Abstract
A very large body of literature has yielded strong biologic and mechanistic plausibility for the consistent observational findings that estrogen is cardioprotective. Recently completed randomized, controlled trials have been interpreted as challenging the doctrine that hormone replacement is cardioprotective for postmenopausal women. However, other than the Estrogen in the Prevention of Atherosclerosis Trial, none of the currently completed (and no ongoing) randomized, controlled trials have appropriately tested the hypothesis generated from observational data that estrogen replacement is cardioprotective. This mainly results from the fact that randomized, controlled trials have not tested the same pattern and type of hormone use in the same population of women observed in the epidemiologic studies. On the other hand, recently completed randomized, controlled trials provide important but limited information concerning the clinical use of a specific regimen of hormone replacement for the prevention of cardiovascular disease in a particular population of postmenopausal women. Observations made from epidemiologic studies will have to be appropriately tested in randomized, controlled trials before any real conclusions can be drawn as to whether hormone replacement is cardioprotective.
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References and Recommended Reading
Grodstein F, Stampfer M: The epidemiology of coronary heart disease and estrogen replacement in postmenopausal women. Prog Cardiol Dis 1995, 38:199–210.
Grodstein F, Stampfer M: Estrogen for women at varying risk of coronary disease. Maturitas 1998, 30:19–26.
Archer DF, Pickar JH, Bottiglioni F, for the Menopause Study Group: Bleeding patterns in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate. Obstet Gynecol 1994, 83:686–692.
Lobo RA, Pickar JH, Wild RA, Walsh B, Hirvonen E, for the Menopause Study Group: Metabolic impact of adding medroxyprogesterone acetate to conjugated estrogen therapy in postmenopausal women. Obstet Gynecol 1994, 84:987–995.
Hulley S, Grady D, Bush T, et al.: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart-disease in postmenopausal women. JAMA 1998, 280:605–613.
Grady D, Herrington D, Bittner V, et al.: Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II). JAMA 2002, 288:49–57.
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.
Design of the Women’s Health Initiative Clinical Trial and Observational Study: the Women’s Health Initiative Study Group.Controlled Clinical Trials 1998, 19:61–109.
Writing Group for the Women’s Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy menopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002, 288:321–333.
Angerer P, Stork S, Kothny W, et al.: Effect of oral postmenopausal hormone replacement on progression of atherosclerosis: a randomized controlled trial. Arterioscler Thromb Vasc Biol 2001, 21:262–268.
Geroulakos G, O’Gorman DJ, Kalodiki E, et al.: The carotid intima-media thickness as a marker of the presence of severe symptomatic coronary artery disease. Eur Heart J 1994, 15:781–785.
Mack WJ, Selzer RH, Hodis HN, et al.: One-year reduction and longitudinal analysis of carotid intima-media thickness associated with colestipol/niacin therapy. Stroke 1993, 24:1779–1783.
Blankenhorn DH, Hodis HN: Duff Memorial Lecture: arterial imaging and atherosclerosis reversal. Arterioscler Thromb 1994, 14:177–192.
The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group: Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998, 339:1349–1357.
Hodis HN, Mack WJ, Lobo RA, et al., for the Estrogen in the Prevention of Atherosclerosis Trial Research Group: Estrogen in the prevention of atherosclerosis: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001, 135:939–953.
Angerer P, Kothny W, Stork S, von Schacky C: Hormone replacement therapy and distensibility of carotid arteries in postmenopausal women: a randomized controlled trial. J Am Coll Cardiol 2000, 36:1789–1796.
Blacher J, Guerin AP, Pannier B, et al.: Impact of aortic stiffness on survival in end-stage renal disease. Circulation 1999, 99:2434–2439.
Selzer RH, Hodis HN, Kwong-Fu H, et al.: Evaluation of computerized edge tracking for quantifying intima-media thickness of the common carotid artery from B-mode ultrasound images. Atherosclerosis 1994, 111:1–11.
Selzer RH, Mack WJ, Lee PL, et al.: Improved common carotid elasticity and intima-media thickness measurement from computer analysis of sequential ultrasound frames. Atherosclerosis 2001, 154:185–193.
Espeland MA, Applegate WB, Furberg CD, et al., for the ACAPS Investigators: Estrogen replacement therapy and progression of intimal-medial thickness in the carotid arteries of postmenopausal women. Am J Epidemiol 1995, 142:1011–1019.
Pullar T, Kumar S, Tindall H, Feely M: Time to stop counting the tablets? Clin Pharmacol Ther 1989, 46:163–168.
Pledger GW: Compliance in clinical trials: impact on design, analysis and interpretation. Epilepsy Res 1988, (suppl):125–133.
Falkeborn M, Persson I, Adami HO, et al.: The risk of acute myocardial infarction after oestrogen and oestrogen-progestogen replacement. Br J Obstet Gynaecol 1992, 99:821–828.
Grodstein F, Stampfer MJ, Manson JE, et al.: Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996, 335:453–461.
Adams MR, Register TC, Golden DL, Wagner JD, Williams JK: Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis. Arterioscler Thromb Vasc Biol 1997, 17:217–221.
The Writing Group for the PEPI Trial: Effect 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.
Williams JK, Anthony MS, Honore EK, et al.: Regression of atherosclerosis in female monkeys. Arterioscler Thromb Vasc Biol 1995, 15:827–836.
Clarkson TB, Anthony MS, Morgan TM: Inhibition of postmenopausal atherosclerosis progression: a comparison of the effects of conjugated equine estrogens and soy phytoestrogens. J Clin Endocrinol Metab 2001, 86:41–47.
Clarkson TB, Anthony MS, Jerome CP: Lack of effect of raloxifene on coronary artery atherosclerosis of postmenopausal monkeys. J Clin Endocrinol Metab 1988, 83:721–726.
Clarkson TB: The new conundrum: do estrogens have any cardiovascular benefit? Int J Fertil 2002, 47:61–68.
Dollar AL, Kragel AH, Fernicola DJ, et al.: Composition of atherosclerotic plaques in coronary arteries in women <40 years of age with fatal coronary artery disease and implications for plaque reversibility. Am J Cardiol 1991, 67:1223–1227.
Post WS, Goldschmidt-Clemont 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.
Losordo DW, Kearney M, Kim EA, et al.: Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women. Circulation 1994, 89:1501–1510.
Wissler RW: Atherosclerosis: its pathogenesis in perspective. Adv Cardiol 1974, 13:10–31.
Wilson RB, Miller RA, Middleton CC, et al.: Atherosclerosis in rabbits fed a low cholesterol diet for five years. Arteriosclerosis 1982, 2:228–240.
Walsh BW, Kuller LH, Wild RA, et al.: Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 1998, 279:1445–1451.
Shewmon DA, Stock JL, Rosen CJ, et al.: Tamoxifen and estogen lower circulating lipoprotein(a) concentrations in healthy postmenopausal women. Arterioscler Thromb 1994, 14:1586–1593.
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.
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.
Cushman M, Costantino JP, Tracy RP, et al.: Tamoxifen and cardiac risk factors in healthy women: suggestion of an anti-inflammatory effect. Arterioscler Thromb Vasc Biol 2001, 21:255–261.
Williams JK, Wagner JD, Li Z, Golden DL, Adams MR: Tamoxifen inhibits arterial accumulation of LDL degradation products and progression of coronary artery atherosclerosis in monkeys. Arterioscler Thromb Vasc Biol 1997, 17:403–408.
Fisher B, Costantino JP, Wickerham DL, et al. for the National Surgical Adjuvant Breast and Bowel Project Investigators: Tamoxifen for prevention of breast cancer: report of the national surgical adjuvant breast and bowel project P-1 study. J Natl Cancer Inst 1998, 90:1371–1388.
Reis SE, Costantino JP, Wickerham DL, et al., for the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial Investigators: Cardiovascular effects of tamoxifen in women with and without heart disease: breast cancer prevention trial. J Natl Cancer Inst 2001, 93:16–21.
Rutqvist LE, Mattsson A, for the Stockholm Breast Cancer Study Group: Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomixed trial of adjuvant tamoxifen. J Natl Cancer Inst 1993, 85:1398–1406.
McDonald CC, Stewart HJ, for the Scottish Breast Cancer Committee: Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial. BMJ 1991, 303:435–437.
McDonald CC, Alexander FE, Whyte BW, Forrest AP, Stewart HJ, for the Scottish Cancer Trials Breast Group: Cardiac and vascular morbidity in women receiving adjuvant tamoxifen for breast cancer in a randomized trial. BMJ 1995, 311:977–980.
Barret-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 Evalustion) randomized trial. JAMA 2002, 287:847–857.
Mendelsohn ME, Karas RH: The time has come to stop letting the HERS tale wag the dogma. Circulation 2001, 104:2256–2259.
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.
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Hodis, H.N., Mack, W.J. & Lobo, R. What is the cardioprotective role of hormone replacement therapy?. Curr Atheroscler Rep 5, 56–66 (2003). https://doi.org/10.1007/s11883-003-0069-z
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DOI: https://doi.org/10.1007/s11883-003-0069-z