Current Atherosclerosis Reports

, Volume 4, Issue 5, pp 387–395

Postmenopausal hormone replacement therapy and atherosclerosis

  • Jennifer E. Ho
  • Lori Mosca


The role of postmenopausal hormone replacement therapy (HRT) in the prevention of cardiovascular disease (CVD) has evolved since estrogen was first proposed to be vasoprotective. The discovery of novel molecular signaling pathways involving the estrogen receptor in vascular cells and the elucidation of numerous biologic mechanisms have suggested that HRT may exert its potentially beneficial or adverse cardiovascular effects through multiple mechanisms. Estrogen has genomic, as well as rapid nongenomic, effects that alter vasodilation, coagulation, inflammation, and the vascular injury response, some of which may have potentially beneficial or adverse cardiovascular consequences. Current guidelines do not support the use of HRT in the secondary prevention of CVD, and recent results of primary prevention trials show evidence of increased early cardiovascular risk and no overall health benefit with combination estrogen-progestin treatment. The role of estrogen alone in the primary prevention of CVD awaits the results of ongoing trials. The key to the use of estrogen replacement therapy for the prevention of CVD may be to target therapy before atherosclerosis is evident, and to identify women with genetic susceptibility who may be at increased risk for an adverse outcome associated with therapy.


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References and Recommended Reading

  1. 1.
    American Heart Association: 2001 Heart and Stroke Statistical Update. Dallas, Texas: American Heart Association. 2000.Google Scholar
  2. 2.
    Kannel WB, Wilson PW: Risk factors that attenuate the female coronary disease advantage. Arch Intern Med 1995, 155:57–61.PubMedCrossRefGoogle Scholar
  3. 3.
    Mendelsohn ME, Karas RH: The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999, 340:1801–1811.PubMedCrossRefGoogle Scholar
  4. 4.
    Losordo DW, Kearney M, Kim EA, Jekanowski J, Isner JM: Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women. Circulation 1994, 89:1501–1510.PubMedGoogle Scholar
  5. 5.
    Zhu Y, Bian Z, Lu P, et al.: Abnormal vascular function and hypertension in mice deficient in estrogen receptor beta. Science 2002, 295:505–508.PubMedCrossRefGoogle Scholar
  6. 6.
    Chen Z, Yuhanna IS, Galcheva-Gargova Z, et al.: Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest 1999, 103:401–406.PubMedGoogle Scholar
  7. 7.
    Haynes MP, Sinha D, Russell KS, et al.: Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3-kinase-Akt pathway in human endothelial cells. Circ Res 2000, 87:677–682.PubMedGoogle Scholar
  8. 8.
    Simoncini T, Hafezi-Moghadam A, Brazil DP, et al.: Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 2000, 407:538–541.PubMedCrossRefGoogle Scholar
  9. 9.
    Espeland MA, Marcovina SM, Miller V, et al.: Effect of postmenopausal hormone therapy on lipoprotein(a) concentration. PEPI Investigators. Postmenopausal Estrogen/Progestin Interventions. Circulation 1998, 97:979–986.PubMedGoogle Scholar
  10. 10.
    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.CrossRefGoogle Scholar
  11. 11.
    Brinton EA: Oral estrogen replacement therapy in postmenopausal women selectively raises levels and production rates of lipoprotein A-I and lowers hepatic lipase activity without lowering the fractional catabolic rate. Arterioscler Thromb Vasc Biol 1996, 16:431–440.PubMedGoogle Scholar
  12. 12.
    Nabulsi AA, Folsom AR, White A, et al.: Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. The Atherosclerosis Risk in Communities Study Investigators. N Engl J Med 1993, 328:1069–1075.PubMedCrossRefGoogle Scholar
  13. 13.
    Sack MN, Rader DJ, Cannon RO 3rd: Oestrogen and inhibition of oxidation of low-density lipoproteins in postmenopausal women. Lancet 1994, 343:269–270.PubMedCrossRefGoogle Scholar
  14. 14.
    Mendelsohn ME, Karas RH: Estrogen and the blood vessel wall. Curr Opin Cardiol 1994, 9:619–626.PubMedCrossRefGoogle Scholar
  15. 15.
    White RE, Darkow DJ, Lang JL: Estrogen relaxes coronary arteries by opening BKCa channels through a cGMP-dependent mechanism. Circ Res 1995, 77:936–942.PubMedGoogle Scholar
  16. 16.
    Koh KK, Home MK 3rd, Cannon RO 3rd: Effects of hormone replacement therapy on coagulation, fibrinolysis, and thrombosis risk in postmenopausal women. Thromb Haemost 1999, 82:626–633.PubMedGoogle Scholar
  17. 17.
    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.PubMedGoogle Scholar
  18. 18.
    Agrawal R, Prelevic G, Conway GS, et al.: Serum vascular endothelial growth factor concentrations in postmenopausal women: the effect of hormone replacement therapy. Fertil Steril 2000, 73:56–60.PubMedCrossRefGoogle Scholar
  19. 19.
    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, 85:214–218.PubMedCrossRefGoogle Scholar
  20. 20.
    Vehkavaara S, Westerbacka J, Hakala-Ala-Pietila T, et al.: Effect of estrogen replacement therapy on insulin sensitivity of glucose metabolism and preresistance and resistance vessel function in healthy postmenopausal women. J Clin Endocrinol Metab 2000, 85:4663–4670.PubMedCrossRefGoogle Scholar
  21. 21.
    Grady D, Wenger NK, Herrington D, et al.: Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progest in Replacement Study. Ann Intern Med 2000, 132:689–696.PubMedGoogle Scholar
  22. 22.
    Braunstein JB, Kershner DW, Bray P, et al.: Interaction of hemostatic genetics with hormone therapy: new insights to explain arterial thrombosis in postmenopausal women. Chest 2002, 121:906–920.PubMedCrossRefGoogle Scholar
  23. 23.
    Glueck CJ, Wang P, Fontaine RN, et al.: Effect of exogenous estrogen on atherothrombotic vascular disease risk related to the presence or absence of the factor V Leiden mutation (resistance to activated protein C). Am J Cardiol 1999, 84:549–554.PubMedCrossRefGoogle Scholar
  24. 24.
    Rossouw JE: Hormones, genetic factors, and gender differences in cardiovascular disease. Cardiovasc Res 2002, 53:550–557.PubMedCrossRefGoogle Scholar
  25. 25.
    Psaty BM, Smith NL, Lemaitre RN, et al.: Hormone replacement therapy, prothrombotic mutations, and the risk of incident nonfatal myocardial infarction in postmenopausal women. JAMA 2001, 285:906–913.PubMedCrossRefGoogle Scholar
  26. 26.
    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, 86:4216–4222.PubMedCrossRefGoogle Scholar
  27. 27.
    Ridker PM, Hennekens CH, Rifai N, Buring JE, Manson JE: Hormone replacement therapy and increased plasma concentration of C-reactive protein. Circulation 1999, 100:713–716.PubMedGoogle Scholar
  28. 28.
    Wingrove CS, Garr E, Godsland IF, Stevenson JC: 17beta-oestradiol enhances release of matrix metalloproteinase-2 from human vascular smooth muscle cells. Biochim Biophys Acta 1998, 1406:169–174.PubMedGoogle Scholar
  29. 29.
    Cannon R, Yang BK, Ardans J: Increased serum matrix metalloproteinase-9 expression in postmenopausal women on estrogen therapy [abstract]. J Am Coll Cardiol 1995, 35(suppl 2):303.Google Scholar
  30. 30.
    Fuster V, Badimon J, Chesebro JH, Fallon JT: Plaque rupture, thrombosis, and therapeutic implications. Haemostasis 1996, 26(suppl 4):269–284.PubMedGoogle Scholar
  31. 31.
    Walsh BW, Schiff I, Rosner B, et al.: Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991, 325:1196–1204.PubMedCrossRefGoogle Scholar
  32. 32.
    Gaziano JM, Hennekens CH, O’Donnell CJ, Breslow JL, Buring JE: Fasting triglycerides, high-density lipoprotein, and risk of myocardial infarction. Circulation 1997, 96:2520–2525.PubMedGoogle Scholar
  33. 33.
    Col NF, Pauker SG, Goldberg RJ, et al.: Individualizing therapy to prevent long-term consequences of estrogen deficiency in postmenopausal women. Arch Intern Med 1999, 159:1458–1466.PubMedCrossRefGoogle Scholar
  34. 34.
    Stampfer MJ, Colditz GA: Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med 1991, 20:47–63.PubMedCrossRefGoogle Scholar
  35. 35.
    Grady D, Rubin SM, Petitti DB, et al.: Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992, 117:1016–1037.PubMedGoogle Scholar
  36. 36.
    Grodstein F, Stampfer M: The epidemiology of coronary heart disease and estrogen replacement in postmenopausal women. Prog Cardiovasc Dis 1995, 38:199–210.PubMedCrossRefGoogle Scholar
  37. 37.
    Grodstein F, Manson JE, Colditz GA, et al.: A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000, 133:933–941.PubMedGoogle Scholar
  38. 38.
    Sullivan JM, Vander Zwaag R, Lemp GF, et al.: Postmenopausal estrogen use and coronary atherosclerosis. Ann Intern Med 1988, 108:358–363.PubMedGoogle Scholar
  39. 39.
    Sullivan JM: Coronary arteriography in estrogen-treated postmenopausal women. Prog Cardiovasc Dis 1995, 38:211–222.PubMedCrossRefGoogle Scholar
  40. 40.
    Grodstein F, Manson JE, Stampfer MJ: Postmenopausal hormone use and secondary prevention of coronary events in the nurses’ health study a prospective, observational study. Ann Intern Med 2001, 135:1–8.PubMedGoogle Scholar
  41. 41.
    Wenger NK, Knatterud GL, Canner PL: Early risks of hormone therapy in patients with coronary heart disease. JAMA 2000, 284:41–43.PubMedCrossRefGoogle Scholar
  42. 42.
    Alexander KP, Newby LK, Hellkamp AS, et al.: Initiation of hormone replacement therapy after acute myocardial infarction is associated with more cardiac events during follow-up. J Am Coll Cardiol 2001, 38:1–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Heckbert SR, Kaplan RC, Weiss NS, et al.: Risk of recurrent coronary events in relation to use and recent initiation of postmenopausal hormone therapy. Arch Intern Med 2001, 161:1709–1713.PubMedCrossRefGoogle Scholar
  44. 44.
    Matthews KA, Kuller LH, Wing RR, Meilahn EN, Plantinga P: Prior to use of estrogen replacement therapy, are users healthier than nonusers? Am J Epidemiol 1996, 143:971–978.PubMedGoogle Scholar
  45. 45.
    Mosca L: Estrogen and atherosclerosis. J Invest Med 1998, 46:381–386.Google Scholar
  46. 46.
    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, 280:605–613.PubMedCrossRefGoogle Scholar
  47. 47.
    Herrington DM, Reboussin DM, Brosnihan KB, et al.: Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000, 343:522–529.PubMedCrossRefGoogle Scholar
  48. 48.
    Schulman S, Thiemann D, Ouyang P, et al.: Effects of acute hormone therapy on recurrent ischemia in postmenopausal women with unstable angina. J Am Coll Cardiol 2001, 37:648A.Google Scholar
  49. 49.
    Clarke S, Kelleher J, Lloyd-Jones H: Transdermal hormone replacement therapy for the secondary prevention of coronary artery disease in postmenopausal women [abstract]. Eur Heart J 2000, 21:212.Google Scholar
  50. 50.
    Viscoli CM, Brass LM, Kernan WN, et al.: A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001, 345:1243–1249.PubMedCrossRefGoogle Scholar
  51. 51.
    Pettiti DB: Hormone replacement therapy and heart disease prevention: experimentation trumps observation [editorial]. JAMA 1998, 280:650–652.CrossRefGoogle Scholar
  52. 52.
    Post WS, Goldschmidt-Clermont PJ, Wilhide CC, et al.: Methylation of the estrogen receptor gene is associated with aging and atherosclerosis in the cardiovascular system. Cardiovasc Res 1999, 43:985–991.PubMedCrossRefGoogle Scholar
  53. 53.
    Dollar AL, Kragel AH, Fernicola DJ, Waclawiw MA, Roberts WC: Composition of atherosclerotic plaques in coronary arteries in women less than 40 years of age with fatal coronary artery disease and implications for plaque reversibility. Am J Cardiol 1991, 67:1223–1227.PubMedCrossRefGoogle Scholar
  54. 54.
    Hodis HN, Mack WJ, Lobo RA, et al.: Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001, 135:939–953.PubMedGoogle Scholar
  55. 55.
    Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002, 288:321–333.CrossRefGoogle Scholar
  56. 56.
    Gruber CJ, Tschugguel W, Schneeberger C, Huber JC: Production and actions of estrogens. N Engl J Med 2002, 346:340–352.PubMedCrossRefGoogle Scholar
  57. 57.
    Ansbacher R: The pharmacokinetics and efficacy of different estrogens are not equivalent. Am J Obstet Gynecol 2001, 184:255–263.PubMedCrossRefGoogle Scholar
  58. 58.
    Meschia M, Bruschi F, Soma M, et al.: Effects of oral and transdermal hormone replacement therapy on lipoprotein(A) and lipids: a randomized controlled trial. Menopause 1998, 5:157–162.PubMedGoogle Scholar
  59. 59.
    Vehkavaara S, Hakala-Ala-Pietila T, Virkamaki A, et al.: Differential effects of oral and transdermal estrogen replacement therapy on endothelial function in postmenopausal women. Circulation 2000, 102:2687–2693.PubMedGoogle Scholar
  60. 60.
    Lobo RA, Bush T, Carr BR, Pickar JH: Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism. Fertil Steril 2001, 76:13–24.PubMedCrossRefGoogle Scholar
  61. 61.
    Dewell A, Hollenbeck CB, Bruce B: The effects of soy-derived phytoestrogens on serum lipids and lipoproteins in moderately hypercholesterolemic postmenopausal women. J Clin Endocrinol Metab 2002, 87:118–121.PubMedCrossRefGoogle Scholar
  62. 62.
    Clarkson TB: Soy, soy phytoestrogens and cardiovascular disease. J Nutr 2002, 132:566S-569S.PubMedGoogle Scholar
  63. 63.
    Anderson JW, Johnstone BM, Cook-Newell ME: Meta-analysis of the effects of soy protein intake on serum lipids [comment]. N Engl J Med 1995, 333:276–282.PubMedCrossRefGoogle Scholar
  64. 64.
    Ruiz-Larrea MB, Mohan AR, Paganga G, et al.: Antioxidant activity of phytoestrogenic isoflavones. Free Radic Res 1997, 26:63–70.PubMedCrossRefGoogle Scholar
  65. 65.
    Cummings SR, Eckert S, Krueger KA, et al.: The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA 1999, 281:2189–2197.PubMedCrossRefGoogle Scholar
  66. 66.
    Khovidhunkit W, Shoback DM: Clinical effects of raloxifene hydrochloride in women. Ann Intern Med 1999, 130:431–439.PubMedGoogle Scholar
  67. 67.
    Clarke SC, Schofield PM, Grace AA, Metcalfe JC, Kirschenlohr HL: Tamoxifen effects on endothelial function and cardiovascular risk factors in men with advanced atherosclerosis. Circulation 2001, 103:1497–1502.PubMedGoogle Scholar
  68. 68.
    Blum A, Schenke WH, Hathaway L, et al.: Effects of estrogen and the selective estrogen receptor modulator raloxifene on markers of inflammation in postmenopausal women. Am J Cardiol 2000, 86:892–895.PubMedCrossRefGoogle Scholar
  69. 69.
    Saitta A, Altavilla D, Cucinotta D, et al.: Randomized, double-blind, placebo-controlled study on effects of raloxifene and hormone replacement therapy on plasma no concentrations, endothelin-1 levels, and endothelium-dependent vasodilation in postmenopausal women. Arterioscler Thromb Vasc Biol 2001, 21:1512–1519.PubMedGoogle Scholar
  70. 70.
    Rutqvist LE, Mattsson A: Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of adjuvant tamoxifen. The Stockholm Breast Cancer Study Group. J Natl Cancer Inst 1993, 85:1398–1406.PubMedCrossRefGoogle Scholar
  71. 71.
    McDonald CC, Alexander FE, Whyte BW, Forrest AP, Stewart HJ: Cardiac and vascular morbidity in women receiving adjuvant tamoxifen for breast cancer in a randomised trial. The Scottish Cancer Trials Breast Group. BMJ 1995, 311:977–980.PubMedGoogle Scholar
  72. 72.
    McDonald CC, Stewart HJ: Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial. The Scottish Breast Cancer Committee. BMJ 1991, 303:435–437.PubMedCrossRefGoogle Scholar
  73. 73.
    Barrett-Connor E, Grady D, Sashegyi A, et al.: Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA 2002, 287:847–857.PubMedCrossRefGoogle Scholar
  74. 74.
    Mosca L: Rationale and overview of the Raloxifene Use for the Heart (RUTH) trial. Ann N Y Acad Sci 2001, 949:181–185.PubMedCrossRefGoogle Scholar
  75. 75.
    Cummings DM: Postmenopausal hormone replacement therapy. Clin Fam Pract 2002, 4:135–154.CrossRefGoogle Scholar
  76. 76.
    Harlap S: The benefits and risks of hormone replacement therapy: an epidemiologic overview. Am J Obstet Gynecol 1992, 166(6 Pt 2):1986–1992.PubMedGoogle Scholar
  77. 77.
    Grodstein F, Stampfer MJ, Falkeborn M, Naessen T, Persson I: Postmenopausal hormone therapy and risk of cardiovascular disease and hip fracture in a cohort of Swedish women. Epidemiology 1999, 10:476–480.PubMedCrossRefGoogle Scholar
  78. 78.
    Miyagawa K, Rosch J, Stanczyk F, Hermsmeyer K: Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nat Med 1997, 3:324–327.PubMedCrossRefGoogle Scholar
  79. 79.
    Koh KK, Jin DK, Yang SH, et al.: Vascular effects of synthetic or natural progestagen combined with conjugated equine estrogen in healthy postmenopausal women. Circulation 2001, 103:1961–1966.PubMedGoogle Scholar
  80. 80.
    Pike MC, Spicer DV, Dahmoush L, Press MF: Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. Epidemiol Rev 1993, 15:17–35.PubMedGoogle Scholar
  81. 81.
    Tanis BC, van den Bosch MA, Kemmeren JM, et al.: Oral contraceptives and the risk of myocardial infarction. N Engl J Med 2001, 345:1787–1793.PubMedCrossRefGoogle Scholar
  82. 82.
    Herrington DM, Howard TD, Hawkins GA, et al.: Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med 2002, 346:967–974.PubMedCrossRefGoogle Scholar
  83. 83.
    Mikkola TS, Clarkson TB: Estrogen replacement therapy, atherosclerosis, and vascular function. Cardiovasc Res 2002, 53:605–619.PubMedCrossRefGoogle Scholar
  84. 84.
    Mosca L: The role of hormone replacement therapy in the prevention of postmenopausal heart disease. Arch Intern Med 2000, 160:2263–2272.PubMedCrossRefGoogle Scholar
  85. 85.
    Mosca L, Collins P, Herrington DM, et al.: Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 2001, 104:499–503.PubMedGoogle Scholar
  86. 86.
    Manson J, Martin KA: Clinical practice: postmenopausal hormone replacement therapy. N Engl J Med 2001, 345:34–40.PubMedCrossRefGoogle Scholar
  87. 87.
    Fletcher SW, Colditz GA: Failure of estrogen plus progestin therapy for prevention. JAMA 2002, 288:366–368.PubMedCrossRefGoogle Scholar
  88. 88.
    Mosca L, Grundy SM, Judelson D, et al.: Guide to preventive cardiology for w women. AHA/ACC Scientific Statement Consensus panel statement. Circulation 1999, 99:2480–2484.PubMedGoogle Scholar

Copyright information

© Current Science Inc 2002

Authors and Affiliations

  • Jennifer E. Ho
    • 1
  • Lori Mosca
    • 1
  1. 1.Columbia-Weill Cornell Preventive Cardiology ProgramNew York Presbyterian HospitalNew YorkUSA

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