total | 87 |
Baseline characteristics
| Characteristic | Pre2 | Peri1 | Peri2 | Post1 | Post2 | Pre1 | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 17 Participants | 21 Participants | 12 Participants | 11 Participants | 12 Participants | 85 Participants |
| Age, Continuous | 33 years STANDARD_DEVIATION 7 | 49 years STANDARD_DEVIATION 3 | 50 years STANDARD_DEVIATION 4 | 56 years STANDARD_DEVIATION 5 | 60 years STANDARD_DEVIATION 6 | 32 years STANDARD_DEVIATION 8 | 47 years STANDARD_DEVIATION 11 |
| Body Mass | 64.2 kg STANDARD_DEVIATION 11 | 65.6 kg STANDARD_DEVIATION 8.1 | 68.7 kg STANDARD_DEVIATION 11.9 | 70.5 kg STANDARD_DEVIATION 14.7 | 69.7 kg STANDARD_DEVIATION 9.3 | 66.8 kg STANDARD_DEVIATION 15.6 | 67.6 kg STANDARD_DEVIATION 11.7 |
| Body Mass Index (BMI) | 24.4 kg/m2 STANDARD_DEVIATION 5.3 | 24.1 kg/m2 STANDARD_DEVIATION 3.2 | 25.2 kg/m2 STANDARD_DEVIATION 3.9 | 26.7 kg/m2 STANDARD_DEVIATION 5.9 | 26.5 kg/m2 STANDARD_DEVIATION 2.7 | 23.8 kg/m2 STANDARD_DEVIATION 5.6 | 25.1 kg/m2 STANDARD_DEVIATION 4.4 |
| Diastolic Blood Pressure | 72 mmHg STANDARD_DEVIATION 5 | 71 mmHg STANDARD_DEVIATION 9 | 73 mmHg STANDARD_DEVIATION 6 | 73 mmHg STANDARD_DEVIATION 8 | 74 mmHg STANDARD_DEVIATION 10 | 70 mmHg STANDARD_DEVIATION 7 | 72 mmHg STANDARD_DEVIATION 8 |
| Glucose | 4.6 mmol/L STANDARD_DEVIATION 0.6 | 4.5 mmol/L STANDARD_DEVIATION 0.3 | 4.7 mmol/L STANDARD_DEVIATION 0.5 | 5.0 mmol/L STANDARD_DEVIATION 0.7 | 4.6 mmol/L STANDARD_DEVIATION 0.6 | 4.7 mmol/L STANDARD_DEVIATION 0.3 | 4.7 mmol/L STANDARD_DEVIATION 0.5 |
| High-density Lipoprotein | 1.3 mmol/L STANDARD_DEVIATION 0.2 | 1.3 mmol/L STANDARD_DEVIATION 0.2 | 1.3 mmol/L STANDARD_DEVIATION 0.3 | 1.3 mmol/L STANDARD_DEVIATION 0.3 | 1.3 mmol/L STANDARD_DEVIATION 0.3 | 1.1 mmol/L STANDARD_DEVIATION 0.1 | 1.3 mmol/L STANDARD_DEVIATION 0.3 |
| Insulin | 42 pmol/L | 28 pmol/L | 28 pmol/L | 28 pmol/L | 31 pmol/L | 38 pmol/L | 35 pmol/L |
| Low-density Lipoprotein | 2.2 mmol/L STANDARD_DEVIATION 0.7 | 2.7 mmol/L STANDARD_DEVIATION 1 | 2.4 mmol/L STANDARD_DEVIATION 0.5 | 2.9 mmol/L STANDARD_DEVIATION 0.8 | 2.8 mmol/L STANDARD_DEVIATION 0.9 | 2.3 mmol/L STANDARD_DEVIATION 0.5 | 2.6 mmol/L STANDARD_DEVIATION 0.8 |
| Region of Enrollment United States | 12 participants | 17 participants | 21 participants | 12 participants | 13 participants | 12 participants | 87 participants |
| Sex: Female, Male Female | 12 Participants | 17 Participants | 21 Participants | 12 Participants | 13 Participants | 12 Participants | 87 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Systolic Blood Pressure | 110 mmHg STANDARD_DEVIATION 7 | 113 mmHg STANDARD_DEVIATION 14 | 115 mmHg STANDARD_DEVIATION 11 | 117 mmHg STANDARD_DEVIATION 14 | 120 mmHg STANDARD_DEVIATION 14 | 109 mmHg STANDARD_DEVIATION 8 | 114 mmHg STANDARD_DEVIATION 12 |
| Total Cholesterol | 4.0 mmol/L STANDARD_DEVIATION 0.9 | 4.5 mmol/L STANDARD_DEVIATION 0.9 | 4.2 mmol/L STANDARD_DEVIATION 0.6 | 4.7 mmol/L STANDARD_DEVIATION 0.9 | 4.7 mmol/L STANDARD_DEVIATION 0.9 | 3.7 mmol/L STANDARD_DEVIATION 0.7 | 4.3 mmol/L STANDARD_DEVIATION 0.9 |
| VO2peak | 31.0 ml/kg/min STANDARD_DEVIATION 5.5 | 27.7 ml/kg/min STANDARD_DEVIATION 4 | 27.5 ml/kg/min STANDARD_DEVIATION 5.8 | 24.8 ml/kg/min STANDARD_DEVIATION 3.9 | 24.1 ml/kg/min STANDARD_DEVIATION 2.9 | 35.3 ml/kg/min STANDARD_DEVIATION 6 | 28.2 ml/kg/min STANDARD_DEVIATION 5.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 | 0 / 19 | 0 / 21 | 0 / 13 | 0 / 15 |
| other Total, other adverse events | 8 / 12 | 4 / 12 | 9 / 19 | 8 / 21 | 5 / 13 | 4 / 15 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 19 | 0 / 21 | 0 / 13 | 0 / 15 |
Outcome results
Primary
Arterial Stiffness (Carotid Artery Compliance) During Saline
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
Population: Early and late perimenopausal were collapsed into 1 perimenopausal group
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pre1 | Arterial Stiffness (Carotid Artery Compliance) During Saline | Baseline | 1.31 mm2/mm Hg×10-1 | Standard Deviation 0.27 |
| Pre1 | Arterial Stiffness (Carotid Artery Compliance) During Saline | GnRHant alone | 1.27 mm2/mm Hg×10-1 | Standard Deviation 0.27 |
| Pre1 | Arterial Stiffness (Carotid Artery Compliance) During Saline | GnRHant + Add-Back | 1.29 mm2/mm Hg×10-1 | Standard Deviation 0.26 |
| Pre2 | Arterial Stiffness (Carotid Artery Compliance) During Saline | GnRHant + Add-Back | 1.14 mm2/mm Hg×10-1 | Standard Deviation 0.38 |
| Pre2 | Arterial Stiffness (Carotid Artery Compliance) During Saline | Baseline | 1.34 mm2/mm Hg×10-1 | Standard Deviation 0.18 |
| Pre2 | Arterial Stiffness (Carotid Artery Compliance) During Saline | GnRHant alone | 1.19 mm2/mm Hg×10-1 | Standard Deviation 0.34 |
| Peri1 | Arterial Stiffness (Carotid Artery Compliance) During Saline | Baseline | 0.90 mm2/mm Hg×10-1 | Standard Deviation 0.27 |
| Peri1 | Arterial Stiffness (Carotid Artery Compliance) During Saline | GnRHant alone | 0.89 mm2/mm Hg×10-1 | Standard Deviation 0.27 |
| Peri1 | Arterial Stiffness (Carotid Artery Compliance) During Saline | GnRHant + Add-Back | 0.98 mm2/mm Hg×10-1 | Standard Deviation 0.27 |
| Peri2 | Arterial Stiffness (Carotid Artery Compliance) During Saline | GnRHant alone | 0.94 mm2/mm Hg×10-1 | Standard Deviation 0.29 |
| Peri2 | Arterial Stiffness (Carotid Artery Compliance) During Saline | Baseline | 1.02 mm2/mm Hg×10-1 | Standard Deviation 0.33 |
| Peri2 | Arterial Stiffness (Carotid Artery Compliance) During Saline | GnRHant + Add-Back | 0.94 mm2/mm Hg×10-1 | Standard Deviation 0.27 |
| Post1 | Arterial Stiffness (Carotid Artery Compliance) During Saline | GnRHant alone | 0.85 mm2/mm Hg×10-1 | Standard Deviation 0.24 |
| Post1 | Arterial Stiffness (Carotid Artery Compliance) During Saline | GnRHant + Add-Back | 0.92 mm2/mm Hg×10-1 | Standard Deviation 0.27 |
| Post1 | Arterial Stiffness (Carotid Artery Compliance) During Saline | Baseline | 0.89 mm2/mm Hg×10-1 | Standard Deviation 0.25 |
| Post2 | Arterial Stiffness (Carotid Artery Compliance) During Saline | GnRHant + Add-Back | 0.80 mm2/mm Hg×10-1 | Standard Deviation 0.19 |
| Post2 | Arterial Stiffness (Carotid Artery Compliance) During Saline | Baseline | 0.74 mm2/mm Hg×10-1 | Standard Deviation 0.23 |
| Post2 | Arterial Stiffness (Carotid Artery Compliance) During Saline | GnRHant alone | 0.79 mm2/mm Hg×10-1 | Standard Deviation 0.22 |
Primary
Endothelial Function
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
Population: Numbers for some groups are reduced because of poor ultrasound image quality.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pre1 | Endothelial Function | Baseline | 9.8 % Diameter Change | Standard Deviation 2.5 |
| Pre1 | Endothelial Function | Acute Vitamin C Infusion Day 7 | 8.4 % Diameter Change | Standard Deviation 3.1 |
| Pre1 | Endothelial Function | Day 7 of GnRHant plus treatment | 10.6 % Diameter Change | Standard Deviation 3.3 |
| Pre1 | Endothelial Function | Day 4 of GnRHant alone | 7.1 % Diameter Change | Standard Deviation 2.3 |
| Pre2 | Endothelial Function | Acute Vitamin C Infusion Day 7 | 11.2 % Diameter Change | Standard Deviation 4.8 |
| Pre2 | Endothelial Function | Day 4 of GnRHant alone | 8.9 % Diameter Change | Standard Deviation 2.7 |
| Pre2 | Endothelial Function | Baseline | 11.3 % Diameter Change | Standard Deviation 2.5 |
| Pre2 | Endothelial Function | Day 7 of GnRHant plus treatment | 7.8 % Diameter Change | Standard Deviation 3 |
| Peri1 | Endothelial Function | Day 7 of GnRHant plus treatment | 9.6 % Diameter Change | Standard Deviation 3.3 |
| Peri1 | Endothelial Function | Day 4 of GnRHant alone | 5.8 % Diameter Change | Standard Deviation 2 |
| Peri1 | Endothelial Function | Baseline | 7.7 % Diameter Change | Standard Deviation 2.6 |
| Peri1 | Endothelial Function | Acute Vitamin C Infusion Day 7 | 9.3 % Diameter Change | Standard Deviation 3.4 |
| Peri2 | Endothelial Function | Day 7 of GnRHant plus treatment | 6.1 % Diameter Change | Standard Deviation 2.7 |
| Peri2 | Endothelial Function | Day 4 of GnRHant alone | 6.6 % Diameter Change | Standard Deviation 2 |
| Peri2 | Endothelial Function | Baseline | 6.1 % Diameter Change | Standard Deviation 2.7 |
| Peri2 | Endothelial Function | Acute Vitamin C Infusion Day 7 | 11.2 % Diameter Change | Standard Deviation 3.6 |
| Post1 | Endothelial Function | Acute Vitamin C Infusion Day 7 | 7.8 % Diameter Change | Standard Deviation 3.4 |
| Post1 | Endothelial Function | Day 4 of GnRHant alone | 4.9 % Diameter Change | Standard Deviation 1.5 |
| Post1 | Endothelial Function | Baseline | 5.4 % Diameter Change | Standard Deviation 1.7 |
| Post1 | Endothelial Function | Day 7 of GnRHant plus treatment | 8.4 % Diameter Change | Standard Deviation 2.4 |
| Post2 | Endothelial Function | Day 4 of GnRHant alone | 4.9 % Diameter Change | Standard Deviation 1.4 |
| Post2 | Endothelial Function | Baseline | 5.3 % Diameter Change | Standard Deviation 2.2 |
| Post2 | Endothelial Function | Acute Vitamin C Infusion Day 7 | 6.7 % Diameter Change | Standard Deviation 2.8 |
| Post2 | Endothelial Function | Day 7 of GnRHant plus treatment | 4.2 % Diameter Change | Standard Deviation 1.7 |
p-value: 0.05Mixed Models Analysis
Other Pre-specified
Endothelin-1 (ET-1)
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
Population: Data are presented from women who completed endothelial function testing and whom had usable images
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pre1 | Endothelin-1 (ET-1) | GnRHant alone | 5.5 pg/mL | Standard Deviation 1.7 |
| Pre1 | Endothelin-1 (ET-1) | Baseline | 5.2 pg/mL | Standard Deviation 1.5 |
| Pre1 | Endothelin-1 (ET-1) | GnRhant+Add-back | 6.0 pg/mL | Standard Deviation 1.1 |
| Pre2 | Endothelin-1 (ET-1) | GnRHant alone | 5.5 pg/mL | Standard Deviation 0.9 |
| Pre2 | Endothelin-1 (ET-1) | Baseline | 5.2 pg/mL | Standard Deviation 0.9 |
| Pre2 | Endothelin-1 (ET-1) | GnRhant+Add-back | 5.0 pg/mL | Standard Deviation 0.7 |
| Peri1 | Endothelin-1 (ET-1) | GnRHant alone | 6.0 pg/mL | Standard Deviation 1.8 |
| Peri1 | Endothelin-1 (ET-1) | Baseline | 5.9 pg/mL | Standard Deviation 1.3 |
| Peri1 | Endothelin-1 (ET-1) | GnRhant+Add-back | 5.9 pg/mL | Standard Deviation 1.6 |
| Peri2 | Endothelin-1 (ET-1) | GnRHant alone | 5.9 pg/mL | Standard Deviation 0.9 |
| Peri2 | Endothelin-1 (ET-1) | Baseline | 6.2 pg/mL | Standard Deviation 1.6 |
| Peri2 | Endothelin-1 (ET-1) | GnRhant+Add-back | 5.7 pg/mL | Standard Deviation 1.9 |
| Post1 | Endothelin-1 (ET-1) | GnRHant alone | 6.5 pg/mL | Standard Deviation 2.1 |
| Post1 | Endothelin-1 (ET-1) | Baseline | 6.2 pg/mL | Standard Deviation 1.4 |
| Post1 | Endothelin-1 (ET-1) | GnRhant+Add-back | 6.0 pg/mL | Standard Deviation 1.8 |
| Post2 | Endothelin-1 (ET-1) | Baseline | 6.4 pg/mL | Standard Deviation 1.1 |
| Post2 | Endothelin-1 (ET-1) | GnRhant+Add-back | 6.4 pg/mL | Standard Deviation 0.9 |
| Post2 | Endothelin-1 (ET-1) | GnRHant alone | 6.5 pg/mL | Standard Deviation 0.9 |
Other Pre-specified
Estradiol
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
Population: Data are for subsample of women who completed FMD with useuable data
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pre1 | Estradiol | GnRHant alone | 147 pmol/L |
| Pre1 | Estradiol | Baseline | 229 pmol/L |
| Pre1 | Estradiol | GnRhant+Add-back | 202 pmol/L |
| Pre2 | Estradiol | GnRHant alone | 127 pmol/L |
| Pre2 | Estradiol | Baseline | 270 pmol/L |
| Pre2 | Estradiol | GnRhant+Add-back | 134 pmol/L |
| Peri1 | Estradiol | GnRHant alone | 92 pmol/L |
| Peri1 | Estradiol | Baseline | 360 pmol/L |
| Peri1 | Estradiol | GnRhant+Add-back | 187 pmol/L |
| Peri2 | Estradiol | GnRHant alone | 99 pmol/L |
| Peri2 | Estradiol | Baseline | 147 pmol/L |
| Peri2 | Estradiol | GnRhant+Add-back | 106 pmol/L |
| Post1 | Estradiol | GnRHant alone | 37 pmol/L |
| Post1 | Estradiol | Baseline | 39 pmol/L |
| Post1 | Estradiol | GnRhant+Add-back | 165 pmol/L |
| Post2 | Estradiol | Baseline | 37 pmol/L |
| Post2 | Estradiol | GnRhant+Add-back | 37 pmol/L |
| Post2 | Estradiol | GnRHant alone | 37 pmol/L |
p-value: 0.05Mixed Models Analysis
Other Pre-specified
Plasma Norepinephrine
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
Population: Data are presented from women who completed endothelial function testing and whom had useable images.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pre1 | Plasma Norepinephrine | Baseline | 161 pg/mL |
| Pre1 | Plasma Norepinephrine | GnRHant alone | 144 pg/mL |
| Pre1 | Plasma Norepinephrine | GnRhant+Add-back | 146 pg/mL |
| Pre2 | Plasma Norepinephrine | Baseline | 184 pg/mL |
| Pre2 | Plasma Norepinephrine | GnRHant alone | 156 pg/mL |
| Pre2 | Plasma Norepinephrine | GnRhant+Add-back | 217 pg/mL |
| Peri1 | Plasma Norepinephrine | Baseline | 227 pg/mL |
| Peri1 | Plasma Norepinephrine | GnRhant+Add-back | 231 pg/mL |
| Peri1 | Plasma Norepinephrine | GnRHant alone | 235 pg/mL |
| Peri2 | Plasma Norepinephrine | GnRHant alone | 233 pg/mL |
| Peri2 | Plasma Norepinephrine | Baseline | 247 pg/mL |
| Peri2 | Plasma Norepinephrine | GnRhant+Add-back | 217 pg/mL |
| Post1 | Plasma Norepinephrine | GnRhant+Add-back | 204 pg/mL |
| Post1 | Plasma Norepinephrine | Baseline | 231 pg/mL |
| Post1 | Plasma Norepinephrine | GnRHant alone | 280 pg/mL |
| Post2 | Plasma Norepinephrine | GnRHant alone | 217 pg/mL |
| Post2 | Plasma Norepinephrine | Baseline | 242 pg/mL |
| Post2 | Plasma Norepinephrine | GnRhant+Add-back | 221 pg/mL |
Other Pre-specified
Progesterone
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
Population: Data presented are from those women who had FMD with usable images
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pre1 | Progesterone | GnRHant alone | 1.3 nmol/L |
| Pre1 | Progesterone | Baseline | 1.8 nmol/L |
| Pre1 | Progesterone | GnRhant+Add-back | 1.0 nmol/L |
| Pre2 | Progesterone | GnRHant alone | 1.7 nmol/L |
| Pre2 | Progesterone | Baseline | 2.1 nmol/L |
| Pre2 | Progesterone | GnRhant+Add-back | 1.0 nmol/L |
| Peri1 | Progesterone | GnRHant alone | 1.0 nmol/L |
| Peri1 | Progesterone | Baseline | 1.1 nmol/L |
| Peri1 | Progesterone | GnRhant+Add-back | 0.8 nmol/L |
| Peri2 | Progesterone | GnRHant alone | 1.0 nmol/L |
| Peri2 | Progesterone | Baseline | 1.3 nmol/L |
| Peri2 | Progesterone | GnRhant+Add-back | 1.6 nmol/L |
| Post1 | Progesterone | GnRHant alone | 1.0 nmol/L |
| Post1 | Progesterone | Baseline | 1.1 nmol/L |
| Post1 | Progesterone | GnRhant+Add-back | 1.0 nmol/L |
| Post2 | Progesterone | Baseline | 0.9 nmol/L |
| Post2 | Progesterone | GnRhant+Add-back | 0.6 nmol/L |
| Post2 | Progesterone | GnRHant alone | 0.6 nmol/L |
p-value: 0.05Mixed Models Analysis
Other Pre-specified
Supine Brachial Blood Pressures
Time frame: Baseline, day 4 of GnRHant and day 7 of GnRHant and estradiol or placebo treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pre1 | Supine Brachial Blood Pressures | Day 4 of GnRHant alone | 107 mmHg | Standard Deviation 7 |
| Pre1 | Supine Brachial Blood Pressures | Baseline | 102 mmHg | Standard Deviation 10 |
| Pre1 | Supine Brachial Blood Pressures | Day 7 of GnRHant plus treatment | 103 mmHg | Standard Deviation 10 |
| Pre2 | Supine Brachial Blood Pressures | Day 4 of GnRHant alone | 111 mmHg | Standard Deviation 13 |
| Pre2 | Supine Brachial Blood Pressures | Baseline | 108 mmHg | Standard Deviation 9 |
| Pre2 | Supine Brachial Blood Pressures | Day 7 of GnRHant plus treatment | 110 mmHg | Standard Deviation 14 |
| Peri1 | Supine Brachial Blood Pressures | Day 4 of GnRHant alone | 112 mmHg | Standard Deviation 12 |
| Peri1 | Supine Brachial Blood Pressures | Baseline | 111 mmHg | Standard Deviation 13 |
| Peri1 | Supine Brachial Blood Pressures | Day 7 of GnRHant plus treatment | 108 mmHg | Standard Deviation 13 |
| Peri2 | Supine Brachial Blood Pressures | Day 4 of GnRHant alone | 108 mmHg | Standard Deviation 13 |
| Peri2 | Supine Brachial Blood Pressures | Baseline | 109 mmHg | Standard Deviation 15 |
| Peri2 | Supine Brachial Blood Pressures | Day 7 of GnRHant plus treatment | 109 mmHg | Standard Deviation 16 |
| Post1 | Supine Brachial Blood Pressures | Day 4 of GnRHant alone | 116 mmHg | Standard Deviation 9 |
| Post1 | Supine Brachial Blood Pressures | Baseline | 117 mmHg | Standard Deviation 10 |
| Post1 | Supine Brachial Blood Pressures | Day 7 of GnRHant plus treatment | 112 mmHg | Standard Deviation 10 |
| Post2 | Supine Brachial Blood Pressures | Baseline | 123 mmHg | Standard Deviation 13 |
| Post2 | Supine Brachial Blood Pressures | Day 7 of GnRHant plus treatment | 111 mmHg | Standard Deviation 8 |
| Post2 | Supine Brachial Blood Pressures | Day 4 of GnRHant alone | 115 mmHg | Standard Deviation 8 |
Other Pre-specified
Total Antioxidant Status (TAS)
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
Population: Data are presented from participants that completed the endothelial function testing and who had usable images.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pre1 | Total Antioxidant Status (TAS) | GnRhant+Add-back | 1.4 nmol/L | Standard Deviation 0.1 |
| Pre1 | Total Antioxidant Status (TAS) | GnRHant alone | 1.4 nmol/L | Standard Deviation 0.2 |
| Pre1 | Total Antioxidant Status (TAS) | Baseline | 1.4 nmol/L | Standard Deviation 0.2 |
| Pre2 | Total Antioxidant Status (TAS) | GnRHant alone | 1.5 nmol/L | Standard Deviation 0.1 |
| Pre2 | Total Antioxidant Status (TAS) | Baseline | 1.4 nmol/L | Standard Deviation 0.2 |
| Pre2 | Total Antioxidant Status (TAS) | GnRhant+Add-back | 1.4 nmol/L | Standard Deviation 0.1 |
| Peri1 | Total Antioxidant Status (TAS) | GnRhant+Add-back | 1.3 nmol/L | Standard Deviation 0.1 |
| Peri1 | Total Antioxidant Status (TAS) | Baseline | 1.3 nmol/L | Standard Deviation 0.2 |
| Peri1 | Total Antioxidant Status (TAS) | GnRHant alone | 1.3 nmol/L | Standard Deviation 0.2 |
| Peri2 | Total Antioxidant Status (TAS) | GnRhant+Add-back | 1.3 nmol/L | Standard Deviation 0.1 |
| Peri2 | Total Antioxidant Status (TAS) | Baseline | 1.3 nmol/L | Standard Deviation 0.1 |
| Peri2 | Total Antioxidant Status (TAS) | GnRHant alone | 1.3 nmol/L | Standard Deviation 0.2 |
| Post1 | Total Antioxidant Status (TAS) | GnRhant+Add-back | 1.3 nmol/L | Standard Deviation 0.2 |
| Post1 | Total Antioxidant Status (TAS) | GnRHant alone | 1.3 nmol/L | Standard Deviation 0.1 |
| Post1 | Total Antioxidant Status (TAS) | Baseline | 1.3 nmol/L | Standard Deviation 0.2 |
| Post2 | Total Antioxidant Status (TAS) | GnRhant+Add-back | 1.3 nmol/L | Standard Deviation 0.2 |
| Post2 | Total Antioxidant Status (TAS) | Baseline | 1.3 nmol/L | Standard Deviation 0.2 |
| Post2 | Total Antioxidant Status (TAS) | GnRHant alone | 1.4 nmol/L | Standard Deviation 0.3 |