© 2001 American Heart Association, Inc.
Editorials |
Hormone Replacement Therapy and Endothelial Function
The Exception That Proves the Rule?
From the Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Mass.
Address correspondence to Joseph A. Vita, MD, Section of Cardiology, Boston Medical Center, 88 East Newton St C-818, Boston, MA 02118. E-mail jvita{at}bu.edu
The endothelium plays a central role in the regulation of vascular homeostasis by releasing paracrine factors that influence vascular tone, thrombosis, and inflammation in the arterial wall.1 A principal endothelial product responsible for homeostasis is nitric oxide (NO), which is synthesized by the endothelial isoform of NO synthase2 in response to a number of stimuli, including increased shear stress that accompanies increased arterial flow.3 Atherosclerosis and its risk factors are characterized by an impairment of endothelial NO-dependent vasodilation,1 and the magnitude of this defect in the coronary circulation predicts cardiovascular disease events, raising the possibility of a pathogenic relationship.4,5
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This notion of a causal relation between endothelial dysfunction and cardiovascular events is also supported by intervention data. For example, lipid-lowering therapy, angiotensin-converting enzyme inhibition, smoking cessation, and exercise all reverse endothelial dysfunction and have proven benefitial against cardiovascular disease events.1 This concordance between improved endothelial function and reduced cardiovascular events has prompted speculation that changes in endothelial function are partially responsible for the benefits.6–8 Thus, endothelial dysfunction could potentially be used as a surrogate marker for cardiovascular disease risk in study of risk reduction therapies.3
Hormone replacement therapy has received considerable attention as a means for primary and secondary prevention of cardiovascular disease. This interest was initially based on population-based studies linking a reduced incidence of cardiovascular disease to hormone replacement therapy.9–11 Estrogen has many potential benefits, including favorable influence on serum lipids and thrombotic factors, and there is substantial evidence that chronic estrogen treatment also improves endothelial function in postmenopausal women (Table). Despite these apparent benefits, a relatively large-scale randomized clinical trial of hormone replacement therapy (conjugated equine estrogen plus medroxyprogesterone acetate) for secondary prevention of cardiovascular disease (HERS) failed to demonstrate a benefit from estrogen.24 Furthermore, in a separate study, neither the combination of estrogen and progesterone nor estrogen alone had any effect on angiographic extent of coronary artery disease.25 As a consequence of these findings, a consensus panel concluded that hormone replacement therapy has no role in either the primary or secondary prevention of cardiovascular disease, pending the results of ongoing clinical trials.11 These data highlight an apparent lack of concordance between the effects of estrogen treatment on endothelial function and clinical outcome, fueling speculation against the clinical relevance of endothelial function.26
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In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Herrington and colleagues23 report the effect of hormone replacement therapy on endothelium-dependent vasodilation in 1662 women participating in the Cardiovascular Health Study, a longitudinal study of cardiovascular risk factors in the elderly. The authors used vascular ultrasound to measure flow-mediated dilation of the brachial artery, a response that has been shown to be NO-dependent27 and to correlate with responses in the coronary circulation.28 As with the coronary circulation, endothelial dysfunction in the brachial artery improves with many risk reduction therapies,1,3 and a preliminary study suggests that brachial artery endothelial dysfunction is an independent predictor of short-term cardiovascular disease events in high risk patients.29
Overall, Herrington and colleagues23 found no significant difference in endothelium-dependent vasodilation in the 291 women with current or previous hormone replacement therapy (largely unopposed estrogen) compared with the women who had never received replacement therapy. When the subjects’ data were stratified according to current versus previous therapy, or to unopposed estrogen versus estrogen-progesterone combination therapy, the results were unchanged. Interestingly, when the patients were stratified according to age, the presence of cardiovascular disease, cardiovascular medication use, and risk factors, there was a benefit of hormone replacement therapy that was restricted to younger, lower-risk women. The authors concluded that the beneficial effects of estrogen might be limited to women without established cardiovascular disease. The strengths of the study include the large, well-characterized patient cohort, the careful and well-validated methodology for assessment of brachial vasodilation, and the rigorous statistical approach.
How do these findings relate to the HERS results? The women in the study by Herrington et al23 were substantially older than women in other studies of hormone replacement therapy and endothelial function. In contrast to all previous studies except one that involved only 4 subjects, this study is the only one that included patients with known cardiovascular disease (Table). Thus, the subjects were much more comparable to the HERS patient population, and the results are parallel. When women without cardiovascular disease or cardiovascular disease risks were considered, the results from Herrington and colleagues23 are similar to previous studies of chronic unopposed estrogen and endothelial function. It remains unclear why older women with established cardiovascular disease would have a reduced response to estrogen treatment, but as pointed out by the authors, there currently is evidence for reduced expression of the estrogen receptor in women with advancing age30 and with cardiovascular disease.31 Although the current study showed no effect of progesterone therapy on endothelial function, many of the previous studies suggest that inclusion of medroxyprogesterone reduces or eliminates the benefits of estrogen, and these findings also are concordant with HERS.
The study by Herrington and colleagues23 has several limitations. First, it was observational in nature and not a randomized trial. Thus, the hormone combination and duration of treatment varied, and many women were no longer receiving therapy at the time of the ultrasound study. Second, given the overall negative result, the subgroup analysis showing a benefit in younger, healthier subjects must be considered exploratory in nature. Third, the small number of subjects in certain subgroups limits the findings. For example, only 32 women had no cardiovascular disease, risk factors, or cardiovascular medication use, and a relatively small number of patients were receiving estrogen and progesterone in combination. Fourth, the study did not include an examination of nitroglycerin-mediated dilation, so the apparent effect of hormone replacement therapy in low-risk subjects must be interpreted as an effect on vascular function, rather than on endothelial function. Finally, the degree of brachial artery dilation was rather low compared with previous studies. As the authors acknowledge, this discrepancy is likely related to the older subject age, the lower arm cuff position, and the use of a 4-minute, rather than 5-minute period of cuff occlusion to induce hyperemia. Despite these limitations, this study represents a relatively large-scale and careful study of the effects of hormone replacement therapy on endothelial function in older, higher risk women.
Thus, when a more comparable population is studied, the effects of hormone replacement therapy on endothelial function do seem to parallel the HERS results, supporting the utility of endothelial function as a surrogate endpoint. The available endothelial function studies would predict a beneficial effect of unopposed estrogen for the primary prevention of cardiovascular disease in healthy women that are closer to menopause. This question will be addressed in ongoing clinical trials, including the Women’s Health Initiative. If it turns out that unopposed estrogen has benefit, any clinical recommendations will have to be considered carefully, because of the potential for pro-carcinogenic effects of unopposed estrogen. It remains quite conceivable that these and other adverse effects will outweigh any beneficial effects on the vasculature. Use of newer selective estrogen receptor modulations (SERMs) may be another way to take advantage of the benefits of estrogen without inducing its adverse effects. These agents have already been shown to have beneficial effects on endothelial function,32 and thus would be predicted to have benefit against cardiovascular disease.
Footnotes
Drs. Vita and Keaney are supported by NIH grants HL55993, HL60886, HL 52936, and DK55656. Dr. Keaney is an Established Investigator of the American Heart Association.
References
1. Gokce N, Keaney JFJ, Vita JA. Endotheliopathies: clinical manifestations of endothelial dysfunction.In: Loscalzo J, Shafer AI, eds. Thrombosis and Hemorrhage. Baltimore, Md: Williams and Wilkins; 1998: 901–924.
2.
Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A. 1987; 84: 9265–9269.
3. Corretti M, Anderson TJ, Benjamin EJ, Celermajer DS, Charbonneau F, Creager M, Daley WL, Deanfield JE, Drexler H, Gerhard M, Herrington DM, Vallance P, Vita JA, Vogel RA. Guidelines for the ultrasound assessment of endothelium-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. In press.
4.
Schächinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long- term outcome of coronary heart disease. Circulation. 2000; 101: 1899–1906.
5.
Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000; 101: 948–954.
6.
Levine GN, Keaney JFJ, Vita JA. Cholesterol reduction in cardiovascular disease: clinical benefits and possible mechanisms. N Engl J Med. 1995; 332: 512–521.
7.
Vita JA, Keaney JF Jr. Exercise: toning up the endothelium? N Engl J Med. 2000; 342: 503–505.
8.
Vogel RA, Corretti MC. Estrogens, progestins, and heart disease: can endothelial function divine the benefit? Circulation. 1998; 97: 1223–1226.
9.
Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. JAMA. 1991; 265: 1861–1867.
10.
Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med. 1999; 340: 1801–1811.
11.
Mosca L, Collins P, Herrington DM, Mendelsohn ME, Pasternak RC, Robertson RM, Schenck-Gustafsson K, Smith SC Jr, Taubert KA, Wenger NK. Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation. 2001; 104: 499–503.
12.
Lieberman EH, Gerhard MD, Uehata A, Walsh BW, Selwyn AP, Ganz P, Yeung AC, Creager MA. Estrogen improves endothelium-dependent, flow mediated vasodilation in post menopausal women. Ann Intern Med. 1994; 121: 936–941.
13. Herrington DM, Braden GA, Williams JK, Morgan TM. Endothelial dependent coronary vasomotor responsiveness in postmenopausal women with and without estrogen replacement therapy. Am J Cardiol. 1994; 73: 951–952.[Medline] [Order article via Infotrieve]
14.
Rosselli M, Imthurn B, Keller PJ, Jackson EK, Dubey RK. Circulating nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17 beta-estradiol and norethisterone acetate: a two-year follow-up study. Hypertension. 1995; 25: 848–853.
15. McCrohon JA, Adams MR, McCredie RJ, Robinson J, Pike A, Abbey M, Keech AC, Celermajer DS. Hormone replacement therapy is associated with improved arterial physiology in healthy post-menopausal women. Clin Endocrinol. 1996; 45: 435–441.[Medline] [Order article via Infotrieve]
16.
Gerhard M, Walsh MW, Tawakol A, Haley EA, Creager SJ. Estradiol therapy combined with progesterone and endothelium-dependent vasodilation in postmenopausal women. Circulation. 1998; 98: 1158–1163.
17.
Sorenson 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: 1234–1238.
18. Bush DE, Jones CE, Bass KM, Walters GK, Bruza JM, Ouyang P. Estrogen replacement reverses endothelial dysfunction in postmenopausal women. Am J Med. 1998; 104: 552–558.[Medline] [Order article via Infotrieve]
19. Arora S, Veves A, Caballaro AE, Smakowski P, LoGerfo FW. Estrogen improves endothelial function. J Vasc Surg. 1998; 27: 1141–1146.[Medline] [Order article via Infotrieve]
20.
Koh KK, Cardillo C, Bui MN, Hathaway L, Csako G, Waclawiw MA, Panza JA, Cannon RO,III. Vascular effects of estrogen and cholesterol-lowering therapies in hypercholesterolemic postmenopausal women. Circulation. 1999; 99: 354–360.
21.
Koh KK, Jin DK, Yang SH, Lee SK, Hwang HY, Kang MH, Kim W, Kim DS, Choi IS, Shin EK. Vascular effects of synthetic or natural progestagen combined with conjugated equine estrogen in healthy postmenopausal women. Circulation. 2001; 103: 1961–1966.
22.
Wakatsuki A, Okatani Y, Ikenoue N, Fukaya T. Effect of medroxyprogesterone acetate on endothelium-dependent vasodilation in postmenopausal women receiving estrogen. Circulation. 2001; 104: 1773–1778.
23.
Herrington DM, Espeland MA, Crouse JR III, Robertson J, Riley WA, McBurnie MA, Burke GL. Estrogen replacement and brachial artery flow-mediated vasodilation in older women. Arterioscler Thromb Vasc Biol. 2001; 21: 1955–1961
24.
Hulley 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: Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA. 1998; 280: 605–613.
25.
Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE, Furberg CD, Kowalchuk GJ, Stuckey TD, Rogers WJ, Givens DH, Waters D. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med. 2000; 343: 522–529.
26.
Cannon RO. Cardiovascular benefit of cholesterol-lowering therapy: does improved endothelial vasodilator function matter? Circulation. 2000; 102: 820–822.
27. Lieberman EH, Gerhard MD, Uehata A, Selwyn AP, Ganz P, Yeung AC, Creager MA. Flow-induced vasodilation of the human brachial artery is impaired in patients <40 years of age with coronary artery disease. Am J Cardiol. 1996; 78: 1210–1214.[Medline] [Order article via Infotrieve]
28. Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D, Leiberman E, Ganz P, Creager MA, Yeung AC, Selwyn AP. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol. 1995; 26: 1235–1241.[Abstract]
29. Gokce N, Keaney JF Jr, Menzoian JO, Watkins M, Hunter L, Duffy SJ, Vita JA. Impaired brachial artery endothelial function predicts perioperative cardiovascular events in patients undergoing vascular surgery. Circulation. 2001; 104 (suppl II): II-328.Abstract 1582.
30.
Post WS, Goldschmidt-Clermont PJ, Wilhide CC, Heldman AW, Sussman MS, Ouyang P, Milliken EE, Issa JP. Methylation of the estrogen receptor gene is associated with aging and atherosclerosis in the cardiovascular system. Cardiovasc Res. 1999; 43: 985–991.
31.
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.
32.
Saitta A, Altavilla D, Cucinotta D, Morabito N, Frisina N, Corrado F, D’Anna R, Lasco A, Squadrito G, Gaudio A, Cancellieri F, Arcoraci V, Squadrito F. 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.
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