Download PDF
Thromb Haemost 2000; 83(06): 944-948
DOI: 10.1055/s-0037-1613947
Commentary
Schattauer GmbH

Reduced Expression of Endothelial Cell Markers after Long-term Transdermal Hormone Replacement Therapy in Women with Coronary Artery Disease

Ingebjørg Seljeflot
1   From the Research Forum, Ullevål University Hospital, Oslo, Norway
,
Harald Arnesen
2   Department of Medicine, Ullevål University Hospital, Oslo, Norway
,
Ann-Elin Hofstad
2   Department of Medicine, Ullevål University Hospital, Oslo, Norway
,
Ingrid Os
2   Department of Medicine, Ullevål University Hospital, Oslo, Norway
› Author Affiliations
Further Information

Publication History

Received 18 November 1999

Accepted after revision 04 February 2000

Publication Date:
14 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

The effects of 12 months hormone replacement therapy (HRT) on biochemical markers associated with endothelial function were studied in 98 postmenopausal women with CAD, who were randomized to transdermal HRT or a control group.

A significant reduction in the levels of von Willebrand factor in the HRT-group compared to controls was seen after 3 months, maintained after 12 months (p <0.001). Significant reduction in the HRT-group compared to controls was also seen in VCAM-1 after 3 months, sustained after 12 months (p = 0.013 and p = 0.045, respectively), and E-selectin was reduced by about 20% after 3 months on HRT, the reduction being statistically significant after 12 months (p <0.001). Significantly reduced levels of ICAM-1 were also seen after 12 months (p = 0.048). No effects could be observed on tPA-antigen or thrombomodulin.

The reduction in procoagulant and proinflammatory markers of endothelial function after long-term transdermal HRT could indicate a beneficial effect on the endothelium and thus a potentially modulating effect on the progression of atherosclerosis in women with CAD.

Key words

Hormone replacement therapy - endothelial cell markers - atherosclerosis - procoagulant activity - inflammation
 

  • References

  • 1 Gordon T, Kannel WB, Hjortland MC, McNamara PM. Menopause and coronary heart disease. The Framingham Study. Ann Intern Med 1978; 89: 157-61.
    CrossrefPubMedGoogle Scholar
  • 2 Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen theraphy and cardiovascular disease: 10-year follow-up from the Nurses’ Health Study. N Engl J Med 1991; 325: 756-62.
    CrossrefPubMedGoogle Scholar
  • 3 Grady D, Rubin SM, Petitti DB, Fox CS, Blake D, Ettinger B, Ernster VL, Cummings SR. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992; 117: 1016-37.
    CrossrefPubMedGoogle Scholar
  • 4 Sullivan JM, Vander Zwaag R, Hughes JP, Maddock V, Kroetz FW, Ramanthan KB, Mirvis DM. Estrogen replacement therapy and coronary artery disease. Arch Intern Med 1990; 150: 2557-62.
    CrossrefPubMedGoogle Scholar
  • 5 Hully S, Grady D, Bush T, Furberg C, Herrington D, 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 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
  • 7 The writing group of 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
  • 8 Falkeborn M, Persson I, Adami H, Bergstrøm R, Eaker E, Mohsen HLR, Naessen T. The risk of acute myocardial infarction after oestrogen-progestogen replacement. Br J Pharmacol 1992; 99: 821-8.
    PubMedGoogle Scholar
  • 9 Brathena RK, Anklesaria BS, Ganatra AM, Pinto R. The influence of transdermal oestradiol replacement therapy and medroxyprogesterone acetate on lipids and lipoproteins. Br J Clin Pharmacol 1998; 45: 170-2.
    PubMedGoogle Scholar
  • 10 Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801-9.
    CrossrefPubMedGoogle Scholar
  • 11 Roqué M, Heras M, Roig E, Masotti M, Rigol M, Betriu A, Balasch J, Sanz G. Short-term effects of transdermal estrogen replacement therapy on coronary vascular reactivity in postmenopausal women with angina pectoris and normal results of coronary angiograms. J Am Coll Cardiol 1998; 31: 139-43.
    CrossrefPubMedGoogle Scholar
  • 12 Al-Khalili F, Eriksson M, Landgren BM, Schenck-Gustafsson K. Effects of conjugated estrogen on peripheral flow-mediated vasodilation in postmenopausal women. Am J Cardiol 1998; 82: 215-8.
    CrossrefPubMedGoogle Scholar
  • 13 Sørensen KE, Dorup I, Hermann AP, Mosekilde L. Combined hormone replacement therapy does not protect women against the age-related decline in endothelium-dependent vasomotor function. Circulation 1998; 97: 1234-8.
    CrossrefPubMedGoogle Scholar
  • 14 Liao W. Endotoxin: Possible roles in initiation and development of atherosclerosis. J Lab Clin Med 1996; 128: 452-60.
    CrossrefPubMedGoogle Scholar
  • 15 Blann AD, Collum CN. Circulating endothelial cell/leucocyte adhesion molecules in atherosclerosis. Thromb Haemost 1994; 72: 151-4.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Fassbender K, Mössner R, Motsch L, Kischka U, Grau A, Hennerici M. Circulating selectin- and immunoglobulin-type adhesion molecules in acute ischemic stroke. Stroke 1995; 26: 1361-4.
    CrossrefPubMedGoogle Scholar
  • 17 Hackman A, Abe Y, Insull Jr W, Pownall H, Smith L, Dunn K, Gotto Jr AM, Ballantyne CM. Levels of soluble cell adhesion molecules in patients with dyslipidemia. Circulation 1996; 93: 1334-8.
    CrossrefPubMedGoogle Scholar
  • 18 Ridker PM, Hennekens CH, Roitman-Johnson B, Stampfer MJ, Allen J. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet 1998; 351: 88-92.
    CrossrefPubMedGoogle Scholar
  • 19 Seigneur M, Dufourcq P, Conri C, Constans J, Mercie P, Pruvost JA, Amiral J, Midy D, Baste J-C, Boisseau MR. Levels of plasma thrombomodulin are increased in atheromatous arterial disease. Thromb Res 1993; 71: 423-31.
    CrossrefPubMedGoogle Scholar
  • 20 Badimon L, Badimon JJ, Chesebro JH, Fuster V. von Willebrand factor and cardiovascular disease. Thromb Haemost 1993; 70: 111-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Ridker PM, Vaughan DE, Stampfer MJ, Manson J, Hennekens CH. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993; 341: 1165-8.
    CrossrefPubMedGoogle Scholar
  • 22 Os I, Hofstad AE, Brekke M, Abdelnoor M, Nesheim BI, Jacobsen AF, Birkeland K, Larsen A, Midtbø K, Westheim A. The EWA (Estrogen in Women with Atherosclerosis) Study: A randomized study of the use of hormone replacement therapy in women with angiographically verified coronary artery disease. Characteristics of the study population. Effects on lipids and lipoproteins. J Intern Med. 2000 247. 03 X.
    PubMedGoogle Scholar
  • 23 Dean AG, Dean JA, Burton AH, Dicker RC. Epi Info, Version 5. USD, Inc., Stone Mountain; Georgia, USA: 1990
  • 24 Blann A, Seigneur M. Endothelial cell markers in peripheral disease and vascular surgery. Critical Ischaemia 1996; 06: 87-95.
    PubMedGoogle Scholar
  • 25 Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris: European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med 1995; 332: 635-41.
    CrossrefPubMedGoogle Scholar
  • 26 Lip GYH, Blann AD, Jones AF, Beevers DG. Effects of hormone-replacement therapy on hemostatic factors, lipid factors, and endothelial function in women undergoing surgical menopause: Implication for prevention of atherosclerosis. Am Heart J 1997; 134: 764-71.
    CrossrefPubMedGoogle Scholar
  • 27 Blann AD, Dobrotova M, Kubisz P, McCollum CN. von Willebrand factor, soluble P-selectin, tissue plasminogen activator and plasminogen activator inhibitor in atherosclerosis. Thromb Haemost 1995; 74: 626-30.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Chong BH, Murray B, Berndt MC, Dunlop LC, Brighton T, Chesterman CN. Plasma P-selectin is increased in thrombotic consumptive platelet disorders. Blood 1994; 83: 1535-41.
    PubMedGoogle Scholar
  • 29 van Baal WM, Emeis JJ, Kenemans P, Kessel H, Peters-Muller ERA, Schalkwijk CG, van der Mooren MJ, Stehouwer CDA. Short-term hormone replacement therapy: reduced plasma levels of soluble adhesion molecules. Eur J Clin Invest 1999; 29: 913-21.
    CrossrefPubMedGoogle Scholar
  • 30 Caulin-Glaser T, Farrell WJ, Pfau SE, Zaret B, Bunger K, Setaro JF, Brennan JJ, Bender JR, Cleman MW, Cabin HS, Remetz MS. Modulation of circulating cellular adhesion molecules in postmenopausal women with coronary artery disease. J Am Coll Cardiol 1998; 31: 1555-60.
    CrossrefPubMedGoogle Scholar
  • 31 Scarabin PY, Alhenc-Gelas M, Oger E, Plu-Bureau G. Hormone replacement therapy and circulating ICAM-1 in postmenopausal women. A randomised controlled trial. Thromb Haemost 1999; 81: 673-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 von Holst T, Salbach B, Kübler W, Salbach PB. Hormone replacement therapy and levels of soluble adhesion molecules in postmenopausal women. J Am Coll Cardiol. 1999 33. Suppl. A, Abstract 1221-111.
    PubMedGoogle Scholar
  • 33 Koh KK, Bui MN, Mincemoyer R, Cannon RO. Effects of hormone therapy on inflammatory cell adhesion molecules in postmenopausal healthy women. Am J Cardiol 1997; 80: 1505-7.
    CrossrefPubMedGoogle Scholar
  • 34 Koh KK, Cardillo C, Minh N. et al. Vascular effects of estrogen and cholesterol-lowering therapies in hyper cholesterolemic postmenopausal women. Circulation 1999; 99: 354-60.
    CrossrefPubMedGoogle Scholar
  • 35 Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 1999; 14: 115-26.
    PubMedGoogle Scholar
  • 36 Sack MN, Rader DJ, Cannon RO. Oestrogen and inhibition of oxidation of low-density lipoproteins in postmenopausal women. Lancet 1994; 343: 269-70.
    CrossrefPubMedGoogle Scholar
  • 37 Barnes PJ, Karin M. Nuclear factor-KB – A pivotal transcription factor in chronic inflammatory disease. N Engl J Med 1997; 336: 1066-71.
    CrossrefPubMedGoogle Scholar
  • 38 Collins T. Biology of disease: endothelial nuclear factor-KB and the initiation of the atherosclerotic lesion. Lab Invest 1993; 68: 499-508.
    PubMedGoogle Scholar
  • 39 Caulin-Glaser T, Watson CA, Pardi R, Bender JR. Effects of 17 13-estradiol on cytokine-induced endothelial cell adhesion molecules expression. J Clin Invest 1996; 98: 36-42.
    CrossrefPubMedGoogle Scholar
  • 40 Marui N, Offermann MK, Swerlick R, Kunsch C, Rosen CA, Ahmad M, Alexander RW, Medford RM. Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidantsensitive mechanism in human vascular endothelial cells. J Clin Invest 1993; 92: 1866-74.
    CrossrefPubMedGoogle Scholar
  • 41 Kuhnvelten WN, Pippirs U. Novel connections between NADPH-induced lipid peroxidation and cytochrome P450 inactivation, and antioxidant and enzyme protective properties of estradiol in gonadal membranes. Free Radic Res 1997; 26: 125-33.
    CrossrefPubMedGoogle Scholar
  • 42 Best PJM, Berger PB, Miller VM, Lerman A. The effects of estrogen replacement therapy on plasma nitric oxide and endothelin-1 levels in postmenopausal women. Ann Intern Med 1998; 128: 285-8.
    CrossrefPubMedGoogle Scholar
  • 43 De Caterina R, Libby P, Peng H-B, Thannickal VJ, Rajavashisth TB, Gimbrone MA, Shin WS, Liao JK. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 1995; 96: 60-8.
    CrossrefPubMedGoogle Scholar
  • 44 Miller VM, Vanhoutte PM. Progesterone and modulation of endothelium-dependent responses in canine coronary arteries. Am J Physiol 1991; 261: R1022-7.
    PubMedGoogle Scholar
  • 45 Tranquilli AL, Mazzanti L, Cugini AM, Cester N, Garzetti GG, Romanini C. Transdermal estradiol and medroxyprogesterone acetate in hormone replacement therapy are both antioxidants. Gynecol Endocrinol 1995; 09: 137-41.
    CrossrefPubMedGoogle Scholar
  • 46 Massafra C, Buonocore G, Gioia D, Sargentini I, Farina G. Effects of estrogens and medroxyprogesteone-acetate treatment on erythrocyte antioxidant enzyme activities and malondialdehyde plasma levels in amenorrheic women. J Clin Endocrinol Metab 1997; 82: 173-5.
    PubMedGoogle Scholar