© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Both Raloxifene and Estrogen Reduce Major Cardiovascular Risk Factors in Healthy Postmenopausal Women
A 2-Year, Placebo-Controlled Study
From the Ageing Women Project: the Department of Endocrinology (G.W.d.V.-d.R., C.N), Research Institute for Endocrinology, Reproduction, and Metabolism, the Department of Internal Medicine (C.D.A.S.), and the Department of Obstetrics and Gynaecology (V.M., P.K.), Institute for Cardiovascular Research-Vrije Universiteit, University Hospital Vrije Universiteit, Amsterdam, The Netherlands; the Gaubius Laboratory, TNO-PG (P.M., C.K.), Leiden, The Netherlands; and Lilly Research Laboratories (F.C., S.W.), Indianapolis, Ind.
Correspondence to Coen Netelenbos, MD, PhD, Department of Endocrinology, University Hospital Vrije Universiteit, De Boelelaan 1117, Postbus 7057, 1007 MB Amsterdam, the Netherlands. E-mail C.netelen{at}azvu.nl
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Abstract |
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Abstract—Currently raloxifene, a selective estrogen receptor modulator, is being investigated as a potential alternative for postmenopausal hormone replacement to prevent osteoporosis and cardiovascular disease. We compared the 2-year effects of raloxifene on a wide range of cardiovascular risk factors with those of placebo and conjugated equine estrogens (CEEs). Analyses were based on 56 hysterectomized but otherwise healthy postmenopausal women aged 54.8±3.5 (mean±SD) years who entered this double-blind study and who were randomly assigned to raloxifene hydrochloride 60 mg/d (n=15) or 150 mg/d (n=13), placebo (n=13), or CEEs 0.625 mg/d (n=15). At baseline and after 6, 12, and 24 months of treatment, we assessed serum lipids, blood pressure, glucose metabolism, C-reactive protein, and various hemostatic parameters. Compared with placebo, both raloxifene and CEEs lowered the level of low density lipoprotein cholesterol by 0.53 to 0.79 mmol/L (all P<0.04) and lowered, at 24 months, the level of fibrinogen by 0.71 to 0.86 g/L (all P<0.05). The effects of raloxifene and CEEs did not differ significantly. In contrast to raloxifene, from 6 months on CEEs increased high density lipoprotein cholesterol by 0.25 to 0.29 mmol/L and reduced plasminogen activator inhibitor-1 antigen by 30.6 to 48.6 ng/mL (all P<0.02 versus both placebo and raloxifene). CEEs transiently increased C-reactive protein by 1.0 mg/L at 6 months (P<0.05 versus placebo) and prothrombin-derived fragment F1+2 by 0.79 nmol/L at 12 months (P<0.001 versus placebo). Finally, from 12 months on, CEEs increased triglycerides by 0.33 to 0.56 mmol/L (all P<0.05 versus both placebo and raloxifene). Our findings suggest that in healthy postmenopausal women, raloxifene and estrogen monotherapy have similar beneficial effects on low density lipoprotein cholesterol and fibrinogen levels. These treatments differ, however, in their effects on high density lipoprotein cholesterol, triglycerides, and plasminogen activator inhibitor-1 and possibly in their effects on prothrombin fragment F1+2 and C-reactive protein.
Key Words: raloxifene • estrogen • lipids • coagulation • fibrinolysis
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Introduction |
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Observational studies among postmenopausal women have found that the use of estrogens with or without progestogens is associated with a reduction of the risk of osteoporosis,1 2 cardiovascular disease,3 4 5 and overall mortality.6 The results of the recently published HERS study (Heart Estrogen-progestin Replacement Study), the only randomized trial so far, were therefore disappointing, in that it showed no beneficial effect of postmenopausal hormone replacement therapy on cardiovascular morbidity and/or mortality.7 It did concern, however, a secondary prevention study of conjugated equine estrogens (CEEs) continuously combined with medroxyprogesterone acetate. Results of that study may therefore not be extrapolated to healthy postmenopausal women nor to other regimens of hormone replacement therapy. Disadvantages of the prolonged use of hormone replacement with estrogens and progestogens include an increase in the risk of breast cancer,8 9 a possible increase in the risk of endometrial carcinoma,10 and the recurrence of vaginal bleeding.
To increase the benefit-risk ratio of hormone replacement therapy, so-called designer estrogens are being developed: nonhormonal agents that bind with high affinity to the estrogen receptor and exhibit tissue-specific, estrogen-agonist or -antagonist effects. The tissue specificity of designer estrogens may be related to the existence of (at least) 2 different isoforms of the estrogen receptor with distinct signaling properties, depending on the ligand and the response element.11 12 Raloxifene, a nonsteroidal benzothiophene derivative, is a designer estrogen of which relatively much experience has been gained. It possesses beneficial estrogen-agonist effects on bone13 and cardiovascular risk factors13 14 but estrogen-antagonist effects on the endometrium13 and breast tissue.15 However, in ovariectomized monkeys fed an atherogenic diet, long-term treatment with raloxifene in contrast to CEEs did not reduce coronary artery plaque size.16 The long-term effects of raloxifene on cardiovascular risk factors have not been extensively investigated. Therefore, we compared the effects of raloxifene on serum lipids, blood pressure, glucose metabolism, and hemostatic cardiovascular risk factors with those of placebo and CEEs in a group of hysterectomized but otherwise healthy postmenopausal women in a double-blind, randomized study of 2 years’ duration.
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Methods |
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Subjects
Sixty postmenopausal, hysterectomized but otherwise healthy women (mean±SD age 54.8±3.5 years) were included in the study. Hysterectomy had been performed because of a benign endometrial abnormality (n=50), uterine prolapse (n=8), and/or a benign ovarian abnormality (n=5). Postmenopausal status was defined as a serum estradiol level
73 pmol/L and a follicle-stimulating hormone
level 
40 IU/L. Exclusion criteria were a history of breast carcinoma
and/or recent thromboembolism; evidence of liver disease and/or renal
dysfunction; use of lipid-lowering drugs and/or anticonvulsives; and
use of sex steroids and/or corticosteroids more
recently than 6 months before the start of the study. Hypertension was
not an exclusion criterion. Four participants dropped out of the study
before the first postbaseline visit. Reasons for withdrawal were
incorrect inclusion (placebo group), nausea (raloxifene 150-mg group),
personal conflict (placebo group), and death due to a traffic accident
(raloxifene 150-mg group). These subjects were excluded from the
analyses. Analyses in this report are therefore based
on 56 women randomly assigned to 1 of 4 treatment groups: placebo
(n=13), CEEs 0.625 mg/d (n=15), and raloxifene hydrochloride 60 mg/d
(n=15) and 150 mg/d (n=13). All women received 500 mg of elemental
calcium per day. To monitor compliance, at each visit the subjects
returned the unused medication, which was then counted. If a subject
had missed >30% of the study medication during 2 separate time
periods, she was regarded as severely noncompliant. The study was
conducted on an outpatient basis according to the principles of the
Declaration of Helsinki and was approved by the medical ethics
committee of the Academic Hospital Vrije Universiteit of Amsterdam.
Informed consent was obtained from all volunteers after oral and
written information was supplied.
General Procedures
At baseline and at 12-month intervals, smoking status (yes or
no), body mass index (weight/height2), and blood
pressure were assessed. Blood pressure (mean of 4 readings) was
measured on the left arm after 10 minutes of rest by using an automated
device (BP-8800, Colin). Hypertension was defined as a systolic
blood pressure 160 mm Hg and/or a diastolic blood
pressure 95 mm Hg and/or the use of antihypertensive drugs. At
baseline and after 6, 12, and 24 months of treatment, blood samples
were collected between 8:30 and 11:30 AM after an overnight
fast. Circulating levels of insulin, all markers of coagulation and
fibrinolysis, and C-reactive protein (CRP) were assayed
at the end of the study in a single run. A carefully standardized
procedure17 was applied for samples to be used for
determination of markers of coagulation and
fibrinolysis.
Laboratory Variables
At baseline, we measured serum levels of estradiol
(radioimmunoassay; Double Antibody, DPC) and of follicle-stimulating
hormone (microparticle enzyme immune assay; IMX, Abbott
Laboratories).
At baseline and after 6, 12, and 24 months of treatment, we measured serum total cholesterol (TC), HDL cholesterol (HDL-C), and triglycerides (TGs; all with enzymatic methods from Boehringer Mannheim). LDL cholesterol (LDL-C) was calculated by the Friedewald formula. Serum insulin was measured by an immunoradiometric assay (Biosource Diagnostics; intra-assay CV 5%). Coagulation activity was assessed by measuring fibrinogen (thrombin time method according to Clauss; STA fibrinogen kit, Boehringer Mannheim), factor VII antigen (enzyme immunoassay; Asserchrom, Diagnostica Stago), the prothrombin-derived fragment 1+2 (F1+2), and thrombin-antithrombin complexes (both by enzyme immunoassay; Enzygnost, Behringwerke, with detection limits of 0.02 nmol/L and 0.5 µg/L, respectively). Fibrinolytic activity was determined by measuring tissue-type plasminogen activator antigen (tPA; ELISA Imulyse t-PA, Biopool, with a detection limit of 1.5 µg/L), plasminogen activator inhibitor-1 antigen (PAI-1 enzyme immunoassay; Innotest PAI-1, Innogenetics, with a detection limit of 2.5 µg/L), and plasmin-antiplasmin complexes (PAP) and D-dimer (both by enzyme immunoassay; Enzygnost, Behringwerke, with a detection limit of 10 and 0.5 µg/L, respectively). Intra-assay CVs were all <10% except for tPA, for which they were <12%. Because inflammation may play a role in the pathogenesis of atherothrombotic disease,18 we also measured levels of CRP with a sensitive (detection limit of 0.01 mg/L) in-house enzyme immunoassay with antibodies supplied by Dako. The intra-assay CVs were <10%.
Statistical Analyses
The statistician did not have any contact with the participants,
and the physicians did not know the randomization codes. Data are given
as mean±SD. For variables for which the residuals of the fitted
least-squares model were not normally distributed, logarithmic
transformation gave approximately symmetrical distributions that were
used for all statistical analyses described below. For these
variables, geometric means with their 95% CIs are
presented. At baseline, we assessed the general characteristics
for the 4 different treatment groups and compared these by either 1-way
ANOVA or by Fisher’s exact test. Additionally, at 12 and 24 months,
the prevalence of hypertension in each of the treatment groups was
assessed and compared by Fisher’s exact test. Missing values were
replaced by carrying forward the last available postbaseline value.
Analyses of particular importance were those comparing any
raloxifene group to either the placebo group or the CEE group. Pairwise
comparisons were carried out within the framework of the ANOVA by using
the treatment group least-square means (LSMEANS) and the pooled
variance of the LSMEANS; pairwise differences between any 2 treatment
groups were established by contrasting the differences in the treatment
LSMEANS by using the pooled variance. Tests of within-group changes
versus baseline were carried out with Student’s t tests.
Any pairwise differences were examined for significance only after an
overall treatment group difference had been established. Overall
changes from baseline were evaluated by using repeated-measures ANOVA.
This was accomplished by using the Statistical Analysis System
MIXED procedure, in which the model included
effects for therapy, visit, and therapy-by-visit interaction. These
analyses assumed an autoregressive covariance
structure. Finally, Pearson correlations were used to assess
associations between markers of fibrinolysis.
Statistical tests resulting in P<0.05 were judged to be
significant. All analyses were performed with SAS version 6.08
running under the MVS operating system.
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Results |
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Table 1
shows the baseline
values of all variables measured for all women included in the
study. At baseline there were no significant differences among the 4
groups except for the mean follicle-stimulating hormone level, which
was 
25% lower in the raloxifene 150-mg group than in the placebo
and CEE groups. Fifty-two women completed the 2-year follow-up. Four
women withdrew before the first postbaseline visit and 4 after this
visit. For the latter 4, who remained in the analyses, the
reasons for leaving the study were development of a deep venous
thrombosis (after 6.5 months; raloxifene 60-mg group), carcinoma of the
bladder (after 9.5 months; CEE group), and personal conflict (after 9.5
and 12.1 months; raloxifene 60-mg and placebo groups). There was no
severe noncompliance, as defined in Methods, in any of the treatment
groups.
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Lipid Levels
At 24 months, raloxifene at 60 and 150 mg/d decreased the mean
serum TC by 0.67 and 0.59 mmol/L, respectively (P<0.03
versus both placebo and CEE groups; Table 2). CEEs did not affect the serum TC. For
LDL-C, the overall change from baseline in the placebo group differed
significantly from the overall change from baseline in both the CEE and
the raloxifene groups (P=0.002; the
Figure). From 6 months onward, both
raloxifene and CEEs decreased the mean LDL-C to a similar extent (by
0.52 to 0.79 mmol/L, P<0.05 versus placebo). Compared
with placebo, raloxifene did not change HDL-C, whereas CEEs increased
the mean HDL-C (P<0.02 versus both placebo and raloxifene).
Compared with placebo, TG serum levels were not affected by raloxifene;
in contrast, from 12 months on, TG levels were raised by CEEs
(P<0.05 versus both placebo and raloxifene).
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,
raloxifene 60 mg; 
, raloxifene 150 mg; 
, CEEs 0.625 mg.
#P=0.06;
^P=0.07;
**P<0.01; ***P<0.001.
Blood Pressure
Compared with placebo, neither raloxifene nor CEEs significantly
affected systolic or diastolic blood pressure (data
not shown). Two participants started antihypertensive therapy during
the study. One participant stopped her antihypertensive medication. At
none of the time points measured, however, did the prevalence of
hypertension differ significantly among the groups.
Biochemical Markers of Coagulation
The overall change in fibrinogen from baseline in the placebo
group tended to be different from the overall change from baseline in
both the CEE and raloxifene groups (P=0.06; the
Figure
). Compared with placebo, at 24 months raloxifene and CEEs
decreased the mean fibrinogen level by 0.71 to 0.86 g/L
(P<0.04; Table 3). At none of
the follow-up measurements was the effect between raloxifene and CEEs
significantly different. Compared with placebo, neither raloxifene nor
CEEs affected factor VII antigen or thrombin-antithrombin complex.
Compared with placebo, raloxifene did not significantly affect the mean
F1+2; at 12 months, CEEs transiently increased the mean F1+2 by 0.79
nmol/L (P<0.001).
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Biochemical Markers of Fibrinolysis
In the placebo group, an increase in PAI-1 (by 8.4, 13, and 5.3
µg/L, respectively; all P<0.08; the Figure) and a
decrease in the tPA–PAI-1 ratio (all P<0.05; data not
shown) were seen at all 3 time points [Table 4]. Compared with placebo, the levels of
tPA and PAI-1 did not change significantly with raloxifene therapy, nor
did the tPA–PAI-1 ratio. In contrast, compared with placebo, at 6 and
24 months CEEs reduced the mean tPA level by 2.04 and 2.25 µg/L,
respectively (P<0.05 versus both placebo and raloxifene).
From 6 months on, CEEs decreased the mean PAI-1 level by 30.6 to 48.6
µg/L (P<0.02 versus both placebo and raloxifene) as well
as the mean tPA–PAI-1 ratio. The increase in the tPA–PAI-1 ratio was
significant versus placebo at 6 and 12 months (P<0.002).
The overall change in PAI-1 from baseline in the CEE group differed
significantly from the overall change from baseline in the other groups
(P<0.001, the Figure). PAP as well as D-dimer showed
wide scatter and did not change significantly in any of the groups.
There was, however, at all time points an inverse correlation between
PAI-1 and PAP (r=-0.38 to -0.62; all P<0.005)
and a positive correlation between the tPA–PAI-1 ratio and PAP
(r=0.48 to 0.68; P<0.001) in the entire group.
Furthermore, any change versus baseline in PAI-1 was negatively
associated with any change versus baseline in PAP (r=-0.42
to -0.62; P<0.002), and any change in the tPA–PAI-1 ratio
was positively associated with any change in PAP (r=0.51 to
0.55; P<0.001). No consistent association existed
between the level of PAI-1 or the tPA–PAI-1 ratio and D-dimer.
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CRP and Carbohydrate Metabolism
Compared with placebo, raloxifene did not change CRP levels; at 6
months of treatment, however, CEE induced a transient increase
(P=0.006, Table 5). The
overall increase from baseline in the CEE group differed marginally
from the overall change from baseline in both the placebo and
raloxifene treatment groups (P=0.07; the Figure).
Compared with placebo, neither raloxifene nor CEEs showed a significant
effect on fasting levels of glucose and/or insulin.
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Additional Analyses
Adjustment for smoking habits by ANCOVA did not materially affect
the results (data not shown).
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Discussion |
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There were 2 main findings. First, both raloxifene and CEEs lowered LDL-C and fibrinogen levels. Second, CEEs, but not raloxifene, decreased PAI-1 and increased HDL-C, TG, F1+2, and CRP levels. These results suggest that both CEEs and raloxifene are associated with a sustained improvement of the cardiovascular risk profile but that there are important differences between these agents.
Comparable Effects of Raloxifene and CEEs
The sustained decrease in LDL-C and fibrinogen levels after
both CEE and raloxifene treatment may be considered beneficial from the
cardiovascular point of view.19 20 LDL-C
may promote cardiovascular disease by the induction of
endothelial dysfunction21 and fibrinogen
by its effects on hemostasis, blood rheology, platelet aggregation,
and endothelial function.20 The effects of
CEEs22 23 and raloxifene13 14 on LDL-C levels
that we found are in line with earlier studies. Similarly, previous
studies have shown that estrogen replacement was associated with a
diminished increase or a slight decrease in fibrinogen levels over
time23 24 and that treatment with tamoxifen25
and raloxifene14 decreased fibrinogen levels. Our study
confirms and extends these data14 by showing that the
effects of raloxifene increase with time. It is thought that estrogens
and, presumably, raloxifene reduce LDL-C levels by enhancing LDL
clearance as a result of hepatic LDL receptor
induction.26 27 How estrogens and selective estrogen
receptor modulators influence fibrinogen levels is not known.
Different Effects of Raloxifene and CEEs
In contrast to CEEs, raloxifene did not affect the levels of
HDL-C, TG, PAI-1, tPA, F1+2, and/or CRP. Observational studies have
shown that cardiovascular prognosis is adversely
affected by a decrease in HDL-C28 29 and by an increase in
TG,28 30 PAI-1,31 32 33 tPA,33 34
and CRP.35 36 37
It is therefore reasonable to assume that the increase in HDL-C observed with CEEs, which is thought to be mediated at least partly by an effect on hepatic lipase,38 39 represents a favorable change. The CEE-associated increase in TG may be innocuous, as this likely reflects enhanced synthesis of large, nonatherogenic, VLDL particles.22 Our results are in agreement with earlier reports on the effects of estrogen22 23 and raloxifene13 14 on HDL-C and TG. The mechanistic basis of the difference between CEEs and raloxifene, however, is not known.
It is less clear how the effects of CEEs on the markers of hemostasis, PAI-1, tPA, and F1+2, should be interpreted. The CEE-induced decrease in both PAI-1 and tPA could be regarded as beneficial, because PAI-1 is an essential antagonist of fibrinolysis and because the antigen levels of tPA primarily reflect the levels of circulating tPA–PAI-1 complexes. Although the level of PAP, a marker of fibrinolysis activation , and of D-dimer, a degradation product of cross-linked fibrin, did not increase significantly, for the whole group any decrease in PAI-1 was significantly associated with an increase in PAP (r=-0.42 to -0.62; P<0.002), and any increase in the tPA–PAI ratio was significantly associated with an increase in PAP (r=0.51 to 0.55; P<0.001). Our data concerning the effects of CEEs on fibrinolysis are consistent with previous experience.40 41 42 43 44 45 None of these previous studies, however, had a duration of >1 year, nor did they include a placebo group. Oral estrogens may decrease both PAI-1 and tPA levels by affecting adipose tissue metabolism46 or by the upregulation of the hepatic clearance of tPA–PAI-1 complexes.47 48 Our study suggests no important influence of raloxifene on fibrinolysis.
CEEs, but not raloxifene, transiently increased levels of F1+2, a marker of activated coagulation, which is in accordance with previous experience in short-term trials.14 43 45 49 Raloxifene may thus have some advantage over CEEs in this respect. The temporary character of the F1+2 increase is reminiscent of the results of the HERS study, which, in the first year of hormone use, showed more coronary events in the hormone group than in the placebo group.7
It must be noted that part of the changes induced by CEEs may result from the hepatic first-pass effect of oral estrogen. With respect to some cardiovascular parameters, transdermal estrogen administration may have effects that are similar to those of oral raloxifene. For example, transdermal estrogen does not affect circulating levels of TG,22 HDL-C,50 PAI-1,40 42 45 and F1+2.45 This may have implications for the choice of prescription: transdermal estrogen or raloxifene, for example, may be preferred in subjects with hypertriglyceridemia. So far, however, the implications with regard to clinical events of the differential effects of oral versus transdermal estrogen are unclear.
In contrast to raloxifene, CEEs transiently increased levels of CRP. There appear to be no previous published data on this issue. Even slightly increased CRP levels are a strong predictor of an adverse cardiovascular prognosis in both men35 36 and women.37 The interpretation of these findings is unclear and includes at least 2 concepts: that elevated CRP levels reflect the hepatic response to inflammation in the vascular wall,36 an important component of atherosclerosis, and that CRP itself activates processes that lead to vascular damage.51 The contrasting effects of CEEs on fibrinogen (decrease) and CRP (increase) argue somewhat against a CEE-associated increase in inflammatory activity but do not exclude it. This issue requires further investigation.
No Effect of Raloxifene and CEEs
Finally, we assessed the effects of CEEs and raloxifene on factor
VII antigen, glucose, and insulin levels and on blood pressure and
found no differences compared with placebo. This conclusion is limited,
however, by the fact that we used relatively insensitive methods to
assess these variables.
Study Limitations and Conclusions
We included only hysterectomized women, which enabled us to study
the effects of conjugated estrogen without the addition of a
progestogen and to compare the effects of raloxifene with estrogen-only
therapy. This study had some limitations. First, it was relatively
small, and we therefore cannot exclude relatively small treatment
effects. Second, besides the effects described in this article,
estrogen replacement and potentially raloxifene may have important
direct (ie, LDL-C–independent) effects on
endothelium-dependent and -independent vascular
function.52 53 54 55
In conclusion, this study, which comprised hysterectomized but otherwise healthy postmenopausal women aged 45 to 60 years, clearly shows that with respect to cardiovascular risk factors, raloxifene behaves as a partial estrogen agonist. Like CEEs, raloxifene showed a favorable influence on 2 generally recognized risk markers of cardiovascular disease, ie, LDL-C and fibrinogen levels. Unlike CEEs, however, it neither increased HDL-C nor decreased PAI-1 levels. Both raloxifene and CEEs express beneficial effects on bone mineral density; in contrast to CEEs, raloxifene seems not to influence the endometrium and breast tissue. In healthy postmenopausal women, raloxifene may thus be an attractive alternative for estrogen replacement in the prevention of cardiovascular disease and osteoporosis. Further prospective, randomized trials with clinical end points, however, are necessary to prove that CEEs and raloxifene improve cardiovascular prognosis in postmenopausal women.
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Acknowledgments |
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We are grateful to Ans Nicolaas-Merkus for her excellent assistance in the execution of the study.
Received February 1, 1999; accepted April 9, 1999.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Cauley JA, Seeley DG, Ensrud K, Ettinger B, Black D, Cummings SR. Estrogen replacement therapy and fractures in older women. Ann Intern Med. 1995;122:9–16.
2. Kiel DP, Felson DT, Anderson JJ, Wilson PWF, Moskowitz MA. Hip fracture and the use of estrogen in postmenopausal women. N Engl J Med. 1987;317:1169–1174.[Abstract]
3. 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]
4. Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, Ernster VL, Cummings SR. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016–1037.
5.
Grodstein F, Stampfer MJ, Manson JE, Colditz GA,
Willett WC, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen
and progestin use and the risk of cardiovascular
disease. N Engl J Med. 1996;335:453–461.
6.
Grodstein F, Stampfer MJ, Colditz GA, Willett
WC, Manson JE, Joffe M, Rosner B, Fuchs C, Hankinson SE, Hunter DJ,
Hennekens CH, Speizer FE. Postmenopausal hormone replacement therapy
and mortality. N Engl J Med. 1997;336:1769–1775.
7.
Hulley S, Grady D, Bush T, Furberg C, Herrington
D, Riggs B, Vittinghof E, for the Heart, and Estrogen/progestin
Replacement Study (HERS) Research group. Randomized trial of estrogen
plus progestin for secondary prevention of coronary heart
disease in postmenopausal women. JAMA. 1998;280:605–613.
8.
Colditz GA, Hankinson SE, Hunter DJ, Willett WC,
Manson JE, Stampfer MJ, Hennekens C, Rosner B, Speizer FE. The use of
estrogens and progestins and the risk of breast cancer in
postmenopausal women. N Engl J Med. 1995;332:1589–1593.
9. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer. Lancet. 1997;350:1047–1059.[Medline] [Order article via Infotrieve]
10. Beresford SAA, Weiss NS, Voigt LF, McKnight B. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet. 1997;349:458–461.[Medline] [Order article via Infotrieve]
11.
Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson
J, Kushner PJ, Scanlan TS. Differential ligand activation of estrogen
receptors ER
and ERß at AP1 sites. Science. 1997;277:1508–1510.
12.
Barkhem T, Carlsson B, Nilsson Y, Enmark E,
Gustafsson J, Nilsson S. Differential response of estrogen
receptor and estrogen receptor ß to partial estrogen
agonists/antagonists. Mol Pharmacol. 1998;54:105–112.
13.
Delmas PD, Bjarnason NH, Mitlak BH, Ravoux A,
Shah AS, Huster WJ, Draper M, Christiansen C. The effect of raloxifene
on bone mineral density, serum cholesterol, and uterine
endometrium in postmenopausal women. N Engl J Med. 1997;337:1641–1647.
14.
Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M,
Lawrence JB, Shah AS, Anderson PW. Effects of raloxifene on serum
lipids and coagulation factors in healthy postmenopausal women.
JAMA. 1998;279:1445–1451.
15. Husten L. Raloxifene reduces breast-cancer risk. Lancet. 1999;353:44.
16.
Clarkson TB, Anthony MS, Jerome CP. Lack of
effect of raloxifene on coronary artery
atherosclerosis of postmenopausal monkeys. J
Clin Endocrinol Metab. 1998;83:721–726.
17. Kluft C, Meijer P. Update: blood collection and handling procedures for assessment of plasminogen activators and inhibitors (Leiden Fibrinolysis Workshop). Fibrinolysis. 1996;1996:10:171–179.
18. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992;326:242–250.[Medline] [Order article via Infotrieve]
19. Eaker ED, Castelli WP. Coronary heart disease and its risk factors among women in the Framingham study. In: Weger NK, ed. Coronary Heart Disease in Women: Proceedings of an NIH Workshop. New York, NY: Haymarket-Doyma; 1987:122–130.
20.
Ernst E, Resch KL. Fibrinogen as a
cardiovascular risk factor: a meta-analysis and
review of the literature. Ann Intern Med. 1993;118:956–963.
21. Kinlay S, Selwyn AP, Delagrange D, Creager MA, Libby P, Ganz P. Biological mechanisms for the clinical success of lipid-lowering in coronary artery disease and the use of surrogate end-points [review]. Curr Opin Lipidol. 1996;7:389–397.[Medline] [Order article via Infotrieve]
22. 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]
23.
The writing group for the PEPI trial. Effects of
estrogen or estrogen/progestin regimens on heart disease risk factors
in postmenopausal women. JAMA. 1995;273:199–208.
24.
Meade TW for MRC General Practice Research
Framework. Randomised comparison of oestrogen versus oestrogen plus
progestogen hormone replacement therapy in women with hysterectomy.
BMJ. 1996;312:473–478.
25. Grey AB, Stapleton JP, Evans MC, Reid IR. The effect of the anti-estrogen tamoxifen on cardiovascular risk factors in postmenopausal women. J Clin Endocrinol Metab. 1995;80:3191–3195.[Abstract]
26.
Windler E, Kovanen PT, Chao YS, Brown MS, Havel
RJ, Goldstein JL. The estradiol-stimulated lipoprotein receptor of rat
liver. J Biol Chem. 1980;255:10464–10471.
27.
Ma PTS, Yamamoto T, Goldstein JL, Brown MS.
Increased mRNA for low density lipoprotein in livers of rabbits treated
with 17-ethinyl estradiol. Proc Natl Acad Sci
U S A. 1986;83:792–796.
28.
Miller Bass K, Newschaffer CJ, Klag MJ, Bush TL.
Plasma lipoprotein levels as predictors of
cardiovascular death in women. Arch Intern
Med. 1993;153:2209–2216.
29.
Gordon DJ, Probstfield JL, Garrison RJ,
Neaton JD, Castelli WP, Knoke JD, Jacobs DR, Bangdiwala S, Tyroler HA.
High-density lipoprotein cholesterol and
cardiovascular disease: four prospective American
studies. Circulation. 1989;79:8–15.
30. Castelli WP. The triglyceride issue: a view from Framingham. Am Heart J. 1986;112:432–437.[Medline] [Order article via Infotrieve]
31. Hamsten A, de Faire U, Walldius G, Dahlén G, Szamosi A, Landou C, Blombäck M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet. 1987;2:3–9.[Medline] [Order article via Infotrieve]
32.
Cortellaro M, Cofrancesco E, Boschetti C, Mussoni
L, Donati MB, Cardillo M, Catalano M, Gabrielli L, Lombardi B, Specchia
G, Tavazzi L, Tremoli E, Pozzoli E, Turri M. Increased fibrin turnover
and high PAI-1 activity as predictors of ischemic events in
atherosclerotic patients: a case-control study. Arterioscler
Thromb. 1993;13:1412–1417.
33.
Juhan-Vague I, Pyke SDM, Alessi MC, Jespersen J,
Haverkate F, Thompson SG. Fibrinolytic factors and the risk of
myocardial infarction or sudden death in patients with angina pectoris.
Circulation. 1996;94:2057–2063.
34. Ridker PM, Hennekens CH, Stampfer MJ, Manson JE, Vaughan DE. Prospective study of endogenous tissue plasminogen activator and the risk of stroke. Lancet. 1994;343:940–943.[Medline] [Order article via Infotrieve]
35. Haverkate F, Thompson SG, Pyke SDM, Gallimore JR, Pepys MB. Production of C-reactive protein and the risk of coronary events in stable and unstable angina. Lancet. 1997;349:462–466.[Medline] [Order article via Infotrieve]
36.
Ridker PM, Cushman M, Stampfer MJ, Tracy RP,
Hennekens CH. Inflammation, aspirin, and the risk of
cardiovascular disease in apparently healthy men.
N Engl J Med. 1997;336:973–979.
37.
Ridker PM, Buring JE, Shih J, Matias M, Hennekens
CH. Prospective study of C-reactive protein and the risk of future
cardiovascular events among apparently healthy women.
Circulation. 1998;98:731–733.
38. Applebaum-Bowden D, McLean P, Steinmetz A., Fontana D, Matthys C, Warnick GR, Cheung M, Albers JJ, Hazzard WR. Lipoprotein, apolipoprotein, and lipolytic enzyme changes following estrogen administration in postmenopausal women. J Lipid Res. 1989;30:1895–1906.[Abstract]
39. Basdevant A, de Lignieres B, Simon P, Blache D, Ponsin G, Guy-Grand B. Hepatic lipase activity during oral and parental 17ß-estradiol replacement therapy: high-density lipoprotein increase may not be antiatherogenic. Fertil Steril. 1991;55:1112–1117.[Medline] [Order article via Infotrieve]
40.
Kon Koh K, Mincemoyer R, Bui MN, Csako G, Pucino
F, Guetta V, Waclawiw M, Cannon RO. Effects of hormone-replacement
therapy on fibrinolysis in postmenopausal women.
N Engl J Med. 1997;336:683–690.
41.
Gebara OCE, Mittleman MA, Sutherland P, Lipinska
I, Matheney T, Xu P, Welty FK, Wilson PWF, Levy D, Muller JE, Tofler
GH. Association between increased estrogen status and increased
fibrinolytic potential in the Framingham Offspring Study.
Circulation. 1995;91:1952–1958.
42. Kroon U, Silfverstolpe G, Tengborn L. The effects of transdermal estradiol and oral conjugated estrogens on haemostatic variables. Thromb Haemost.1994;71:420–423.
43. van Wersch JWJ, Ubachs JMH, van den Ende A, van Enk A. The effect of two regimens of hormone replacement therapy on the haemostatic profile in postmenopausal women. Eur J Clin Chem Clin Biochem. 1994;32:449–453.[Medline] [Order article via Infotrieve]
44. Katz RJ, Hsia J, Walker P, Jacobs H, Kessler C. Effects of hormone replacement therapy on the circadian pattern of atherothrombotic risk factors. Am J Cardiol. 1996;78:876–880.[Medline] [Order article via Infotrieve]
45.
Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne
P, Agher R, Aiach M. Effects of oral and transdermal
estrogen/progesterone regimens on blood coagulation and
fibrinolysis in postmenopausal women: a randomized
controlled trial. Arterioscler Thromb Vasc Biol. 1997;17:3071–3078.
46. Juhan-Vague I, Alessi MC. PAI-1, obesity, insulin resistance, and risk of cardiovascular events. Thromb Haemost. 1997;78:656–660.[Medline] [Order article via Infotrieve]
47.
Orth K, Madison EL, Gething M-J, Sambrook JF,
Herz J. Complexes of tissue-type plasminogen
activator and its serpin inhibitor
plasminogen-activator inhibitor
type 1 are internalized by means of the low density lipoprotein
receptor-related protein/2-macroglobulin
receptor. Proc Natl Acad Sci U S A. 1992;89:7422–7426.
48.
Bu G, Williams S, Strickland DK, Schwartz AL. Low
density lipoprotein receptor-related
protein/2-macroglobulin receptor is an
hepatic receptor for tissue-type plasminogen
activator. Proc Natl Acad Sci U S A. 1992;89:7427–7431.
49. Caine YG, Bauer KA, Barzegar S, ten Cate H, Sacks FM, Walsh BW, Schiff I, Rosenberg RD. Coagulation activation following estrogen administration to postmenopausal women. Thromb Haemost. 1992;68:392–395.[Medline] [Order article via Infotrieve]
50. Walsh BW, Li H, Sacks FM. Effects of postmenopausal hormone replacement with oral and transdermal estrogen on high density lipoprotein metabolism. J Lipid Res. 1994;35:2083–2093.[Abstract]
51. Hack CE, Wolbink G, Schalkwijk C, Speijer H, Hermens WTh, van den Bosch H. A role for secretory phospholipase A2 and C-reactive protein in the removal of injured cells [review]. Immunol Today. 1997;18:111–115.[Medline] [Order article via Infotrieve]
52. Reis SE, Gloth ST, Blumenthal RS, Resar JR, Zacur HA, Gerstenblith G, Brinker JA. Ethinyl estradiol acutely attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. Circulation. 1994;89:552–560.
53.
Collins P, Rosano GMC, Sarrel PM, Ulrich L,
Adamopoulos S, Beale CM, McNeill JG, Poole-Wilson PA.
17ß-Estradiol attenuates acetylcholine-induced coronary
arterial constriction in women but not men with
coronary heart disease. Circulation. 1995;92:24–30.
54.
Lieberman EH, Gerhard MD, Uehata A, Walsh BW,
Selwyn AP, Ganz P, Yeung AC, Creager MA. Estrogen improves
endothelium-dependent, flow-mediated vasodilation in
postmenopausal women. Ann Intern Med. 1994;121:936–941.
55.
Gilligan DM, Badar DM, Panza JA, Quyyumi AA,
Cannon RO III. Acute vascular effects of estrogen in postmenopausal
women. Circulation. 1994;90:786–791.
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