To clarify the effects of estrogen, with or without progestin, on high density lipoprotein
(HDL) in postmenopausal women.
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.
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.
age >55 years without natural menses for at least 5 years or a serum FSH levels >40 IU/L
without natural menses for at least 1 y or bilateral oophorectomy documented coronary
history of breast or endometrial carcinoma history of deep-vein thrombosis or pulmonary
embolism previous or planned coronary bypass gallstones fasting TG levels >400 mg/dl
uncontrolled diabetes uncontrolled hypertension serum creatinine >2 mg/dl a >70% stenosis
of the left main coronary artery.