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Original Studies |
Brigham and Women’s Hospital (B.W.W.), Boston, Massachusetts 02115; Lilly Research Laboratories (S.P., R.A.D., D.A.C., P.W.A.), Indianapolis, Indiana 46285; Oklahoma University Health Sciences Center (R.A.W.), Oklahoma City, Oklahoma 73190; and University of Vermont (R.P.T.), Burlington, Vermont 05405
Address all correspondence and requests for reprints to: Brian W. Walsh, M.D., Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. E-mail: bwwalsh{at}bics.bwh.harvard.edu
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Abstract |
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We conclude that HRT and raloxifene lower serum homocysteine levels to a comparable extent in postmenopausal women. Whereas cardiovascular risk predicted by C-reactive protein in healthy postmenopausal women is not influenced by raloxifene, the relationship between elevated C-reactive protein levels with HRT and cardiovascular disease events requires further study.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As the commonly employed markers of cardiovascular risk failed to predict the initial increased incidence of cardiovascular disease events in women receiving HRT, we evaluated the effect of hormone treatment and raloxifene, a selective estrogen receptor modulator, on newer markers for cardiovascular risk: C-reactive protein and homocysteine. Elevated levels of C-reactive protein, a circulating marker of inflammation, predict future myocardial infarction in patients with unstable angina (3) and the risk of a first myocardial infarction, ischemic stroke, and peripheral arterial disease in healthy men and women (4, 5, 6). Moderate elevations in circulating homocysteine levels also predict a significantly greater risk of coronary artery disease (7). Raloxifene has estrogen agonist effects on some cardiovascular risk factors (8). However, the effects of HRT and raloxifene on C-reactive protein and homocysteine have not been compared directly in healthy postmenopausal women. Here we report the effects of continuous combined HRT and raloxifene on circulating levels of C-reactive protein and homocysteine in a large randomized, placebo-controlled trial with healthy postmenopausal women.
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Materials and Methods |
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Details of the study design and results of the primary efficacy variables of this study (serum lipids and coagulation markers) were previously described (8). In brief, postmenopausal women with an intact uterus were eligible if they were between 45–72 yr of age and had amenorrhea for at least 12 months. Women who had undergone hysterectomy also were eligible if they were between 50–72 yr of age. Postmenopausal status was confirmed by measurement of serum FSH and estradiol levels. Body mass index was required to be between 18–31 kg/m2.
This prospective, double blind, placebo-controlled, randomized, parallel study was conducted at eight sites in the United States. The study was approved by the ethical review board at each site, and all women gave written informed consent. Three hundred and ninety eligible subjects were randomly assigned to one of four therapy groups: 1) 60 mg/day raloxifene HCl (Eli Lilly & Co., Indianapolis, IN), 2) 120 mg/day raloxifene HCl, 3) HRT [0.625 mg conjugated equine estrogen (Wyeth-Ayerst Laboratories, Inc., Philadelphia, PA) and 2.5 mg medroxyprogesterone acetate (Wyeth-Ayerst Laboratories, Inc.) given in a continuous combined fashion], or 4) placebo. Randomization was performed using a computer-generated random number table (Clinpro/LBL, Clinical Systems, Inc., Garden City, NY). All treatments were administered for 6 months, taken as two tablets and two capsules of blinded study medication each morning. Dietary intake of folate and vitamin B6 was determined by a self-administered questionnaire at baseline (9). Subjects were advised to not alter their diet during the trial.
Measurements
Sample collection and storage. Phlebotomy was performed on fasted (at least 12 h) subjects during the week before randomization and during the 24th week of treatment. Blood was centrifuged within 45 min of collection at 3000 x g for 10 min at 4 C. Serum samples were frozen and shipped to a central laboratory (Covance, Indianapolis, IN) and were stored at -70 C until assayed. Specimens were discarded if they were received thawed. In all treatment groups, greater than 90% of the samples were analyzed for homocysteine or C-reactive protein.
Laboratory analysis. C-Reactive protein was measured in serum using an enzyme-linked immunosorbent assay based upon purified protein and polyclonal anti-C-reactive protein antibodies (Calbiochem, San Diego, CA) (10). This assay was standardized against the WHO First International Reference Standard. Sensitivity was 0.08 µg/mL, and intra- and interassay coefficients of variation were 3.0% and 6.0%, respectively. The reference interval was 0.21–5.06 µg/mL.
Homocysteine was measured in serum using a commercial assay (Chromosystems, Munich, Germany) after reduction and protein precipitation. Homocysteine was determined by high pressure liquid chromatography with fluorescence detection (11). The assay sensitivity was 1 µmol/L, the intraassay coefficient of variation was 4.4%, and the reference interval was 5.5–17 µmol/L.
Statistical methods
The primary analysis was change and percent change from baseline to end point (6 months) for C-reactive protein and homocysteine using a two-way ANOVA with treatment and investigators as fixed effects in the model. No treatment by investigator interaction was found in any of the variables for each of the eight investigators. Analyses were performed according to the intent to treat principle (12), using data from all randomly assigned subjects who had both a baseline and an end point result.
As the distribution in change and percent change in homocysteine and C-reactive protein were skewed, median changes with SEs of medians (calculated using the d-delete jackknife method) were used as indicators of central tendency (13). The residuals of these variables were not normally distributed; therefore, the ANOVA was performed on ranked-transformed data. Subgroup analyses were performed to determine whether the baseline to end point changes in serum homocysteine levels observed were influenced by age, body mass index, smoking status, alcohol intake, dietary intake of folate or vitamin B6, or baseline levels of low density lipoprotein cholesterol or homocysteine.
As an acute phase reactant in serum (14), the level of C-reactive protein is highly sensitive to the presence of acute infection and other inflammatory conditions or stimuli. Therefore, in addition to the overall analysis described above, women who reported infections requiring antibiotic therapy within 2 months of a visit or surgery requiring hospitalization were identified, and the data were reanalyzed after excluding their results. This excluded 33 values: 7 in the placebo group, 6 in the 60 mg/day raloxifene group, 10 in the 120 mg/day raloxifene group, and 10 in the HRT group. In addition, women with baseline C-reactive protein levels greater than 10 mg/L, considered the threshold level for the existence of a marked, acute inflammatory condition (10), were identified, and the data were reanalyzed after excluding these women from the analysis. This excluded 13 values: 5 in the placebo group, 3 in the 60 mg/day raloxifene group, 3 in the 120 mg/day raloxifene group, and 2 in the HRT group. A final analysis was performed after excluding women with either infection/surgery or values of C-reactive protein above 10 mg/L at baseline. This excluded 44 values: 11 in the placebo group, 8 in the 60 mg/day raloxifene group, 13 in the 120 mg/day raloxifene group, and 12 in the HRT group.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Serum lipids, fibrinogen, homocysteine, and the dietary intake of
folate and vitamin B6 were not significantly different among the
treatment groups at baseline (Table 1
).
There was a significant difference in the serum C-reactive protein
levels among groups at baseline, most likely due to the lower values in
the women assigned to HRT (Table 1). To adjust for this difference, the
baseline C-reactive protein level was included as a covariate in all
subsequent analyses.
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). In contrast, HRT
significantly increased C-reactive protein levels compared with
baseline, placebo, and both raloxifene groups (all P <
0.001) after 6 months (Fig. 1). At 6 months of therapy, absolute
changes in serum C-reactive protein were (median ±
SE, mg/L): placebo, 0.0 ± 0.02; 60 mg/day
raloxifene, -0.03 ± 0.06; 120 mg/day raloxifene, -0.04 ±
0.02; and HRT, 0.79 ± 0.11. There was no significant correlation
between the effect of HRT to increase the C-reactive protein level
and the serum concentration of C-reactive protein at baseline
(r = 0.18; P = 0.141). HRT increased C-reactive
protein levels to a comparable extent in women who did and did not
report vaginal bleeding (100 ± 51% and 83 ± 12%,
respectively; P = 0.148 for subgroup comparison) and in
hysterectomized and nonhysterectomized women (77 ± 23% and
86 ± 10%, respectively; P = 0.730 for subgroup
comparison). Exclusion of women with infection receiving antibiotic
treatment within 2 months of either the baseline or end point visit,
women undergoing surgery requiring hospitalization, and/or women with a
C-reactive protein level at baseline above 10 mg/L also did not alter
the findings.
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). The effects of both doses of
raloxifene and HRT to lower homocysteine were comparable and not
significantly different (P > 0.2). At 6 months of
therapy, the absolute changes in serum homocysteine levels were
(median ± SE; micromoles per L): placebo,
0.0 ± 0.2; 60 mg/day raloxifene, -1.0 ± 0.2; 120 mg/day
raloxifene, -0.6 ± 0.2; and HRT, -0.7 ± 0.4. The effects
of raloxifene and HRT were not influenced significantly by any of the
tested baseline characteristics.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Observational studies report increased levels of C-reactive protein associated with administration of unopposed estrogen (15) and oral contraceptives (16). These data suggest that the increase in C-reactive protein observed in women assigned to HRT in this study was caused by the estrogen component of the regimen rather than the progestin. Moreover, these data suggest that, in contrast to some of estrogen’s effects (17, 18), medroxyprogesterone acetate does not inhibit estrogen’s effect to increase C-reactive protein levels in postmenopausal women.
The potential clinical importance of the HRT-mediated increase in C-reactive protein levels requires further investigation. In a prospective study, healthy postmenopausal women with moderate increases in C-reactive protein levels within the range of 1.5–7.3 mg/L had a graded 2- to 5-fold increase in the risk of future cardiovascular events (4). Thus, moderate increases in C-reactive protein levels even within the range generally considered normal are associated with significant increases in the risk of future cardiovascular events. Among postmenopausal women with existing coronary artery disease, initiation of HRT resulted in an increase in the incidence of coronary heart disease events during the first year of the HERS trial (2), and in a retrospective study was associated with a higher incidence of hospitalization for unstable angina during the first year after an initial myocardial infarction (19). However, the effect of HRT on C-reactive protein levels in postmenopausal women with coronary artery disease has not been reported. Further clinical studies are required to determine whether increased C-reactive protein levels induced by HRT influences cardiovascular risk in postmenopausal women with or without existing coronary artery disease.
This study confirms previous reports that HRT lowers serum homocysteine levels in postmenopausal women by 12–14% (20, 21). The homocysteine-lowering effect of HRT seen in the current study was only 7% (21), which could be due to the use of medroxyprogesterone acetate in the HRT preparation. A previous smaller study in 52 hysterectomized women demonstrated that 60 and 150 mg/day raloxifene produced a nonsignificant 4% and a significant 14% decrease, respectively, in serum homocysteine levels after 24 months (22). The present study shows that both doses of raloxifene lower homocysteine levels in postmenopausal women regardless of hysterectomy status. The effect of raloxifene to lower homocysteine levels by 6–8% is comparable to the 7% reduction observed with tamoxifen in a recently reported, randomized, placebo-controlled trial in healthy postmenopausal women (23). The impact of this degree of homocysteine lowering on the incidence of cardiovascular disease events is unknown. The risk of myocardial infarction and death from ischemic heart disease in men with no history of cardiovascular disease was estimated to increase by 84% and 41%, respectively, for each 5 µmol/L increase in the serum homocysteine level (24). Accordingly, independent of other factors and if sustained over time, the median 0.6–1.0 µmol/L decrease in homocysteine levels observed in the present study might be expected to lower the incidence of coronary heart disease by as much as 6–17%.
A number of pathophysiological mechanisms by which C-reactive protein and homocysteine may increase the risk of cardiovascular disease have been proposed. C-Reactive protein activates the complement cascade (25), the components of which have been implicated in early stages of atherogenesis (26), and has been colocalized with complement components in atherosclerotic lesions of human coronary arteries (27). Furthermore, C-reactive protein stimulates the release of inflammatory cytokines from human macrophages (28) and may promote coagulation by stimulating the release of tissue factor from the endothelium (29). Increased levels of circulating homocysteine causes endothelial dysfunction (30, 31) and increases the level of circulating adhesion molecules and coagulation markers (31) in humans, potentially via a prooxidant effect on the vascular endothelium. All of these mechanisms could potentially be involved in the role of C-reactive protein and homocysteine as risk factors for coronary artery disease.
In conclusion, continuous combined HRT significantly increases C-reactive protein levels, whereas raloxifene has no significant effect on C-reactive protein in healthy postmenopausal women. HRT and raloxifene significantly decrease serum homocysteine levels by a comparable extent in healthy postmenopausal women. It remains to be determined whether these effects influence cardiovascular outcomes in postmenopausal women. A controlled, clinical trial to determine the effect of raloxifene therapy on the incidence of cardiovascular events in postmenopausal women is ongoing.
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Acknowledgments |
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Footnotes |
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Received July 13, 1999.
Revised September 30, 1999.
Accepted October 5, 1999.
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References |
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IL-1ß, and TNF-, and expression of mRNA by human alveolar
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E. Barrett-Connor, D. Grady, A. Sashegyi, P. W. Anderson, D. A. Cox, K. Hoszowski, P. Rautaharju, K. D. Harper, and for the MORE Investigators Raloxifene and Cardiovascular Events in Osteoporotic Postmenopausal Women: Four-Year Results From the MORE (Multiple Outcomes of Raloxifene Evaluation) Randomized Trial JAMA, February 20, 2002; 287(7): 847 - 857. [Abstract] [Full Text] [PDF]
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 R. Marcus, M. Wong, H. Heath III, and J. L. Stock Antiresorptive Treatment of Postmenopausal Osteoporosis: Comparison of Study Designs and Outcomes in Large Clinical Trials with Fracture as an Endpoint Endocr. Rev., February 1, 2002; 23(1): 16 - 37. [Abstract] [Full Text] [PDF]
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B. Andersson, G. Johannsson, G. Holm, B.-A. Bengtsson, A. Sashegyi, I. Pavo, T. Mason, and P. W. Anderson Raloxifene Does Not Affect Insulin Sensitivity or Glycemic Control in Postmenopausal Women with Type 2 Diabetes Mellitus: A Randomized Clinical Trial J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 122 - 128. [Abstract] [Full Text] [PDF]
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 V. C. Jordan, S. Gapstur, and M. Morrow Selective Estrogen Receptor Modulation and Reduction in Risk of Breast Cancer, Osteoporosis, and Coronary Heart Disease J Natl Cancer Inst, October 3, 2001; 93(19): 1449 - 1457. [Abstract] [Full Text] [PDF]
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 S. H.-J. Hsu, W.-C. Cheng, M.-W. Jang, and K.-S. Tsai Effects of Long-Term Use of Raloxifene, a Selective Estrogen Receptor Modulator, on Thyroid Function Test Profiles Clin. Chem., October 1, 2001; 47(10): 1865 - 1867. [Full Text] [PDF]
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D. M. Herrington, K. B. Brosnihan, B. E. Pusser, E. W. Seely, P. M. Ridker, N. Rifai, and D. B. MacLean Differential Effects of E and Droloxifene on C-Reactive Protein and Other Markers of Inflammation in Healthy Postmenopausal Women J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4216 - 4222. [Abstract] [Full Text] [PDF]
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A. Saitta, D. Altavilla, D. Cucinotta, N. Morabito, N. Frisina, F. Corrado, R. D'Anna, A. Lasco, G. Squadrito, A. Gaudio, et al. Randomized, Double-Blind, Placebo-Controlled Study on Effects of Raloxifene and Hormone Replacement Therapy on Plasma NO Concentrations, Endothelin-1 Levels, and Endothelium-Dependent Vasodilation in Postmenopausal Women Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1512 - 1519. [Abstract] [Full Text] [PDF]
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M. D. P. Luyer, S. Khosla, W. G. Owen, and V. M. Miller Prospective Randomized Study of Effects of Unopposed Estrogen Replacement Therapy on Markers of Coagulation and Inflammation in Postmenopausal Women J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3629 - 3634. [Abstract] [Full Text] [PDF]
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 S. Yamada, T. Gotoh, Y. Nakashima, K. Kayaba, S. Ishikawa, N. Nago, Y. Nakamura, Y. Itoh, and E. Kajii Distribution of Serum C-Reactive Protein and Its Association with Atherosclerotic Risk Factors in a Japanese Population : Jichi Medical School Cohort Study Am. J. Epidemiol., June 15, 2001; 153(12): 1183 - 1190. [Abstract] [Full Text] [PDF]
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R. P. Tracy Is Visceral Adiposity the "Enemy Within"? Arterioscler Thromb Vasc Biol, June 1, 2001; 21(6): 881 - 883. [Full Text] [PDF]
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 N. N. Chan, T. M.M. Tan, and S. J. Hurel Hyperhomocysteinemia and Macroangiopathy in Type 2 Diabetes Diabetes Care, June 1, 2001; 24(6): 1123 - 1124. [Full Text]
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M. Buysschaert and M.P. Hermans Response to Chan et al.: Hyperhomocysteinemia and Macroangiopathy in Type 2 Diabetes Diabetes Care, June 1, 2001; 24(6): 1124 - 1125. [Full Text]
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G. Sesmilo, B. M. K. Biller, J. Llevadot, D. Hayden, G. Hanson, N. Rifai, and A. Klibanski Effects of Growth Hormone (GH) Administration on Homocyst(e)ine Levels in Men with GH Deficiency: A Randomized Controlled Trial J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1518 - 1524. [Abstract] [Full Text]
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M. Cushman, J. P. Costantino, R. P. Tracy, K. Song, L. Buckley, J. D. Roberts, and D. N. Krag Tamoxifen and Cardiac Risk Factors in Healthy Women : Suggestion of an Anti-inflammatory Effect Arterioscler Thromb Vasc Biol, February 1, 2001; 21(2): 255 - 261. [Abstract] [Full Text] [PDF]
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P < 0.001 compared with placebo; 
,
P < 0.001 compared with raloxifene.