© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Menopause Is Associated With Reduced Protection From Postprandial Lipemia
Presented in part at the Scientific Conference on Hormonal, Metabolic, and Cellular Influences on Cardiovascular Disease in Women of the American Heart Association, San Diego, Calif, October 19–21, 1995, and the 66th Congress of the European Atherosclerosis Society, Florence, Italy, July 13–17, 1996.
From the Departments of Internal Medicine and Endocrinology, Laboratory of Lipid Metabolism, University Medical Center Utrecht, the Netherlands. Dr de Bruin is now at the Department of Medicine and Endocrinology, Maastricht University Medical School, Maastricht, Netherlands.
Correspondence to André P. van Beek, MD, PhD, Departments of Internal Medicine and Endocrinology, F02.124, PO Box 85.500, 3508 GA Utrecht, Netherlands. E-mail vanbeek.hopian{at}gironet.nl
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Abstract |
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Abstract—Deficiency of endogenous estrogens has been associated with a higher incidence of coronary heart disease (CHD) in women. We investigated whether natural menopause is associated with reduced protection from postprandial lipemia, which represents a risk indicator of CHD. Twenty-three postmenopausal women (mean age, 50±1 [SD] years; body mass index, 24.6±2.8 kg/m2) and 21 premenopausal women matched for age and body mass index (age, 49±1 years; body mass index, 24.1±2.6 kg/m2) underwent an oral vitamin A fat-loading test. Vitamin A is a marker of the metabolism of chylomicrons and chylomicron remnants. All women were normolipidemic, were in good health, were nonsmokers, and used no medication. Postprandial lipids and vitamin A were measured at hourly intervals up to 12 hours. In postmenopausal women, plasma total cholesterol and LDL cholesterol concentrations were significantly higher. Fasting plasma triglyceride (TG) concentrations were 1.14±0.57 mmol/L in postmenopausal women and 0.88±0.33 mmol/L in premenopausal women (P=NS). In the postprandial phase, postmenopausal women had higher plasma TG (13.0±6.1 versus 9.5±3.3 mmol · L-1 · h-1; P=0.024) and vitamin A (54.1±22.9 versus 35.9±9.6 mg · L-1 · h-1; P=0.001) responses. To correct for the possible confounding effect of fasting TG, 13 postmenopausal women were carefully matched with 19 premenopausal women. Although fasting TG levels were identical (0.72±0.20 versus 0.73±0.21 mmol/L), differences in postprandial vitamin A (45.3±14.5 versus 33.0±7.7 mg · L-1 · h-1; P=0.006) and incremental TG (ie, after subtraction of baseline TG) (3.2±1.8 versus 2.3±1.0 mmol · L-1 · h-1; P=0.023) persisted between postmenopausal and premenopausal women. Natural menopause is associated with aggravated postprandial lipemia in women matched for age and body mass index. Higher postprandial lipemia potentially explains the relation of TGs and CHD mortality risk in postmenopausal women.
Key Words: chylomicrons • estrogens • coronary heart disease • risk factors • lipids
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Introduction |
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Deficiency of endogenous estrogens has been associated with a higher incidence of coronary heart disease (CHD). Women with an artificially early menopause by bilateral oophorectomy have an increased risk of myocardial infarction.1 An early natural menopause poses an excess risk of CHD as well.2 The decrease in risk in women who take estrogen replacement3 is further evidence that the excess risk of CHD in women with a bilateral oophorectomy is a consequence of estrogen deficiency. How this effect is mediated remains unclear. One current hypothesis is that endogenous estrogen deficiency leads to an adverse lipid profile, which in turn results in an enhanced risk of CHD. It has consistently been shown that LDL cholesterol is raised after the menopause.4 5 The results of the statin studies emphasize the importance of LDL as a risk factor in women. However, large prospective studies reveal that LDL cholesterol is not a very strong predictor of cardiovascular disease in women.6 7 In contrast, triglycerides (TGs) are better predictors,6 although their predictive power has been underestimated in epidemiological studies.8 Exaggerated postprandial lipemia has invariably been observed in normolipidemic men with CHD9 10 11 and in 1 study of normolipidemic women with CHD.12 Moreover, the progression rate of CHD was related to the postprandial levels of chylomicron remnants.13
We investigated whether the presence of natural menopause is associated with reduced protection from postprandial lipemia in normolipidemic women matched for age and body mass index.
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Methods |
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Subjects
Women were recruited by means of advertisements in local newspapers between May 1994 and May 1996. A questionnaire on health and menopausal status was sent to all responders. Women were defined as postmenopausal when they reported their last menses to have been at least 12 months previously and had elevated follicle-stimulating hormone (FSH, >40 IU/L) levels at screening and test days. Women were considered premenopausal when they had had an unchanged and regular menstrual pattern during the previous 5 years, without typical climacteric complaints, and had compatible low FSH levels (
20 IU/L).
All healthy women, ranging in age from 47 to 52 years, were eligible
for screening when they had a uterus and 2 ovaries in situ, used no
medication currently or in the preceding year, and did not smoke.
During a screening visit, the participant’s medical history was taken
with special attention to the menstrual cycle, and a physical
examination was performed. At this visit, plasma
cholesterol, TG, FSH, and estradiol levels were also
determined. All postmenopausal and premenopausal women who were
normolipidemic at screening (cholesterol <6.5 mmol/L
and TG <2.0 mmol/L, representing the 75th percentile
for Dutch women in this age group) and had body mass indices between 19
and 30 kg/m2 were enrolled in the study. All
participants gave their written informed consent before the study. The
study was approved by the ethical committee of the Academic
Hospital Utrecht.
Oral Fat-Tolerance Test
Cream consisting of 40% fat (wt/vol) with a ratio of
polyunsaturated to saturated fatty acid of 0.06, 0.001%
cholesterol (wt/vol), and 2.8% carbohydrates (wt/vol) was
given as a single fat source in a dose of 50 g
fat/m2 body surface area. Vitamin A was added to
the cream in a dose of 60 000 IU aqueous retinyl palmitate (RP)/50 g
fat (125 mL cream). Vitamin A, a lipid-soluble vitamin, is incorporated
in chylomicrons as RP and is a marker for these intestinal
lipoproteins. After an overnight fast of 12 hours, participants were
admitted to the clinical research center at 8 AM. Blood
samples were obtained before the test meal and hourly thereafter up to
12 hours in tubes containing EDTA. To prevent breakdown of RP, all
blood samples were protected from light. Water and decaffeinated coffee
or tea, but no food, were allowed during the test. None of the subjects
had diarrhea or other symptoms of malabsorption. The average cream fat
load was 88±7 g in postmenopausal and 88±6 g in premenopausal
women.
Laboratory Assays and Measurements
A rapid single-spin ultracentrifugation
method was used at hourly intervals to separate lipoproteins into a
fraction with a Svedberg flotation unit >1000 (Sf>1000) that contains
chylomicrons, large chylomicron remnants, and large hepatic
lipoproteins and a remaining infranatant fraction (Sf<1000) containing
small chylomicron remnants and all other
lipoproteins.14 15 Whole plasma and lipoprotein fractions
were assayed for cholesterol and TGs with commercial
enzymatic reagents. The concentration of RP was measured by
high-performance liquid chromatography. HDLs
were prepared by the heparin-MnCl2–dextran
sulfate precipitation method. LDLs were prepared by density gradient
ultracentrifugation. Measurements of hormones were
performed in baseline blood samples. FSH and luteinizing hormone were
determined by ELISAs, estrone, and estradiol by competitive
radioimmunoassays.16 ApoE genotypes and
postheparin lipolytic enzyme activities were measured as
described.16
Statistical Analysis
Data are given as mean±SD. Postprandial responses are expressed
as TG or RP area under the time curve (AUC) or under the incremental
time curve (
AUC, ie, the increment after subtraction of
baseline concentrations) from baseline to 8 hours postprandially. The
unpaired t test was used to detect the significance of mean
differences. To correct for the potentially confounding effect of
baseline TGs, 13 postmenopausal women were matched to 19 premenopausal
women with 1 single criterion: a difference in plasma TG <0.05
mmol/L. If >1 premenopausal woman met the matching criterion, all case
subjects were selected and averaged out, resulting in a 1:1 matching.
To determine the significance of mean differences in this subgroup
analysis, a paired t test was used. Statistical
calculations were performed with SPSS 6.1 for Windows.
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Results |
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Study Groups
Baseline characteristics of the 2 groups are shown in Table 1
. Both groups were of similar age
and body composition. In women who had had a natural menopause, plasma
cholesterol and LDL cholesterol concentrations
were significantly increased, and plasma apoB tended to be raised.
Fasting plasma TGs were elevated in postmenopausal women, but this did
not reach statistical significance. Although low TG values (<0.5
mmol/L) were observed in both groups, 25% of the normolipidemic
postmenopausal women had fasting TG concentrations >1.5 mmol/L,
compared with 10% of the premenopausal women.
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Daily energy and fat intakes were not different for the 2 groups (data not shown). ApoE genotypes for the 2 groups were highly comparable: E2/E3 (postmenopausal, 0; premenopausal, 3), E2/E4 (2, 0), E3/E3 (15, 14), E3/E4 (5, 3) and E4/E4 (1, 1). Hepatic lipase activity was higher in postmenopausal women (409±53 versus 336±71 mU/mL; P<0.001). LPL activities were not different between the 2 groups (199±57 and 176±58 mU/mL for postmenopausal and premenopausal women, respectively).
Postprandial Responses
After an oral fat-tolerance test, time curves in postmenopausal
women for TGs (Figure, panel A) and RP
(Figure, panel B) were higher than in premenopausal women. The
mean (incremental) postprandial TG response (TG AUC and TG AUC) and
chylomicron response (RP AUC) were significantly larger in
postmenopausal women (Table 2). The
statistically significant differences clearly appeared in Sf>1000
lipoprotein fractions with both TGs and RP (ie, chylomicrons, large
chylomicron remnants, and large hepatic TG-rich lipoproteins) but were
also measured in Sf<1000 lipoproteins with RP (ie, mainly small
chylomicron remnants). All women in both groups had returned to fasting
plasma TG concentrations after 8 hours after ingestion of the test
meal, and TG levels continued to drop in the next 4 hours. This
decrease was more exaggerated in postmenopausal women. The mean
difference in plasma TGs between postmenopausal and premenopausal women
at baseline and at 8, 10, and 12 hours after the fat load was 30%,
15%, 7%, and 4%, respectively. To correct for the possible
confounding effects of fasting TGs, postmenopausal and premenopausal
women were precisely matched for baseline TGs (Table 3). All matched pairs had fasting TG
levels <1.2 mmol/L, and differences in fasting TG in matched
pairs were not exceeding 0.05 mmol/L. Time curves for TGs and RP
(figure, panels C and D, respectively) showed again that
postmenopausal women had higher postprandial lipemia than premenopausal
women. Despite identical fasting TGs, the mean (and incremental) plasma
TG responses (TG AUC and TG AUC) were significantly higher in
postmenopausal women. The chylomicron response (RP AUC) was also higher
after the menopause. This difference was caused by the Sf>1000
lipoprotein fraction, which contained mainly the chylomicrons and large
chylomicron remnants.
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) and premenopausal (
) women (A and B) and after
matching for fasting TGs (C and D).
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Discussion |
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The present results showed differences in postprandial TG and chylomicron response between postmenopausal and premenopausal women with similar age, body mass index, daily energy and fat intake, apoE genotype, LPL activity, and HDL concentrations even after careful matching for fasting TGs. The main differences were found in the vitamin A concentrations in the Sf>1000 fraction, which contains chylomicrons and large chylomicron remnants.
We studied nonsmoking women of similar age and body mass index, because smoking, obesity, and age influence both lipid metabolism and the occurrence of menopause.17 In theory, the selection of age-matched groups might be a problem, because the fact that menopause was reached at a different chronological age could be an indication of underlying differences between the groups that also relate to lipid metabolism.18 We believe that this is not the case, because no data exist in the literature to support such an idea. We studied 2 groups of healthy women within a narrow age limit who were at the lower and higher ends of the normal distribution for age at menopause. It is unlikely that underlying differences, rather than menopause per se, have blurred the study results. Age at menopause is determined primarily by the number of ovarian follicles.19
Menopausal changes in fasting plasma lipids in our study were highly comparable to those found by others in longitudinal5 20 or cross-sectional4 21 studies, with the exception of TGs. We found that fasting TGs were 30% higher in postmenopausal women. Other studies found no significant increase5 or higher levels after the menopause, with values ranging from 12%4 to 18%.21 This variability in findings can be explained in 2 ways. First, different definitions of menopausal status were used in the literature, and therefore, variable groups, with conceivably varying differences in plasma lipids, were identified. It is likely that changes in lipids are not instantaneous but rather gradual, expressing ongoing decline of ovarian function.20 Second, the distinct possibility should be recognized that regulation of plasma TGs in premenopausal women is different from that in postmenopausal women. Ninety percent of the premenopausal women had plasma TG levels <1.5 mmol/L at baseline, in contrast to only 75% of the postmenopausal women, whereas very low fasting TG concentrations (<0.5 mmol/L) were observed in both groups. Thus, after the menopause, there is a larger population-based variation in fasting TGs. This was also observed after an oral fat load, showing higher postchallenge peak TG levels and lower compensatory trough levels. Thus, concomitant with the loss of endogenous estrogens, the tight regulation of plasma TGs is lost.
The postprandial differences in TG and vitamin A in the Sf>1000 fractions suggest a difference in the metabolism of chylomicrons and large chylomicron remnants, because fat intake and postheparin lipoprotein lipase activity were similar. This can be explained in several ways. First, higher concentrations of hepatic TG-rich lipoproteins may have resulted in enhanced competition at the level of the common lipolytic pathway.22 However, after correction for endogenous TGs in the fasting state, these differences persisted. Second, there may have been a different composition of chylomicrons, eg, reduced size or different apoprotein composition. Furthermore, the deficiency of endogenous estrogens may lead to a decreased chylomicron clearance capacity. This is supported by a report on the effects of estrogen replacement on chylomicron metabolism in postmenopausal women.16
In conclusion, substantial and significant differences in postprandial lipid metabolism were found in women who differed only in their menopausal status and therefore in their endogenous estrogen production. The loss of protection from postprandial lipemia associated with the postmenopausal state potentially explains the lipid contribution to the increased risk of coronary artery disease and has the potential to be therapeutically corrected by nutritional or pharmaceutical interventions.
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Acknowledgments |
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This work was made possible by the Dutch Heart Foundation (grant NHS 93.140). Dr de Bruin is a recipient of the Pioneer grant of the Dutch Organization of Fundamental Research (NWO). The authors wish to thank H.E. Westerveld for the study design and grant application.
Received December 8, 1998; accepted March 24, 1999.
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References |
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