Download PDF
Thromb Haemost 2001; 85(04): 619-625
DOI: 10.1055/s-0037-1615643
Review Articles
Schattauer GmbH

Effects of Oral and Transdermal Estrogen Replacement Therapy on Markers of Coagulation, Fibrinolysis, Inflammation and Serum Lipids and Lipoproteins in Postmenopausal Women

Satu Vehkavaara
1   Department of Medicine, Division of Diabetes, University of Helsinki
,
Angela Silveira
2   Karolinska Institutet, King Gustaf V Research Institute, Karolinska Hospital, Stockholm, Sweden
,
Tiina Hakala-Ala-Pietilä
3   Family Federation of Finland, Helsinki, Finland
,
Antti Virkamäki
1   Department of Medicine, Division of Diabetes, University of Helsinki
*   Minerva Foundation Institute for Medical Research, Helsinki, Finland
,
Outi Hovatta
4   Karolinska Institutet, Department of Obstetrics and Gynaecology, Huddinge University Hospital, Huddinge, Sweden
,
Anders Hamsten
2   Karolinska Institutet, King Gustaf V Research Institute, Karolinska Hospital, Stockholm, Sweden
,
Marja-Riitta Taskinen
1   Department of Medicine, Division of Diabetes, University of Helsinki
,
Hannele Yki-Järvinen
1   Department of Medicine, Division of Diabetes, University of Helsinki
› Author Affiliations
Further Information

Publication History

Received 17 August 2000

Accepted after resubmission 14 November 2000

Publication Date:
08 December 2017 (online)

    Permissions and Reprints

Summary

We compared the effects of oral estradiol (2 mg), transdermal estradiol (50 g), and placebo on measures of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in 27 postmenopausal women at baseline and after 2 and 12 weeks of treatment. Oral and transdermal estradiol induced similar increases in serum free estradiol concentrations. Oral therapy increased the plasma concentrations of factor VII antigen (FVIIag) and activated factor VII (FVIIa), and the plasma concentration of the prothrombin activation marker prothrombin fragment 1+2 (F1+2). Oral but not transdermal estradiol therapy significantly lowered plasma plasminogen activator inhibitor-1 (PAI-1) antigen and tissue-type plasminogen activator (tPA) antigen concentrations and PAI-1 activity, and increased D-dimer concentrations, suggesting increased fibrinolysis. The concentration of soluble Eselectin decreased and serum C-reactive protein (CRP) increased significantly in the oral but not in the transdermal or placebo groups. In the oral but not in the transdermal or placebo estradiol groups low-density-lipoprotein (LDL) cholesterol, apolipoprotein B and lipoprotein (a) concentrations decreased while high-density-lipoprotein (HDL) cholesterol, apolipoprotein AI and apolipoprotein AII concentrations increased significantly. LDL particle size remained unchanged. In summary, oral estradiol increased markers of fibrinolytic activity, decreased serum soluble E-selectin levels and induced potentially antiatherogenic changes in lipids and lipoproteins. In contrast to these beneficial effects, oral estradiol changed markers of coagulation towards hypercoagulability, and increased serum CRP concentrations. Transdermal estradiol or placebo had no effects on any of these parameters. These data demonstrate that oral estradiol does not have uniformly beneficial effects on cardiovascular risk markers and that the oral route of estradiol administration rather than the circulating free estradiol concentration is critical for any changes to be observed.

Keywords

Atherosclerosis - hemostasis - estradiol - cholesterol - triglycerides
 

  • References

  • 1 Mosca L, Manson JE, Sutherland SE, Langer RD, Manolio T, Barrett-Connor E. Cardiovascular disease in women: statement for healthcare professionals from the American Cardiovascular disease in women: statement for healthcare professionals from the American Heart Association. Circulation 1997; 96: 2468-82.
    CrossrefPubMedGoogle Scholar
  • 2 Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med 1991; 20: 47-63.
    CrossrefPubMedGoogle Scholar
  • 3 Psaty BM, Heckbert SR, Atkins D, Lemaitre R, Koepsell TD, Wahl PW, Siscovick DS, Wagner EH. The risk of myocardial infarction associated with the combined use of estrogens and progestins in postmenopausal women. Arch Intern Med 1994; 154: 1333-9.
    CrossrefPubMedGoogle Scholar
  • 4 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: 453-61.
    CrossrefPubMedGoogle Scholar
  • 5 Hulley S, Grady D, Bush T, Furberg C, Herrington DM, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280: 605-13.
    CrossrefPubMedGoogle Scholar
  • 6 Cushman M, Meilahn EN, Psaty BM, Kuller LH, Dobs AS, Tracy RP. Hormone replacement therapy, inflammation, and hemostasis in elderly women. Arterioscler Thromb Vasc Biol 1999; 19: 893-9.
    CrossrefPubMedGoogle Scholar
  • 7 Cushman M, Legault C, Barrett-Connor E, Stefanick ML, Kessler C, Judd HL, Sakkinen PA, Tracy RP. Effect of postmenopausal hormones on inflammation-sensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Study. Circulation 1999; 100: 717-22.
    CrossrefPubMedGoogle Scholar
  • 8 Vehkavaara S, Hakala-Ala-Pietilä T, Virkamäki A, Bergholm R, Ehnholm C, Hovatta O, Taskinen M-R, Yki-Järvinen H. Differential effects of oral and transdermal estrogen replacement therapy on endothelial function in postmenopausal women. Circulation 2000; 102: 2687-93.
    CrossrefPubMedGoogle Scholar
  • 9 Taves DR. Minimization: a new method of assigning patients to treatment and control groups. Clin Pharmacol Ther; 1974; 15: 443-53.
    CrossrefPubMedGoogle Scholar
  • 10 Clauss A. Gerinnungsphysiologische Schellmetode zur Bestimmung des Fibrinogens. Acta Haemat 1957; 17: 237-46.
    CrossrefPubMedGoogle Scholar
  • 11 Taskinen M-R, Kuusi T, Helve E, Nikkilä E, Yki-Järvinen H. Insulin therapy induces antiatherogenic changes of serum lipoproteins in non-insulin-dependent diabetes. Arteriosclerosis 1988; 8: 168-77.
    CrossrefPubMedGoogle Scholar
  • 12 Kashyap ML, Hynd BA, Robinson K. A rapid and simple method for measurement of total protein in very low density lipoprotein by Lowry assay. J Lipid Res 1980; 21: 491-5.
    PubMedGoogle Scholar
  • 13 Jauhiainen M, Koskinen P, Ehnholm C, Frick MH, Mänttäri M, Manninen V, Huttunen JK. Lipoprotein(a) and coronary heart disease risk: a nested case-control study of the Helsinki Heart Study participants. Atherosclerosis 1991; 89: 59-67.
    CrossrefPubMedGoogle Scholar
  • 14 Heikkinen A-M, Niskanen L, Ryynänen M, Komulainen MH, Tuppurainen MT, Parviainen L, Saarikoski S. Is the response of serum lipids and lipoproteins to postmenopausal hormone replacement therapy modified by ApoE genotype?. Arterioscler Thromb Vasc Biol 1999; 19: 402-7.
    CrossrefPubMedGoogle Scholar
  • 15 Havekes LM, Knijff de P, Beisiegel U, Havinga J, Smit M, Klasen E. A rapid micromethod for apolipoprotein E phenotyping directly in serum. J Lipid Res 1987; 28: 455-63.
    PubMedGoogle Scholar
  • 16 Lahdenperä S, Puolakka J, Pyörälä T, Luotola H, Taskinen M-R. Effects of postmenopausal estrogen/progestin replacement therapy on LDL particles;comparison of transdermal and oral treatment regimens. Atherosclerosis 1996; 122: 153-62.
    CrossrefPubMedGoogle Scholar
  • 17 Mertens R, Liedke RJ, Batjer JD. Evaluation of radioimmunoassay for estradiol in unextracted serum. Clin Chem 1983; 31: 359-70.
    PubMedGoogle Scholar
  • 18 Campagnoli C, Biglia N, Altare F, Lanza MG, Lesca L, Cantamessa C, Peris C, Fiorucci GC, Sismondi P. Differential effects of oral conjugated estrogens and transdermal estradiol on insulin-like growth factor 1, growth hormone and sex hormone binding globulin serum levels. Gynecol Endocrinol 1993; 7: 251-8.
    CrossrefPubMedGoogle Scholar
  • 19 Dunn JF, Nisula BC, Rodbard D. Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab 1981; 53: 58-68.
    CrossrefPubMedGoogle Scholar
  • 20 Hemmilä I, Dakubu S, Mukkala V-M, Siitari H, Lövgren T. Europium as a label in time-resolved immunofluorometric assays. Atherosclerosis 1984; 137: 335-43.
    PubMedGoogle Scholar
  • 21 Ludbrook J. Repeated measurements and multiple comparisons in cardiovascular research. Cardiovasc Res 1994; 28: 303-11.
    CrossrefPubMedGoogle Scholar
  • 22 Mattsson LA, Bohnet HG, Gredmark T, Torhorst J, Hornig F, Huls G. Continuous, combined hormone replacement: randomized comparison of transdermal and oral preparations. Obstet Gynecol 1999; 94: 61-5.
    PubMedGoogle Scholar
  • 23 Ryan JK, Engel LL. The interconversion of estrone and estradiol by human tissue slices. Endocrinology 1953; 52: 287-91.
    CrossrefPubMedGoogle Scholar
  • 24 Sandberg A, Slaunwhite WR. Studies on phenolic steroids in human subjects. II. The metabolic fate and hepato-biliary-enteric circulation of C14-estrone and C14-estradiol in women. J Clin Invest 1957; 36: 1266-78.
    CrossrefPubMedGoogle Scholar
  • 25 Morrissey JH. Tissue factor interactions with factor VII: measurement and clinical significance of factor VIIa in plasma. Blood Coagul Fibrinol 1995; 6: S14-9.
    CrossrefPubMedGoogle Scholar
  • 26 Salomaa V, Rasi V, Pekkanen J, Vahtera E, Jauhiainen M, Vartiainen E, Ehnholm C, Tuomilehto J, Myllylä G. Association of hormone replacement therapy with hemostatic and other cardiovascular risk factors. The FINRISK hemostasis study. Arterioscl Thromb Vasc Biol 1995; 15: 1549-55.
    CrossrefPubMedGoogle Scholar
  • 27 Nabulsi AA, Folsom AR, White A, Patsch W, Heiss G, Wu KK, Szklo M. Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. N Engl J Med 1993; 328: 1069-75.
    CrossrefPubMedGoogle 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: 420-3.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Andersen LF, Gram J, Skouby SO, Jespersen J. Effects of hormone replacement therapy on hemostatic cardiovascular risk factors. Am J Obstet Gynecol 1999; 180: 283-9.
    CrossrefPubMedGoogle Scholar
  • 30 Hoibraaten E, Os I, Seljeflot I, Andersen TO, Hofstad A, Sandset PM. The effects of hormone replacement therapy on hemostatic variables in women with angiographically verified coronary artery disease. Results from the estrogen in women with atherosclerosis study. Thromb Res 2000; 98: 19-27.
    CrossrefPubMedGoogle Scholar
  • 31 Scarabin P-Y, Plu-Bureau G, Bara L, Bonithon-Kopp C, Guize L, Samama M. Haemostatic variables and menopausal status: influence of hormone replacement therapy. Thromb Haemost 1993; 70: 584-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Caine YG, Bauer KA, Barzegar S, ten Cate H, Sacks FM, Walsh BW, Schiff I, Rosenberg RD. Coagulation activation following estrogen administration to postmenopausal women. Thromb Haemost 1992; 68: 392-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Teede HJ, McGrath BP, Smolich JJ, Malan E, Kotsopoulos D, Liang YL, Peverill RE. Postmenopausal hormone replacement therapy increases coagulation activity and fibrinolysis. Arterioscler Thromb Vasc Biol 2000; 20: 1404-9.
    CrossrefPubMedGoogle Scholar
  • 34 Notelovitz M, Kitchens C, Ware M, Hirschberg K, Coone L. Combination estrogen and progestogen replacement therapy does not adversely affect coagulation. Obstet Gynecol 1983; 62: 596-600.
    PubMedGoogle Scholar
  • 35 Perez GS, Garcia RL, Castellsague J, Duque OA. Hormone replacement therapy and risk of venous thromboembolism: population based case-control study. BMJ 1997; 314: 796-800.
    CrossrefPubMedGoogle Scholar
  • 36 Gebara OC, Mittleman MA, Sutherland P, Lipinska I, Matheney T, Xu P, Welty FK, Wilson PW, Levy D, Muller JE. Association between increased estrogen status and increased fibrinolytic potential in the Framingham Offspring Study. Circulation 1995; 91: 1952-8.
    CrossrefPubMedGoogle Scholar
  • 37 Shahar E, Folsom AR, Salomaa VV, Stinson VL, McGovern PG, Shimakawa T, Chambless LE, Wu KK. 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
  • 38 Koh KK, Mincemoyer R, Bui MN, Csako G, Pucino F, Guetta V, Waclawiw M, Cannon RO. Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women. N Engl J Med 1997; 336: 683-90.
    CrossrefPubMedGoogle Scholar
  • 39 Koh KK, Cardillo C, Bui MN, Hathaway L, Csako G, Waclawiw M, Panza JA, Cannon III RO. Vascular effects of estrogen and cholesterol-lowering therapies in hypercholesterolemic postmenopausal women. Circulation 1999; 99: 354-60.
    CrossrefPubMedGoogle Scholar
  • 40 Heeschen C, Hamm CW, Bruemmer J, Simoons ML. Predictive value of C-reactive protein and troponin T in patients with unstable angina: a comparative analysis. CAPTURE Investigators. Chimeric c7E3 AntiPlatelet Therapy in Unstable angina REfractory to standard treatment trial. J Am Coll Cardiol 2000; 35: 1535-42.
    CrossrefPubMedGoogle Scholar
  • 41 Ridker PM, Hennekens CH, Buring JE, Rifai N. 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
  • 42 Blann AD, Amiral J, McCollum CN. Prognostic value of increased soluble thrombomodulin and increased soluble E-selectin in ischaemic heart disease. Eur J. Haematol 1997; 59: 115-20.
    PubMedGoogle Scholar
  • 43 Blann AD, Miller JP, McCollum CN. von Willebrand factor and soluble E-selectin in the prediction of cardiovascular disease progression in hyper-lipidaemia. Atherosclerosis 1997; 132: 151-6.
    CrossrefPubMedGoogle Scholar
  • 44 Blann AD, Seigneur M, Steiner M, Boisseau MR, McCollum CN. Circulating endothelial cell markers in peripheral vascular disease: relationship to the location and extent of atherosclerotic disease. Eur J. Clin Invest 1997; 27: 916-21.
    CrossrefPubMedGoogle Scholar
  • 45 Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar V, Sacks FM. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991; 325: 1196-204.
    CrossrefPubMedGoogle Scholar
  • 46 Moorjani S, Dupont A, Labrie F, De Lignieres B, Cusan L, Dupont P, Mailloux J, Lupien P-J.. Changes in plasma lipoprotein and apoprotein composition in relation to oral versus percutaneous administration of estrogen alone or in cyclic association with utrogestan in menopausal women. J Clin Endocrinol Metab 1991; 73: 373-9.
    CrossrefPubMedGoogle Scholar
  • 47 Judd H. Efficacy of transdermal estradiol. Am J Obst Gynecol 1987; 156: 1326-31.
    CrossrefPubMedGoogle Scholar
  • 48 Chetkowski RJ, Meldrum DR, Steingold KA, Randle D, Lu JK, Eggena P, Hersham JM, Alkjaersig NK, Fletcher AP, Judd HL. Biological effects of transdermal estradiol. N Engl J Med 1986; 314: 1615-20.
    CrossrefPubMedGoogle Scholar
  • 49 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
  • 50 Davidson MH, Testolin LM, Maki KC, von Duvillard S, Drennan KB. A comparison of estrogen replacement, pravastatin, and combined treatment for the management of hypercholesterolemia in postmenopausal women. Arch Intern Med 1997; 157: 1186-92.
    CrossrefPubMedGoogle Scholar
  • 51 Granfone A, Campos H, McNamara JR, Schaefer MM, Lamon-Fava S, Ordovas JM, Schaefer EJ. Effects of estrogen replacement on plasma lipoproteins and apolipoproteins in postmenopausal, dyslipidemic women. Metabolism 1992; 41: 1193-8.
    CrossrefPubMedGoogle Scholar
  • 52 Walsh BW, Spiegelman D, Morrissey M, Sacks FM. Relationship between serum estradiol levels and the increases in high- density lipoprotein levels in postmenopausal women treated with oral estradiol. J Clin Endocrinol Metab 1999; 84: 985-9.
    PubMedGoogle Scholar