(Circulation. 1999;100:713-716.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Hormone Replacement Therapy and Increased Plasma Concentration of C-Reactive Protein
From the Division of Preventive Medicine (P.M.R., C.H.H., J.E.B., J.E.M.) and Cardiovascular Diseases (P.M.R.), Brigham and Women's Hospital; the Department of Ambulatory Care and Prevention (J.E.B., C.H.H.); and the Childrens' Hospital Medical Center (N.R.), Harvard Medical School, Boston, Mass.
Correspondence to Paul M. Ridker, MD, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail pmridker{at}bics.bwh.harvard.edu
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Abstract |
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Background—It has been hypothesized that postmenopausal hormone replacement therapy (HRT) may increase levels of C-reactive protein (CRP), a marker of inflammation associated with increased risk of future cardiovascular events. However, data evaluating this hypothesis are sparse and limited to older women.
Methods and Results—CRP levels were evaluated in a cross-sectional survey of 493 healthy postmenopausal women; mean age was 51 years. Overall, median CRP levels were 2 times higher among women taking HRT than among women not taking HRT (0.27 versus 0.14 mg/dL; P=0.001). This difference was present in all subgroups evaluated, including those with no history of hypertension, hyperlipidemia, obesity, diabetes, or cigarette consumption or a family history of premature coronary artery disease (all P< 0.01). Compared with nonusers of HRT, median CRP levels were higher among women using estrogen alone (P=0.003) and women using estrogen plus progesterone (P=0.03); however, there was no significant difference in CRP levels between users of different HRT preparations. In multivariate analysis, the relationship between HRT use and CRP remained significant after control for body mass index, age, diabetes, hypertension, hyperlipidemia, alcohol use, and cigarette consumption (P=0.001).
Conclusions—In this cross-sectional survey, CRP levels were increased among apparently healthy postmenopausal women taking HRT. The potential impact of HRT on inflammatory parameters should be investigated in ongoing clinical trials.
Key Words: inflammation • hormones • C-reactive protein • risk factors
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the recent Heart and Estrogen/progestin Replacement Study (HERS), an increase in early cardiovascular events was reported in association with randomized assignment to hormone replacement therapy (HRT) (relative risk during year 1=1.5, 95% CI 1.0 to 2.3).1 Although this observation may represent a chance effect and must be interpreted with caution, data from the HERS trial have been of concern because they raise the possibility that initiation of HRT might be associated with transiently increased thrombotic risk.
A potential explanation of this effect has been proposed by Cushman and colleagues,2 who reported that levels of C-reactive protein (CRP) were elevated among elderly women undergoing HRT. Because elevated levels of CRP are a risk factor for future cardiovascular events,3 4 5 6 7 8 9 this observation raises the possibility that HRT may have proinflammatory effects that might increase plaque vulnerability.
To date, available data suggesting that HRT is associated with elevated CRP levels derive primarily from elderly women enrolled in the Cardiovascular Health Study (CHS) (mean age 73 years).2 In that study, the association of HRT and CRP was most apparent in women with elevated body mass index. Thus, to provide further data regarding this hypothesis, we evaluated whether HRT was associated with increased levels of CRP in a group of otherwise healthy postmenopausal women representative of those deciding whether or not to use HRT.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We measured CRP levels in 493 postmenopausal women participating in the Women's Health Study (WHS), an ongoing trial of aspirin and vitamin E in the primary prevention of cancer and cardiovascular disease among apparently healthy women.10 Baseline blood samples collected in EDTA were obtained before randomization and were stored at -170°C until laboratory analysis. At enrollment, participants provided questionnaire data concerning lifestyle practices and potential risk factors for both cardiovascular disease and cancer. Included in the baseline data collection were questions concerning use of HRT and whether any such use consisted of estrogen alone or of estrogen plus progesterone. All women evaluated had no prior history of cardiovascular disease, cancer, or chronic inflammatory condition. None of the women had been participants in a prior evaluation of inflammation in the WHS.5
Plasma samples obtained at baseline were thawed and assayed for CRP by
use of a high-sensitivity assay with a coefficient of variation below
5% (hs-CRP, Dade Behring). Because distributions of CRP are skewed,
differences in median levels according to HRT status were tested with
the rank sum test. We used the Student t test and the
2 statistic to compare differences in baseline
cardiovascular risk factors among study women according
to HRT status. Multivariate analysis was used
to evaluate the relationship between HRT use and log-normalized levels
of CRP after adjustment for any baseline differences between study
groups.
For comparison, we also evaluated CRP levels using the high-sensitivity Dade Behring assay in a group of 291 middle-aged men participating in the Physicians' Health Study (PHS).11 Like participants in the WHS, men in the PHS were free of cardiovascular disease, cancer, or chronic inflammatory condition at the time of blood sampling.
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Results |
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Table 1
shows baseline
characteristics of the WHS participants according to HRT status. Women
undergoing HRT were older (52.4 versus 49.6 years), less likely to have
diabetes (4.9% versus 13.2%), and had a lower mean body mass index
(24.1 versus 25.2 kg/m2) than women not using HRT
(all P< 0.05). There were no significant differences
between groups in terms of smoking status,
hyperlipidemia, hypertension, exercise frequency,
alcohol use, or a family history of coronary artery disease
(CAD).
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Overall, median CRP levels were 2 times higher among women using HRT
than among women not using HRT (0.27 versus 0.14 mg/dL;
P=0.001). This difference was present in all low-risk
subgroups evaluated, including those with no history of hypertension,
hyperlipidemia, family history of CAD, cigarette
consumption, diabetes, or obesity (all P< 0.01) (Table 2).
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As shown in the Figure, the distribution
of CRP was higher for women using HRT than for those not using HRT,
both for the total cohort (P=0.001) and for those using
estrogen alone (P=0.003) or estrogen plus progesterone
(P=0.03). By contrast, there was no difference in the
distribution of CRP in comparisons of women not using HRT and men
participating in the PHS. Furthermore, there was no difference in CRP
distributions between women taking estrogen alone compared with
estrogen plus progesterone.
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To evaluate further the potential impact of HRT on CRP distributions,
we computed cutpoints for each increasing quartile of CRP for each of
the major study groups. Quartile cutpoints for men and women not using
HRT were similar; however, for women using HRT, the cutpoints
determining each successive quartile of CRP were higher, particularly
at the upper end of the distribution (Table 3).
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In multivariate analysis, the relationship between HRT and log-normalized levels of CRP among WHS participants remained significant after control for body mass index (kg/m2), age (years), diabetes, hypertension, hyperlipidemia, alcohol use, and smoking. This was true for the total study group (P=0.001) and for those taking estrogen alone (P=0.001), as well as for those taking combined estrogen plus progesterone (P=0.002).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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These cross-sectional data indicate that plasma concentrations of CRP are significantly higher among healthy postmenopausal women using HRT than among similar women not using HRT. This association was present in all subgroups of women evaluated, including those with no history of cigarette consumption or obesity, 2 factors known to influence CRP levels. Furthermore, although women using HRT had significantly higher levels of CRP than women not using HRT, the distribution of CRP in this latter group was not different from that observed among apparently healthy middle-aged men. We found no difference in CRP levels between women using estrogen alone and women using estrogen plus progesterone.
The current data corroborate findings from the CHS that suggested that CRP levels were elevated among elderly women using HRT compared with nonusers.2 That study evaluated older women who had been undergoing HRT for long periods of time. Thus, the current data extend these observations to a group of women representative of those who have more recently started HRT.
The current data and those from the CHS are cross-sectional and cannot address causality. Nonetheless, evidence supporting an association between HRT and CRP is accumulating. For example, in randomized data deriving from the Postmenopausal Estrogen/Progestin Intervention (PEPI) study, assignment to HRT compared with placebo was associated with increased levels of CRP, which were maintained on long-term follow-up.12 Similarly, in a short-term study of postmenopausal women initiating HRT, CRP levels were found to increase among those assigned to micronized estradiol.13 Neither of these interventional studies found a concomitant increase in plasma fibrinogen level associated with HRT use. Thus, although these latter studies suggest that any effect of HRT on CRP is unlikely to reflect a generalized acute-phase response or simple hepatic induction, this possibility cannot be excluded and requires direct experimental testing.
In the present study, estrogen alone and estrogen plus progesterone were associated with increased levels of CRP. These data thus suggest that the addition of progesterone does not have a major influence on CRP levels, at least when given in combination with estrogen.
The clinical impact of these accumulating data is uncertain but may have implications for women initiating HRT. Specifically, because elevated levels of CRP are associated with increased cardiovascular risk among otherwise healthy women,5 it has been hypothesized that the initiation of HRT increases CRP levels and results in heightened plaque instability and a propensity to thrombosis.2 12 In a previous report from the WHS in which a different high-sensitivity assay for CRP was used, those women with CRP levels in the highest quartile had a 7-fold increase in risk of subsequent myocardial infarction and stroke compared with women with CRP levels in the lowest quartile (95% CI 2.7 to 19.9; P=0.0001).5 However, the number of clinical events accrued in the WHS to date limits the power to detect any evidence of interaction between HRT, CRP, and incident cardiovascular events. On the other hand, in the HERS trial, a potential increase in early cardiovascular events was reported among women initiating HRT.1 Although this observation may simply reflect the play of chance and must be interpreted with caution, accumulating data concerning CRP raise the possibility that HRT may have proinflammatory effects.
In summary, in this cross-sectional survey, CRP levels were significantly increased among apparently healthy postmenopausal women taking HRT, regardless of whether the HRT formulation consisted of estrogen alone or estrogen plus progesterone. Whether these observations have clinical relevance requires further investigation. We therefore believe the potential impact of HRT on inflammatory parameters should be directly investigated in ongoing clinical trials, particularly those that can provide longitudinal data and differentiate between transdermal and oral estrogen preparations. In this regard, the successful completion of ongoing large-scale randomized trials of HRT, such as the Women's Health Initiative, is crucial.
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Acknowledgments |
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This study was supported by grants from the National Heart, Lung, and Blood Institute (HL 58755), and by an Established Investigator Award from the American Heart Association (Dr Ridker).
Received February 22, 1999; revision received May 25, 1999; accepted June 2, 1999.
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References |
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A. Imhof, M. Frohlich, H. Loewel, N. Helbecque, M. Woodward, P. Amouyel, G. D.O. Lowe, and W. Koenig Distributions of C-reactive Protein Measured by High-Sensitivity Assays in Apparently Healthy Men and Women from Different Populations in Europe Clin. Chem., April 1, 2003; 49(4): 669 - 672. [Full Text] [PDF]
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 C. R. Isasi, R. J. Deckelbaum, R. P. Tracy, T. J. Starc, L. Berglund, and S. Shea Physical Fitness and C-Reactive Protein Level in Children and Young Adults: The Columbia University BioMarkers Study Pediatrics, February 1, 2003; 111(2): 332 - 338. [Abstract] [Full Text] [PDF]
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P. M Ridker Clinical Application of C-Reactive Protein for Cardiovascular Disease Detection and Prevention Circulation, January 28, 2003; 107(3): 363 - 369. [Full Text] [PDF]
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T. A. Pearson, G. A. Mensah, R. W. Alexander, J. L. Anderson, R. O. Cannon III, M. Criqui, Y. Y. Fadl, S. P. Fortmann, Y. Hong, G. L. Myers, et al. Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: A Statement for Healthcare Professionals From the Centers for Disease Control and Prevention and the American Heart Association Circulation, January 28, 2003; 107(3): 499 - 511. [Full Text] [PDF]
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M. A. Albert, R. J. Glynn, and P. M Ridker Alcohol Consumption and Plasma Concentration of C-Reactive Protein Circulation, January 28, 2003; 107(3): 443 - 447. [Abstract] [Full Text] [PDF]
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D. M. Herrington Hormone Replacement Therapy and Heart Disease: Replacing Dogma With Data Circulation, January 7, 2003; 107(1): 2 - 4. [Full Text] [PDF]
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L. E. Rabbani, N. A. Seminario, R. R. Sciacca, H. J. Chen, and E.-G. V. Giardina Oral conjugated equine estrogen increases plasma von Willebrand factor in postmenopausal women J. Am. Coll. Cardiol., December 4, 2002; 40(11): 1991 - 1999. [Abstract] [Full Text] [PDF]
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 V. Schachinger and A. M. Zeiher Atherogenesis--recent insights into basic mechanisms and their clinical impact Nephrol. Dial. Transplant., December 1, 2002; 17(12): 2055 - 2064. [Full Text] [PDF]
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 P. M. Ridker, N. Rifai, L. Rose, J. E. Buring, and N. R. Cook Comparison of C-Reactive Protein and Low-Density Lipoprotein Cholesterol Levels in the Prediction of First Cardiovascular Events N. Engl. J. Med., November 14, 2002; 347(20): 1557 - 1565. [Abstract] [Full Text] [PDF]
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V. Stangl, G. Baumann, and K. Stangl Coronary atherogenic risk factors in women Eur. Heart J., November 2, 2002; 23(22): 1738 - 1752. [Full Text] [PDF]
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P. Garnero, C. Jamin, C.-L. Benhamou, C. Pelissier, and C. Roux Effects of tibolone and combined 17{beta}-estradiol and norethisterone acetate on serum C-reactive protein in healthy post-menopausal women: a randomized trial Hum. Reprod., October 1, 2002; 17(10): 2748 - 2753. [Abstract] [Full Text] [PDF]
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T. J. Wang, B.-H. Nam, P. W.F. Wilson, P. A. Wolf, D. Levy, J. F. Polak, R. B. D'Agostino, and C. J. O'Donnell Association of C-Reactive Protein With Carotid Atherosclerosis in Men and Women: The Framingham Heart Study Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1662 - 1667. [Abstract] [Full Text] [PDF]
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E. A. Bermudez, N. Rifai, J. Buring, J. E. Manson, and P. M. Ridker Interrelationships Among Circulating Interleukin-6, C-Reactive Protein, and Traditional Cardiovascular Risk Factors in Women Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1668 - 1673. [Abstract] [Full Text] [PDF]
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K. K. Koh, J. Y. Ahn, D. K. Jin, B.-K. Yoon, H. S. Kim, D. S. Kim, M.-S. Shin, J. W. Son, I. S. Choi, and E. K. Shin Effects of Continuous Combined Hormone Replacement Therapy on Inflammation in Hypertensive and/or Overweight Postmenopausal Women Arterioscler Thromb Vasc Biol, September 1, 2002; 22(9): 1459 - 1464. [Abstract] [Full Text] [PDF]
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K. K. Koh Effects of estrogen on the vascular wall: vasomotor function and inflammation Cardiovasc Res, September 1, 2002; 55(4): 714 - 726. [Full Text] [PDF]
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A. D. Pradhan, J. E. Manson, J. E. Rossouw, D. S. Siscovick, C. P. Mouton, N. Rifai, R. B. Wallace, R. D. Jackson, M. B. Pettinger, and P. M Ridker Inflammatory Biomarkers, Hormone Replacement Therapy, and Incident Coronary Heart Disease: Prospective Analysis From the Women's Health Initiative Observational Study JAMA, August 28, 2002; 288(8): 980 - 987. [Abstract] [Full Text] [PDF]
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M. K.C. Ng, P. Y. Liu, A. J. Williams, S. Nakhla, L. P. Ly, D. J. Handelsman, and D. S. Celermajer Prospective Study of Effect of Androgens on Serum Inflammatory Markers in Men Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): 1136 - 1141. [Abstract] [Full Text] [PDF]
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D. M. Herrington, E. Vittinghoff, F. Lin, J. Fong, F. Harris, D. Hunninghake, V. Bittner, H. G. Schrott, R. S. Blumenthal, R. Levy, et al. Statin Therapy, Cardiovascular Events, and Total Mortality in the Heart and Estrogen/Progestin Replacement Study (HERS) Circulation, June 25, 2002; 105(25): 2962 - 2967. [Abstract] [Full Text] [PDF]
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 J. B. Braunstein, D. W. Kershner, P. Bray, G. Gerstenblith, S. P. Schulman, W. S. Post, and R. S. Blumenthal Interaction of Hemostatic Genetics With Hormone Therapy : New Insights To Explain Arterial Thrombosis in Postmenopausal Women Chest, March 1, 2002; 121(3): 906 - 920. [Abstract] [Full Text] [PDF]
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S. S. Levinson and R. J. Elin What Is C-Reactive Protein Telling Us About Coronary Artery Disease? Arch Intern Med, February 25, 2002; 162(4): 389 - 392. [Full Text] [PDF]
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R. S. Eidelman, G. A. Lamas, C. H. Hennekens, and P. M. Ridker Aspirin, Postmenopausal Hormones, and C-Reactive Protein Arch Intern Med, February 25, 2002; 162(4): 480 - 481. [Full Text] [PDF]
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T. S Mikkola and T. B Clarkson Estrogen replacement therapy, atherosclerosis, and vascular function Cardiovasc Res, February 15, 2002; 53(3): 605 - 619. [Abstract] [Full Text] [PDF]
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H. N. Hodis, W. J. Mack, R. A. Lobo, D. Shoupe, A. Sevanian, P. R. Mahrer, R. H. Selzer, C.-r. Liu, C.-h. Liu, S. P. Azen, et al. Estrogen in the Prevention of Atherosclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial Ann Intern Med, December 4, 2001; 135(11): 939 - 953. [Abstract] [Full Text] [PDF]
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D. M. Herrington and K. P. Klein Genome and Hormones: Gender Differences in Physiology: Invited Review: Pharmacogenetics of estrogen replacement therapy J Appl Physiol, December 1, 2001; 91(6): 2776 - 2784. [Abstract] [Full Text] [PDF]
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D.M. Herrington Effects of oestrogen on cardiovascular events in postmenopausal women Eur. Heart J. Suppl., October 1, 2001; 3(suppl_M): M7 - M11. [Abstract] [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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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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M. A. Albert, E. Danielson, N. Rifai, P. M Ridker, and for the PRINCE Investigators Effect of Statin Therapy on C-Reactive Protein Levels: The Pravastatin Inflammation/CRP Evaluation (PRINCE): A Randomized Trial and Cohort Study JAMA, July 4, 2001; 286(1): 64 - 70. [Abstract] [Full Text] [PDF]
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K. P. Alexander, L. K. Newby, A. S. Hellkamp, R. A. Harrington, E. D. Peterson, S. Kopecky, A. Langer, P. O'Gara, C. M. O'Connor, R. N. Daly, et al. Initiation of hormone replacement therapy after acute myocardial infarction is associated with more cardiac events during follow-up J. Am. Coll. Cardiol., July 1, 2001; 38(1): 1 - 7. [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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L. K. Heilbronn, M. Noakes, and P. M. Clifton Energy Restriction and Weight Loss on Very-Low-Fat Diets Reduce C-Reactive Protein Concentrations in Obese, Healthy Women Arterioscler Thromb Vasc Biol, June 1, 2001; 21(6): 968 - 970. [Abstract] [Full Text] [PDF]
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E. Barinas-Mitchell, M. Cushman, E. N. Meilahn, R. P. Tracy, and L. H. Kuller Serum Levels of C-reactive Protein Are Associated with Obesity, Weight Gain, and Hormone Replacement Therapy in Healthy Postmenopausal Women Am. J. Epidemiol., June 1, 2001; 153(11): 1094 - 1101. [Abstract] [Full Text] [PDF]
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A. M. Sharma, V. Homuth, and F. C. Luft Hormone replacement therapy and blood pressure in normotensive and hypertensive women Nephrol. Dial. Transplant., May 1, 2001; 16(5): 888 - 890. [Full Text] [PDF]
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P. M. Ridker High-Sensitivity C-Reactive Protein : Potential Adjunct for Global Risk Assessment in the Primary Prevention of Cardiovascular Disease Circulation, April 3, 2001; 103(13): 1813 - 1818. [Abstract] [Full Text] [PDF]
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N. Rifai and P. M. Ridker High-Sensitivity C-Reactive Protein: A Novel and Promising Marker of Coronary Heart Disease Clin. Chem., March 1, 2001; 47(3): 403 - 411. [Abstract] [Full Text] [PDF]
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P. Angerer, S. Stork, W. Kothny, P. Schmitt, and C. von Schacky Effect of Oral Postmenopausal Hormone Replacement on Progression of Atherosclerosis : A Randomized, Controlled Trial Arterioscler Thromb Vasc Biol, February 1, 2001; 21(2): 262 - 268. [Abstract] [Full Text] [PDF]
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M. Visser, L. M. Bouter, G. M. McQuillan, M. H. Wener, and T. B. Harris Low-Grade Systemic Inflammation in Overweight Children Pediatrics, January 1, 2001; 107(1): 13e - 13. [Abstract] [Full Text]
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D. Zanger, B. K. Yang, J. Ardans, M. A. Waclawiw, G. Csako, L. M. Wahl, and R. O. Cannon III Divergent effects of hormone therapy on serum markers of inflammation in postmenopausal women with coronary artery disease on appropriate medical management J. Am. Coll. Cardiol., November 15, 2000; 36(6): 1797 - 1802. [Abstract] [Full Text] [PDF]
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X. Garcia-Moll, E. Zouridakis, D. Cole, and J.C. Kaski C-reactive protein in patients with chronic stable angina: differences in baseline serum concentration between women and men Eur. Heart J., October 1, 2000; 21(19): 1598 - 1606. [Abstract] [PDF]
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N. Sattar, N. G. Forouhi, R. A. Wild, M. Cushman, P. A. Sakkinen, R. P. Tracy, C. Legault, E. Barrett-Connor, M. L. Stefanick, C. M. Kessler, et al. C-Reactive Protein and Hormone Replacement Therapy Response Circulation, September 26, 2000; 102 (13): e96 - e97. [Full Text] [PDF]
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D. M. Herrington, D. M. Reboussin, K. B. Brosnihan, P. C. Sharp, S. A. Shumaker, T. E. Snyder, C. D. Furberg, G. J. Kowalchuk, T. D. Stuckey, W. J. Rogers, et al. Effects of Estrogen Replacement on the Progression of Coronary-Artery Atherosclerosis N. Engl. J. Med., August 24, 2000; 343(8): 522 - 529. [Abstract] [Full Text] [PDF]
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R. F. Redberg, N. Rifai, L. Gee, and P. M. Ridker Lack of association of C-reactive protein and coronary calcium by electron beam computed tomography in postmenopausal women: implications for coronary artery disease screening J. Am. Coll. Cardiol., July 1, 2000; 36(1): 39 - 43. [Abstract] [Full Text] [PDF]
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 Postmenopausal estrogen replacement therapy and increased rates of cholecystectomy and appendectomy Can. Med. Assoc. J., May 1, 2000; 162(10): 1421 - 1424.
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W. L. Roberts, R. Sedrick, L. Moulton, A. Spencer, and N. Rifai Evaluation of Four Automated High-Sensitivity C-Reactive Protein Methods: Implications for Clinical and Epidemiological Applications Clin. Chem., April 1, 2000; 46(4): 461 - 468. [Abstract] [Full Text] [PDF]
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 Estrogen May Increase Vascular Inflammation Journal Watch Women's Health, October 1, 1999; 1999(1001): 13 - 13. [Full Text]
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 Does Hormone Replacement Therapy Increase Vascular Inflammation? Journal Watch (General), September 3, 1999; 1999(903): 1 - 1. [Full Text]
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A. Wakatsuki, Y. Okatani, N. Ikenoue, and T. Fukaya Effect of Medroxyprogesterone Acetate on Vascular Inflammatory Markers in Postmenopausal Women Receiving Estrogen Circulation, March 26, 2002; 105(12): 1436 - 1439. [Abstract] [Full Text] [PDF]
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D. M. Herrington, T. D. Howard, K. B. Brosnihan, D. P. McDonnell, X. Li, G. A. Hawkins, D. M. Reboussin, J. Xu, S. L. Zheng, D. A. Meyers, et al. Common Estrogen Receptor Polymorphism Augments Effects of Hormone Replacement Therapy on E-Selectin but Not C-Reactive Protein Circulation, April 23, 2002; 105(16): 1879 - 1882. [Abstract] [Full Text] [PDF]
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