© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Mechanisms Regulating LDL Metabolism in Subjects on Peroral and Transdermal Estrogen Replacement Therapy
From the Department of Internal Medicine and Biocenter Oulu (A.K., M.J.S., Y.A.K.), University of Oulu, and the Oulu Deaconess Institute (J.H.), Oulu, Finland, and the Orion Corp, Orion Pharma (A.-C.B.), Espoo, Finland.
Correspondence to Prof Y. Antero Kesäniemi, MD, PhD, Department of Internal Medicine, University of Oulu, Kajaanintie 50, 90220 Oulu, Finland. E-mail antero.kesaniemi{at}oulu.fi
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—To study the mechanisms of low density lipoprotein (LDL) cholesterol lowering by peroral and transdermal estrogen replacement therapy (ERT), 79 hysterectomized postmenopausal women aged 48 to 62 years were randomized in a double-blind double-dummy trial to receive either peroral estradiol valerate (2 mg/d) or transdermal estradiol gel (1 mg/d) for 6 months. Plasma LDL cholesterol decreased from 4.19±0.83 (mean±SD) to 3.39±0.78 mmol/L (P<0.001) in the peroral group and from 4.11±0.86 to 3.72±0.78 mmol/L (P<0.001) in the transdermal estrogen group. Peroral estrogen did, but transdermal treatment did not, enhance the fractional catabolic rate (FCR) and production of LDL apolipoprotein B (apoB). However, the decrease of LDL cholesterol was related to an increase in FCR for LDL apoB on both peroral and transdermal ERT (r=-0.645, P<0.001 and r=-0.627, P<0.001, respectively). These changes were associated with changes in the serum estrogen level. Both therapies reduced absorption of dietary cholesterol by 6% to 10% (P<0.05). The effects of estrogen were not modified by the polymorphisms of apoE and apoB or cholesterol 7
-hydroxylase. In conclusion, the ERT-induced LDL
cholesterol–lowering effect is related to changes in
estrogen level, which presumably enhance LDL receptor activity, which
is manifested as an increase in FCR for LDL apoB. The small decrease in
the absorption efficiency of dietary cholesterol does not
seem to contribute largely to the cholesterol lowering on
either transdermal or peroral ERT.
Key Words: estrogen replacement therapy • LDL cholesterol • menopause • lipids
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
According to observational studies, up to 50% of cardiovascular mortality in postmenopausal women could be prevented by postmenopausal hormone replacement therapy (HRT).1 2 However, a recent randomized secondary prevention study was not able to confirm these results.3 At any rate, menopause is related to unfavorable alterations in lipids and lipoproteins.4 5 The beneficial changes in lipids and lipoproteins observed during HRT in several previous studies have been assumed to explain 25% to 50% of the reduced cardiovascular risk.1 Peroral estrogens decrease total and LDL cholesterol and Lp(a) and increase HDL cholesterol but also triglycerides, whereas less marked reduction in total and LDL cholesterol and no change in Lp(a), HDL cholesterol, and triglyceride levels have been observed during transdermal estrogen treatments.6 7
The underlying mechanisms of action of estrogen administered via
various routes are poorly known. The serum estrogen level is varied by
the estrogen regimen and the route of estrogen
administration.8 9 After peroral administration, high
levels of estradiol are catabolized into estrone, which induces protein
synthesis in the liver.10 When the transdermal route is
used, induction of hepatic first-pass metabolism can be
avoided, and a more physiological estrone/estradiol
ratio is achieved.11 Mainly based on animal
studies12 13 or the use of pharmacological doses of
estrogen in prostate cancer,14 the explanation for the LDL
cholesterol–lowering effect of estrogens has been the
enhanced LDL receptor activity in the liver. The present study was
designed to investigate whether the commonly used doses of estrogen in
replacement therapy might also affect LDL clearance. Potential
additional mechanisms of LDL lowering, such as changes in
cholesterol absorption, were also studied. In addition, the
influence of the polymorphisms of important regulatory proteins,
eg, apoE, apoB, and cholesterol 7-hydroxylase, on the
lipid response was evaluated. Also, the importance of the route of
administration was elucidated by comparing peroral estradiol valerate
treatment with transdermal estradiol gel therapy.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
The study design and the subjects have been described in detail previously.15 Briefly, 79 hysterectomized postmenopausal women seeking hormone substitution therapy for climacteric symptoms were randomized according to age and body mass index (BMI) to receive either peroral estradiol or transdermal estradiol gel for 6 months. Because the study was focused on the effects of estrogen alone, hysterectomized women were chosen to avoid the need of progesterone for endometrium protection. In this controlled, double-blind, double-dummy trial, the peroral estrogen group (n=39) received a daily tablet containing 2 mg estradiol valerate (Orion Pharma). The transdermal estrogen group (n=40) applied estradiol gel (Divigel, Orion Pharma; Sandrena, NV Organon), which was packed as daily dose units of 1.0 g in stick-pack sachets containing 1.0 mg 17ß-estradiol (0.1% gel). Placebo tablets were taken by the subjects in the gel group, and placebo gel was applied in the peroral group. The dose of the gel chosen for the study was based on findings from earlier pharmacokinetic and clinical studies showing that 1 g of estradiol gel is sufficient to control postmenopausal symptoms in the majority of the patients. Thirty-five women in the peroral group and 38 in the gel group completed the study. One subject in the peroral group discontinued because of breast tenderness, and 2 other women dropped out because of itching and discomfort. One woman in the gel group withdrew because of weight gain, whereas 1 participant in both groups discontinued for personal reasons without having side effects. These dropouts were excluded from the statistical analysis.
The criteria for inclusion were as follows: 45 to 65 years of age, a previous hysterectomy with at least 1 remaining ovary, serum follicle-stimulating hormone >30 IU/L, fasting blood glucose <6.7 mmol/L, and BMI <30 kg/m2. Women having contraindications to estrogen therapy or any diseases or medication interfering with lipid metabolism were excluded. The participants were able to keep their lifestyle and concomitant medication during the study.
Height, weight, and waist and hip circumferences were measured with the subjects wearing lightweight clothes without shoes. BMI (weight in kilograms/height in meters squared) and waist-to-hip ratio (waist circumference in centimeters/hip circumference in centimeters) were used to estimate generalized and abdominal obesity, respectively.
Oral and written information was given to the participants, and written informed consent was obtained from all subjects. The study was approved by the ethics committees of the Oulu University and Oulu Deaconess Institute.
Laboratory Analyses
Blood samples were drawn into EDTA-containing tubes in the
morning after an overnight fast. Plasma was separated by
centrifugation at 1200g (2600 rpm) for 15
minutes (4°C). Total plasma cholesterol and
triglyceride levels were determined by enzymatic
colorimetric methods. VLDL, IDL, and LDL were isolated
by repeated ultracentrifugations according to density,
as described in the Manual of Laboratory Operations of the
Lipid Research Clinics Program.16 HDL
cholesterol was determined from VLDL-free plasma after
precipitation of LDLs with heparin-manganese. LDL
cholesterol was also calculated by the Friedewald
formula,17 and these values were used in the LDL response
analyses.
The protein content of lipoproteins was measured by the method of Lowry et al,18 and the amount of apoB was determined after isopropanol precipitation.19 The plasma total apoA I and apoB concentrations were determined by using a commercial kit with a specific selective chemistry analyzer (KONE Instruments Corp).
LDL turnover assessment was carried out as described previously.20 21 In short, 100 mL of fasting blood was drawn for the isolation of LDL, which was carried out according to the method described by Lindgren et al,22 and the LDL protein was labeled with iodine 125 by use of the iodine monochloride method of McFarlane,23 as modified by Bilheimer et al.24 Radiolabeled LDL was injected in the morning on the day after iodination. Blood samples were collected at 0, 15, and 30 minutes and at 1, 2, and 3 hours and thereafter 3 times a week for 14 days after the injection. The radioactivity of total plasma was measured in each sample. The fractional catabolic rate (FCR) was calculated from the plasma decay curves by using the method described by Matthews.25 The production rate of LDL apoB was calculated from FCR, pool volume, and apoB concentration and expressed as milligrams of LDL apoB produced per day normalized for body weight.
Absorption of dietary cholesterol was measured by the peroral double-isotope continuous-feeding method described by Crouse and Grundy.26 Absolute absorption of dietary cholesterol was calculated by multiplying the daily cholesterol intake with the percentage absorption of dietary cholesterol. Seven-day food records were analyzed by a dietitian with the Finnish Food Database Program, Nutrica.27
ApoE phenotype was determined after delipidation with
isoelectric focusing and immunoblotting
techniques28 29 that made use of commercial antibodies.
The EcoRI and XbaI polymorphisms of the apoB
gene and the cholesterol 7-hydroxylase (CYP7) genes were
determined by polymerase chain reaction as described
previously.30 31
Statistical Analysis
Data analyses were performed with the software packages
SAS (version 6.08) or SPSS for Windows (6.01). The results for
continuous variables are presented as mean±SD. The changes
from baseline to 6 months were analyzed by paired-sample
t test, and the changes between treatments were compared by
independent-sample t test. The effects of estrogen regimens
are presented as mean changes with 95% CI, except the changes
of triglycerides, which are presented as medians
(95% CI). ANOVA with Bonferroni adjustment was used in the group
comparison of apoE phenotypes and the polymorphisms of apoB
and CYP7 genes. In addition, the effect of apoE allele 
4 was
studied by comparing the apoE4-negative (including apoE
phenotypes 2/3 and 3/3) with the apoE4-positive (including apoE
phenotypes 4/2, 4/3, and 4/4) subjects. Because of the skewed
distribution of triglycerides, a nonparametric
Mann-Whitney U test and Wilcoxon signed rank test
were used, as appropriate. Spearman correlation coefficients were
calculated to indicate the associations between variables. Stepwise
multiple regression analysis was performed to estimate the
independent factors contributing to the change in LDL
cholesterol and FCR. A value of P<0.05
(2-sided) was considered to indicate statistical significance.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The mean age of the women in the peroral group (53.1±2.9 [mean±SD] years) was similar to that in the transdermal group (54.1±2.8 years). Table 1
summarizes the body weights, waist-to-hip ratios, and plasma lipid
levels for both groups of women. The body weight and waist-to-hip ratio
remained notably constant during the 6-month treatment on the peroral
and the transdermal therapies. Only a minor insignificant increase of
body weight was observed in the transdermal group.
|
As reported previously,15 serum estrone was increased more in the peroral group (n=35, from 176±92 to 2176±1156 pmol/L) than in the gel group (n=38, from 224±139 to 418±196 pmol/L; P<0.001 between the treatments). Serum estradiol was increased from 87±133 to 352±213 pmol/L with peroral therapy and from 111±177 to 264±161 pmol/L with the gel therapy (P<0.05 between the treatments).
The LDL cholesterol level decreased by 19%, from 4.19±0.83 (mean±SD) to 3.39±0.78 mmol/L, in the peroral group and by 9%, from 4.11±0.86 to 3.72±0.78 mmol/L, in the gel group. Quite similar decreases of total, VLDL, and IDL cholesterol levels were seen in the study groups, whereas only peroral estrogen increased HDL cholesterol (12%) and total triglycerides (10%) and decreased plasma total and LDL apoB (-12% and -9%, respectively).
Fractional cholesterol absorption was reduced by 10% in
the peroral group (P<0.05) and by 6% in the transdermal
group (P<0.05, Table 2).
Absolute absorption of dietary cholesterol also decreased
by 18% (P<0.01) and 9% (P<0.05) for peroral
and transdermal therapies, respectively. No correlation was observed
between the changes in the serum estrogen levels and
cholesterol absorption. The change of total and LDL
cholesterol was positively related to the change in
fractional absorption of dietary cholesterol in the peroral
estrogen group (r=0.427, P<0.05 and
r=0.431, P<0.05, respectively), whereas no
significant correlation was observed in the transdermal group
(r=-0.115, P=NS and r=-0.014,
P=NS, respectively).
|
FCR for LDL apoB increased significantly in the peroral estradiol group
(18%), from 0.294 to 0.345 pools per day, but only a minor
insignificant increase (2%) was observed in the transdermal group
(Table 2
). However, the change in LDL cholesterol
was associated with the change in FCR for LDL apoB in both study groups
(Figure 1). LDL apoB production
was raised by 9% and plasma LDL apoB concentration was lowered by 6%
on the peroral therapy but not on the transdermal gel therapy (Table 2). The change in FCR for LDL apoB correlated with the change in
serum estrogen (r=0.503, P<0.01 for the change
in estrone; r=0.381, P<0.05 for the change in
estradiol) in the peroral group (Figure 2), but no significant correlation was
observed in the gel group. However, the change in the
production of LDL apoB was related to the change of serum
estrone on the peroral and transdermal treatments (r=0.380,
P<0.05 and r=0.362, P<0.05,
respectively), whereas no correlation was observed for the change in
serum estradiol levels. The decrease of LDL apoB was related to the
increase in LDL apoB production (r=0.637,
P<0.001) and FCR for LDL apoB (r=-0.571,
P<0.01) for the group on the peroral estrogen replacement
therapy (ERT) compared with the corresponding relations for the group
on transdermal therapy (r=0.634, P<0.001 and
r=-0.241, P=NS, respectively).
|
|
The apoE phenotype distribution was slightly different in the
study groups: there was 1 subject with apoE2/3 in each group, none with
apoE4/2 in the peroral group, and 1 with apoE4/2 in the transdermal
estradiol group, whereas 26 subjects in the peroral and 20 in the
transdermal group had the apoE3/3 phenotype, 5 and 14 subjects
had the apoE4/3 phenotype, and 3 and 2 subjects had the apoE4/4
phenotype, respectively. When the subjects were
analyzed according to their apoE phenotypes,
significant decreases of total and LDL cholesterol were
observed in all apoE phenotypes, and no differences in response
to the treatments were found between the phenotypes. Also, the
changes in other lipids and lipoproteins, LDL turnover, and
cholesterol absorption were quite equal for the different
apoE phenotypes (data not shown). To study whether the effect
of ERT is modified by the 4 allele of apoE, the subjects were
divided into apoE4-negative (phenotypes apoE2/3 and apoE3/3)
and apoE4-positive (phenotypes apoE4/2, apo4/3, and apo4/4)
groups. Although the influence of both estrogen therapies on serum
lipids and cholesterol absorption, FCR, and
production for LDL apoB varied to some extent between the
apoE4-negative and the apoE4-positive subjects, the differences did not
reach statistical significance (data not shown).
No effects of the EcoRI and XbaI
polymorphisms of the apoB gene on the regulation of LDL and
cholesterol metabolism were observed during ERT
(data not shown). Also, no effect of 7-hydroxylase polymorphism
on lipoprotein or cholesterol metabolism was
observed among the subjects on either treatment (data not shown).
In stepwise multiple regression analysis, the changes in FCR and the production of LDL apoB explained 60% (R2=0.604, P<0.001) of the reduction in LDL cholesterol in the peroral ERT group and 80% (R2=0.798, P<0.001) in the gel group.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In the present study, transdermal estradiol gel and peroral estradiol therapies decreased total, IDL, and LDL cholesterol. The changes in total and IDL cholesterol were similar in the 2 groups, whereas LDL cholesterol was lowered more extensively with the peroral treatment. HDL cholesterol and triglycerides increased in only the peroral estrogen group, whereas VLDL cholesterol was reduced by transdermal ERT. Overall, our results are in agreement with the previous studies.7 9 32 33 34 The magnitude of the lipid changes seemed to be related to the estrogen regimen: peroral treatment has more profound effects than transdermally delivered treatments, such as patches or gel, which were used in the present study. The quality of estrogen is also important, because synthetic estrogens in particular tend to enhance serum triglycerides.35 Different effects on liver metabolism have been suggested as an explanation for the differences in response, because hepatic first-pass metabolism and the induction of hepatic protein synthesis are avoided in transdermal administration.36 Moreover, transdermal estrogen seems to act slowly; hence, 3 to 6 months of treatment is required to a reach maximum effect.7 33 In fact, some short-term studies have failed to reveal any effect on lipid metabolism. The present study of 6-month duration was long enough to elucidate the effects of both therapies. We also found that regardless of the estrogen regimen, the higher the baseline LDL cholesterol, the more effectively was LDL cholesterol decreased (r=-0.381, P=0.001), which is in accord with a previous study suggesting that hypercholesterolemia could be an indication for ERT.37
Could the changes in body weight and fat distribution during the study be responsible for the changes in lipoprotein levels? A slight insignificant weight gain (0.6 kg on average) and an increase in BMI with an unchanged waist-to-hip ratio were noticed in the gel group, but these changes can hardly have any adverse effects on lipid metabolism. In the peroral estrogen group, no change in body weight, BMI, or waist-to-hip ratio was observed. In fact, previous studies34 38 have suggested that HRT may prevent weight gain and the tendency of central fat distribution associated with the menopause.39
VLDL cholesterol decreased and VLDL triglycerides tended to decrease on gel therapy, whereas total triglycerides remained unchanged. Walsh et al40 have suggested that the increased production of triglyceride-rich VLDL causes the rise of plasma triglyceride levels on peroral ERT. Similar to findings in the present study, peroral estrogen was shown to increase FCR more than LDL apoB production, resulting in a decrease of plasma LDL levels.40 These metabolic changes were observed in light LDL particles, whereas the clearance and production of dense LDL were increased equally.41
Arca et al42 have suggested that hypercholesterolemia in postmenopausal women is caused by decreased LDL receptor activity. Previously, pharmacological doses of estrogens used in animal studies13 43 or in the treatment of patients with prostate cancer14 44 have also been shown to increase LDL receptor activity. However, there have been only limited data concerning the doses commonly used in replacement therapy. In accord with previous smaller studies,40 41 the present study showed that the serum estrogen levels usually achieved by ERT also decrease LDL cholesterol, mainly by increasing FCR for LDL apoB, and that the effect is related to the change in serum estrogen. Indeed, the large increases in serum estrogen levels on peroral treatment seemed to result in larger reductions in LDL cholesterol levels, and a correlation between the change in serum estradiol and estrone and the change in LDL cholesterol has been noticed.15 The relation between the increase of FCR and the reduction of LDL cholesterol on both treatments indicates that the change of FCR is important. Although the production rate of LDL apoB was increased in the peroral group, the increase of FCR was more profound, leading to a decrease of LDL cholesterol. Overall, the data of the present study suggest that FCR is the most important factor for the lowering of LDL cholesterol independent of the route of administration and at the current therapeutic doses of estrogen. Previous studies with higher doses of estrogen in men and animals have shown that estrogen stimulates hepatic LDL receptor expression,13 14 44 probably mediated by estrogen receptors.45 46 This is also the most likely explanation for the increased FCR seen in the present study with lower doses of estrogen. On the other hand, estrogen-stimulated transcytosis of LDL has recently been suggested to have some importance in cholesterol lowering when desialylated forms of LDL are removed by asialoglycoprotein receptors.47
One additional mechanism for the LDL lowering by estrogen therapy could be the altered cholesterol absorption. A slight but significant decrease in dietary cholesterol absorption was found with both regimens of ERT, suggesting that part of the beneficial effect noticed in lipids and lipoproteins could be mediated by the diminished absorption of cholesterol. It is possible, however, that the overall absorption of intestinal cholesterol (dietary plus biliary) may not have changed. We determined the absorption of dietary cholesterol, which represents about one third of the total intestinal cholesterol pool. At any rate, the changes in cholesterol absorption were not associated with the changes in FCR or the production of LDL apoB, factors that seemed to have a major role in the regulation of LDL cholesterol.
The polymorphisms of some regulatory proteins, such as apoE, apoB,
and 7-hydroxylase, have been reported to affect the plasma lipid and
lipoprotein levels.29 30 31 48 Also, some studies have
suggested that the response to hypolipidemic therapies could be related
to apoE polymorphism,49 50 even though there are also
contradictory findings.51 52 The present study did not
reveal any such effects of either ERT treatment among these
postmenopausal subjects. Recently, the LDL cholesterol
levels in apoE4-negative subjects were reported to respond more
favorably to HRT than did the levels in apoE4-positive
subjects.53 The differences between that study and our
trial could be due to a number of factors. The study by Heikkinen et
al53 used a combination therapy of estradiol and
cyproterone acetate and introduced a long-term dietary therapy, both of
which might affect the final outcome. Patient selection could also be
important, even though it is unlikely that the hysterectomy in our
study patients could have affected the lipid response. The differences
in the duration of estrogen treatment might also be one factor
explaining the different results. It must also be noticed that because
the 73 subjects of the present study were subdivided by treatment
type and genetic polymorphisms, the numbers in each group became
quite small. Therefore, the power of the present study to find
differences between the apoE, apoB, and 7-hydroxylase
polymorphisms is probably low.
In conclusion, ERT-induced changes in lipids and lipoproteins are related to the achieved estrogen level on peroral and transdermal therapy. The increase of FCR for LDL apoB seems to be the most important factor in the regulation of the LDL level on both treatments, and although peroral ERT slightly enhanced LDL production, the LDL clearance rate was increased more, with the net effect being a decrease in LDL levels. The small decrease in the absorption of dietary cholesterol does not seem to be important for the reduction in serum cholesterol by peroral and transdermal ERT.
|
Acknowledgments |
|---|
This study was supported by the Medical Council of the Finnish Academy and a grant from Orion Research Foundation. The authors are grateful to Jonathan Cohen, PhD, Center for Human Nutrition, Department of Clinical Nutrition, Dallas, Tex, for the analysis of 7
-hydroxylase polymorphisms and to Kaisa Ketonen, Saija
Kortetjärvi, Marja-Leena Kytökangas, Tiina Lapinkari,
Anna-Riitta Malinen, Liisa Mannermaa, Eila Saarikoski, and Leena Ukkola
for skillful technical assistance. Received May 25, 1999; accepted September 3, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. JAMA. 1991;265:1861–1867.
2. Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med. 1991;20:47–63.[Medline] [Order article via Infotrieve]
3.
Hulley S, Grady D, Bush T, Furberg C, Herrington D,
Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin
for secondary prevention of coronary heart disease in
postmenopausal women: Heart and Estrogen/Progestin Replacement Study
(HERS) Research Group. JAMA. 1998;280:605–613.
4. Stevenson JC, Crook D, Godsland IF. Influence of age and menopause on serum lipids and lipoproteins in healthy women. Atherosclerosis. 1993;98:83–90.[Medline] [Order article via Infotrieve]
5. Pansini F, Bergamini C, Bettocchi S Jr, Bassi P, Malfaccini M, Bagni B, Mollica G. Short-term effect of oophorectomy on lipoprotein metabolism. Gynecol Obstet Invest. 1984;18:134–139.[Medline] [Order article via Infotrieve]
6. Crook D, Stevenson JC. Transdermal hormone replacement therapy, serum lipids and lipoproteins. Br J Clin Pract Symp Suppl. 1996;86:17–21.
7. Jensen J, Riis BJ, Ström V, Nilas L, Christiansen C. Long-term effects of percutaneous estrogens and oral progesterone on serum lipoproteins in postmenopausal women. Am J Obstet Gynecol. 1987;156:66–71.[Medline] [Order article via Infotrieve]
8. Stanczyk FZ, Shoupe D, Nunez V, Macias-Gonzales P, Vijod MA, Lobo RA. A randomized comparison of nonoral estradiol delivery in postmenopausal women. Am J Obstet Gynecol. 1988;159:1540–1546.[Medline] [Order article via Infotrieve]
9. Chetkowski RJ, Meldrum DR, Steingold KA, Randle D, Lu JK, Eggena P, Hershman JM, Alkjaersig NK, Fletcher AP, Judd HL. Biologic effects of transdermal estradiol. N Engl J Med. 1986;314:1615–1620.[Abstract]
10.
de Lignieres B, Basdevant A, Thomas G, Thalabard
JC, Mercier-Bodard C, Conard J, Guyene TT, Mairon N, Corvol P,
Guy-Grand B. Biological effects of estradiol-17 beta in postmenopausal
women: oral versus percutaneous administration.
J Clin Endocrinol Metab. 1986;62:536–541.
11. Padwick ML, Endacott J, Whitehead MI. Efficacy, acceptability, and metabolic effects of transdermal estradiol in the management of postmenopausal women. Am J Obstet Gynecol. 1985;152:1085–1091.[Medline] [Order article via Infotrieve]
12.
Windler EE, Kovanen PT, Chao YS, Brown MS, Havel RJ,
Goldstein JL. The estradiol-stimulated lipoprotein receptor of rat
liver: a binding site that membrane mediates the uptake of rat
lipoproteins containing apoproteins B and E. J Biol
Chem. 1980;255:10464–10471.
13.
Kovanen PT, Brown MS, Goldstein JL. Increased binding
of low density lipoprotein to liver membranes from rats treated with 17
alpha-ethinyl estradiol. J Biol Chem. 1979;254:11367–11373.
14. Eriksson M, Berglund L, Rudling M, Henriksson P, Angelin B. Effects of estrogen on low density lipoprotein metabolism in males: short-term and long-term studies during hormonal treatment of prostatic carcinoma. J Clin Invest. 1989;84:802–810.
15. Karjalainen A, Heikkinen J, Savolainen MJ, Bäckström AC, Salinto M, Kesäniemi YA. Metabolic changes induced by peroral oestrogen and transdermal oestradiol gel therapy. Br J Obstet Gynaecol. 1997;104(suppl 16):38–43.
16. Lipid Research Clinics Program. Manual of Laboratory Operations: Lipid and Lipoprotein Analysis, Bethesda, Md: Department of Health, Education, and Welfare, National Institutes of Health; 1974:75–82.
17. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.[Abstract]
18.
Lowry OH, Rosebrough NJ, Farr AL, Randall
RJ. Protein measurement with the Folin phenol reagent. J
Biol Chem. 1951;193:265–275.
19. Egusa G, Brady DW, Grundy SM, Howard BV. Isopropanol precipitation method for the determination of apolipoprotein B specific activity and plasma concentrations during metabolic studies of very low density lipoprotein and low density lipoprotein apolipoprotein B. J Lipid Res. 1983;24:1261–1267.[Abstract]
20. Kesäniemi YA, Grundy SM. Significance of low density lipoprotein production in the regulations of plasma cholesterol level in man. J Clin Invest. 1982;70:13–21.
21. Hörkkö S, Huttunen K, Korhonen T, Kesäniemi YA. Decreased clearance of low-density lipoprotein in patients with chronic renal failure. Kidney Int. 1994;45:561–570.[Medline] [Order article via Infotrieve]
22. Lindgren FT, Jensen LC, Wills RD, Freeman NK. Flotation rates, molecular weights and hydrated densities of the low-density lipoproteins. Lipids. 1969;4:337–344.[Medline] [Order article via Infotrieve]
23. McFarlane AS. Efficient trace-labelling of proteins with iodine. Nature. 1958;182:53.[Medline] [Order article via Infotrieve]
24. Bilheimer DW, Goldstein JL, Grundy SM, Brown MS. Reduction in cholesterol and low density lipoprotein synthesis after portacaval shunt surgery in a patient with homozygous familial hypercholesterolemia. J Clin Invest. 1975;56:1420–1430.
25. Matthews CME. The theory of tracer experiments with iodine-131-labelled plasma proteins. Phys Med Biol. 1957;2:36–53.[Medline] [Order article via Infotrieve]
26. Crouse JR, Grundy SM. Evaluation of a continuous isotope feeding method for measurement of cholesterol absorption in man. J Lipid Res. 1978;19:967–971.[Abstract]
27. Rastas M, Seppänen R, Knuts L, Karvetti R, Varo P. Nutrient Composition of Foods. Helsinki, Finland: Social Insurance Institution; 1993.
28. Menzel H, Utermann G. Apolipoprotein E phenotyping from serum by Western blotting. Electrophoresis. 1986;7:492–495.
29. Ehnholm C, Lukka M, Kuusi T, Nikkilä E, Utermann G. Apolipoprotein E polymorphism in the Finnish population: gene frequencies and relation to lipoprotein concentrations. J Lipid Res. 1986;27:227–235.[Abstract]
30. Ukkola O, Savolainen MJ, Salmela PI, von Dickhoff K, Kesaniemi YA. Apolipoprotein B gene DNA polymorphisms are associated with macro- and microangiopathy in non-insulin-dependent diabetes mellitus. Clin Genet. 1993;44:177–184.[Medline] [Order article via Infotrieve]
31. Wang J, Freeman DJ, Grundy SM, Levine DM, Guerra R, Cohen JC. Linkage between cholesterol 7alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations. J Clin Invest. 1998;101:1283–1291.[Medline] [Order article via Infotrieve]
32. Utian WH. Effect of postmenopausal estrogen therapy on diastolic blood pressure and bodyweight. Maturitas. 1978;1:3–8.[Medline] [Order article via Infotrieve]
33. Whitcroft SI, Crook D, Marsh MS, Ellerington MC, Whitehead MI, Stevenson JC. Long-term effects of oral and transdermal hormone replacement therapies on serum lipid and lipoprotein concentrations. Obstet Gynecol. 1994;84:222–226.[Medline] [Order article via Infotrieve]
34.
The Writing Group for the PEPI Trial. Effects of
estrogen or estrogen/progestin regimens on heart disease risk factors
in postmenopausal women: the Postmenopausal Estrogen/Progestin
Interventions (PEPI) Trial. JAMA. 1995;273:199–208.
35.
Lobo RA. Clinical review 27: effects of hormonal
replacement on lipids and lipoproteins in postmenopausal women.
J Clin Endocrinol Metab. 1991;73:925–930.
36. Van Erpecum KJ, Van Berge Henegouwen GP, Verschoor L, Stoelwinder B, Willekens FL. Different hepatobiliary effects of oral and transdermal estradiol in postmenopausal women. Gastroenterology. 1991;100:482–488.[Medline] [Order article via Infotrieve]
37. Tikkanen MJ, Nikkilä EA, Vartiainen E. Natural oestrogen as an effective treatment for type-II hyperlipoproteinaemia in postmenopausal women. Lancet. 1978;2:490–491.[Medline] [Order article via Infotrieve]
38. Haarbo J, Marslew U, Gotfredsen A, Christiansen C. Postmenopausal hormone replacement therapy prevents central distribution of body fat after menopause. Metabolism. 1991;40:1323–1326.[Medline] [Order article via Infotrieve]
39. Matthews KA, Meilahn E, Kuller LH, Kelsey SF, Caggiula AW, Wing RR. Menopause and risk factors for coronary heart disease. N Engl J Med. 1989;321:641–646.[Abstract]
40. Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar V, Sacks FM. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med. 1991;325:1196–1204.[Abstract]
41.
Campos H, Walsh BW, Judge H, Sacks FM. Effect of
estrogen on very low density lipoprotein and low density lipoprotein
subclass metabolism in postmenopausal women. J
Clin Endocrinol Metab. 1997;82:3955–3963.
42.
Arca M, Vega GL, Grundy SM.
Hypercholesterolemia in postmenopausal women:
metabolic defects and response to low-dose
lovastatin. JAMA. 1994;271:453–459.
43. Colvin PL Jr. Estrogen increases low-density lipoprotein receptor-independent catabolism of apolipoprotein B in hyperlipidemic rabbits. Metabolism. 1996;45:889–896.[Medline] [Order article via Infotrieve]
44. Angelin B, Olivecrona H, Reihner E, Rudling M, Ståhlberg D, Eriksson M, Ewerth S, Henriksson P, Einarsson K. Hepatic cholesterol metabolism in estrogen-treated men. Gastroenterology. 1992;103:1657–1663.[Medline] [Order article via Infotrieve]
45.
Parini P, Angelin B, Rudling M. Importance of estrogen
receptors in hepatic LDL receptor regulation. Arterioscler Thromb
Vasc Biol. 1997;17:1800–1805.
46.
Croston GE, Milan LB, Marschke KB, Reichman M, Briggs
MR. Androgen receptor-mediated antagonism of estrogen-dependent low
density lipoprotein receptor transcription in cultured
hepatocytes. Endocrinology. 1997;138:3779–3786.
47.
Burgess JW, Stanley KK. Estrogen-stimulated
transcytosis of desialylated ligands and 2 macroglobulin in rat
liver. Biochim Biophys Acta. 1997;1359:48–58.[Medline]
[Order article via Infotrieve]
48.
Schaefer EJ, Lamon-Fava S, Johnson S, Ordovas JM,
Schaefer MM, Castelli WP, Wilson PW. Effects of gender and menopausal
status on the association of apolipoprotein E phenotype with
plasma lipoprotein levels: results from the Framingham Offspring Study.
Arterioscler Thromb. 1994;14:1105–1113.
49. Carmena R, Roederer G, Mailloux H, Lussier-Cacan S, Davignon J. The response to lovastatin treatment in patients with heterozygous familial hypercholesterolemia is modulated by apolipoprotein E polymorphism. Metabolism. 1993;42:895–901.[Medline] [Order article via Infotrieve]
50. Nestruck AC, Bouthillier D, Sing CF, Davignon J. Apolipoprotein E polymorphism and plasma cholesterol response to probucol. Metabolism. 1987;36:743–747.[Medline] [Order article via Infotrieve]
51. Sanllehy C, Casals E, Rodriguez-Villar C, Zambon D, Ojuel J, Ballesta AM, Ros E. Lack of interaction of apolipoprotein E phenotype with the lipoprotein response to lovastatin or gemfibrozil in patients with primary hypercholesterolemia. Metabolism. 1998;47:560–565.[Medline] [Order article via Infotrieve]
52. Korhonen T, Hannuksela ML, Seppänen S, Kervinen K, Kesäniemi YA, Savolainen MJ. The effect of apolipoprotein E phenotype on cholesterol ester transfer protein activity, plasma lipids and apolipoprotein A I levels in hypercholesterolemic patients on colestipol and lovastatin treatment. Eur J Clin Pharmacol. 1999;54:903–910.[Medline] [Order article via Infotrieve]
53.
Heikkinen AM, Niskanen L, Ryynänen M, Komulainen
MH, Tuppurainen MT, Parviainen M, Saarikoski S. Is the response of
serum lipids and lipoproteins to postmenopausal hormone replacement
therapy modified by apoE genotype? Arterioscler Thromb
Vasc Biol. 1999;19:402–407.
This article has been cited by other articles:
 |
|
 |
|
  K. Kavanagh, M. A. Davis, L. Zhang, M. D. Wilson, T. C. Register, M. R. Adams, L. L. Rudel, and J. D. Wagner Estrogen Decreases Atherosclerosis in Part by Reducing Hepatic Acyl-CoA:Cholesterol Acyltransferase 2 (ACAT2) in Monkeys Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1471 - 1477. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Tanaka, R. Koga, H. Tsuda, K. Imai, S. Abe, T. Masuda, M. Iwamoto, E. Nakazono, T. Kamohara, N. Kinukawa, et al. Subcutaneous Fat Accumulation Shows a Beneficial Correlation with Serum Cholesterol in Postmenopausal Japanese Women Experimental Biology and Medicine, September 1, 2007; 232(8): 1064 - 1070. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Kellokoski, S. M. Poykko, A. H. Karjalainen, O. Ukkola, J. Heikkinen, Y. A. Kesaniemi, and S. Horkko Estrogen Replacement Therapy Increases Plasma Ghrelin Levels J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2954 - 2963. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. R. Pirwany, N. Sattar, I. A. Greer, C. J. Packard, and R. Fleming Supraphysiological concentrations of estradiol in menopausal women given repeated implant therapy do not adversely affect lipid profiles Hum. Reprod., March 1, 2002; 17(3): 825 - 829. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||