Estrogen, HDL, and Coronary Heart Disease in Women
Condition: Cardiovascular Diseases; Coronary Disease; Heart Diseases; Coronary Arteriosclerosis
MeSH terms: Cardiovascular Diseases; Heart Diseases; Coronary Disease; Coronary Artery Disease; Myocardial Ischemia; Arteriosclerosis
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

Intervention name(s): Estrogens, Conjugated (USP); Medroxyprogesterone 17-Acetate; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 0.625 mg/day QID for 3 years; 2.5 mg/day QID for 3 years; 2 pills/day QID for 3 years
Other intervention name(s): Premarin; Provera; Sugar Pill
Intervention MeSH terms: Medroxyprogesterone Acetate; Medroxyprogesterone; Estrogens; Estrogens, Conjugated (USP)
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Health Services Research