(Circulation. 1995;92:5-8.)
© 1995 American Heart Association, Inc.
Articles |
How Do We Explain the Clinical Benefits of Estrogen?
From Bedside to Bench
From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.
Correspondence to Peter Ganz, MD, Brigham and Women's Hospital, Cardiac Catheterization Laboratory, L2-196, 75 Francis St, Boston, MA 02115.
Key Words: estrogen replacement therapy • atherosclerosis • Editorials • endothelium
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Introduction |
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Cardiovascular disease claims the lives of 500 000 women in the United States every year.1 Although women are largely protected from clinical coronary disease before the menopause, they rapidly develop increased risk thereafter.2 Both experimental and clinical data suggest that this loss of protection results from a deficiency of endogenous estrogens. Estrogen replacement therapy markedly attenuates the development of dietary atherosclerosis in ovariectomized monkeys.3 4 In epidemiological studies, postmenopausal women taking estrogen replacement therapy experience up to 50% fewer adverse coronary events, with the greatest benefit occurring in women with coronary artery disease.5 6 These observations indicate that estrogen replacement therapy may have an important role in primary and secondary prevention of cardiovascular disease.
Any therapy intended to reduce the risk of fatal and nonfatal myocardial infarction or of sudden coronary death must alter the biology of atherosclerosis, prevent plaque rupture (the proximate cause of sudden coronary occlusion), or reduce its consequences. Vulnerable plaques typically contain a large pool of extracellular lipid, surrounded by a dense inflammatory infiltrate, and are covered by only a thin fibrous cap.7 8 9 10 11 12 Estrogen, directly or indirectly, might retard the development of such plaques, favorably affect the vulnerability of existing plaques, or reduce the risk of coronary occlusion by preventing formation of an occlusive thrombus, a consequence of plaque rupture.13 14 In addition, estrogen may attenuate vasomotor dysfunction, a possible trigger of plaque rupture.
Estrogen may protect women from cardiovascular disease in part through modification of the lipid profile. Premenopausal women have reduced LDL and elevated HDL cholesterol compared with men.15 After menopause, women develop a more atherogenic lipid profile as LDL cholesterol levels rise, HDL cholesterol levels fall, and lipoprotein(a) levels increase.16 17 18 19 20 Estrogen replacement reverses these adverse changes in lipoprotein profile and diminishes cardiovascular risk.21 22 23 24 However, multiple regression analyses of large-scale studies and inferences drawn from the decrease in cardiovascular events in men associated with lipid profile modification indicate that the beneficial changes in lipoprotein levels resulting from estrogen replacement therapy account for only 25% to 50% of the observed risk reduction, suggesting that additional factors are involved.25 Cardioprotective mechanisms unrelated to lipid lowering are also evident in women with heterozygous familial hypercholesterolemia.26 Despite higher levels of total and LDL cholesterol, these (mostly young) women have a reduced incidence and a markedly delayed onset of the clinical manifestations of coronary disease compared with their male counterparts.
Estrogen modifies directly the functions of the endothelium and vascular smooth muscle. In health, the vascular endothelium provides a surface that is vasodilatory, anticoagulant, and antiadhesive for leukocytes and that inhibits proliferation of vascular smooth muscle cells.27 Although discovered as an endothelium-derived vasodilator factor,28 nitric oxide may retard atherogenesis by inhibiting monocyte adhesion,29 30 synthesis of factors chemotactic for monocytes,31 smooth muscle cell proliferation,32 and platelet aggregation.33 34 Experimental and clinical studies suggest that dysfunctional endothelium in atherosclerosis or in the presence of risk factors loses these favorable effects.27 35 36 37 38 39 The impact of estrogen deficiency on the endothelium has been evaluated by observing endothelial function following replacement of estrogen. In these studies, estrogen enhances endothelium-dependent vasodilation in normocholesterolemic ovariectomized animals as well as in ovariectomized monkeys with dietary atherosclerosis.3 40 41 This improvement is associated with augmentation of nitric oxide and vasodilator prostaglandin levels.
Estrogen replacement therapy also corrects coronary endothelium-dependent vasodilation in postmenopausal women with atherosclerosis. Intravenous administration of 17ß-estradiol, conjugated estrogens, and ethinyl estradiol rapidly improves coronary responses to acetylcholine.42 43 44 45 Long-term estrogen replacement restores coronary responses to acetylcholine in monkeys with dietary atherosclerosis and augments endothelium-dependent dilation in hypercholesterolemic, postmenopausal women.3 46 Serum nitrate and nitrite levels are higher in postmenopausal women receiving long-term estrogen replacement, suggesting enhanced production of nitric oxide.47
The molecular mechanisms by which estrogen replacement modulates endothelial function are not well defined. Steroid hormones such as estrogen bind to highly specific cytoplasmic receptors.48 They form a mobile cytoplasmic steroid-receptor complex that ultimately translocates to the nucleus and binds directly to nonhistone proteins on the DNA to activate transcription of genes. Long-term administration of estrogen upregulates the transcription of nitric oxide synthase and enhances its activity in nonvascular tissue.49 Whether such upregulation occurs in vascular tissues must be determined. It is unlikely that acute improvement in endothelium-dependent vasodilation, observed in as little as 15 minutes, can be explained by this classic steroid-hormone receptor interaction.42 43 44 45 Receptor-independent mechanisms, such as the ability of estrogen to act as an antioxidant, have therefore been postulated to account for the rapid restoration of endothelium-dependent vasodilation.50
Treatment with a number of antioxidant agents restores endothelium-dependent vasodilation in atherosclerosis. Impairment of endothelium-dependent vasodilation in atherosclerosis is related in part to increased production of oxygen-derived free radicals.51 Oxygen-derived free radicals can directly inactivate nitric oxide in the vascular wall, as well as indirectly damage endothelium by oxidizing LDL particles.52 53 54 Estrogens possess antioxidant activity related to the presence of a phenolic ring, eg, in estriol and 17ß-estradiol.55 When estradiol is administered to ovariectomized swine with dietary atherosclerosis, endothelium-dependent vasorelaxation is restored in conjunction with evidence of protection of LDL from oxidation.50 Susceptibility of LDL to oxidation is also reduced in postmenopausal women taking replacement estrogen.56 The observed rapid benefit of estrogen cannot be explained by reduced LDL oxidation and would require that estrogen decrease oxygen-derived free radicals directly in the arterial wall.
Changes in the vasculature following estrogen replacement are not confined to the endothelium and may involve vascular smooth muscle, extracellular matrix, and the formation of collaterals. Estrogen modulates the reactivity of vascular smooth muscle. Contraction of vascular smooth muscle in response to the administration of endothelin 1 or the calcium channel agonist BAY K 8644 is inhibited by estrogen treatment in animals.57 58 Estrogen increases potassium conductance in vascular smooth muscle, a change that would favor vasodilation.59 Extracellular matrix composition may be modified by estrogen therapy, affecting its contribution to vessel wall stability.60 For example, estradiol treatment changes the proportion of collagen and elastin and the ratio of procollagen type I to procollagen type III in blood vessels.61 62 63 The impact of these findings on the vulnerability of atherosclerotic plaques to rupture must be established. The enlargement of preexistent collateral channels in the presence of a severe stenosis is likely to lessen the impact of a subsequent coronary occlusion.64 65 66 67 Formation of collaterals involves transformation of preexisting collaterals to mature collaterals through a process of vascular remodeling.68 Under in vitro conditions, estrogen treatment enhances migration and proliferation of endothelial cells and facilitates their organization into tubular networks, steps that are critical to angiogenesis.69 In vivo models have demonstrated that estrogen potentiates the angiogenic effect of fibroblast growth factor. The applicability of these findings in patients with clinical coronary disease must be investigated.
In this issue of Circulation, Collins and colleagues70 report that coronary vasodilation to acetylcholine is restored 20 minutes after administration of 17ß-estradiol in postmenopausal women with coronary disease but not in men. This unexpected finding of a gender-specific benefit suggests that the rapid improvement in endothelial function cannot be accounted for by the proposed receptor-independent actions of estrogen and that estrogen receptors are required. The males in this study presumably have fewer estrogen receptors than the females, accounting for a lack of effect. Interestingly, estrogen can upregulate its own receptors,71 permitting males to respond. Estrogen increases transcription of nitric oxide synthase in male guinea pigs, but with a marked delay compared with females.49 This lag phase may be due to upregulation of estrogen receptors needed in male guinea pigs. The findings of the study by Collins et al could be explained by a novel interaction of estrogen with its steroid receptor. This hormone-receptor complex could activate nontranscriptional signaling events in the cytoplasm, resulting in prompt improvement in endothelium-dependent vasodilation.
Actions of estrogen have been elucidated that tend to correct the characteristic disturbances associated with the biology of atherosclerosis. Resorption of extracellular lipid as a result of improvement in lipoprotein metabolism and reversal of endothelial dysfunction may be particularly important effects of estrogen, expected to retard atherogenesis and enhance the stability of existing plaques. As this study by Collins et al70 points out, the molecular basis of improvement in endothelial function is not yet clearly understood. The intriguing findings of this study force us to rethink our views of the mechanisms by which estrogen improves endothelium-dependent vasodilation and should stimulate new directions in research.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association, Inc.
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References |
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D. M. Herrington, D. M. Reboussin, K. B. Brosnihan, P. C. Sharp, S. A. Shumaker, T. E. Snyder, C. D. Furberg, G. J. Kowalchuk, T. D. Stuckey, W. J. Rogers, et al. Effects of Estrogen Replacement on the Progression of Coronary-Artery Atherosclerosis N. Engl. J. Med., August 24, 2000; 343(8): 522 - 529. [Abstract] [Full Text] [PDF]
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I. Zachary, A. Mathur, S. Yla-Herttuala, and J. Martin Vascular Protection : A Novel Nonangiogenic Cardiovascular Role for Vascular Endothelial Growth Factor Arterioscler. Thromb. Vasc. Biol., June 1, 2000; 20(6): 1512 - 1520. [Abstract] [Full Text] [PDF]
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J. G. Murphy and R. A. Khalil Gender-specific reduction in contractility and [Ca2+]i in vascular smooth muscle cells of female rat Am J Physiol Cell Physiol, April 1, 2000; 278(4): C834 - C844. [Abstract] [Full Text] [PDF]
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J. K. Crews, J. G. Murphy, and R. A. Khalil Gender Differences in Ca2+ Entry Mechanisms of Vasoconstriction in Wistar-Kyoto and Spontaneously Hypertensive Rats Hypertension, October 1, 1999; 34(4): 931 - 936. [Abstract] [Full Text] [PDF]
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D. M. Herrington, B. L. Werbel, W. A. Riley, B. E. Pusser, and T. M. Morgan Individual and combined effects of estrogen/progestin therapy and lovastatin on lipids and flow-mediated vasodilation in postmenopausal women with coronary artery disease J. Am. Coll. Cardiol., June 1, 1999; 33(7): 2030 - 2037. [Abstract] [Full Text] [PDF]
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S. H. Zuckerman, G. F. Evans, J. A. Schelm, P. I. Eacho, and G. Sandusky Estrogen-Mediated Increases in LDL Cholesterol and Foam Cell–Containing Lesions in Human ApoB100CETP Transgenic Mice Arterioscler. Thromb. Vasc. Biol., June 1, 1999; 19(6): 1476 - 1483. [Abstract] [Full Text] [PDF]
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J. K. Crews and R. A. Khalil Antagonistic Effects of 17ß-Estradiol, Progesterone, and Testosterone on Ca2+ Entry Mechanisms of Coronary Vasoconstriction Arterioscler. Thromb. Vasc. Biol., April 1, 1999; 19(4): 1034 - 1040. [Abstract] [Full Text] [PDF]
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M. J. Landzberg, D. J. Roberts, and E. J. Mark Case 4-1999- A 38-Year-Old Woman with Increasing Pulmonary Hypertension after Delivery N. Engl. J. Med., February 11, 1999; 340(6): 455 - 464. [Full Text] [PDF]
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E. Simpson Why Do the Clinical Sequelae of Estrogen Deficiency Affect Women More than Men?a J. Clin. Endocrinol. Metab., June 1, 1998; 83(6): 2214 - 2215. [Full Text]
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B. Bruck, U. Brehme, N. Gugel, S. Hanke, G. Finking, C. Lutz, N. Benda, F. W. Schmahl, R. Haasis, and H. Hanke Gender-Specific Differences in the Effects of Testosterone and Estrogen on the Development of Atherosclerosis in Rabbits Arterioscler. Thromb. Vasc. Biol., October 1, 1997; 17(10): 2192 - 2199. [Abstract] [Full Text]
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 S. R. Heckbert, N. S. Weiss, T. D. Koepsell, R. N. Lemaitre, N. L. Smith, D. S. Siscovick, D. Lin, and B. M. Psaty Duration of Estrogen Replacement Therapy in Relation to the Risk of Incident Myocardial Infarction in Postmenopausal Women Arch Intern Med, June 23, 1997; 157(12): 1330 - 1336. [Abstract] [PDF]
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 H. Abedi and I. Zachary Vascular Endothelial Growth Factor Stimulates Tyrosine Phosphorylation and Recruitment to New Focal Adhesions of Focal Adhesion Kinase and Paxillin in Endothelial Cells J. Biol. Chem., June 13, 1997; 272(24): 15442 - 15451. [Abstract] [Full Text] [PDF]
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H. Schunkert, A.H. J. Danser, H.-W. Hense, F. H.M. Derkx, S. Kurzinger, and G. A.J. Riegger Effects of Estrogen Replacement Therapy on the Renin-Angiotensin System in Postmenopausal Women Circulation, January 7, 1997; 95(1): 39 - 45. [Abstract] [Full Text]
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J. M. Sullivan Estrogen Replacement Circulation, December 1, 1996; 94(11): 2699 - 2702. [Full Text]
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Y. D. Kim, B. Chen, J. Beauregard, P. Kouretas, G. Thomas, M. Y. Farhat, A. K. Myers, and D. E. Lees 17ß-Estradiol Prevents Dysfunction of Canine Coronary Endothelium and Myocardium and Reperfusion Arrhythmias After Brief Ischemia/Reperfusion Circulation, December 1, 1996; 94(11): 2901 - 2908. [Abstract] [Full Text]
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