Clinical trial NCT00608062: Sex Hormones and Atherosclerosis Prevention in Perimenopausal Women
Official title: Biological Mechanisms of Arterial Stiffening With Age and Estrogen Deficiency
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Arterial Stiffening
Aging
Menopause
Keywords: endothelial function
women
female
estrogen deficiency
sex hormones
adiposity
oxidative stress
antioxidants
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2008-02-06
Enrollment: 155
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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

Eligibility criteria: 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

Primary outcomes:
measure: Arterial Stiffness (Carotid Artery Compliance) During Saline
timeFrame: Baseline, day 4 of GnRHant and day 7 of GnRHant and estradiol or placebo treatment
measure: Endothelial Function
timeFrame: Baseline, day 4 of GnRHant and Day 7 of GnRHant and estradiol or placebo treatment
Secondary outcomes:
Other outcomes:
measure: Supine Brachial Blood Pressures
timeFrame: Baseline, day 4 of GnRHant and day 7 of GnRHant and estradiol or placebo treatment
measure: Estradiol
timeFrame: Baseline, day 4 of GnRHant and day 7 of GnRHant and estradiol or placebo treatment
measure: Progesterone
timeFrame: Baseline, Day 4 GnRHant, Day 7 GnRHant+Add-back
measure: Total Antioxidant Status (TAS)
timeFrame: Baseline, Day 4 GnRHant, Day 7 GnRHant+Add-back
measure: Endothelin-1 (ET-1)
timeFrame: Baseline, Day 4 GnRHant, Day 7 GnRHant+Add-back
measure: Plasma Norepinephrine
timeFrame: Baseline, Day 4 GnRHant, Day 7 GnRHant+Add-back
Locations:
city: Aurora
country: United States
facility: University of Colorado Anschutz Medical Center, Clinical Translational Research Center and Exercise Research Laboratory
state: Colorado
Study officials:
affiliation: University of Colorado, Denver
name: Kerrie L Moreau, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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. doi: 10.1016/s0008-6363(02)00777-0.
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. doi: 10.1161/01.HYP.0000165678.63373.8c. Epub 2005 May 2.
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. doi: 10.1161/01.cir.101.19.2258.
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. doi: 10.1161/01.res.0000038304.62046.4c.
citation: 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.
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.
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.
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.