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Thromb Haemost 2005; 93(06): 1108-1116
DOI: 10.1160/TH04-09-0608
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Baseline associations between postmenopausal hormone therapy and inflammatory, haemostatic, and lipid biomarkers of coronary heart disease

The Women’s Health Initiative Observational Study
Robert D. Langer
1   Department of Family and Preventive Medicine, University of California, San Diego, La Jolla, California, USA
,
Aruna D. Pradhan
2   Brigham and Women's Hospital, Department of Cardiology, Boston, Massachusetts, USA
,
Cora E. Lewis
3   Division of Preventive Medicine, University of Alabama at Birmingham, Medical Towers, Birmingham, Alabama, USA
,
JoAnn E. Manson
4   Department of Medicine, Brigham and Women's Hospital, Division of Preventive Medicine, Boston, Massachusetts, USA
,
Jacques E. Rossouw
5   National Heart Lung and Blood Institute, Rockledge Center, Bethesda, Maryland, USA
,
Susan L. Hendrix
6   Wayne State University, Hutzel Women’s Hospital, Detroit, Michigan, USA
,
Andrea Z. LaCroix
7   Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
,
Paul M. Ridker
4   Department of Medicine, Brigham and Women's Hospital, Division of Preventive Medicine, Boston, Massachusetts, USA
› Author Affiliations
Further Information

Publication History

Received 17 September 2004

Accepted after revision 28 March 2005

Publication Date:
11 December 2017 (online)

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Summary

Clinical trials of postmenopausal hormone therapy (PHT) have found an early increase in cardiovascular events, and have not demonstrated the reduction in coronary heart disease (CHD) predicted from changes in conventional risk factors or found in observational studies, suggesting that PHT may increase coronary risk through other pathways. We compared baseline levels of C-reactive protein (CRP), interleukin-6 (IL-6), sICAM-1, tissue plasminogen activator antigen (tPA-antigen), D-dimer, homocysteine, triglycerides, total-, HDL- and LDL- cholesterol in 304 cases with incident CHD and 304 controls, according to self-reported use of PHT. Subjects were selected from the 75,343 participants in the WHI Observational Study without baseline cardiovascular disease or cancer. PHT was associated with higher CRP, HDL and triglycerides, and lower tPA-antigen and homo-cysteine. CRP was highest in users of unopposed conjugated equine estrogen. Levels of IL-6, sICAM-1, D-dimer and total cholesterol did not differ between PHT users and non-users. Trans-dermal estrogen users had low levels of D-dimer and CRP. Among users of estrogen plus progestin (EP), CRP, IL-6, tPA-antigen, D-dimer, total cholesterol and triglycerides were higher in women with incident coronary events than controls. Estrogen alone (E) controls shared only the tPA-antigen association, but had higher HDL and lower LDL than E cases. In non-users CRP, tPA-antigen and D-dimer were associated with incident CHD. In summary, risk markers differed by PHT category. Some associations differed between women with and without incident CHD, especially for EP, where inflammatory and thrombotic markers were higher in cases. These associations remain speculative pending confirmation in randomized trials.

Keywords

Postmenopausal hormone therapy - estrogens - coronary heart disease - inflammatory factors - haemostatic factors
 

  • References

  • 1 Writing Group for the Women's Health Initiative. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002; 288: 321-33.
    CrossrefPubMedGoogle Scholar
  • 2 Hulley S, Grady D, Bush T. et al. 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.
    CrossrefPubMedGoogle Scholar
  • 3 Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative Steering Committee. JAMA 2004; 291: 1701-12.
    CrossrefPubMedGoogle Scholar
  • 4 Herrington DM, Reboussin DM, Brosnihan KB. et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000; 343: 522-9.
    CrossrefPubMedGoogle Scholar
  • 5 Hodis HN, Mack WJ, Azen SP. et al. Women's Estrogen- Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial Research Group. Hormone therapy and the progression of coronary-artery atherosclerosis atherosclerosis in postmenopausal women. N Engl J Med 2003; 349: 535-45.
    CrossrefPubMedGoogle Scholar
  • 6 Waters DD, Alderman EL, Hsia J. et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA 2002; 288: 2432-40.
    CrossrefPubMedGoogle Scholar
  • 7 The PEPI Investigators. Effects of estrogen or estrogen/ progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995; 273: 199-208.
    CrossrefPubMedGoogle Scholar
  • 8 Kannel WB. Metabolic risk factors for coronary heart disease in women: perspective from the Framingham Study. Am Heart J 1987; 114: 413-9.
    CrossrefPubMedGoogle Scholar
  • 9 Gordon DJ, Probstfield JL, Garrison RJ. et al. Highdensity lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989; 79: 8-15.
    CrossrefPubMedGoogle Scholar
  • 10 Castelli WP, Garrison RJ, Wilson PW. et al. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA. 1986: 256
    PubMedGoogle Scholar
  • 11 National Institutes of Health, National Heart, Lung, and Blood Institute. Women’s Health Initiative. Available at. www.nhlbi.nih.gov/whi/HT-en.htm
    PubMedGoogle Scholar
  • 12 Manson JE, Hsia J, Johnson KC. et al. Women's Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003; 349: 523-34.
    CrossrefPubMedGoogle Scholar
  • 13 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.
    CrossrefPubMedGoogle Scholar
  • 14 Meilahn EN, Kuller LH, Matthews KA. et al. Haemostatic factors according to menopausal status and use of hormone replacement therapy. Ann Epidemiol 1992; 2: 445-55.
    CrossrefPubMedGoogle Scholar
  • 15 Nabulsi A, Folsom AR, White A. Association of hormone replacement therapy with various cardiovascular risk factors in postmenopausal women. N Eng J Med 1993; 328: 1069-75.
    CrossrefPubMedGoogle Scholar
  • 16 Scarabin PY, Plu-Bureau G, Bara L. et al. Haemostatic variables and menopausal status: influence of h mone replacement therapy. Thromb Haemost 1993; 70: 584-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Vaughan DE, Rouleau JL, Ridker PM. et al. Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. HEART Study Investigators. Circulation 1997; 96: 442-7.
    CrossrefPubMedGoogle Scholar
  • 18 Wright RA, Flapan AD, Alberti KG. et al. Effects of captopril therapy on endogenous fibrinolysis in men with recent, uncomplicated myocardial infarction. J Am Coll Cardiol 1994; 24: 67-73.
    CrossrefPubMedGoogle Scholar
  • 19 van Baal WM, Emeis JJ, van der Mooren MJ et al. Impaired procoagulant-anticoagulant balance during hormone replacement therapy? A randomised, placebo- controlled 12-week study. Thromb Haemost 2000; 83: 29-34.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Scarabin PY, Alhenc-Gelas M, Plu-Bureau G. et al. 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: 3071-8.
    CrossrefPubMedGoogle Scholar
  • 21 Caine YG, Bauer KA, Barzegar S. et al. Coagulation activation following estrogen administration to postmenopausal women. Thromb Haemost 1992; 68: 392-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 de Valk-de Roo GW, Stehouwer CD, Meijer P. et al. Both raloxifene and estrogen reduce major cardiovascular risk factors in healthy postmenopausal women: A 2-year, placebo-controlled study. Arterioscler Thromb Vasc Biol 1999; 19: 2993-3000.
    CrossrefPubMedGoogle Scholar
  • 23 Kroon UB, Silfverstolpe G, Tengborn L. The effects of transdermal estradiol and oral conjugated estrogens on haemostasis variables. Thromb Haemost 1994; 71: 420-3.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Saleh AA, Dorey LG, Dombrowski MP. et al. Thrombosis and hormone replacement therapy in postmenopausal women. Am J Obstet Gynecol 1993; 169: 1554-7.
    CrossrefPubMedGoogle Scholar
  • 25 Shahar E, Folsom AR, Salomaa VV. et al. Relation of hormone-replacement therapy to measures of plasma fibrinolytic activity. Atherosclerosis Risk in Communities (ARIC) Study Investigators. Circulation 1996; 93: 1970-5.
    CrossrefPubMedGoogle Scholar
  • 26 Koh KK, Mincemoyer R, Bui MN. et al. Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women. N Engl J Med 1997; 336: 683-90.
    CrossrefPubMedGoogle Scholar
  • 27 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 randomized, controlled trial. J Clin Endocrinol Metab 2000; 85: 214-8.
    PubMedGoogle Scholar
  • 28 Straub RH, Hense HW, Andus T. et al. Hormone replacement therapy and interrelation between serum i interleukin- 6 and body mass index in postmenopausal women: a population-based study [see comments]. J Clin Endocrinol Metab 2000; 85: 1340-4.
    CrossrefPubMedGoogle Scholar
  • 29 Cushman M, Legault C, Barrett-Connor E. et al. Effect of postmenopausal hormones on inflammationsensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Study. Circulation 1999; 100: 717-22.
    CrossrefPubMedGoogle Scholar
  • 30 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.
    CrossrefPubMedGoogle Scholar
  • 31 Ridker PM, Hennekens CH, Rifai N. et al. Hormone replacement therapy and increased plasma concentration of C-reactive protein. Circulation 1999; 100: 713-6.
    CrossrefPubMedGoogle Scholar
  • 32 Barnabei VM, Phillips TM, Hsia J. Plasma homocysteine in women taking hormone replacement therapy: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. J Women’s Health Gend Based Med 1999; 8: 1167-72.
    PubMedGoogle Scholar
  • 33 van Baal WM, Smolders RG, van der Mooren MJ et al. Hormone replacement therapy and plasma homocysteine levels. Obstet Gynecol 1999; 94: 485-91.
    PubMedGoogle Scholar
  • 34 Berger PB, Herrmann RR, Dumesic DA. The effect of estrogen replacement therapy on total plasma homocysteine in healthy postmenopausal women. Mayo Clin Proc 2000; 75: 18-23.
    CrossrefPubMedGoogle Scholar
  • 35 Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group. Control Clin Trials 1998; 19: 61-109.
    CrossrefPubMedGoogle Scholar
  • 36 Ridker PM, Buring JE, Shih J. et al. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998; 98: 731-3.
    CrossrefPubMedGoogle Scholar
  • 37 van Baal WM, Kenemans P, van der Mooren MJ et al. Increased C-reactive protein levels during shortterm hormone replacement therapy in healthy postmenopausal women. Thromb Haemost 1999; 81: 925-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Kvasnicka Jr J, Zivny J. Changes in serum levels of C-reactive protein and the soluble adhesion molecules, sE-selectin and sICAM-1, after transdermal 17-beta estradiol replacement. Ceska Gynekol 2001; 66: 161-5.
    PubMedGoogle Scholar
  • 39 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.
    CrossrefPubMedGoogle Scholar
  • 40 Vehkavaara S, Silveira A, Hakala-Ala-Pietila T. et al. Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thromb Haemost 2001; 85: 619-25.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Hoibraaten E, Qvigstad E, Andersen TO. et al. The effects of hormone replacement therapy (HT) on haemostatic variables in women with previous venous thromboembolism--results from a randomized, doubleblind, clinical trial. Thromb Haemost 2001; 85: 775-81.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Teede HJ, McGrath BP, Smolich JJ. et al. Postmenopausal hormone replacement therapy increases coagulation activity and fibrinolysis. Arterioscler Thromb Vasc Biol 2000; 20: 1404-9.
    CrossrefPubMedGoogle Scholar
  • 43 Koh KK, Mincemoyer R, Minh NB. et al. Effects of hormone replacement therapy on fibrinolysis in postmenopausal women. N Engl J Med 1997; 336: 683-90.
    CrossrefPubMedGoogle Scholar
  • 44 Van Baal WM, Emeis JJ, Kenemans P. et al. Shortterm hormone replacement therapy: reduced plasma levels of soluble adhesion molecules. Eur J Clin Invest 1999; 29: 913-21.
    CrossrefPubMedGoogle Scholar
  • 45 Scarabin PY, Vissac AM, Kirzin JM. et al. Elevated plasma fibrinogen and increased fibrin turnover among healthy women who both smoke and use low-dose oral contraceptives--a preliminary report. Thromb Haemost 1999; 82: 1112-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 46 Lip GY, Blann AD, Jones AF. et al. Effects of hormone- replacement therapy on haemostatic factors, lipid factors, and endothelial function in women undergoing surgical menopause: implications for prevention of atherosclerosis. Am Heart J 1997; 134: 764-71.
    CrossrefPubMedGoogle Scholar
  • 47 Andersen LF, Gram J, Skouby SO. et al. Effects of hormone replacement therapy on haemostatic cardiovascular risk factors. Am J Obstet Gynecol 1999; 180: 283-9.
    CrossrefPubMedGoogle Scholar
  • 48 Hak AE, Bak AA, Lindemans J. et al. The effect of hormone replacement therapy on serum homocysteine levels in perimenopausal women: a randomized controlled trial. Atherosclerosis 2001; 158: 437-43.
    CrossrefPubMedGoogle Scholar
  • 49 Ventura P, Cagnacci A, Malmusi S. et al. Continuous combined hormone replacement therapy with oral 17beta-estradiol and norethisterone acetate improves homocysteine metabolism in postmenopausal women. Menopause 2001; 8: 252-8.
    CrossrefPubMedGoogle Scholar
  • 50 Miyagawa K, Rösch J, Stanczyk F. et al. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nat Med 1997; 3: 324-7.
    CrossrefPubMedGoogle Scholar