PDF herunterladen
Thromb Haemost 1999; 82(02): 626-633
DOI: 10.1055/s-0037-1615889
Research Article
Schattauer GmbH

Effects of Hormone Replacement Therapy on Coagulation, Fibrinolysis, and Thrombosis Risk in Postmenopausal Women

Kwang Kon Koh
1   Department of Internal Medicine, Heart Center, Gachon Medical College, Inchon, SOUTH KOREA
,
McDonald K. Horne III
2   Cardiology Branch (KKK, ROC); National Heart, Lung, and Blood Institute, Hematology Section (MKH), Clinical Pathology Department, National Institutes of Health, Bethesda, MD, USA
,
Richard O. Cannon III
2   Cardiology Branch (KKK, ROC); National Heart, Lung, and Blood Institute, Hematology Section (MKH), Clinical Pathology Department, National Institutes of Health, Bethesda, MD, USA
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
09. Dezember 2017 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Introduction

In the United States and other developed countries, more women die from cardiovascular disease than from any other disease. The Nurses’ Health Study, among others, has suggested that postmenopausal women who take estrogen therapy have fewer cardiovascular events over time compared with untreated women.1,2 The favorable effects of orally-administered estrogen on lipoprotein levels, namely reductions in low-density lipoprotein (LDL) cholesterol and lipoprotein(a) levels, and increases in high-density lipoprotein (HDL) cholesterol levels, likely account for much of this apparent benefit. These effects have not yet, however, been proven in randomized clinical trials. Because estrogen has a multitude of biological effects, many other potential mechanisms by which estrogen provides protection against atherosclerosis and its consequences are currently being studied.

Atherosclerosis is associated with chronic inflammation in response to injury and with a number of risk factors, such as elevated serum cholesterol, smoking, diabetes, and hypertension.3 Local activation of platelets and thrombus formation adjacent to atheromatous plaques, especially where ruptured or eroded, is now recognized to be of pathophysiological importance in the acute and chronic clinical expression of this disease.4 Thus, the favorable effects of estrogen on hemostasis may be relevant to the progression of atherosclerosis and associated clinical manifestations.

In this regard, several groups have reported on the favorable effects of hormone replacement therapy on fibrinolysis in postmenopausal women. These results might be interpreted as protection by estrogen against the propagation of thrombi that could result in myocardial ischemia and infarction. On the other hand, coagulation activation and increased risk of thromboemboli and myocardial infarction have also been reported with hormone replacement therapy in postmenopausal women. In an effort to gain a better understanding of the complex effects of estrogen on hemostasis, this chapter will review a number of observational trials and treatment studies conducted in postmenopausal women receiving estrogen therapy.

 

  • References

  • 1 Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the Nurses’ Health Study. N Engl J Med 1991; 325: 756-762.
    CrossrefPubMedGoogle Scholar
  • 2 Stampfer MJ, Coditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med 1991; 20: 47-63.
    CrossrefPubMedGoogle Scholar
  • 3 Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801-809.
    CrossrefPubMedGoogle Scholar
  • 4 Libby P. Molecular basis of the acute coronary syndromes. Circulation 1995; 91: 2844-2850.
    CrossrefPubMedGoogle Scholar
  • 5 Meade TW, Imerson JD, Haines AP, Stirling Y, Thompson SG. Menopausal status and haemostatic variables. Lancet 1983; 1: 22-24.
    PubMedGoogle Scholar
  • 6 Balleisen L, Bailey J, Epping P-H, Shulte H, van de Loo J. Epidemiological study on factor VII, factor VIII and fibrinogen in an industrial population: I. Baseline data on the relation to age, gender, body weight, smoking, alcohol, pill using, and menopause. Thromb Haemost 1985; 54: 475-479.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 7 Scarabin P-Y, Bonithon-Knopp C, Bara L, Malmejac A, Guize L, Samama M. Factor VII activation and menopausal status. Thromb Res 1990; 57: 227-234.
    CrossrefPubMedGoogle Scholar
  • 8 Bonithon-Kopp C, Scarabin P-Y, Darne B, Malmejac A, Guize L. Menopause-related changes in lipoproteins and some other cardiovascular risk factors. Int J Epidemiol 1990; 19: 42-48.
    CrossrefPubMedGoogle Scholar
  • 9 Meade TW, Dyer S, Howarth DJ, Imeson JD, Stirling Y. Antithrombin III and procoagulant activity: sex differences and effect of the menopause. Br J Haematol 1990; 74: 77-81.
    CrossrefPubMedGoogle Scholar
  • 10 Folsom AR, Wu KK, Davis CE, Conlan MG, Sorlie PD, Szklo M. Population correlates of plasma fibrinogen and factor VII, putative cardiovascular risk factors. Atherosclerosis 1991; 91: 191-205.
    CrossrefPubMedGoogle Scholar
  • 11 The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA 1995; 273: 199-208.
    CrossrefPubMedGoogle Scholar
  • 12 Gebara OCE, Mittleman MA, Sutherland P, Lipinska I, Matheney T, Xu P, Weltry FK, Wilson PWF, Levy D, Muller JE, Tofler GH. Association between increased estrogen status and increased fibinolytic potential in the Framingham Offspring Study. Circulation 1995; 91: 1952-1958.
    CrossrefPubMedGoogle Scholar
  • 13 Scarabin P-Y, Plu-Bureau G, Bara L, Bonithon-Kopp C, Guize L, Samama MM. Haemostatic variables and menopausal status: influence of hormone replacement therapy. Thromb Haemost 1993; 70: 584-587.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 14 Pinto S, Rostagno C, Coppo M, Paniccia R, Prisco D, Bruni V, Rosati D, Abbate R. No signs of increased thrombin generation in menopause. Thromb Res 1990; 58: 645-651.
    CrossrefPubMedGoogle Scholar
  • 15 Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and risk of cardiovascular disease. The Framingham Study. JAMA 1987; 258: 1183-1186.
    CrossrefPubMedGoogle Scholar
  • 16 Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blomback M, Wiman B. Plasminogen activator inhibitor in plasma; risk factor for recurrent myocardial infarction. Lancet 1987; 2: 3-9.
    PubMedGoogle Scholar
  • 17 Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993; 342: 1076-1079.
    CrossrefPubMedGoogle Scholar
  • 18 Cortellaro M, Cofrancesco E, Boschetti C, Mussoni MB, Donati M, Cardillo M, Catalono M, Gabrielli L, Lombardi G, Specchia G, Tarazzi L, Tremoli E, Pozzoli E, Turri M. for the PLAT Group. Increased fibrin turnover and high PAI-1 activity as predictors of ischemic events in atherosclerotic patients. A case-control study. Arterioscler Thromb Vasc Biol 1993; 12: 1412-1417.
    PubMedGoogle Scholar
  • 19 Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348: 977-980.
    CrossrefPubMedGoogle Scholar
  • 20 Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal estrogens. Lancet 1996; 348: 981-983.
    CrossrefPubMedGoogle Scholar
  • 21 Gutthann SP, Garcia Rodriguez LA, Castellsague J, Oliart AD. Hormone replacement therapy and risk of venous thromboembolism: population based case-control study. BMJ 1997; 314: 796-800.
    CrossrefPubMedGoogle Scholar
  • 22 Grodstein F, Stampfer MJ, Goldhaber SZ, Manson JE, Colditz GA, Speizer FE, Willett WC, Hennekens CH. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 1996; 348: 983-987.
    CrossrefPubMedGoogle Scholar
  • 23 Hulley S, Grady D, Bush T, Furberg C, Herrington DM, Riggs B, Vittinghoff 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.
    CrossrefPubMedGoogle Scholar
  • 24 The Coronary Drug Project Research Group. The Coronary Drug Project: initial findings leading to modifications of its research protocol. JAMA 1970; 214: 1303-1313.
    CrossrefPubMedGoogle Scholar
  • 25 Mann JI, Vessey MP, Thorogood M, Doll R. Myocardial infarction in young women with special references to oral contraceptive practice. BMJ 1975; 2: 241-245.
    CrossrefPubMedGoogle Scholar
  • 26 Mammen EF. Oral contraceptives and blood coagulation: a critical review. Am J Obstet Gynecol 1982; 142: 781-790.
    CrossrefPubMedGoogle Scholar
  • 27 Caine YG, Bauer KA, Barzegar S, Ten Cate H, Sacks FM, Walsh BM, Schiff I, Rosenberg RD. Coagulation activation following estrogen administration to postmenopausal women. Thromb Haemost 1992; 68: 392-395.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 28 Kroon U-B, Silfverstolpe G, Tengborn L. The effects of transdermal estradiol and oral conjugated estrogens on haemostasis variables. Thromb Haemost 1994; 71: 420-423.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 29 Scarabin P-Y, 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.
    CrossrefPubMedGoogle Scholar
  • 30 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.
    CrossrefPubMedGoogle Scholar
  • 31 Shahar E, Folsom AR, Salomaa VV, Stinson VL, McGovern PG, Shimakawa T, Chambless LE, Wu KK. for the Atherosclerosis Risk in Communities (ARIC) Study Investigators. Relation of hormone-replacement therapy to measures of plasma fibrinolytic activity. Circulation 1996; 93: 1970-1975.
    CrossrefPubMedGoogle Scholar
  • 32 Sporrong T, Mattson L-A, Samsioe G, Stigendal L, Hellgren M. Haemostatic changes during continuous oestradiol–progestogen treatment of postmenopausal women. Br J Obstet Gynaecol 1990; 97: 939-944.
    CrossrefPubMedGoogle Scholar
  • 33 Gilabert J, Estelles A, Cano A, Espana F, Barrachina R, Grancha S, Aznar J, Tortajada M. The effect of estrogen replacement therapy with or without progestin on the fibrinolytic system and caogulation inhibitors in postmenopausal status. Am J Obstet Gynecol 1995; 173: 1849-1854.
    CrossrefPubMedGoogle Scholar
  • 34 Koh KK, Mincemoyer R, Bui MN, Csako G, Pucino F, Guetta V, Waclawiw M, Cannon III RO. Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women. N Engl J Med 1997; 336: 683-690.
    CrossrefPubMedGoogle Scholar
  • 35 Etingin OR, Hajjar DP, Hajjar KA, Harpel PC, Nachman RL. Lipoprotein(a) regulates plasminogen activator inhibitor-1 expression in endothelial cells: a potential mechanism in thrombogenesis. J Biol Chem 1991; 266: 2459-2465.
    PubMedGoogle Scholar
  • 36 Kugiyama K, Sakamoto T, Misumi I, Sugiyama S, Ohgushi M, Ogawa H, Horiguchi M, Yasue M. Transferable lipids in oxidized low-density lipoprotein stimulate plasminogen activator inhibitor1 and inhibit tissue-type plasminogen activator release from endothelial cells. Circ Res 1993; 73: 335-343.
    CrossrefPubMedGoogle Scholar
  • 37 Schneider DJ, Sobel BE. Augmentation of synthesis of plasminogen activator inhibitor type 1 by insulin and insulin-like growth factor type I: implications for vascular disease in hyperinsulinemic states. Proc Natl Acad Sci USA 1991; 88: 9959-9963.
    CrossrefPubMedGoogle Scholar
  • 38 Kooistra T. The use of cultured human endothelial cells and hepatocytes as an in vitro model system to study modulation of endogenous fibrinolysis. Fibrinolysis 1990; 4 (Suppl. 02) 33-39.
    PubMedGoogle Scholar
  • 39 Quax PHA, van den Hoogen CM, Verheijen JH, Padro T, Zeheb R, Gelehrter TD, van Berkel TJ, Kuiper J, Emeis JJ. Endotoxin induction of plasminogen activator and plasminogen activator inhibitor type 1 mRNA in rat tissues in vivo. J Biol Chem 1990; 265: 15560-15563.
    PubMedGoogle Scholar
  • 40 Sawdey MS, Loskutoff DJ. Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-α, and transforming growth factor-β. J Clin Invest 1991; 88: 1346-1353.
    CrossrefPubMedGoogle Scholar
  • 41 Beebe DP, Aronson DL. Turnover of human tissue plasminogen activator (t-PA) in rabbits. Thromb Res 1986; 43: 663-674.
    CrossrefPubMedGoogle Scholar
  • 42 Korninger C, Stassen J-M, Collen D. Turnover of human extrinsic (tissue-type) plasminogen activator in rabbits. Thromb Haemost 1981; 46: 658-661.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 43 Bu G, Williams S, Strickland DK, Schwartz AL. Low density lipoprotein receptor-related protein/α2-macroglobulin receptor is an hepatic receptor for tissue-type plasminogen activator. Proc Natl Acad Sci USA 1992; 89: 7427-7431.
    CrossrefPubMedGoogle Scholar
  • 44 Orth K, Madison EL, Gething M-J, Sambrook JF, Hertz J. Complexes of tissue-type plasminogen activator and its serpin inhibitor plasminogen-activator inhibitor type 1 are internalized by means of the low density lipoptoretin receptor-related protein/α2-macroglobulin receptor. Proc Natl Acad Sci USA 1992; 89: 7422-7426.
    CrossrefPubMedGoogle Scholar
  • 45 Nykjaer A, Petersen CM, Moller B, Jensen PH, Moestrup SK, Holtet TL, Etzerodt M, Thogersen HC, Munch M, Andreasen PA, Gliemann J. Purifed α2-macroglobulin receptor/LDL receptor-related protein binds urokinase-plasminogen activator inhibitor type-1 complex. J Biol Chem 1992; 267: 14543-14546.
    PubMedGoogle Scholar
  • 46 Windler E, Kovanen PT, Chao YS, Brown MS, Havel RJ, Goldstein JL. The estradiol-stimulated lipoprotein receptor of rat liver: a binding site that membrane mediates the uptake of rat lipoproteins containing apoproteins containing apoproteins B and E. J Biol Chem 1980; 225: 10464-10471.
    PubMedGoogle Scholar
  • 47 Koh KK, Horne MK III, Csako G, Waclawiw MA, Cannon III RO. Relation of fibrinolytic potentiation by estrogen to coagulation path-way activation in postmenopausal women. Am J Cardiol. In press.
    PubMedGoogle Scholar
  • 48 Chandler WL, Trimble SL, Lou W-C, Mornin D. Effect of PAI-1 levels on the molar concentrations of active tissue plasminogen activator (t-PA) and t-PA/PAI-1 complex in plasma. Blood 1990; 76: 930-937.
    PubMedGoogle Scholar
  • 49 Sato M, Rippy MK, Bryant HU. Ralxoifene, tamoxifen, nafoxidine, and or effects on reproductive and nonreproductive tissues in ovariectomized rats. FASEB J 1996; 10: 905-912.
    CrossrefPubMedGoogle Scholar
  • 50 Horwitz KB, Jackson TA, Bain DL, Richer JK, Takimoto GS, Tung L. Nuclear receptor coactivators and corepressors. Mol Endocrinol 1996; 10: 1167-1177.
    PubMedGoogle Scholar
  • 51 Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med 1998; 339: 1609-1618.
    CrossrefPubMedGoogle Scholar
  • 52 Guetta V, Lush RM, Figg WD, Waclawiw MA, Cannon III RO. Effects of the antiestrogen tamoxifen on low-density lipoprotein concentrations and oxidation in postmenopausal women. Am J Cardiol 1995; 76: 1072-1073.
    CrossrefPubMedGoogle Scholar
  • 53 Fisher B, Constantino J, Redmond C, Poisson R, Bowman D, Couture J, Dimitrov NV, Wolmark N, Wickerham DL, Fisher ER, Margolese R, Robidoux A, Shibata H, Terz J, Paterson AHG, Feldman AI, Farrar W, Evans J, Lickley HL, Ketner M. and other National Surgical Adjuvant Breast and Bowel Project Investigators. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 1989; 320: 479-484.
    CrossrefPubMedGoogle Scholar
  • 54 Pritchard KI, Paterson AHG, Paul NA, Zee B, Fine S, Paker J. for the National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group. Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. J Clin Oncol 1996; 14: 2731-2737.
    CrossrefPubMedGoogle Scholar
  • 55 Fisher B, Constatino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N. and other National Surgical Adjuvant Breast and Bowel Project Investigators. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel P-I Study. J Natl Cancer Inst 1998; 90: 1371-1388.
    CrossrefPubMedGoogle Scholar
  • 56 Yang NN, Venugopalan M, Hardikar S, Glasebrook A. Identification of an estrogen response element activated by metaboliites of 17β-estradiol and raloxifene. Science 1996; 273: 1222-1225.
    CrossrefPubMedGoogle Scholar
  • 57 Anzano MA, Peer CW, Smith JM, Mullen LT, Shrader MW, Logsdon DL, Driver CL, Brown CC, Roberts AB, Sporn MB. Chemoprevention of mammary carcinogenesis in the rat: combined use of raloxifene and 9-cis-retinoic acid. J Natl Cancer Inst 1996; 88: 123-125.
    CrossrefPubMedGoogle Scholar
  • 58 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.
    CrossrefPubMedGoogle Scholar