Sex Hormones and Atherosclerosis Prevention in Perimenopausal Women

Aging Clinical Trial

— SHAPE  

Official title:

Biological Mechanisms of Arterial Stiffening With Age and Estrogen Deficiency

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00608062
• Other study ID #: 06-0537
• Secondary ID: R01AG027678
• Status: Completed
• Phase: N/A
• Start date: March 2007
• Est. completion date: October 25, 2012

Study information

• Verified date: December 2020
• Source: University of Colorado, Denver
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 155
• Est. completion date: October 25, 2012
• Est. primary completion date: October 25, 2012
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Aging
• Arterial Stiffening
• Menopause

Intervention

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
• 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)
• Transdermal placebo patch
Starting on day 4 of the injections following testing time point two; continue for 3 days and retest (day 7)

Locations

Country	Name	City	State
United States	University of Colorado Anschutz Medical Center, Clinical Translational Research Center and Exercise Research Laboratory	Aurora	Colorado

Sponsors (2)

Lead Sponsor	Collaborator
University of Colorado, Denver	National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

References & Publications (8)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Supine Brachial Blood Pressures		Baseline, day 4 of GnRHant and day 7 of GnRHant and estradiol or placebo treatment
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	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
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.	Baseline, day 4 of GnRHant and Day 7 of GnRHant and estradiol or placebo treatment