Differential effects of oral and transdermal postmenopausal estrogen replacement therapies on C-reactive protein

Summary

C-reactive protein (CRP) is one of the main independent predictors of cardiovascular events. Oral post-menopausal estro-gen replacement therapy (ERT) increases CRP levels, but the effect of transdermal ERT is not well documented.

CRP, interleukine-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels were evaluated in a randomised study of 196 healthy postmenopausal women, who were allocated to receive continuous oral estradiol-17β, (n=63) or transdermal estradiol-17β, (n=68) both combined with micronised progesterone, or placebo (n=65). Oral estrogen increased CRP levels compared with both placebo (p=0.010) and transdermal estrogen (p=0.004) at 6 months. There was no significant effect of transdermal estro-gen on CRP levels compared with placebo (p=0.997). No significant difference was found in the median changes for IL-6 and TNF-α between the three treatment groups.

In conclusion, transdermal estrogen has no significant effect on CRP levels at 6 months, but CRP concentrations increased significantly with oral estrogen although no changes in cytokine levels were detected. The clinical relevance of these effects remains to be determined.

Keywords

Oral estrogen replacement therapy - transdermal estrogen replacement therapy - inflammation - C-reactive protein - interleu-kine-6 - tumor necrosis factor alpha - randomised trial

• References

• 1 Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 1999; 340: 115-26.
• 2 Engler RL, Schmid-Schonbein GW, Pavelec RS. Leukocyte capillary plugging in myocardial ischemia and reperfusion in the dog. Am J Pathol 1983; 111: 98-111
• 3 Carson SD, Johnson DR. Consecutive enzyme cascades: complement activation at the cell surface triggers increased tissue factor activity. Blood 1990; 762: 361-7.
• 4 Hamilton KK, Hattori R, Esmon CT. et al. Complement proteins C5b-9 induce vesiculation of the endothelial plasma membrane and expose catalytic surface for the assembly of the prothrombinase enzyme complex. J Biol Chem 1990; 265: 3809-14.
• 5 Hugo F, Hamdoch T, Mathey D. et al. Quantitative measurement of SC5b-9 and C5b-9(m) in infarcted areas of human myocardium. Clin Exp Immunol 1990; 81: 132-6.
• 6 Mathey D, Schofer J, Schäfer HJ. et al. Early accumulation of the terminal complement-complex in the ischaemic myocardium after reperfusion. Eur Heart J 1994; 15: 418-23.
• 7 Ridker PM, Cushman M, Stampfer MJ. et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973-9.
• 8 Koenig W, Sund M, Frölich M. et al. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men. Results from MONICA (Monitoring trends and determinants in cardiovascular disease) Augsburg cohort study 1984-1992.. Circulation 1999; 99: 237-42.
• 9 Ridker PM, Hennekens CH, Buring JE. et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342: 836-43.
• 10 Kuller LH, Tracy RP, Shaten J. et al. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study: Multiple Risk Factor Intervention Trial. Am J Epidemiol 1996; 144: 537-47.
• 11 Haverkate F, Thompson SG, Pyke SD. et al. Production of C-reactive protein and risk of coronary events in stable and unstable angina: European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Lancet 1997; 349: 462-6.
• 12 Libby P, Ridker PM. Novel inflammatory markers of coronary risk. Theory versus practice. Circulation 1999; 100: 1148-50.
• 13 Ridker PM, Rifai N, Stampfer MJ. et al. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101: 1767-72.
• 14 Ridker PM, Rifai N, Pfeffer M. et al. For the Cholesterol And Recurrent Events (CARE) Investigators. Elevation of tumor necrosis factor –α and increased risk of recurrent coronary events after myocardial infarction. Circulation 2000; 101: 2149-53.
• 15 Lowe GDO, Upton MN, Rumley A. et al. Different effects of oral and transdermal hormone replacement therapies on factor IX, APC resistance, t-PA, PAI and C-reactive protein. Thromb Haemost 2001; 86: 550-6.
• 16 Van Baal WM, Kenemans P, Van der Mooren MJ. et al. Increased C-reactive protein levels during short-term hormone replacement therapy in healthy postmenopausal women. Thromb Haemost 1999; 81: 925-8.
• 17 Cushman M, Legault C, Barrett-connor E. et al. Effect of postmenopausal hormones on inflammation-sensitive proteins. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Study. Circulation 1999; 100: 717-22.
• 18 Ridker PM, Hennekens CH, Rifai N. et al. Hormone replacement therapy and increased plasma concentration of C-reactive protein. Circulation 1999; 100: 713-6.
• 19 Cushman M, Meilahn EN, Psaty BM. et al. Hormone replacement therapy, inflammation, and hemostasis in elderly women. Arterioscler Thromb Vasc Biol 1999; 19: 893-9.
• 20 Wakatsuki A, Okatani Y, Ikenoue N. et al. Effect of medroxyprogesterone acetate on vascular inflammatory markers in postmenopausal women receiving estrogen. Circulation 2002; 105: 1436-9.
• 21 Hulley S, Grady D, Bush T. et al. for the HERS Research Group. 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: 605-13.
• 22 Writing group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women Principal results from the Women’s Health Initiative randomised controlled trial. JAMA 2002; 288: 321-33.
• 23 Post MS, van der Mooren MJ, Stehouwer CDA. et al. Effects of transdermal and oral oestrogen replacement therapy on C-reactive protein levels in postmenopausal women : a randomised, placebo-controlled trial. Thromb Haemost 2002; 88: 605-10.
• 24 Oger E, Alhenc-Gelas M, Plu-Bureau G. et al. Association of circulating cellular adhesion molecules with menopausal status and hormone replacement therapy. Time-dependent change in transdermal, but not oral estrogen users. Thromb Res 2001; 101: 35-43.
• 25 Sattar N, Perera M, Small M. et al. Hormone replacement therapy and sensitive C-reactive protein concentrations in women with type-2 diabetes. Lancet 1999; 354: 487-8.
• 26 Howard BV, Magee MF. Diabetes and cardiovascular disease. Curr Atheroscler Rep 2000; 2: 476-81.
• 27 Vehkavaara S, Silveira A Hakala-Ala-Pietilä. et al. Effects of oral and transdermal estro-gen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thromb Haemost 2001; 85: 619-25.
• 28 Walsh BW, Paul S, Wild RA. et al. The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women: a randomised, controlled trial. J Clin Endocrinol Metab 2000; 85: 214-8.
• 29 Clarke SC, Kelleher J, Lloyd-Jones H. et al. A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT Atherosclerosis Study. Br J Obstet Gynaecol 2002; 109: 1056-62.
• 30 De Lignieres B, Basdevant A, Thomas G. et al. Biological effects of estradiol-17β in postmenopausal women: oral versus percutaneous administration. J Clin Endocrinol metab 1986; 62: 536-41.
• 31 Van Baal WM, Kooistra T, Stehouver DA. Cardiovascular disease risk and hormone replacement therapy (HRT): a review based on randomised, controlled studies in postmenopausal women. Curr Med Chem 2000; 7: 499-517.
• 32 Van Snik J. Interleukin-6: an overview. Annu Rev Immunol 1993; 8: 253-78.
• 33 Ng SB, Tan YN. Guy GR Differential induction of the interleukin-6 gene by tumor necrosis factor and interleukin-1. J Biol Chem 1994; 269: 19021-7.
• 34 Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J 1990; 265: 621-36.
• 35 Baumann H, Gauldie J. Regulation of hepatic acute phase plasma protein genes by hepatocyte stimulating factors and other mediators of inflammation. Mol Biol Med 1990; 7: 147-159.
• 36 Castell JV, Gomez-Lechon MJ, David M. et al. Acute-phase response of human hepatocytes: regulation of acute-phase protein synthesis by interleukin-6. Hepatology 1990; 12: 1179-86.
• 37 Harris TB, Ferrucci L, Tracy RP. et al. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med 1999; 106: 506-12.
• 38 Herrington DM, Brosnihan KB, Pusser BE. et al. Differential effects of E and droloxifene on C-reactive protein and other markers of inflammation in healthy postmenopausal women. J Clin Endocrinol Metab 2001; 86: 4216-22.
• 39 Walsh BW, Cox DA, Sashegyi A. et al. Role of tumor necrosis factor-α and interleukin-6 in the effects of hormone replacement therapy and raloxifene on C-reactive protein in postmenopausal women. Am J Cardiol 2001; 88: 825-8.
• 40 Kon Koh K, Schenke WH, Waclawiw MA. et al. Cannon RO 3rd. Statin attenuates increase in C-reactive protein during estrogen replacement therapy in postmenopausal women. Circulation 2002; 105: 1531-3.