Sex Hormones and Atherosclerosis Prevention in Perimenopausal Women

Study Overview
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Brief Summary
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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
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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

Official Title
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Biological Mechanisms of Arterial Stiffening With Age and Estrogen Deficiency

Conditions
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Arterial Stiffening, Aging, Menopause

Intervention / Treatment
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* Drug: GnRHant - Ganirelix acetate
* Drug: Transdermal estradiol patch
* Drug: Transdermal placebo patch


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pre1<br>Premenopausal - GnRHant plus estradiol | Drug: GnRHant - Ganirelix acetate<br>* 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<br>* Other names: Ganirelix;Drug: Transdermal estradiol patch<br>* 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)<br>|
| Placebo Comparator: Pre2<br>Premenopausal - GnRHant plus placebo | Drug: GnRHant - Ganirelix acetate<br>* 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<br>* Other names: Ganirelix;Drug: Transdermal placebo patch<br>* Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)<br>|
| Experimental: Peri1<br>Perimenopausal (early) - GnRHant plus estradiol | Drug: GnRHant - Ganirelix acetate<br>* 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<br>* Other names: Ganirelix;Drug: Transdermal estradiol patch<br>* 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)<br>|
| Placebo Comparator: Peri2<br>Perimenopausal (early) - GnRHant plus placebo | Drug: GnRHant - Ganirelix acetate<br>* 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<br>* Other names: Ganirelix;Drug: Transdermal placebo patch<br>* Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)<br>|
| Experimental: Peri3<br>Perimenopausal (late) - GnRHant plus estradiol | Drug: GnRHant - Ganirelix acetate<br>* 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<br>* Other names: Ganirelix;Drug: Transdermal estradiol patch<br>* 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)<br>|
| Placebo Comparator: Peri4<br>Perimenopausal (late) - GnRHant plus placebo | Drug: GnRHant - Ganirelix acetate<br>* 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<br>* Other names: Ganirelix;Drug: Transdermal placebo patch<br>* Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)<br>|
| Experimental: Post1<br>Postmenopausal - GnRHant plus estradiol | Drug: GnRHant - Ganirelix acetate<br>* 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<br>* Other names: Ganirelix;Drug: Transdermal estradiol patch<br>* 0.075mg/d starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)<br>|
| Placebo Comparator: Post2<br>Postmenopausal - GnRHant plus placebo | Drug: GnRHant - Ganirelix acetate<br>* 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<br>* Other names: Ganirelix;Drug: Transdermal placebo patch<br>* Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)<br>|

What is the study measuring?
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Primary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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endothelial function, women, female, estrogen deficiency, sex hormones, adiposity, oxidative stress, antioxidants