Double blind, randomized study of estradiol replacement therapy on markers of inflammation, coagulation and fibrinolysis


      Estrogen replacement therapy (ERT) has been found to be associated with increased cardiovascular risk in the first year after initiation of ERT. We compared the effects of oral and transdermal estradiol (E2) replacement therapy on markers of inflammation, coagulation and fibrinolysis in a randomized double-blind trial. Forty-three healthy women were randomized 6 weeks after surgically induced menopause to receive treatment with either oral or transdermal E2 over a period of 28 weeks. At baseline and after 28 weeks, levels of serum lipids and lipoproteins, and markers of coagulation, fibrinolysis and inflammation were determined. Among fibrinolytic parameters, oral E2 shortened euglobulin clot lysis time (P<0.05) and reduced tissue type plasminogen activator antigen (P=0.01) and plasminogen activator inhibitor activity (P<0.05). Among coagulation parameters, both routes of E2 replacement decreased fibrinogen levels (P=0.002 for oral and P=0.007 for transdermal E2). Oral E2 resulted in an increase in C-reactive protein (CRP) from 2.15 (0.71–4.05) to 3.41 (1.12–5.92) mg/l (P=0.04), while transdermal E2 showed no effect. Levels of serum amyloid A (SAA), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) did not change significantly after oral and transdermal E2. Oral E2 significantly improved the lipid profile, while transdermal E2 had a less pronounced effect. Both oral and transdermal E2 significantly reduced fasting glucose. Oral E2 was associated with a pro-inflammatory response, but at the same time improved fibrinolytic capacity, showed no pro-coagulatory effects, and acted beneficially on lipids and lipoproteins. There was no influence of transdermal E2 on markers of coagulation activation, fibrinolysis and inflammation, but it decreased fibrinogen levels significantly. Further studies are needed to explore the clinical relevance of these observations.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Gordon T
        • Kannel W.B
        • Hjortland M.C
        • McNamara P.M
        Menopause and coronary heart disease. The Framingham study.
        Ann. Intern. Med. 1978; 89: 157-161
        • Rosenberg L
        • Hennekens C.H
        • Rosner B
        • Belanger C
        • Rothman K.J
        • Speizer F.E
        Early menopause and the risk of myocardial infarction.
        Am. J. Obstet. Gynecol. 1981; 139: 47-51
        • Johansson B.W
        • Kaij L
        • Kullander S
        • Lennér S
        • Svanberg L
        • Åstedt B
        On some late effects of bilateral oophorectomy in the age range 15–30 years.
        Acta Obstetr. Gynecol. Scand. 1975; 54: 449-461
        • Lip G.Y.H
        • Blann A.D
        • Jones A.F
        • Beevers D.G
        Effects of hormone-replacement therapy on hemostatic factors, lipid factors, and endothelial function in women undergoing surgical manopause: implications for prevention of atherosclerosis.
        Am. Heart J. 1997; 134: 764-771
        • Stampfer M.J
        • Colditz G.A
        Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence.
        Prev. Med. 1991; 20: 47-63
        • Grodstein F
        • Stampfer M.J
        • Manson J.E
        • et al.
        Postmenopausal estrogen and progestin use and the risk of cardiovascular disease.
        New Engl. J. Med. 1996; 335: 453-461
        • Mijatovic V
        • van der Mooren M.J
        • Stehouwer C.D.A
        • Netelenbos J.C
        • Kenemans P
        Postmenopausal hormone replacement, risk estimators for coronary artery disease and cardiovascular protection.
        Gynecol. Endocrinol. 1999; 13: 130-144
        • Hulley S
        • Grady D
        • Bush T
        • et al.
        Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.
        J. Am. Med. Assoc. 1998; 280: 605-613
        • Writing group for the Women's health initiative investigators
        Risks and benefits of estrogen plus pregestin in healthy postmenopausal women. Principal results from the Women's health initiative randomized controlled trial.
        J. Am. Med. Assoc. 2002; 288: 321-333
        • Van Baal W.M
        • Kenemans P
        • van der Mooren M.J
        • Kessel H
        • Emeis J.J
        • Stehouwer C.D.A
        Increased C-reactive protein levels during short-term hormone replacement therapy in healthy postmenopausal women.
        Thromb. Haemost. 1999; 81: 925-928
        • Ridker P.M
        • Hennekens C.H
        • Rifai N
        • Buring J.E
        • Manson J.E
        Hormone replacement therapy and increased plasma concentration of C-reactive protein.
        Circulation. 1999; 100: 713-716
        • 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: 717-722
        • Ridker P.M
        • Buring J.E
        • Shih J
        • Matias M
        • Hennekens C.H
        Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women.
        Circulation. 1998; 98: 731-733
        • Koenig W
        • Sund M
        • Fröhlich M
        • et al.
        C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men.
        Circulation. 1999; 99: 237-242
        • Ridker P.M
        • Hennekens C.H
        • Buring J.E
        • Rifai N
        C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.
        New Engl. J. Med. 2000; 342: 836-843
        • Liuzzo G
        • Biasucci L.M
        • Gallimore J.R
        • et al.
        The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina.
        New Engl. J. Med. 1994; 331: 417-424
        • Walsh B.W
        • Cox D.A
        • Sashegyi A
        • Dean R.A
        • Tracy R.P
        • Anderson P.W
        Role of tumor necrosis factor-a and interleukin-6 in the effects of hormone replacement therapy and raloxifene on C-reactive protein in postmenopausal women.
        Am. J. Cardiol. 2001; 88: 825-828
        • Van Baal M.W
        • Emeis J.J
        • van der Mooren M.J
        • Kessel H
        • Kenemans P
        • Stehouwer C.D.A
        Impaired procoagulant-anticoagulant balance during hormone replacement therapy? A randomized, placebo-controlled 12-week study.
        Thromb. Haemost. 2000; 83: 29-34
        • Koh K.K
        • Mincemoyer R
        • Bui M.N
        • et al.
        Effects of hormone replacement therapy on fibrinolysis in postmenopausal women.
        New Engl. J. Med. 1997; 336: 683-690
        • Hoibraaten E
        • Os I
        • Seljeflot I
        • Andersen T.O
        • Hofstad A.E
        • Sandset P.M
        The effects of hormone replacement therapy on haemostatic variables in women with angiographically verified coronary artery disease: results from the estrogen in women with atherosclerosis study.
        Thromb. Res. 2000; 98: 19-27
        • Teede H.J
        • McGrath B.P
        • Smolich J.J
        • et al.
        Postmenopausal hormone replacement therapy increases coagulation activity and fibrinolysis.
        Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1404-1409
        • 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
        • Chetkowski R.J
        • Meldrum D.R
        • Steingold K.A
        • et al.
        Biologic effects of transdermal estradiol.
        New Engl. J. Med. 1986; 314: 1615-1620
        • Powers M.S
        • Schenkel L
        • Darley P.E
        • Good W.R
        • Balestra J.C
        • Place V.A
        Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17 β-estradiol: comparison with conventional oral estrogens used for hormone replacement.
        Am. J. Obstet. Gynecol. 1985; 152: 1099-1106
        • Mcmanus J
        • McEneny J
        • Thompson W
        • Young I.S
        The effect of hormone replacement therapy on the oxidation of low density lipoprotein in postmenopausal women.
        Atherosclerosis. 1997; 135: 73-81
        • Haines C
        • Chung T
        • Chang A
        • Masarei J
        • Tomlinson B
        • Wong E
        Effect of oral estradiol on Lp(a) and other lipoproteins in postmenopausal women.
        Arch. Intern. Med. 1996; 156: 866-872
        • Crook D
        • Cust M.P
        • Gangar K.F
        • et al.
        Comparison of transdermal and oral estrogen/progestin hormone replacement therapy: effects on serum lipids and lipoproteins.
        Am. J. Obstet. Gynecol. 1992; 166: 950-955
        • Vehkavaara S
        • Silveira A
        • Hakala-Ala Pietilå 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: 619-625
        • Lowe G.D.O
        • Upton M.N
        • Rumley A
        • McConnachie A
        • O'Reilly D.S.J
        • Watt G.C.M
        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: 550-556
        • Visser M
        • Bouter L.M
        • McQuillan G.M
        • Wener M.H
        • Harris T.B
        Elevated C-Reactive protein levels in overweight and obese adults.
        J. Am. Med. Assoc. 1999; 282: 2131-2135
        • Yamada T
        Serum amyloid A (SAA): a concise review of biology, assay methods and clinical usefulness.
        Clin. Chem. Lab. Med. 1999; 37: 381-388
        • Buchweitz M.E
        • Muller-Steinhard M
        • Kressin P
        • Meyhofer-Malik A
        • Diedrich K
        Prospective evaluation of the systemic immune response following abdominal, vaginal, and laparoscopically assisted vaginal hysterectomy.
        Surg. Endosc. 2001; 15: 463-466
        • Gilliland H.E
        • Armstrong M.A
        • Carabine U
        • McMurray T.J
        The choice of anesthetic maintenance technique influences the anti-inflammatory cytokine response to abdominal surgery.
        Anesth. Analg. 1997; 85: 1394-1398
        • Wergeland R
        • Oyen O
        • Bentdal O
        • Stokke O
        MicroCRP a highly sensitive CRP method applied in the monitoring of renal allograft recipients.
        Scand. J. Clin. Lab. Invest. 1999; 59: 405-416
        • Thompson S.G
        • Kienast J
        • Pyke S.D.M
        • Haverkate F
        • van de Loo J.C
        Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris.
        New Engl. J. Med. 1995; 332: 635-641
        • Scarabin P.-Y
        • Alhenc-Gelas M
        • Plu-Bureau G
        • Taisine 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
        • Lindoff C
        • Peterson F
        • Lecander I
        • Martinsson G
        • Åstedt B
        Transdermal estrogen replacement therapy: beneficial effects on hemostatic risk factors for cardiovascular disease.
        Maturitas. 1996; 24: 43-50
        • The writing group for the estradiol clotting factors study
        Effects on haemostasis of hormone replacement therapy with transdermal estradiol and oral sequential madroxyprogesterone acetate: a 1-year, double-blind, placebo-controlled study.
        Thromb. Haemost. 1996; 3: 476-480
        • Alkjaersig N
        • Fletcher A.P
        • de Ziegler D
        • Steingold K.A
        • Meldrum D.R
        • Judd H
        Blood coagulation in postmenopausal women given estrogen treatment: comparison of transdermal and oral administration.
        J. Lab. Clin. Med. 1988; 111: 224-228
        • 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
        • Boneu B
        • Bes G
        • Pelzer H
        • Sie P
        • Boccalon H
        D-dimers, thrombin-antithrombin III complexes and prothrombin fragments F1+2: diagnosis value in clinically suspected deep vein thrombosis.
        Thromb. Haemost. 1991; 65: 28-32
        • Caine Y.G
        • Bauer K.A
        • Barzegar S
        • et al.
        Coagulation activation following estrogen administration to postmenopausal women.
        Thromb. Haemost. 1992; 68: 392-395
        • Pinto S
        • Bruni V
        • Rosati D
        • et al.
        Effects of estrogen replacement therapy on thrombin generation.
        Thromb. Res. 1997; 85: 185-193