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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 10 3534-3538
Copyright © 1999 by The Endocrine Society

Original Studies

Plasma Cholesterol Esterification And Transfer, the Menopause, And Hormone Replacement Therapy in Women1

Nicholas J. Lewis-Barned, Wayne H. F. Sutherland, Robert J. Walker, Heather L. Walker, Sylvia A. de Jong, Elizabeth A. Edwards and Valerie H. Markham

Department of Endocrinology and Diabetes (N.J.L-B.), Gloucestershire Royal Hospital, Gloucester GL1 3NN, United Kingdom; Department of Medicine (W.H.F.S., R.J.W., H.L.W., S.A.deJ., E.A.E., V.H.M.), Dunedin School of Medicine, University of Otago Medical School, Dunedin, New Zealand

Address correspondence and request for reprints to: Nicholas J Lewis-Barned, Department of Diabetes and Endocrinology, Gloucester Royal Hospital, Great Western Road, Gloucester GL1 3NN, United Kingdom; E-mail: nick{at}elmbridge.demon.co.uk


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
With the onset of the menopause, plasma lipids and lipoprotein metabolism changes toward a more atherogenic profile that is improved by HRT. To determine whether cholesterol esterification rate (CER) and transfer of cholesteryl esters from high density lipoproteins to apolipoprotein B-containing lipoproteins are affected by menopause and HRT, plasma newly synthesized cholesteryl ester transfer (NCET) activity, CER and plasma lipids, lipoproteins, and apolipoprotein concentrations were measured in perimenopausal women (age range: 40–55 yr), including 49 premenopausal women and 32 postmenopausal women who were subsequently randomized to receive either placebo or 17-ß estradiol/norethisterone for 6 months. Plasma NCET (P = 0.03) and CER (P = 0.008) were significantly higher in postmenopausal women. Plasma low density lipoprotein cholesterol concentration, high density lipoprotein concentration, and body mass index were independent predictors of plasma NCET in premenopausal women, and plasma triglyceride and apolipoprotein B concentrations were corresponding predictors in postmenopausal women. When data were adjusted for plasma triglyceride, plasma NCET activity was no longer significantly different (P = 0.81) between premenopausal and postmenopausal women. Plasma NCET and CER did not change significantly in postmenopausal women during HRT. These data suggest that the determinants of plasma NCET activity after menopause and increased levels of triglyceride-rich lipoprotein acceptors of cholesteryl esters may lead to increased plasma NCET that is not reduced by HRT in postmenopausal women.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
AFTER menopause, rates of coronary heart disease (CHD) increase in women until they become similar to the corresponding rates in men of a similar age (1). This increased incidence of CHD in postmenopausal women has been attributed in part to adverse changes in plasma lipids and lipoprotein levels (2). Specifically, levels of low density lipoprotein (LDL) increase after menopause. There is evidence that HRT reduces the rate of CHD in postmenopausal women (3, 4). Decreases in plasma LDL cholesterol levels are believed to contribute to the improved risk of CHD in postmenopausal women receiving HRT (5).

Plasma cholesteryl ester transfer activity may be one of several factors modifying cholesterol levels in LDL (22). The cholesteryl ester transfer protein (CETP) catalyzes the transfer of cholesteryl esters from high density lipoproteins (HDL) to apolipoprotein B (apoB)-containing lipoproteins in plasma and is influenced by composition and levels of plasma lipoproteins and a circulating inhibitor of cholesteryl ester transfer (6). Triglyceride-rich, apoB-containing lipoproteins are particularly efficient acceptors of cholesteryl esters transferred from HDL. Cholesteryl ester transfer is an element of the reverse cholesterol transport pathway that moves cholesterol from peripheral tissues to the liver. Initially, tissue cholesterol is bound by HDL and then esterified by the lecithin:cholesterol acyltransferase (LCAT) enzyme. The newly synthesized cholesteryl esters are transferred to apoB containing lipoproteins by CETP activity. Clearance of these lipoproteins by hepatic receptors delivers cell cholesterol to the liver, where it can be excreted from the body. Efficient operation of this pathway is believed to attenuate accumulation of cholesterol in arterial tissue and thereby delay the development of atherosclerosis. Plasma cholesteryl ester transfer activity is increased in patients with hypercholesterolemia (7) and is decreased when plasma levels of LDL cholesterol and apoB are reduced by treatment with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (8, 9, 10). Plasma CETP concentration is not altered by estrogen replacement therapy in postmenopausal women (11). However, levels of CETP are not rate-limiting for cholesteryl ester transfer in normotriglyceridemic subjects (12). The effect of estrogen replacement therapy on plasma cholesteryl ester transfer activity in postmenopausal women has not been widely studied.

The aim of the present study was to compare plasma NCET activity and CER and their relationships with plasma lipoproteins in pre- and postmenopausal women. In addition, the effect of cyclical HRT with 17ß-estradiol (a naturally occurring estrogen in women) and norethisterone was tested in postmenopausal women.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Eighty-one perimenopausal women, age 40–55 yr, were enrolled from women in the Dunedin population through advertisement in the newspaper. A narrow age range was chosen to minimize the effect of age on measured variables. Inclusion criteria were 1) nonsmoker; 2) no history of hypertension, ischemic heart disease, renal disease, or diabetes; 3) receiving no medications, including oral contraceptives; and 4) for postmenopausal women, no previous exposure to HRT. Postmenopausal women were identified using standard criteria including absence of menstruation for at least 6 months and elevated levels of FSH (>35 IU/L) consistent with postmenopausal status. All subjects received a full medical review before participation in the study, and all gave informed written consent. The study was approved by the Southern Regional Health Authority Ethics Committee (Otago).

Study design

The study took place in two parts. A cross-sectional comparison was made between pre- and postmenopausal women, and then a single blind placebo controlled trial of HRT for 6 months in the postmenopausal group was undertaken. The postmenopausal women (n = 32) were randomized to receive either HRT or placebo. HRT consisted of 2 mg 17ß-estradiol for days 1–12, 2 mg 17ß-estradiol and 1 mg norethisterone for 10 days, and 1 mg 17ß-estradiol for 6 days (Trisequens, Novo-Nordisk, Bagsvaerd, Denmark). Clinical and biochemical measurements were made in all women at baseline and again at 3 months and 6 months following the start of HRT or placebo. Measurements included plasma NCET activity, plasma CER, plasma concentrations of lipids, lipoproteins, apolipoproteins, estrogen, FSH, and fasting blood glucose.

All studies took place after an overnight fast at the same time of the day, on day 6 of the woman’s cycle (premenopausal women), and on day 6 of the HRT or placebo cycle (estrogen only phase) in second phase of the study (postmenopausal women). The women were asked to maintain their current lifestyle with no changes in their dietary or exercise habits. This was reviewed at each study visit.

Laboratory methods

Blood was taken into tubes containing EDTA or into plain tubes. Plasma and serum were immediately separated by low speed centrifugation at 4 C. Plasma very low density lipoproteins (VLDL) were separated by ultracentrifuging EDTA plasma according to the protocol of the Lipid Research Clinic (13). High density lipoprotein cholesterol (HDL-C) was measured in the supernatant after precipitation of apoB-containing lipoproteins with dextran sulphate and magnesium chloride (14). HDL3 cholesterol was measured in the supernatant after precipitation of lipoproteins with polyethyleneglycol (15). Cholesterol, free cholesterol, and triglycerides (TG) were measured in plasma and plasma fractions using enzymatic kits and calibrators from Roche Molecular Biochemicals (Mannheim, Germany). Serum apolipoprotein A-I (apoA-I) and apoB concentrations were measured by immunoturbidimetry (16). Glucose was measured by the glucose oxidase method, and insulin was determined by radioimmunoabsorbent assay (Diagnostic Products Inc., Los Angeles, CA). Estradiol and FSH were measured by immunofluorescence assays (National Hormone Assay Service NZ, Christchurch, New Zealand).

Plasma NCET activity was measured by an isotopic method that uses endogenous lipoproteins (17). Briefly, plasma that had been stored at -80 C was thawed and incubated with a [3H]-cholesterol-albumin emulsion for 3 h at 37 C, and the appearance of radiolabelled cholesteryl esters in precipitated apoB-containing lipoproteins was measured. Using the plasma free cholesterol concentration, the NCET rate was calculated. The coefficient of variation for the assay was 10%. Previous studies from this laboratory have shown that NCET activity is similar in fresh and frozen (-80 C) normolipidemic and hyperlipidemic plasma and is closely related to net mass cholesteryl ester transfer measured by chemical methods (18). Plasma CER was measured by a modification of the Stokke and Norum method (17, 19).

Statistical analyses

Unpaired data were compared using the Mann-Whitney U test. Analysis of covariances was used to adjust data for differences between premenopausal and postmenopausal women. Pearson’s product-moment correlation coefficients were used to test for relationships between variables. Two-factor analyses of covariance with repeated measures was used to determine the effect of HRT on measured variables. Two-tailed tests of significance were used, and unless otherwise stated, a P value of less than 0.05 was considered to be statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The characteristics of the pre- and postmenopausal women are shown in Table 1Go. As expected, the postmenopausal women were older and more overweight and had lower plasma estradiol levels and higher FSH levels.


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  		Table 1. Characteristics of the premenopausal and postmenopausal women

 
Table 2Go summarizes plasma NCET activity, CER, lipids, lipoproteins, and apolipoproteins in the women. Plasma NCET, CER, TC, VLDL-C, LDL-C, TG, VLDL-TG, and apoB were significantly higher in postmenopausal compared with premenopausal women. When data were adjusted for plasma TG concentration in analyses of covariance, mean plasma NCET activity was no longer significantly different (P = 0.81) between premenopausal (103 mg/dL/h) and postmenopausal women (104 mg/dL/h). A similar finding was obtained when data were adjusted for plasma apoB concentration (premenopausal 103 mg/dl/h; postmenopausal 104 mg/dL/h; P = 0.95). Plasma TG levels were no longer significantly different (P = 0.33) between premenopausal (105 mg/dL) and postmenopausal women (123 mg/dL) when data were adjusted for age and body mass index (BMI).


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  		Table 2. Plasma newly synthesized cholesteryl ester transfer, cholesterol esterification rate, lipids, lipoprotein, and apolipoproteins concentrations in premenopausal and postmenopausal women

 
Table 3Go summarizes the correlations between plasma NCET activity and characteristics of pre- and postmenopausal women. Because a substantial number of correlation coefficients were calculated, only those at P <=0.01 were considered to be statistically significant. In premenopausal women, plasma NCET activity was significantly and inversely associated with plasma HDL-C, HDL2-C, and apoA-1 levels. In postmenopausal women, similar correlations were recorded with VLDL-C, HDL-C, TG, VLDL-TG, apoB, and plasma CER, but not with TC or LDL-C. In addition, plasma NCET activity was correlated significantly with plasma HDL3-C concentrations in these women. Similar correlations with plasma CER activity were seen in both groups of women. Plasma NCET activity was not correlated significantly with age in pre- and postmenopausal women. Stepwise multiple regression analysis with plasma NCET activity as the dependent variable and plasma LDL-C, HDL-C, TG, apoB, CER, and BMI as independent variables, identified plasma LDL-C and HDL-C concentrations and BMI as significant independent predictors (P < 0.0001) of plasma NCET activity in premenopausal women. Plasma LDL-C accounted for 55% of the variation in plasma NCET, and this increased to 74% when HDL-C was included and to 78% when BMI was included in the model. A similar analysis in postmenopausal women identified plasma TG and apoB concentrations as significant independent predictors (P < 0.00001) of variation in plasma NCET activity. Plasma TG concentration accounted for 72% of the variation in plasma NCET activity, and this increased to 79% when plasma apoB concentration was included in the model.


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  		Table 3. Correlation coefficients between plasma newly synthesized cholesteryl ester transfer activity (mg/dL/h) and age, BMI, plasma lipids lipoproteins, apolipoproteins, and estradiol concentrations in premenopausal and postmenopausal women

 
Table 4Go shows plasma NCET activity and CER activities and concentrations of lipids, lipoproteins, and apolipoproteins in postmenopausal women during HRT or placebo treatment. As expected, plasma TC and LDL-C decreased significantly during HRT. There were no significant differences in the remaining variables.


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  		Table 4. Plasma newly synthesized cholesteryl ester transfer activity, cholesterol esterification rate, and concentrations of lipids and lipoproteins in postmenopausal women during hormone replacement therapy

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Menopause is associated with several metabolic changes including increases in plasma LDL-C and triglyceride-rich lipoproteins (20, 21). Our data suggest that higher levels of TG-rich lipoproteins are associated with increased activity in the segment of the reverse cholesterol transport pathway involving cholesterol esterification and cholesteryl ester transfer, and that these factors are not altered appreciably by 6 months of HRT in postmenopausal women.

In this study, plasma LDL-C, HDL-C, and BMI independently predicted NCET activity in premenopausal women. A number of these relationships have been reported previously (22, 23, 24, 25) but results have been inconsistent. Differences in methods used to measure cholesteryl ester transfer and different subject groups may account for some of this lack of consistency. The close association between plasma NCET and LDL-C that we observed in postmenopausal women may be due to increased transfer of cholesteryl esters into apoB-containing lipoproteins with increased NCET activity or greater numbers of LDL acceptor particles or both. Some workers have suggested that plasma cholesteryl ester transfer activity may be one of the factors that influence cholesterol levels in LDL (22). Also LDL is an acceptor of cholesteryl esters transferred from HDL in plasma from healthy subjects (26). Tato and coworkers (27) have reported that cholesteryl ester transfer activity is increased in normotriglyceridemic subjects with low HDL-C concentrations. The inverse relationship between plasma NCET and HDL-C in our data is in keeping with this finding, which may be due to depletion of HDL cholesteryl esters where cholesteryl ester transfer is accelerated. However, accelerated plasma NCET activity was not accompanied by lower plasma HDL-C levels in postmenopausal women compared with those who were premenopausal. The higher plasma CER may oppose depletion of HDL cholesteryl esters by higher NCET activity in postmenopausal women.

In contrast to the findings in premenopausal women, plasma TG and, to a lesser extent, apoB were potent independent determinants of plasma NCET in postmenopausal women. This may reflect altered lipoprotein metabolism after menopause with higher levels of apoB-containing lipoproteins including those that are rich in TG. TG-rich lipoproteins are important acceptors of cholesteryl esters transferred from HDL (6). Consequently, hypertriglyceridemia is usually associated with increased cholesteryl ester transfer activity (12). In the present study, similar levels of plasma NCET activity in pre- and postmenopausal women, when data were adjusted for variation in plasma TG levels, suggest that higher levels of TG-rich lipoproteins may be mainly responsible for the higher plasma NCET activity in postmenopausal women. While the postmenopausal women were not, on average hypertriglyceridemic, their higher triglycerides within the so-called normal range may indicate the presence of increased levels of TG-rich apoB containing lipoproteins that are particularly efficient acceptors of transferred cholesteryl esters. Older age and increased adiposity account partly for the higher plasma TG and VLDL levels in postmenopausal women. Others have made similar observations (28).

Higher levels of TG-rich lipoproteins are probably also responsible for the accelerated CER that we observed in postmenopausal compared with premenopausal women. Plasma TG levels were correlated with plasma CER in both groups of women, and plasma TG levels are a major determinant of CER (24). The close coordination between cholesterol esterification and transfer in human plasma (29) may underlie the relationship between plasma cholesteryl ester transfer and CER in our data and in previous studies (17).

Plasma CETP concentration measured directly (11) or indirectly (30) is unaffected by HRT. Our findings suggest that increased plasma NCET, which depends on several factors in addition to CETP concentration, is also unchanged by HRT in postmenopausal women. The failure of HRT to influence plasma NCET may be the result of unchanged levels of plasma TG-rich lipoproteins, which we found to be the major determinant of plasma NCET in postmenopausal women.

Recent studies have reported that plasma LCAT activity, CER, and HDL cholesterol are increased during oral HRT with conjugated equine estrogens plus medroxyprogesterone acetate in postmenopausal women (30, 31). The increase in HDL cholesterol may be linked to the increase in plasma LCAT, which is a determinant of HDL cholesterol levels (22). In the present study, by contrast, plasma CER (a measure of LCAT activity) was unaffected by 6 months of HRT with 17ß-estradiol plus norethisterone, which also failed to change plasma NCET and HDL cholesterol levels in postmenopausal women. The different response of HDL cholesterol to HRT between the studies is likely due to the greater androgenic activity of norethisterone compared with medroxyprogesterone acetate. A previous study has also reported unchanged HDL cholesterol levels during HRT with estradiol and norethisterone (32). Whether the androgenic activity of norethisterone is also responsible for unaltered plasma CER in our data remains to be determined.

High plasma NCET activity may contribute to the increased risk of CHD in postmenopausal women. Accelerated transfer of cholesteryl esters into potentially atherogenic apoB-containing lipoproteins may increase the development of atherosclerotic disease if these lipoproteins are not efficiently cleared from the circulation, as is common in postmenopausal women. Elevated plasma NCET has been associated with the presence of angiographically demonstrated coronary artery disease (33). Also, greater progression of coronary artery disease has been reported in patients with the Taq B1B1 CETP genotype, which is accompanied by 30% higher plasma CETP levels compared with the corresponding B2B2 genotype (34). High plasma TG, which appear to be mainly responsible for elevated NCET activity in our postmenopausal women, has been previously identified as an important risk factor for CHD in women older than 50 (35) and remains predictive of coronary events during HRT in women with coronary artery disease (36). Whether elevated plasma NCET contributes to this TG-associated risk remains to be determined.


   Acknowledgments
 
The authors are grateful to the participants in the study. Study treatment was kindly provided by Novo-Nordisk New Zealand. The study was designed, conducted, analyzed, and reported by the investigators, independently of the sponsors.


   Footnotes
 
1 This investigator-initiated study was supported by grants from the National Heart Foundation of New Zealand, and the Laurensen Trust (Otago Medical Research Foundation). Back

Received April 7, 1998.

Revised June 15, 1999.

Accepted June 25, 1999.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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