Sex Hormones and Atherosclerosis Prevention in Perimenopausal Women (SHAPE)

Biological Mechanisms of Arterial Stiffening With Age and Estrogen Deficiency

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.

Study Overview

• Status: Completed
• Conditions: Menopause; Aging; Arterial Stiffening
• Intervention / Treatment: Drug: GnRHant - Ganirelix acetate; Drug: Transdermal estradiol patch; Drug: Transdermal placebo patch

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 Type: Interventional
• Enrollment (Actual): 155
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Anschutz Medical Center, Clinical Translational Research Center and Exercise Research Laboratory

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

8

Arms and Interventions

Participant Group / 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)

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Supine Brachial Blood Pressures		Baseline, day 4 of GnRHant and day 7 of GnRHant and estradiol or placebo treatment
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.	Baseline, day 4 of GnRHant and day 7 of GnRHant and estradiol or placebo treatment
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.	Baseline, Day 4 GnRHant, Day 7 GnRHant+Add-back
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.	Baseline, Day 4 GnRHant, Day 7 GnRHant+Add-back
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.	Baseline, Day 4 GnRHant, Day 7 GnRHant+Add-back
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.	Baseline, Day 4 GnRHant, Day 7 GnRHant+Add-back

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Kerrie L Moreau, PhD, University of Colorado, Denver

Publications and helpful links

General Publications

• 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. doi: 10.1016/s0008-6363(02)00777-0.
• 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. doi: 10.1161/01.HYP.0000165678.63373.8c. Epub 2005 May 2.
• 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. doi: 10.1161/01.cir.101.19.2258.
• 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. doi: 10.1161/01.res.0000038304.62046.4c.
• 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. doi: 10.1113/jphysiol.2003.057042. 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.
• 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.
• Moreau KL, Hildreth KL, Meditz AL, Deane KD, Kohrt WM. Endothelial function is impaired across the stages of the menopause transition in healthy women. J Clin Endocrinol Metab. 2012 Dec;97(12):4692-700. doi: 10.1210/jc.2012-2244. Epub 2012 Sep 11.

Study record dates

Study Major Dates

• Study Start: March 1, 2007
• Primary Completion (Actual): October 25, 2012
• Study Completion (Actual): October 25, 2012

Study Registration Dates

• First Submitted: January 31, 2008
• First Submitted That Met QC Criteria: January 31, 2008
• First Posted (Estimate): February 6, 2008

Study Record Updates

• Last Update Posted (Actual): December 24, 2020
• Last Update Submitted That Met QC Criteria: December 22, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: adiposity; oxidative stress; antioxidants; female; women; endothelial function; estrogen deficiency; sex hormones
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Hormone Antagonists; Estradiol; Ganirelix
• Other Study ID Numbers: 06-0537; R01AG027678 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO