The Applicability of Hormonal Effects on Atherosclerosis in Animals to Heart Disease in Postmenopausal Women

ABSTRACT

The discrepancy between estrogen's beneficial cardiovascular effects found in animal studies and observational studies in women compared with the recently published randomized clinical trials have stimulated a great deal of controversy. Possibilities for the discrepancy include the age of the women, number of years postmenopausal, and amount of atherosclerotic complication (necrosis and inflammation) present when hormone therapy is initiated. Many of the previous benefits of estrogens noted in both animal studies and observational studies were found in primary prevention studies that experimentally refer to a decrease in the progression of atherosclerosis extent rather than prevention of clinical events, which often occur in women with undiagnosed atherosclerotic plaques. In support of this notion, animal studies in which artery damage was present prior to hormone treatment, due to either consumption of an atherogenic diet or balloon injury of the endothelium, found no benefit with estrogen treatment. These animal studies are consistent with the lack of protection found in secondary prevention studies in women. Other areas of concern deal with the route of hormone delivery or dose of hormones used. Higher doses of oral estrogens may result in increased risk of inflammation and thrombosis. Future studies should be directed at studying hormone therapy in relevant ages of women (perimenopausal women) using the lowest effective doses of hormones and comparing oral and parenteral forms of delivery.

KEYWORDS

Atherosclerosis - coronary heart disease - hormones - estrogen - women - monkeys

REFERENCES

• 1 Grodstein F, Manson J E, Colditz G A, Willett W C, Speizer F E, Stampfer M J. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease.  Ann Intern Med. 2000;  133 933-941
• 2 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
• 3 Herrington D M, Reboussin D M, Brosnihan K B et al.. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis.  N Engl J Med. 2000;  343 522-529
• 4 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
• 5 The Women's Health Initiative Steering Committee . Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women's Health Initiative Randomized Controlled Trial.  JAMA. 2004;  291 1701-1712
• 6 Bairey Merz C N, Johnson B D, Sharaf B L et al.. Hypoestrogenemia of hypothalamic origin and coronary artery disease in premenopausal women: a report from the NHLBI-sponsored WISE study.  J Am Coll Cardiol. 2003;  41 413-419
• 7 Grady D, Rubin S M, Petitti D B et al.. Hormone therapy to prevent disease and prolong life in postmenopausal women.  Ann Intern Med. 1992;  117 1016-1037
• 8 Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other considerations.  Annu Rev Public Health. 1998;  19 55-72
• 9 Stampfer M J, Colditz G A, Willett W C et al.. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the Nurses' Health Study.  N Engl J Med. 1991;  325 756-762
• 10 Grodstein F, Stampfer M J, Colditz G A et al.. Postmenopausal hormone therapy and mortality.  N Engl J Med. 1997;  336 1769-1775
• 11 Clarkson T B. The new conundrum: do estrogens have any cardiovascular benefits?.  Int J Fertil. 2002;  47 61-68
• 12 Strong J P, Malcom G T, McMahan C A et al.. Prevalence and extent of atherosclerosis in adolescents and young adults.  JAMA. 1999;  281 727-735
• 13 McGill Jr H C, Stern M P. Sex and atherosclerosis.  Atheroscler Rev. 1979;  4 157-242
• 14 Haines C J, Yim S F, Sanderson J E. The effect of continuous combined hormone replacement therapy on arterial reactivity in postmenopausal women with established angina pectoris.  Atherosclerosis. 2001;  159 467-470
• 15 Herrington D M, Espeland M A, Crouse J R et al.. Estrogen replacement and brachial artery flow-mediated vasodilation in older women.  Arterioscler Thromb Vasc Biol. 2001;  21 1955-1961
• 16 Herrington D M, Braden G A, Williams J K, Morgan T M. Endothelial-dependent coronary vasomotor responsiveness in postmenopausal women with and without estrogen replacement therapy.  Am J Cardiol. 1994;  73 951-952
• 17 Koh K K, Jin D K, Yang S H et al.. Vascular effects of synthetic or natural progestogen combined with conjugated equine estrogen in healthy postmenopausal women.  Circulation. 2001;  103 1961-1966
• 18 Williams J K, Anthony M S, Honore E K et al.. Regression of atherosclerosis in female monkeys.  Arterioscler Thromb Vasc Biol. 1995;  15 827-836
• 19 Angerer P, Störk S, Kothny W, Schmitt P, von Schacky C. Effect of oral postmenopausal hormone replacement on progression of atherosclerosis. A randomized, controlled trial.  Arterioscler Thromb Vasc Biol. 2001;  21 262-268
• 20 Espeland M A, Applegate W, Furberg C D, Lefkowitz D, Rice L, Hunninghake D. Estrogen replacement therapy and progression of intimal-medial thickness in the carotid arteries of postmenopausal women.  Am J Epidemiol. 1995;  142 1011-1019
• 21 Westendorp I CD, Veld I, Bots M L et al.. Hormone replacement therapy and intima-media thickness of the common carotid artery. The Rotterdam study.  Stroke. 1999;  30 2562-2567
• 22 Hodis H N, Mack W J, Lobo R A et al.. Estrogen in the prevention of atherosclerosis.  Ann Intern Med. 2001;  135 939-953
• 23 Hodis H N, Mack W J, Azen S P et al.. for the Women's Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial Research Group. Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women.  N Engl J Med. 2003;  349 535-545
• 24 Wagner J D. Effects of sex steroid treatment on the cardiovascular system. In: Blacker C Infertility and Reproductive Medicine Clinics of North America. Endocrinologic Issues in the Care of the Mature Woman Vol. 12(3) Philadelphia; W.B. Saunders 2001: 511-533
• 25 Haarbo J. Hormone replacement therapy and cardiovascular disease: the rabbit model.  Br J Obstet Gynaecol. 1996;  103(suppl 13) 49-52
• 26 Adams M R, Kaplan J R, Manuck S B et al.. Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys: lack of an effect of added progesterone.  Arteriosclerosis. 1990;  10 1051-1057
• 27 Adams M R. 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
• 28 Clarkson T B, Anthony M S, Wagner J D. A comparison of tibolone and conjugated equine estrogens effects on coronary artery atherosclerosis and bone density of postmenopausal monkeys.  J Clin Endocrinol Metab. 2001;  86 5396-5404
• 29 Cline J M. Surgically postmenopausal monkeys for assessing risk and benefits to the breast and endometrium.  Menopausal Med. 2001;  10 2-5
• 30 Hanke H, Hanke S, Bruck B et al.. Inhibition of the protective effect of estrogen by progesterone in experimental atherosclerosis.  Atherosclerosis. 1996;  121 129-138
• 31 Hanke H, Kamenz J, Hanke S et al.. Effect of 17-β estradiol on pre-existing atherosclerotic lesions: role of the endothelium.  Atherosclerosis. 1999;  147 123-132
• 32 Rosenfeld M E, Kauser K, Martin-McNulty B, Polinsky P, Schwartz S M, Rubanyi G M. Estrogen inhibits the initiation of fatty streaks throughout the vasculature but does not inhibit intra-plaque hemorrhage and the progression of established lesions in apolipoprotein E deficient mice.  Atherosclerosis. 2002;  164 251-159
• 33 Anthony M S, Clarkson T B. Does extent of pretreatment atherosclerosis influence the effects of conjugated equine estrogens on atherosclerosis progression?.  J Am Coll Cardiol. 2002;  39 248 (abst)
• 34 Holm P, Andersen H L, Andersen M L, Erhardtsen E, Stender S. The direct antiatherogenic effect of estrogen is present, absent, or reversed, depending on the state of the arterial endothelium. A time course study in cholesterol-clamped rabbits.  Circulation. 1999;  100 1727-1733
• 35 Losordo D W, Kearney M, Kim E A. Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women.  Circulation. 1994;  89 1501-1510
• 36 Mäkelä S, Savolainen H, Aavik E et al.. Differentiation between vasculoprotective and uterotrophic effects of ligands with different binding affinities to estrogen receptors α and β.  Proc Natl Acad Sci U S A. 1999;  96 7077-7082
• 37 Post W S, Goldschmidt-Clermont P J, Wilhide C C. Methylation of the estrogen receptor gene is associated with aging and atherosclerosis in the cardiovascular system.  Cardiovasc Res. 1999;  43 985-991
• 38 Mendelsohn M E, Karas R H. The protective effects of estrogen on the cardiovascular system.  N Engl J Med. 1999;  340 1801-1811
• 39 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.  N Engl J Med. 2000;  342 836-843
• 40 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
• 41 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
• 42 Desensi A, Omodei U, Robertson C et al.. Effect of transdermal estradiol and oral conjugated equine estrogen on C-reactive protein in retinoid-placebo trial in healthy women.  Circulation. 2002;  106 1224-1228
• 43 Vongpatanasin W, Tuncel M, Wang Z, Arbique D, Mehrad B, Jialal I. Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women.  J Am Coll Cardiol. 2003;  41 1358-1363
• 44 Heinrich P C, Castell J V, Andus T. Interleukin-6 and the acute phase response.  Biochem J. 1990;  265 621-636
• 45 Silvestri A, Gebara O, Vitale C et al.. Increased levels of C-reactive protein after oral hormone replacement therapy may not be related to an increased inflammatory response.  Circulation. 2003;  107 3165-3169
• 46 Naghavi M, Libby P, Falk E et al.. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part I.  Circulation. 2003;  108 1664-1672
• 47 Zanger D, Yang B K, Ardans J et al.. Divergent effects of hormone therapy on serum markers of inflammation in postmenopausal women with coronary artery disease on appropriate medical management.  J Am Coll Cardiol. 2000;  36 1797-1802
• 48 Cano A, Van Baal W M. The mechanisms of thrombotic risk induced by hormone replacement therapy.  Maturitas. 2001;  40 17-38
• 49 Koh K K, Mincemoyer R, Bui M N et al.. Effects of hormone-replacement therapy on fibrinolysis in postmenopausal wowen.  N Engl J Med. 1997;  336 683-690
• 50 Davidson M H, Maki K C, Marx P et al.. Effects of continuous estrogen and estrogen-progestin replacement regimens on cardiovascular risk markers in postmenopausal women.  Arch Intern Med. 2000;  160 3315-3325
• 51 Kessler C M, Szymanski L M, Shamsipour Z, Muesing R A, Miller V T, Larosa J C. Estrogen replacement therapy and coagulation: Relationship to lipid and lipoprotein changes.  Obstet Gynecol. 1997;  89 326-331
• 52 Grady D, Wenger N K, Herrington D et al.. for the Heart and Estrogen/progestin Replacement Study Research Group. Postmenopausal hormone therapy increases venous thromboembolic disease.  Ann Intern Med. 2000;  132 689-696
• 53 Grodstein F, Stampfer M J, Goldhaber S Z et al.. Prospective study of exogenous hormones and risk of pulmonary embolism in women.  Lancet. 1996;  348 983-987
• 54 Lobo R A, Bush T, Carr B R, Pickar J H. 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
• 55 Wakatsuki A, Ikenoue N, Shinohara K, Watanabe K, Fukaya T. Effect of lower dosage of oral conjugated equine estrogen on inflammatory markers and endothelial function in healthy postmenopausal women.  Arterioscler Thromb Vasc Biol. 2004;  24 571-576