Estrogen, HDL, and Coronary Heart Disease in Women

Phase 2

Completed

• Conditions: Cardiovascular Diseases; Coronary Disease; Heart Diseases; Coronary Arteriosclerosis
• Interventions: Drug: Placebo; Drug: Estrogens, Conjugated (USP); Drug: Medroxyprogesterone 17-Acetate

• Registration Number: NCT00083824
• Lead Sponsor: Tufts University

Brief Summary

To clarify the effects of estrogen, with or without progestin, on high density lipoprotein (HDL) in postmenopausal women.

Detailed Description

BACKGROUND:

Coronary heart disease (CHD) is the leading cause of death and disability in postmenopausal women in the United States. Low plasma levels of high-density lipoprotein cholesterol (HDL-C) are a well-established risk factor for CHD. Elevated plasma triglyceride (TG) levels are also a risk factor for CHD in women. HDL particles are heterogeneous in composition (containing apo A-I only, LpAI, or apo A-I and apo A-II, LpAIAII) and charge and size (preBeta1, preBeta2, alpha1-3, preAlpha1-4). Different HDL subpopulations have different physiological functions and therefore may vary in their anti-atherogenic potential. Changes in alpha1 HDL subpopulations are a predictor of coronary disease progression in men. Hormonal replacement therapy (HRT) increases plasma levels of HDL-C, but has adverse effects on TG and C-reactive protein (CRP) levels. While observational studies had indicated a protective role of HRT in CHD, recent intervention studies have shown no CHD protection with the use of HRT. Our preliminary data indicate that there is a large inter-individual variability in HDL subpopulations and TG-rich lipoprotein remnants response to HRT.

The study uses the Estrogen Replacement and Atherosclerosis (ERA) trial which offers a unique opportunity to clarify the effects of estrogen with or without progestin on HDL and its subpopulation and TG-rich particles, and the effect of genetic polymorphisms on the response of these parameters to HRT. In addition, the ERA study will allow testing of the hypothesis that HRT may be of benefit to those postmenopausal women who experience large increases in HDL subpopulations (regardless of their overall effect on HDL cholesterol), without significant changes in TG levels. In addition, by looking at the TG and remnants of TG-rich lipoproteins, this study will enable a dissection of the beneficial and the adverse effects of HRT. The ERA population consists of 309 postmenopausal women who have established CHD and have participated in a randomized, placebo controlled, double-blind study of the effects of placebo (n-105), estrogen (n=100), and estrogen plus progestin (n=104) on the progression of coronary atherosclerosis, as assessed by quantitative coronary angiography. The trial showed no difference in coronary atherosclerosis progression across treatment groups after a mean follow-up of 3.2 years.

DESIGN NARRATIVE:

The study will clarify the effects of estrogen, with or without progestin, on HDL and its subpopulations and on lipoprotein remnants. It will also examine the impact of changes in HDL subpopulations and in lipoprotein remnants during HRT on progression of coronary atherosclerosis. These studies will be conducted in participants in the Estrogen Replacement and Atherosclerosis (ERA) trial, a randomized, placebo-controlled study of HRT and progression of atherosclerosis in postmenopausal women with CHD (n=309), in whom baseline and follow-up angiographic measurements of coronary artery diameter have been obtained. The following HDL parameters will be measured: preBeta1, preBeta2, alpha1-3, preAlpha1-4 HDL subpopulations by 2dGE, LpAI and LpAIAII in plasma and apo C-III in HDL and total plasma by immuno-electrophoresis, lipoprotein remnants by an immunoseparation method, and polymorphisms at gene loci involved in HDL metabolism (lipoprotein lipase, hepatic lipase, cholesteryl ester transfer protein, scavenger receptor B1, and ATPA1 receptor). Hypotheses tested are: 1) these HDL parameters and lipoprotein remnants will be significantly associated with severity of CHD at baseline; and 2) HRT-related changes in these parameters will predict coronary atherosclerosis progression in the ERA participants.

Study Timeline

• Study Start: 2004-03
• Study First Submitted: 2004-06-02
• Study First Submitted QC: 2004-06-03
• Study First Posted: 2004-06-04
• Primary Completion: 2007-02
• Study Completion: 2007-02
• Status Verified: 2016-04
• Last Update Submitted: 2016-04-19
• Last Update Posted: 2016-04-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 309

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sugar Pill	Placebo	Placebo
Estrogens, Conjugated (USP)	Estrogens, Conjugated (USP)	Conjugated Equine Estrogen 0.625 mg/day for 3 years, drug
Medroxyprogesterone 17-acetate	Medroxyprogesterone 17-Acetate	Conjugated Equine Estrogen 0.625 mg/day plus Medroxyprogesterone Acetate 2.5 mg/day
Medroxyprogesterone 17-acetate	Estrogens, Conjugated (USP)	Conjugated Equine Estrogen 0.625 mg/day plus Medroxyprogesterone Acetate 2.5 mg/day

Primary Outcome Measures

Name	Time	Method
HDL subpopulation distribution and composition	1 year	To assess the effect of hormonal replacement therapy on HDL subpopulation profile and HDL composition in postmenopausal women with established CHD

Secondary Outcome Measures

Name	Time	Method
Remnant lipoprotein cholesterol	1 year	To assess the effect of hormonal replacement therapy on remnant lipoprotein cholesterol levels in postmenopausal women with established CHD

Trial Locations

Locations (1)

HNRCA at Tufts University; 🇺🇸 Boston, Massachusetts, United States