© 1999 American Heart Association, Inc.
Original Contributions |
Is the Response of Serum Lipids and Lipoproteins to Postmenopausal Hormone Replacement Therapy Modified by ApoE Genotype?
From the Departments of Obstetrics and Gynecology (A.-M.H., M.H.K., M.T.T., S.S.), Medicine (L.N.), Clinical Genetics (M.R.), and Clinical Chemistry (M.P.), University Hospital of Kuopio, Finland.
Correspondence to Dr. A.-M. Heikkinen, Department of Obstetrics and Gynecology, Kuopio University Hospital, PO Box 1777, FIN-70211 Kuopio, Finland. E-mail anna-mari.heikkinen{at}pp.inet.fi
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Abstract |
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Abstract—Postmenopausal hormone replacement therapy (HRT) has favorable effects on the serum lipid profile, and it also decreases the risk of cardiovascular diseases. The apolipoprotein E genotype has influence on serum levels of lipids and lipoproteins; apoE allele
4 (apoE4) is associated with high
total and LDL cholesterol levels. Genotype also
influences the lipid responses to treatment with diet and statins, but
the effect of HRT in different apoE genotypes is unknown. We
studied the effects of HRT on the concentrations of serum lipids in
apoE4-positive early postmenopausal women (genotypes 3/4 and
4/4) compared with apoE4-negative women (genotypes 2/3 and 3/3)
in a population-based, prospective 5-year study. In all, 232 early
postmenopausal women were randomized into 2 treatment groups: an HRT
group (n=116), which received a sequential combination of 2 mg
estradiol valerate (E2Val) from day 1 to 21 and 1 mg
cyproterone acetate (CPA) from day 12 to 21 (Climen), and a placebo
group (n=116), which received 500 mg/d calcium lactate. Serum
concentrations of total, LDL, and HDL cholesterol and
triglycerides were measured at baseline and after 2 and 5
years of treatment. A total of 154 women completed the final
analysis. During the follow-up period, serum total
cholesterol and LDL cholesterol concentrations
decreased in the HRT group in apoE4-negative women (8.1% and 17.1%,
respectively; P<0.001) but did not change in the HRT
group in apoE4-positive women or in the placebo group. Serum HDL
cholesterol concentrations decreased in the placebo group
(apoE4-negative, 3.9%, P=0.015; apoE4-positive, 8.1%,
P=0.004) but did not change significantly in the HRT
group. Serum triglyceride levels tended to increase in both
study groups and genotypes (15.1% to 36.2%,
P<0.038 to 0.001), but no differences were observed
between the study groups or genotypes, respectively. Our
finding was that in postmenopausal Finnish women LDL
cholesterol levels in apoE4-negative subjects respond more
favorably to HRT than those in apoE4-positive subjects. This finding
has potential importance in postmenopausal women with
hypercholesterolemia, if confirmed in
other studies.
Key Words: ApoE genotype • postmenopausal hormone replacement therapy • LDL cholesterol • prospective study
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Apolipoprotein E (apoE) is a liver polypeptide that has an important role in lipid metabolism by serving as a ligand for the LDL receptor.1 In humans, there are 3 alleles of apoE (
2, 3, and 4) and hence 6 different
genotypes (2/2, 2/3, 2/4, 3/3, 3/4, and 4/4). ApoE
genotype distribution, in particular that of the apoE
allele 4 (apoE4), is associated with total and LDL
cholesterol levels1 2 3 and also with
cardiovascular morbidity.4 5 The
frequencies of apoE genotypes vary in different age, sex, and
race groups.6 7 8 ApoE polymorphism is estimated to
explain 4% to 15% of the variation in LDL cholesterol
concentrations.4 7 In postmenopausal women, this variation
has been reported to be greater than in premenopausal
women.9 The response to cholesterol-lowering
diet and statins has been shown to differ in subjects with different
apoE genotypes.7 8 9 10 11 12 It is well known that
postmenopausal estrogen therapy changes serum lipoprotein
concentrations favorably, which may explain about 25% to 50% of the
cardioprotective effect of estrogen,13 but the association
between apoE genotype and lipoprotein responses to
postmenopausal HRT is not known. The aim of this placebo-controlled, prospective 5-year trial was to investigate the response of HRT (sequential combination of 2 mg estradiol valerate [E2Val] and 1 mg cyproterone acetate [CPA]) with respect to serum lipids in apoE genotypes 3/4 and 4/4 (apoE4-positive subjects) compared with genotypes 2/3 and 3/3 (apoE4-negative subjects) in a population-based, randomized group of early postmenopausal women.
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Materials and Methods |
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Subjects
The population of the present study is a subgroup of the Kuopio Osteoporosis Risk Factor and Prevention Study. In 1989 a postal inquiry was sent to all 14 200 47- to 56-year-old women in Kuopio Province, Eastern Finland, to investigate osteoporosis risk factors among perimenopausal women.14 The 464 voluntary postmenopausal women who had their last menstrual period within 6 to 24 months before the study were included in the clinical osteoporosis prevention trial. Exclusion criteria were restricted to general contraindications for HRT, including history of estrogen-dependent cancer, thromboembolic diseases, and medication-resistant hypertension. The participants were randomized by a computer to 4 treatment groups: E2Val/CPA group, vitamin D3 group, E2Val/CPA+vitamin D3 group, and calcium lactate group (placebo). Random allocation to study groups was carried out by blocks using a computer, the block size being 4, 8, or 12. The study was not blinded as to HRT. The data analyses were done blindly. Those women who wanted to change treatment groups were excluded from the analysis. The personnel involved were unaware of the group allocations. The study design, and in particular the adverse effect of vitamin D on the serum lipid profile, has been described elsewhere in more detail.15 Therefore, for this study, only the women using HRT or placebo without vitamin D3 were included: (1) HRT group (n=116): E2Val (2 mg) on cycle days 1 to 21, combined with CPA (1 mg; Climen, Schering AG) on cycle days 12 to 21, with a treatment-free interval on cycle days 22 to 28; and (2) placebo group (n=116): calcium lactate (Rohto Ltd), 500 mg/d, equivalent to 93 mg Ca2+/d. Study design and formation of the present study population are depicted by the flow diagram (Figure 1
).
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Written informed consent was obtained from the participants, and the study design was approved by the ethics committee of Kuopio University Hospital. The daily calcium intake was calculated as the sum of calcium intake from milk, sour milk, yogurt (120 mg/dL), and cheese (87 mg/slice). This also estimates indirectly the intake of saturated fatty acids, as milk products are the most important source of them in the Finnish diet.16 The weekly duration of physical activity and the smoking and drinking habits were investigated. The weekly consumption of alcohol was calculated as absolute ethanol intake in grams. Each subject visited the outpatient clinic once a year. Fasting blood samples were taken in the morning for determination of the lipid parameter values. If the serum total cholesterol concentration was >6.0 mmol/L, dietary instructions were given. If the serum total cholesterol concentration remained repeatedly above 7.0 mmol/L, the requirement for hypocholesterolemic medication was considered on clinical grounds, and the subject was excluded from the final analysis.
During the 5-year follow-up period 53 women of 232 (22.8%) dropped
out. Prospectively defined stopping rules were same as the exclusion
criteria. In the HRT group (n=116), there were 42 (36.2%) dropouts,
mostly with disorders of bleeding (n=9) or headache (n=7). There were 9
dropouts because of nonmedical reasons. The reasons for the remaining
17 dropouts in the HRT group were miscellaneous, eg, abdominal pain
(n=3) or weight increase or swelling (n=2). In the HRT group, one of
the following events occurred: endometrial carcinoma, myocardial
infarction, and transient cerebral ischemia. In the placebo
group (n=116), 11 women (9.5%) dropped out. The most common reasons
reported were climacteric symptoms or other medical reasons that
required HRT (n=5). One hip fracture and one case of endometrial
hyperplasia occurred in the placebo group. Among the 53 dropouts 2
women died; one in the HRT group because of rectal carcinoma and one in
the placebo group because of malignant melanoma. Additionally, 25 women
(10.8%) were excluded from the final analysis. Eight women
were excluded as a result of interruptions in HRT (
1 month), 2 women
in the HRT group and 4 women in the placebo group because of
hypocholesterolemic medication, 3 women from both
groups because of missing laboratory data, and 5 women because of apoE
genotype 2/4 (Table 1). The
inclusion of these subjects did not alter the conclusions of this study
(data not shown). A total of 154 women (66.4%) were included in the
final analysis (Figure 1
).
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Analyses
The concentrations of total serum cholesterol, LDL
cholesterol, HDL cholesterol, total
triglycerides, follicle-stimulating hormone (FSH), and
estradiol (E2) were measured at baseline and
after 2 and 5 years of treatment from fasting serum samples taken in
the morning.
Serum E2 concentrations were measured by radioimmunoassays (Sorin Biomedica; interassay coefficient of variation [CV] <8.5%) and those of FSH by luminescence immunoassay (Byk-Sangtec; interassay CV<5.6%).
Concentrations of serum total cholesterol and triglycerides were measured enzymatically (CHOD-PAP and GPO-PAP methods; Boehringer) using a Hitachi 717 analyzer. The same cholesterol method was also used for HDL cholesterol after removal of LDL and VLDL through the use of dextran sulfate/MgCl2.17 The concentration of serum LDL cholesterol was calculated by LDL cholesterol=total cholesterol-(HDL cholesterol+0.45xtriglycerides).18 The analytical variations of concentrations of total cholesterol, HDL cholesterol, and total triglycerides within the series have been 1.5%, 4%, and 2%, respectively, at the levels in question using fully automated methods for total cholesterol and triglycerides and semiautomated measurement of HDL cholesterol. The long-term variations in total cholesterol, HDL cholesterol, and triglyceride analyses were followed by assay of quality control fresh samples from Labquality Ltd, and the between-series variations have been below 3%, 7%, and 4.5%, respectively. No drift in the analyte levels was found during the present study.
The apoE genotype was determined from blood leukocytes. DNA was extracted by standard phenol/chloroform extraction.19 ApoE genotypes were analyzed by using the polymerase chain reaction (PCR) as described earlier,20 with slight modifications. The PCR products were digested with HhaI (New England Biolabs). Digested DNA fragments were analyzed using polyacrylamide gel electrophoresis and visualized by ethidium bromide staining.
Statistical Methods
The analyses were carried out on a treatment basis.
Statistical analyses of the longitudinal data were carried out
using analysis of variance for repeated measures (MANOVA). Log
transformation of the data were used if the values were not normally
distributed. The Student's t test for paired data was used
to test the significance of differences within the 4 different
treatment–genotype groups if there was a time-related change
within the group detected by MANOVA. The significance between the
groups was tested using MANOVA. The 5-year LDL cholesterol
levels adjusted for age, body mass index, smoking, apoE4-allele,
and the interaction for HRT and apoE4-allele were examined by
analysis of covariance.
One-way analysis of variance with the Newman-Keuls post hoc test was used to test the significance of differences between lipid concentrations at baseline and the relative lipoprotein changes in the 2 groups. Because the body weight, body mass index, and FSH levels were not normally distributed after log transformation, one-way analysis of variance with the Kruskall-Wallis test was used to test the differences in these parameters between the groups. The Kruskall-Wallis test was also used to test the differences between the study groups with respect to other baseline data.
A P value of <0.05 was considered statistically significant. The results are reported as mean ± standard error of mean (SEM). All the data were analyzed using SPSS for UNIX (SPSS Inc).
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Results |
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Frequencies of apoE alleles and genotypes are outlined according to the treatment group in Table 1
. The distribution of
alleles was similar to that reported earlier in Finnish and Swedish
populations2 6 but with a higher frequency of apoE4
compared with other white populations.21 There were no
statistically significant differences between the study groups in the
baseline characteristics or the laboratory parameters
(Table 2).
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The relative body weight (difference between follow-up and baseline, divided by baseline level, as a percentage) increased similarly in all 4 treatment–genotype groups after 5 years (HRT–apoE4-negative group, 4.7±0.8%; HRT–apoE4-positive group, 3.3±2.0%; placebo–apoE4-negative group, 5.5±1.0%; and placebo–apoE4-positive group, 4.3±1.6%; P=0.708). Concentrations of serum E2 increased in the HRT group but did not change significantly in the placebo group. The 5-year concentrations in serum E2 were identical between apoE4-negative and apoE4-positive subjects (HRT group, 0.19±0.02 and 0.23±0.06 nmol/L, respectively, P=0.507; placebo group, 0.04±0.02 and 0.04±0.02 nmol/L, respectively, P=0.861).
The concentrations of serum total cholesterol decreased in
the HRT group by 5.1% after 2 years (P=0.014) and by 8.1%
after 5 years (P<0.001) in apoE4-negative subjects, but
they did not decrease significantly in apoE4-positive subjects. In the
placebo group, the concentrations of serum total
cholesterol did not change in apoE4-negative subjects,
whereas they had increased by 3.9% after 2 years in apoE4-positive
subjects (P=0.015), but they had returned to the baseline
level after 5 years. The changes between the HRT and the placebo groups
were statistically significant (MANOVA, P<0.001) (Table 3, Figure 2).
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P<0.05,
P<0.01, §P<0.001 by t test for
paired data. HRT apoE4-neg indicates E2 (2 mg) + CPA (1 mg)
cyclically, apoE genotype 2/3 or 3/3; HRT apoE4-pos, E2 (2
mg) + CPA (1 mg) cyclically, apoE genotype 3/4 or 4/4; Placebo
apoE4-neg, calcium lactate (500 mg/d), apoE genotype 2/3 or 3/3; and
Placebo apoE4-pos, calcium lactate (500 mg/d), apoE genotype 3/4 or
4/4.
LDL cholesterol concentrations had decreased in the HRT
group by 10.3% after 2 years (P<0.001) and by 17.1% after
5 years in apoE4-negative subjects (P<0.001). There was a
slight but nonsignificant tendency for decreases in LDL
cholesterol concentrations in the HRT group in
apoE4-positive subjects and in the placebo group in apoE4-negative
subjects, whereas LDL cholesterol concentrations had
increased by 5.7% (P=0.010) in the placebo group in
apoE4-positive subjects after 2 years but had returned to the baseline
level after 5 years. The time-related changes between the treatment
groups were statistically significant (MANOVA, P<0.001)
(Table 3, Figure 2).
Furthermore, in the multivariate model
(analysis of covariance), the LDL
cholesterol levels at 5-year examination were associated
with apoE genotype, taking into account the effects of age,
body mass index, smoking, and interaction between HRT and apoE4
allele (Table 4).
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The concentrations of serum HDL cholesterol had increased
by 4.3% (P=0.042) and 3.1% (P=ns) after 2 and 5
years, respectively, in the HRT group in apoE4-negative subjects, but
no significant changes in apoE4-positive subjects were observed. In the
placebo group, serum HDL cholesterol concentrations had
decreased after 5 years in apoE4-negative subjects by 3.9%
(P=0.015) and in apoE4-positive subjects by 8.1%
(P=0.004). However, no significant changes between the
treatment groups or genotypes were observed (Table 3,
Figure 2).
Serum triglyceride levels increased in all subjects
irrespective of the genotype during the follow-up period. After
5 years, the increase was 36.2% (P<0.001) in the
apoE4-negative HRT group, 26.7% (P=0.030) in the
apoE4-positive HRT group, 15.1% (P<0.001) in the
apoE4-negative placebo group, and 17.2% (P=0.003) in the
apoE4-positive placebo group. No statistically significant differences
between the treatment groups or genotypes were observed (Table 3, Figure 2).
In this study we observed a reduction in LDL cholesterol of
0.4 mmol/L between those with apoE4 allele and those without
it in subjects receiving HRT. When we set the 
(probability
excluding type 1 error) to 5% and ß (probability of type 2 error) to
20% with SD of 0.4 mmol/L, the required sample size will be 16.7
subjects per group. In the HRT group there were 16 subjects with apoE4
allele and 41 without it; therefore, the sample size here is
adequate to show these changes, given the changes are so prominent.
The lipid and lipoprotein concentrations were analyzed yearly. The results of 1-, 3-, and 4-year examinations were in line with the reported 2- and 5-year results (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The new finding in the present study was that the beneficial response of total and, especially, LDL cholesterol to HRT in postmenopausal women was related to the apoE genotype. Additionally, our results confirm the persistence of truly long-term effects of sequential E2 (2 mg) and CPA (1 mg) treatment on serum total and LDL cholesterol. This study was placebo-controlled, population-based, successfully randomized, and well matched regarding baseline characteristics and weight changes during the follow-up period, which all strengthen our findings.
It is well established that postmenopausal estrogen therapy has favorable effects on serum lipoprotein concentrations.22 23 However, a wide variation in the lipid responses has been observed in previous reports, which have been attributed either to the effect of the added progestin,23 24 and by larger responses in hypercholesterolemic subjects.25 It has also been suggested that positive lipid effects of HRT may diminish with the duration of treatment.26
However, there are no studies in which the impact of genetic factors on lipid responses to HRT have been investigated. It is fairly well established that apoE allele 2 is associated with lower and allele 4 with higher serum total and LDL cholesterol concentrations compared with those associated with allele 3.1 3 Furthermore, there is evidence that hormonal status modulates the lipoprotein variation related to apoE genotype.7 8 9 In postmenopausal women, the association between apoE phenotype and LDL cholesterol levels has been stronger than in premenopausal women or in men.9 The relatively high serum total cholesterol levels in subjects with apoE4 have been suggested to respond more favorably to a cholesterol-reducing diet, as these subjects show enhanced absorption of dietary cholesterol, especially in populations consuming diets rich in saturated fat,10 11 27 although this is not confirmed in all studies.28 29 Our findings are unlikely to be caused by different dietary habits between the HRT and placebo groups. During the 5-year follow-up period, LDL cholesterol levels changed relatively little in the placebo group, although menopause should result in an increase of about 10%.30 This most likely reflects the decreased intake of cholesterol and saturated fat during these years in the Finnish population.31
The finding that apoE polymorphism determines the LDL cholesterol response to HRT has not been previously recognized. In the cross-sectional analysis of the Framingham Offspring Study, no association between apoE genotype and serum LDL cholesterol was found, but the number of postmenopausal women using HRT was small.9 Although our finding of this genetic determinant of LDL cholesterol to HRT is a new one, there is evidence that apoE polymorphism may influence the responses to statins in familial and nonfamilial hypercholesterolemia; apoE4-positive subjects have more sluggish response than apoE4-negative ones.12 32 Taken together, apoE polymorphism seems to be a clinically important determinant of the various lipid-lowering interventions: subjects with apoE4 allele have enhanced response to dietary therapy, whereas the response to treatment with statins and postmenopausal HRT is impaired.
ApoE plays a role in liver lipoprotein metabolism and clearance, and LDL receptor affinity varies according to the apoE isoform.1 4 ApoE4 downregulates hepatic LDL receptors, enhances liver lipoprotein uptake, and is associated with increased serum LDL cholesterol concentrations.4 On the other hand, oral estrogen therapy mediates an upregulation of liver LDL receptors and therefore has a LDL-lowering effect.22 Hence it is plausible, on the basis of our findings, to suggest that the upregulation of LDL receptors induced by estrogen is impaired in menopausal subjects with the apoE4 allele. The exact mechanisms remain to be demonstrated.
This study was not originally aimed at examining the interaction between genotype and HRT. There were 42 (36.2%) dropouts in the HRT group. Although this number is very low compared with long-term compliance of HRT, the number of apoE4-positive subjects was relatively low in the HRT group in the final analysis. The magnitude of the effect of apoE4 was rather strong, and therefore the sample sizes are adequate considering the homogeneity of the study population and the large number of apoE4-negative subjects in the present study. However, our findings are limited to the Finnish population and need to be confirmed in other studies.
To conclude, the apoE genotype modulates the response of serum LDL cholesterol to HRT in postmenopausal Finnish women. This finding may be of potential importance, especially in the treatment of hypercholesterolemic postmenopausal subjects, if confirmed in other studies.
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Acknowledgments |
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We thank Schering AG and the Research Foundations of Leiras and Orion for supporting this research. We also thank Sirkka Harle, Seija Oinonen, and Liisi Saarela for technical help and Dr. Nick Bolton for checking the language of the manuscript.
Received November 7, 1997; accepted August 18, 1998.
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 T. Lehtimaki, P. Dastidar, H. Jokela, T. Koivula, S. Lehtinen, C. Ehnholm, and R. Punnonen Effect of Long-Term Hormone Replacement Therapy on Atherosclerosis Progression in Postmenopausal Women Relates to Functional Apolipoprotein E Genotype J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4147 - 4153. [Abstract] [Full Text] [PDF]
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