(Circulation. 1996;93:1928-1937.)
© 1996 American Heart Association, Inc.
Articles |
Cardiovascular Effects of Estrogen and Lipid-Lowering Therapies in Postmenopausal Women
From the Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
Correspondence to Richard O. Cannon III, MD, National Institutes of Health, Bldg 10, Room 7B15, 10 Center Dr MSC 1650, Bethesda, MD 20892-1650.
Key Words: atherosclerosis • lipoproteins • hormones • women • drugs
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Introduction |
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 Top Introduction Lipoprotein Effects of EstrogenCoronary Vasomotor Effects of...Systemic Vasomotor Effects of...Estrogen and Nitric OxideAntioxidant Effects of EstrogenOxidized LDL and Vasomotor...Hemostatic Effects of EstrogenOther Potential Cardiovascular...Combined Effects of Progestin...Lipid-Lowering Therapy as an...Systemic Vasomotor Effects of...Antioxidant Effects of...Lipid-Lowering Therapy and...Cholesterol Reduction Therapy...ConclusionsReferences |
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Despite impressions to the contrary, cardiovascular disease is the leading cause of death among women in the United States, as it is among men.1 However, myocardial infarction and stroke are uncommon in women until their sixth decade and beyond. Clinicians have long suspected that the delay of a decade or more in cardiovascular disease expression in women relative to men is due to the protective effects of estrogen during a woman's reproductive years. Women in the Nurses' Health Study who underwent surgical menopause by bilateral oophorectomy without estrogen replacement had more than twice the risk of subsequent clinically apparent coronary heart disease as postoperative women who received estrogen therapy.2 In recent years, reports from population-based observational studies of favorable effects of estrogen therapy on cardiovascular morbidity and mortality3 4 5 have led to enthusiasm for widespread use of estrogen by postmenopausal women for prevention of cardiovascular disease events. The guidelines for estrogen therapy issued by the American College of Physicians include the statement, "Women who have coronary heart disease or who are at increased risk for coronary heart disease are likely to benefit from hormone therapy."6
However, any potential cardiovascular benefit of estrogen, in addition to other benefits, such as preservation of bone mass, must be weighed against uterine cancer risks and possible breast cancer risks with prolonged use.7 8 Indeed, despite widespread publicity in recent years about heart disease in postmenopausal women and the apparent cardiovascular virtues of estrogen, many women consider their risk of heart disease lower than their risk of breast cancer and, importantly, fear the consequences of breast cancer more than the consequences of heart disease.9 Furthermore, estrogen therapy is associated with side effects in some women, including vaginal bleeding, and is generally not recommended for chronic use by women with a family history of breast cancer. Thus, many postmenopausal women, including those most likely to benefit from estrogen therapy because of established atherosclerosis,3 10 may be unwilling or unable to take estrogen supplementation for several decades in the absence of menopausal symptoms. A review of the current understanding of the cardiovascular effects of estrogen and lipid-lowering therapies suggests that lipid-lowering therapy might achieve cardiovascular benefits similar to those of estrogen therapy and thus be acceptable to women who cannot take or choose not to take prolonged estrogen supplementation in the absence of menopausal symptoms.
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Lipoprotein Effects of Estrogen |
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TopIntroductionLipoprotein Effects of EstrogenCoronary Vasomotor Effects of...Systemic Vasomotor Effects of...Estrogen and Nitric OxideAntioxidant Effects of EstrogenOxidized LDL and Vasomotor...Hemostatic Effects of EstrogenOther Potential Cardiovascular...Combined Effects of Progestin...Lipid-Lowering Therapy as an...Systemic Vasomotor Effects of...Antioxidant Effects of...Lipid-Lowering Therapy and...Cholesterol Reduction Therapy...ConclusionsReferences |
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Before menopause, plasma LDL cholesterol levels are lower and HDL cholesterol levels are higher in women compared with men of the same age. After menopause, LDL cholesterol levels rise, commonly exceeding those of age-matched men, with a shift to smaller, more dense, and potentially more atherogenic particle sizes, and HDL cholesterol levels decline.11 12 13 Orally administered estrogen reduces LDL cholesterol levels and increases HDL cholesterol levels in postmenopausal women with normal or elevated baseline lipid levels.14 15 16 17 18 Transdermally administered 17ß-estradiol has no effect on lipoprotein levels, suggesting that the hepatic effects of estrogen absorbed through the gut are important for changes in lipoprotein levels.17 The reduction in LDL cholesterol levels is probably a result of accelerated conversion of hepatic cholesterol to bile acids19 and increased expression of LDL receptors on cell surfaces,20 resulting in augmented clearance of LDL from the plasma. The increase in HDL levels is due to increased production of apolipoprotein A-I and decreased hepatic lipase activity,17 21 effects that increase levels of HDL2, the HDL subparticle considered the most active in reverse cholesterol transport. VLDL levels increase because of enhanced production of apolipoprotein B and triglycerides,17 but these particles may not be of atherogenic potential.22 Estrogen therapy has also been shown to reduce levels of lipoprotein(a),23 a lipoprotein with structural features of LDL and plasminogen, believed to be proatherogenic and antithrombolytic, that increases in plasma concentration after menopause.24 However, the importance of lipoprotein(a) as an independent risk factor for cardiovascular events is controversial.25 26 27
The favorable effects of orally administered estrogen on lipoproteins could reduce the progression of atherosclerosis or its acute sequelae, as suggested by secondary-prevention cholesterol reduction trials.28 However, analysis of baseline plasma lipid levels of postmenopausal women in the Lipid Research Clinic Follow-up Study suggested that the lipoprotein effects of estrogen did not fully account for the risk reduction in cardiovascular deaths among estrogen users relative to nonusers.3 In the Nurses' Health Study, significant reduction in cardiovascular risk was noted even in current estrogen users who did not report hypercholesterolemia or other conventional risk factors, although lipid measurements were not made in this study.4 Furthermore, atherogenic animal models have shown reduction in the development and extent of atherosclerosis with estrogen administration despite HDL and LDL cholesterol levels similar to those of untreated animals fed the same diet.29 30 31 Thus, the relative importance of estrogen-induced alterations in lipoprotein levels is unresolved at present. Accordingly, other cardiovascular properties of estrogen may also be important in accounting for the cardioprotective effect of the hormone.
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Coronary Vasomotor Effects of Estrogen |
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TopIntroductionLipoprotein Effects of EstrogenCoronary Vasomotor Effects of...Systemic Vasomotor Effects of...Estrogen and Nitric OxideAntioxidant Effects of EstrogenOxidized LDL and Vasomotor...Hemostatic Effects of EstrogenOther Potential Cardiovascular...Combined Effects of Progestin...Lipid-Lowering Therapy as an...Systemic Vasomotor Effects of...Antioxidant Effects of...Lipid-Lowering Therapy and...Cholesterol Reduction Therapy...ConclusionsReferences |
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Over the past 15 years, tremendous interest has been generated by Furchgott and Zawadzki's32 observation that the endothelium importantly regulates the vasomotor tone of underlying smooth muscle. Subsequent studies have shown the release of vasodilating factors such as nitric oxide from the endothelium by both receptor-mediated (eg, acetylcholine, bradykinin, serotonin, thrombin, norepinephrine) and receptor-independent (eg, shear stress) mechanisms.33 34 35 Considerable evidence indicates that nitric oxide activity in the systemic and coronary circulation is impaired in conditions predisposing to atherosclerosis, such as hypercholesterolemia, hypertension, smoking, and aging.36 37 38 39 40 41 However, there may be sex-related differences in the impact of these conditions on endothelial function. Thus, hypercholesterolemic men were found to have significantly greater impairment in acetylcholine-stimulated forearm flow compared with reproductive-age women despite comparable elevation in LDL cholesterol levels.42 Furthermore, the age-associated decline in flow-mediated brachial artery dilation during reactive hyperemia, which activates the endothelium to release nitric oxide by increased shear stress, was reported to be delayed by a decade in women relative to men, with a smaller decline in the magnitude of vasodilation with aging in postmenopausal women relative to aging men.43 These findings suggest that sex hormones may protect endothelial function in women from conditions that alter endothelial function in men.
Several groups have reported that chronic or acute administration of estrogen to estrogen-deficient animals potentiates endothelium-dependent vasodilation of femoral and coronary arteries.44 45 46 In contrast to physiological replacement doses of estrogen, supraphysiological concentrations of estrogen may have direct smooth muscle relaxant effects on epicardial coronary arteries from animals or humans.47 48 49 50 Reis et al51 reported that intravenous ethinyl estradiol administered to 15 postmenopausal women during cardiac catheterization increased basal coronary artery blood flow and dilated epicardial coronary arteries. Furthermore, estradiol prevented acetylcholine-induced decreases in coronary artery diameter and blood flow in a subset of patients who had these responses at baseline. However, the dose of estrogen used in this study was supraphysiological and considerably higher than achievable with conventional hormone therapy. Furthermore, no study was performed by these investigators to ascertain whether vascular effects of estrogen administration were endothelium specific.
We found that 17ß-estradiol infused into the left coronary arteries of 20 postmenopausal women, achieving physiological concentrations in the coronary sinus drainage, did not affect basal coronary blood flow but enhanced acetylcholine-stimulated increases in coronary flow.52 The enhancement of acetylcholine-mediated vasodilation of epicardial coronary arteries was minimal, suggesting that most of the vasodilator effect of estradiol was at the microvascular level. The enhancement of acetylcholine-mediated vasodilation by estradiol was most prominent in women with the most impaired dilator responses to acetylcholine at both the epicardial and microvascular coronary artery levels during baseline testing. No enhancement of nitroprusside-stimulated flow was noted after estradiol administration, indicative of selective potentiation of endothelium-dependent vasodilation by estradiol at physiological concentrations. Consistent with these findings was the report of Herrington et al,53 in which four postmenopausal women chronically taking conjugated equine estrogen at conventional dosages had epicardial coronary artery dilator responses to intracoronary acetylcholine as opposed to constrictor responses to the same concentrations of acetylcholine noted in six untreated postmenopausal women, with similar dilator responses to nitroglycerin in the two groups.
Collins and coworkers54 recently reported that intracoronary 17ß-estradiol at physiological dosage prevented acetylcholine-induced epicardial coronary artery constriction and potentiated acetylcholine-stimulated coronary blood flow in nine postmenopausal women but not in seven men of similar age and coronary artery disease extent. This observation suggests that the immediate vascular effects of estrogen may be receptor mediated.
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Systemic Vasomotor Effects of Estrogen |
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TopIntroductionLipoprotein Effects of EstrogenCoronary Vasomotor Effects of...Systemic Vasomotor Effects of...Estrogen and Nitric OxideAntioxidant Effects of EstrogenOxidized LDL and Vasomotor...Hemostatic Effects of EstrogenOther Potential Cardiovascular...Combined Effects of Progestin...Lipid-Lowering Therapy as an...Systemic Vasomotor Effects of...Antioxidant Effects of...Lipid-Lowering Therapy and...Cholesterol Reduction Therapy...ConclusionsReferences |
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We found that 17ß-estradiol infused into the brachial arteries of 40 postmenopausal women achieving physiological concentrations in the brachial vein enhanced acetylcholine-stimulated forearm blood flow.55 The 20 women in this study with risk factors for atherosclerosis also had slight potentiation of endothelium-independent (nitroprusside) blood flow during estradiol infusion. In contrast, the 20 women without risk factors, who had greater baseline forearm blood flow responses to both acetylcholine and nitroprusside compared with the 20 women with risk factors, showed selective enhancement in endothelium-dependent vasodilation during estradiol infusion. Three weeks of administration of estradiol to 33 postmenopausal women, via a transdermal patch preparation so as not to affect lipoprotein plasma levels, did not change basal forearm blood flow, vascular resistance, or blood pressure. Furthermore, the blood flow responses to acetylcholine were no different from pretreatment measurements, possibly because of lower plasma levels of estradiol achieved during chronic administration compared with the acute infusion study.56 When plasma levels were raised by reinfusion of estradiol while the patch preparation was still in effect, potentiation of acetylcholine-stimulated flow was restored. The lack of sustained improvement in systemic microvascular dilator function with plasma estrogen levels achievable with chronic therapy may account for the absence of a blood pressure–lowering effect in Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial participants18 or in hypertensive postmenopausal women on estrogen therapy.57
Larger arteries may respond differently from the microcirculation to chronic estrogen administration. Lieberman et al58 reported that oral estradiol administration to 13 postmenopausal women for 9 weeks enhanced flow-mediated brachial artery dilator responses during postischemic hyperemia without potentiation of the vasodilator response to nitroglycerin. However, the use of an oral estrogen preparation probably caused reduction in LDL and elevation in HDL plasma levels, changes that could have improved endothelial function independent of a direct effect of estrogen on brachial artery vasomotor tone.59 60 61 62 63 64 As in our study, no hormonal effects on blood pressure were noted.
The acute vascular effects of estrogen most likely account for the improvement in time to 1-mm ST-segment depression and the total duration of treadmill exercise of 11 postmenopausal women with coronary artery disease after sublingual 17ß-estradiol administration compared with exercise after placebo in a randomized, double-blind study.65 Because the peak heart rate–systolic blood pressure product was not significantly augmented by estradiol administration, systemic vasodilating effects of acutely administered estradiol may have accounted for improvement in exercise in this study. Whether similar anti-ischemic benefits can be achieved with chronic estrogen therapy associated with lower plasma estrogen levels is unknown.
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Estrogen and Nitric Oxide |
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TopIntroductionLipoprotein Effects of EstrogenCoronary Vasomotor Effects of...Systemic Vasomotor Effects of...Estrogen and Nitric OxideAntioxidant Effects of EstrogenOxidized LDL and Vasomotor...Hemostatic Effects of EstrogenOther Potential Cardiovascular...Combined Effects of Progestin...Lipid-Lowering Therapy as an...Systemic Vasomotor Effects of...Antioxidant Effects of...Lipid-Lowering Therapy and...Cholesterol Reduction Therapy...ConclusionsReferences |
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The mechanism of the acute and chronic vascular effects of estrogen, which appears to be largely endothelium dependent in postmenopausal women at physiological or conventional pharmacological plasma concentrations of the hormone, is unknown. Estrogen may block the release of endothelium-derived constricting factors66 67 or enhance the release or bioavailability of nitric oxide from endothelial cells, resulting in increased cGMP in underlying smooth muscle and vasorelaxation.68 69 70 Preliminary studies indicate that 17ß-estradiol augments nitric oxide release in human umbilical vein endothelial cells and in porcine and bovine aortic endothelial cells in culture,71 72 although another preliminary study did not confirm this finding in cultured bovine aortic endothelial cells.73 Postmenopausal women on estrogen therapy were found to have higher serum levels of nitrite and nitrate, indicators (in part) of vascular nitric oxide release, than at baseline or compared with untreated controls.74 Augmented release of nitric oxide by estrogen might account not only for enhancement of endothelium-dependent vasodilation but also for much of the antiatherogenic effects of estrogen by inhibition of platelet aggregation, platelet and inflammatory cell attachment to the vessel wall, and release of factors that stimulate growth and migration of smooth muscle cells.75 76
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Antioxidant Effects of Estrogen |
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TopIntroductionLipoprotein Effects of EstrogenCoronary Vasomotor Effects of...Systemic Vasomotor Effects of...Estrogen and Nitric OxideAntioxidant Effects of EstrogenOxidized LDL and Vasomotor...Hemostatic Effects of EstrogenOther Potential Cardiovascular...Combined Effects of Progestin...Lipid-Lowering Therapy as an...Systemic Vasomotor Effects of...Antioxidant Effects of...Lipid-Lowering Therapy and...Cholesterol Reduction Therapy...ConclusionsReferences |
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Over the past decade, evidence has accumulated indicating that oxidative modification of LDL greatly increases its atherogenicity77 78 and that antioxidants may reduce the extent of atherosclerosis in animals and reduce cardiovascular events in humans.79 80 81 Several groups have examined in vitro the antioxidant properties of estrogen,82 83 84 85 86 87 88 89 90 91 92 93 94 which shares structural similarity with lipophilic antioxidants such as probucol and vitamin E; all have hydroxyphenol groups, with the hydrogen atom of the hydroxy group and its single electron easily donated to lipid peroxyl free radicals, thus terminating chain propagation of oxidation along the fatty acids of lipoprotein membrane phospholipids.95 96
We found that the acute administration of 17ß-estradiol into the
brachial arteries of postmenopausal women significantly delayed the
onset and rate of copper-catalyzed oxidation of LDL isolated from
ipsilateral brachial venous blood after 20 minutes of infusion compared
with baseline samples.92 After estradiol administration
via a transdermal preparation for 3 weeks, LDL was protected from
oxidation by a degree similar to that noted in the short-term
infusion study but at estradiol plasma levels approximately one third
of that achieved during the short-term study. The plasma levels of
estradiol achieved in the brachial venous plasma in these studies were
within the physiological range (
1 nmol/L
concentration), 1000-fold lower than concentrations required to protect
LDL from oxidation when added in vitro.
When we added 1 nmol/L 17ß-estradiol directly to plasma from postmenopausal women not on hormone therapy and let it stand for up to 48 hours, no change in copper-catalyzed oxidation of LDL was noted compared with paired plasma samples without estradiol (seven experiments, unpublished observations). This suggests that the antioxidant effects of estradiol may not be a result of direct protection of LDL from oxidant stress but rather may result from the release of antioxidant substances from the vessel wall.
We also investigated the possibility that 17ß-estradiol at 1 mg/d transdermal delivery for 3 weeks and vitamin E (800 IU/d for 6 weeks) might act synergistically to protect LDL from oxidation when administered to postmenopausal women.93 However, despite the protection of LDL from oxidation by each agent administered independently, there was no additive or synergistic antioxidant effect when they were coadministered to postmenopausal women in this study.
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Oxidized LDL and Vasomotor Function |
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TopIntroductionLipoprotein Effects of EstrogenCoronary Vasomotor Effects of...Systemic Vasomotor Effects of...Estrogen and Nitric OxideAntioxidant Effects of EstrogenOxidized LDL and Vasomotor...Hemostatic Effects of EstrogenOther Potential Cardiovascular...Combined Effects of Progestin...Lipid-Lowering Therapy as an...Systemic Vasomotor Effects of...Antioxidant Effects of...Lipid-Lowering Therapy and...Cholesterol Reduction Therapy...ConclusionsReferences |
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In addition to its contribution to atherogenesis, oxidized LDL may impair endothelium-dependent vasomotor function.97 98 99 100 101 Keaney et al94 reported that treatment of estrogen-deficient miniature swine with 17ß-estradiol for 16 weeks normalized the impaired endothelium-dependent vasodilator responsiveness of rings from coronary arteries compared with estrogen-deficient animals. The estrogen-replaced group had time to onset of copper-catalyzed oxidation of LDL comparable to that of the sham-operated controls and significantly greater than the time to onset of oxidation of LDL from the oophorectomized untreated group, with a high correlation between the time to onset of oxidation of LDL and the extent of vascular relaxation in response to bradykinin and to substance P.
However, despite an antioxidant effect of 17ß-estradiol after 3 weeks of transdermal administration (0.1 mg/d),92 we saw no improvement in forearm endothelium-dependent microvascular dilator responsiveness compared with pretreatment measurements.56 This finding was consistent with our study of the effects of antioxidant vitamins in hypercholesterolemic subjects: Despite 71% prolongation of the time to copper-catalyzed oxidation of their LDL after 1 month of daily vitamins C (1 g), E (800 IU), and ß-carotene (30 mg), we found no improvement in forearm blood responses to endothelium-dependent or endothelium-independent agonists compared with pretreatment measurements.102
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Hemostatic Effects of Estrogen |
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TopIntroductionLipoprotein Effects of EstrogenCoronary Vasomotor Effects of...Systemic Vasomotor Effects of...Estrogen and Nitric OxideAntioxidant Effects of EstrogenOxidized LDL and Vasomotor...Hemostatic Effects of EstrogenOther Potential Cardiovascular...Combined Effects of Progestin...Lipid-Lowering Therapy as an...Systemic Vasomotor Effects of...Antioxidant Effects of...Lipid-Lowering Therapy and...Cholesterol Reduction Therapy...ConclusionsReferences |
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The influence of estrogen on coagulation factors associated with acute coronary syndromes has been of concern because of thrombotic complications associated with estrogen use in the past, such as the increased risk of myocardial infarction in men randomized to high-dose (5 mg) conjugated equine estrogen in the Coronary Drug Project.103 However, recent studies of women taking conventional dosages of estrogen therapy (most commonly, conjugated equine estrogen 0.625 mg/d) have reported favorable effects of estrogen on hemostatic factors implicated in acute coronary syndromes. In the Atherosclerosis Risk in the Community Study104 and the PEPI Trial,18 users of estrogen (alone or in combination with a progestin) had lower plasma levels of fibrinogen than nonusers. In the Framingham Offspring Study, reproductive-age women had lower plasma levels of PAI-1 and higher levels of TPA compared with men of comparable age or postmenopausal women not taking estrogen.105 However, postmenopausal women on estrogen therapy had PAI-1 and TPA levels similar to those of reproductive-age women.
The mechanism of the apparently favorable hemostatic effects of estrogen is unknown. Oxidatively modified LDL depresses endothelial release of TPA, and both oxidatively modified LDL and lipoprotein(a) promote synthesis of PAI-1 by increased transcription of PAI-1 mRNA.106 107 Thus, the effect of estrogen on TPA and PAI-1 may in part be due to antioxidant protection of LDL and reduction in lipoprotein(a) plasma levels.
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Other Potential Cardiovascular Effects of Estrogen |
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TopIntroductionLipoprotein Effects of EstrogenCoronary Vasomotor Effects of...Systemic Vasomotor Effects of...Estrogen and Nitric OxideAntioxidant Effects of EstrogenOxidized LDL and Vasomotor...Hemostatic Effects of EstrogenOther Potential Cardiovascular...Combined Effects of Progestin...Lipid-Lowering Therapy as an...Systemic Vasomotor Effects of...Antioxidant Effects of...Lipid-Lowering Therapy and...Cholesterol Reduction Therapy...ConclusionsReferences |
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In addition to presumably favorable effects of estrogen on lipoprotein levels, vasomotor function, LDL oxidation, and coagulation, other biological properties of estrogen have been proposed to contribute to the hormone's cardiovascular benefit. Estrogen has been shown in animal models or cell culture to reduce collagen and elastin synthesis108 109 110 111 and enhance their degradation in arterial tissue,112 reduce smooth muscle cell proliferation,113 114 decrease platelet aggregation,115 116 and promote angiogenesis.117 Prostacyclin, a potent vasodilator and inhibitor of platelet aggregation, has been shown in various studies to be potentiated or inhibited by estrogen.118 119 120 121 122 123 124 Recently, hormone therapy (estradiol valerate and norethisterone) administered to 28 postmenopausal women for 6 months reduced serum angiotensin-converting enzyme levels by 20%, in contrast to no change in serum levels of 16 untreated women during the same interval.125
Estrogen has also been reported to have potentially deleterious
cardiovascular effects, including potentiation of
vascular contraction in response to norepinephrine by
augmented neuronal spillover,126 by increased
-adrenergic receptor affinity for
norepinephrine,127 and by a
cyclooxygenase-dependent
mechanism.128 However, the relevance of these properties
of estrogen determined from animal and cell culture studies to
postmenopausal women taking conventional dosages of estrogen therapy is
unknown at present.
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Combined Effects of Progestin and Estrogen in Postmenopausal Women |
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TopIntroductionLipoprotein Effects of EstrogenCoronary Vasomotor Effects of...Systemic Vasomotor Effects of...Estrogen and Nitric OxideAntioxidant Effects of EstrogenOxidized LDL and Vasomotor...Hemostatic Effects of EstrogenOther Potential Cardiovascular...Combined Effects of Progestin...Lipid-Lowering Therapy as an...Systemic Vasomotor Effects of...Antioxidant Effects of...Lipid-Lowering Therapy and...Cholesterol Reduction Therapy...ConclusionsReferences |
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The majority of observational population-based studies reporting reduced cardiovascular mortality in estrogen users have not separately analyzed cardiovascular risk of women taking a combination of estrogen and a progestin compound because of the infrequent use of combination therapy until recent years. Over the past decade, and recently confirmed in the PEPI Trial, unopposed estrogen has been found to cause endometrial dysplasia and carcinoma, with protection of the uterus from these effects by the addition of a progestin.7 18 Although several nonrandomized studies have reported that the risk of myocardial infarction was reduced by combined estrogen-progestin therapy at least as much as by estrogen alone,129 130 131 recent animal studies indicate that the addition of a progestin may attenuate or negate many of the presumably beneficial vascular effects of estrogen.132 133 In the PEPI Trial, women randomized to conjugated equine estrogen and continuous or cyclical medroxyprogesterone acetate had smaller increases from baseline in HDL cholesterol levels than women randomized to unopposed estrogen.18 Such an effect on HDL levels could compromise the cardioprotective effect of estrogen, given the inverse association between HDL cholesterol levels and cardiovascular disease in women.3 134 Combined progestin/17ß-estradiol administration to postmenopausal women was not found to increase serum nitrite and nitrate levels, in contrast to increases in these largely oxidized products of endothelium-released nitric oxide measured in the same women when taking estrogen alone.74 In the Framingham Offspring Study, postmenopausal women taking a combination of estrogen and progestin had higher levels of PAI-1 than women on unopposed estrogen when adjustments were made for age, risk factors, and other covariants.105 Thus, it is possible that the addition of a progestin compound to estrogen in women, although protecting the uterus from the harmful effects of unopposed estrogen, might negate some of the beneficial cardiovascular effects of unopposed estrogen.
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Lipid-Lowering Therapy as an Alternative to Estrogen Therapy |
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TopIntroductionLipoprotein Effects of EstrogenCoronary Vasomotor Effects of...Systemic Vasomotor Effects of...Estrogen and Nitric OxideAntioxidant Effects of EstrogenOxidized LDL and Vasomotor...Hemostatic Effects of EstrogenOther Potential Cardiovascular...Combined Effects of Progestin...Lipid-Lowering Therapy as an...Systemic Vasomotor Effects of...Antioxidant Effects of...Lipid-Lowering Therapy and...Cholesterol Reduction Therapy...ConclusionsReferences |
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An understanding of the cardiovascular effects of estrogen permits comparison with lipid-lowering therapy as a treatment alternative for postmenopausal women at risk for cardiovascular disease who cannot or will not take chronic hormone therapy. For example, reduction in LDL and increases in HDL cholesterol levels can be achieved pharmacologically to a comparable or greater magnitude than changes in lipoprotein levels achieved with estrogen therapy, with improvement in endothelium-dependent relaxation of coronary arteries in humans.60 61 62 63 64 Egashira et al61 reported that 6 months of treatment of nine hypercholesterolemic coronary artery disease patients (six men, three women) with pravastatin decreased LDL cholesterol levels by 39% and significantly attenuated the epicardial coronary artery constrictor response to intracoronary acetylcholine and potentiated acetylcholine-stimulated coronary blood flow compared with baseline values. The epicardial coronary artery dilator responses to isosorbide dinitrate and the coronary flow responses to papaverine were unaltered by treatment. Although no placebo group was included in this study, the findings are consistent with an endothelium-specific beneficial effect of cholesterol-lowering therapy on epicardial and resistance coronary arteries.
Treasure et al62 treated 23 coronary artery disease patients (13 men, 10 women) whose total cholesterol levels ranged from 160 to 300 mg/dL with lovastatin or placebo in addition to diet for 4.5 months in a randomized, double-blind study. In the lovastatin group, LDL cholesterol was reduced by 26% and HDL cholesterol increased by 11% compared with baseline values. Significant reduction in the epicardial coronary artery constrictor response to intracoronary acetylcholine compared with baseline values was observed in the lovastatin group but not in the placebo group. The epicardial coronary artery dilator responses to nitroglycerin were unaltered by therapy. Anderson et al63 treated 49 coronary artery disease patients (37 men and 12 women) whose total cholesterol levels ranged from 180 to 280 mg/dL with lovastatin and cholestyramine, lovastatin and probucol, or placebo in addition to diet for 1 year. Lovastatin and cholestyramine produced a 38% reduction in LDL and a nonsignificant change in HDL levels; lovastatin and probucol resulted in a 41% reduction in LDL and 21% reduction in HDL levels compared with baseline values. There was significant attenuation of the epicardial coronary artery vasoconstrictor response to intracoronary acetylcholine in the lovastatin-probucol group (possibly enhanced by the antioxidant effects of probucol on LDL) and a trend toward improvement in this response in the lovastatin-cholestyramine response. There was no change in the vasoconstrictor response to acetylcholine in the placebo group. Although the coronary artery responses of men and women who received lipid-lowering therapy in these studies were not analyzed separately for sex differences, given the relatively small population sizes in each study, it seems unlikely that all vascular benefit was manifest in men but not in women.
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Systemic Vasomotor Effects of Lipid-Lowering Therapy |
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TopIntroductionLipoprotein Effects of EstrogenCoronary Vasomotor Effects of...Systemic Vasomotor Effects of...Estrogen and Nitric OxideAntioxidant Effects of EstrogenOxidized LDL and Vasomotor...Hemostatic Effects of EstrogenOther Potential Cardiovascular...Combined Effects of Progestin...Lipid-Lowering Therapy as an...Systemic Vasomotor Effects of...Antioxidant Effects of...Lipid-Lowering Therapy and...Cholesterol Reduction Therapy...ConclusionsReferences |
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Goode and Heagerty64 isolated small (<330-µm ID) arteries from subcutaneous biopsies performed in 18 hypercholesterolemic patients (11 men, 7 women; average age, 51 years) and demonstrated impaired dilator responses to acetylcholine and, to a lesser degree, nitroprusside compared with responses in small arteries from 16 sex-matched control subjects of similar age with normal cholesterol levels. Ten of these patients (sex not reported) underwent repeat biopsies
10 months
after lipid-lowering therapy, which reduced LDL levels by 56%.
Significant improvement in vasodilator responses to acetylcholine and
nitroprusside were observed in these patients compared with their
baseline values. Of note, systolic and diastolic
blood pressures in these 10 patients were significantly lower on
treatment compared with pretreatment values. Thus, lipid-lowering therapy may improve systemic vasomotor function as well as coronary vasomotor function. To the extent that such improvement indicates augmented nitric oxide bioavailability, other endothelial properties may also benefit, such as reduced platelet aggregation, inflammatory cell adhesion, and smooth muscle cell migration.75 76 77
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Antioxidant Effects of Cholesterol Reduction Therapy |
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TopIntroductionLipoprotein Effects of EstrogenCoronary Vasomotor Effects of...Systemic Vasomotor Effects of...Estrogen and Nitric OxideAntioxidant Effects of EstrogenOxidized LDL and Vasomotor...Hemostatic Effects of EstrogenOther Potential Cardiovascular...Combined Effects of Progestin...Lipid-Lowering Therapy as an...Systemic Vasomotor Effects of...Antioxidant Effects of...Lipid-Lowering Therapy and...Cholesterol Reduction Therapy...ConclusionsReferences |
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Reduction in cholesterol levels may reduce the susceptibility of LDL to oxidation. Thus, Kleinveld et al135 reported that 18 weeks of pravastatin or simvastatin administered to 23 hypercholesterolemic patients (15 men, 8 women) decreased LDL cholesterol levels by 36% and significantly reduced the rate and extent of copper-catalyzed LDL oxidation. LDL particles after therapy were changed in composition to contain less lipid relative to protein, possibly rendering the particle less susceptible to oxidation.136 Properties of HMG-CoA reductase inhibitors other than reduction in LDL levels and changes in particle composition may also be of antioxidant importance. In this regard, Giroux et al137 reported that simvastatin diminished superoxide anion formation and LDL oxidation by human macrophages in tissue culture. Protection of LDL from oxidation could increase nitric oxide bioavailability and improve endothelium-dependent vasomotor, anti-inflammatory, and anticoagulant properties of the endothelium.75 76 77 78 98 99 100 101
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Lipid-Lowering Therapy and Thrombosis |
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TopIntroductionLipoprotein Effects of EstrogenCoronary Vasomotor Effects of...Systemic Vasomotor Effects of...Estrogen and Nitric OxideAntioxidant Effects of EstrogenOxidized LDL and Vasomotor...Hemostatic Effects of EstrogenOther Potential Cardiovascular...Combined Effects of Progestin...Lipid-Lowering Therapy as an...Systemic Vasomotor Effects of...Antioxidant Effects of...Lipid-Lowering Therapy and...Cholesterol Reduction Therapy...ConclusionsReferences |
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Several lipid-lowering agents may potentiate fibrinolysis independent of alterations in plasma lipoproteins. Thus, Fujii's group138 139 showed that gemfibrozil and niacin decrease PAI-1 synthesis in hepatoma cell cultures both in the basal state and after stimulation of the cell lines with mitogens such as transforming growth factor-ß1. The reduction in PAI-1 secretion appeared disproportionate to the reduction in PAI-1 mRNA, suggesting posttranscriptional as well as transcriptional inhibitory effects of these agents. This group also reported that niacin administered to rats for 3 weeks significantly reduced dexamethasone-stimulated PAI-1 plasma levels. Although the effects of gemfibrozil and niacin on plasma PAI-1 levels have not been reported in humans, the HMG-CoA reductase inhibitor pravastatin reduced PAI-1 plasma levels in hypercholesterolemic subjects.140 The intracellular mechanism of PAI-1 inhibition by these pharmacologically diverse agents, and whether or not endothelial synthesis of PAI-1 is affected by these agents, are unknown. Niacin lowers plasma levels of lipoprotein(a) in hypercholesterolemic subjects,141 which may secondarily reduce PAI-1 levels by decreased transcription of PAI-1 mRNA.107
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Cholesterol Reduction Therapy and Prevention of Cardiovascular Events |
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TopIntroductionLipoprotein Effects of EstrogenCoronary Vasomotor Effects of...Systemic Vasomotor Effects of...Estrogen and Nitric OxideAntioxidant Effects of EstrogenOxidized LDL and Vasomotor...Hemostatic Effects of EstrogenOther Potential Cardiovascular...Combined Effects of Progestin...Lipid-Lowering Therapy as an...Systemic Vasomotor Effects of...Antioxidant Effects of...Lipid-Lowering Therapy and...Cholesterol Reduction Therapy...ConclusionsReferences |
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As recently reviewed by Rich-Edwards et al,142 the majority of prospective observational studies have reported a positive association between coronary heart disease and total plasma cholesterol levels and an inverse association between coronary heart disease and HDL cholesterol levels in women. The benefit of cholesterol reduction for prevention of atherosclerosis progression143 144 145 146 or reduction in cardiovascular events147 148 149 150 151 in patients with coronary artery disease has been evaluated in a few trials that included women, albeit small numbers in most of these trials. Kane et al145 analyzed the coronary angiograms of 72 patients (41 women) with heterozygous familial hypercholesterolemia randomized to diet plus cholesterol reduction therapy versus diet alone, with baseline angiograms compared with angiograms performed 26 months later. The 22 women randomized to pharmacological treatment had lipoprotein changes comparable to those of men (38% reduction in LDL cholesterol in both groups; 27% increase in HDL cholesterol in women, 29% increase in men). Treatment resulted in significant regression of coronary atherosclerosis in these women compared with control women, comparable to the effect of treatment in men.
In the Canadian Coronary Atherosclerosis
Intervention Trial, 62 women (6 of whom were on hormone therapy) who
had serum cholesterol levels between 220 and 300 mg/dL and
angiographic evidence of coronary artery
atherosclerosis were randomized to
lovastatin (titrated to reduce LDL cholesterol
to 
130 mg/dL) versus placebo in a double-blind
trial.146 Lovastatin reduced LDL
cholesterol levels by 32%. Two years later, follow-up
coronary angiography was performed in 54 of these women: The 25
lovastatin-treated women had significantly less
progression of preexisting stenoses and less development of new
lesions compared with the 29 placebo-treated women. The benefit of
therapy for coronary atherosclerosis was
similar to that measured in the 245 men who also underwent
follow-up coronary angiography.
Atherosclerotic plaque regression and stabilization by reduction in atheroma lipid content may account for the significant reduction in coronary events reported in secondary prevention trials.152 In the Scandinavian Simvastatin Survival Study, 4444 patients with coronary artery disease (3617 men, 827 women) who had serum cholesterol levels between 212 and 309 mg/dL were randomized to simvastatin versus placebo in addition to diet and conventional antianginal therapy.151 After a median of 5.4 years of treatment, the simvastatin group had a 35% reduction in LDL and 8% increase in HDL cholesterol levels compared with pretreatment values and a 30% reduction in total mortality, primarily due to fewer fatal ischemic cardiac events, compared with the placebo group. Of the 827 women in the study, 25 in the placebo group and 27 in the simvastatin group died, representing an overall 50% lower mortality rate than placebo-treated men. However, women randomized to simvastatin had significantly fewer major coronary events (coronary death, nonfatal myocardial infarction, resuscitation from cardiac arrest) than women in the control group (59 versus 91), with risk reduction (0.65 [95% CI, 0.47 to 0.91]) comparable to that observed in men in this study (0.66 [95% CI, 0.58 to 0.76]).
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Conclusions |
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TopIntroductionLipoprotein Effects of EstrogenCoronary Vasomotor Effects of...Systemic Vasomotor Effects of...Estrogen and Nitric OxideAntioxidant Effects of EstrogenOxidized LDL and Vasomotor...Hemostatic Effects of EstrogenOther Potential Cardiovascular...Combined Effects of Progestin...Lipid-Lowering Therapy as an...Systemic Vasomotor Effects of...Antioxidant Effects of...Lipid-Lowering Therapy and...Cholesterol Reduction Therapy...ConclusionsReferences |
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Estrogen therapy has been associated with reduced cardiovascular risk, with multiple biologically plausible mechanisms demonstrated in postmenopausal women to account for this benefit. Although several studies in progress, including the Women's Health Initiative, may ultimately prove that estrogen therapy both prolongs the duration and improves the quality of life of postmenopausal women as a group, many women at risk for cardiovascular disease and concerned about their health may still be unwilling to take estrogen compounds for decades because of side effects and cancer concerns. Furthermore, the addition of a progestin compound to estrogen for women with a uterus may compromise to some degree the cardiovascular benefit of estrogen. The available data suggest that pharmacological alteration of lipoprotein levels in hypercholesterolemic women may achieve many if not most of the cardiovascular effects reported with estrogen administration. Lipid-lowering therapy should also be considered for mildly hypercholesterolemic or even normocholesterolemic postmenopausal women with atherosclerosis, consistent with National Cholesterol Education Program II guidelines for lowering LDL cholesterol to <100 mg/dL.153
Comparison of the effects of estrogen and lipid-lowering therapies in postmenopausal women, including those not considered hypercholesterolemic, would be of considerable interest to women at risk for or with established atherosclerosis faced with the prospect of decades of therapy to delay the progression and expression of cardiovascular disease.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We greatly appreciate the secretarial assistance of Toni Julia in the typing of the manuscript.
Received September 6, 1995; revision received December 4, 1995; accepted December 10, 1995.
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References |
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TopIntroductionLipoprotein Effects of EstrogenCoronary Vasomotor Effects of...Systemic Vasomotor Effects of...Estrogen and Nitric OxideAntioxidant Effects of EstrogenOxidized LDL and Vasomotor...Hemostatic Effects of EstrogenOther Potential Cardiovascular...Combined Effects of Progestin...Lipid-Lowering Therapy as an...Systemic Vasomotor Effects of...Antioxidant Effects of...Lipid-Lowering Therapy and...Cholesterol Reduction Therapy...ConclusionsReferences |
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1. National Center for Health Statistics. Vital Statistics of the United States, 1989, Vol II: Mortality, Part A. Washington, DC: Government Printing Office; 1993. DHHS Publication (PHS) 93-1101.
2. Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speizer FE, Hennekens CH. Menopause and the risk of coronary heart disease in women. N Engl J Med. 1987;316:1105-1110. [Abstract]
3.
Bush TL, Barrett-Connor E, Cowan LD, Criqui MH,
Wallace RB, Suchindran CM, Tyroler HA, Rifkind BM.
Cardiovascular mortality and noncontraceptive use of
estrogen in women: results from the Lipid Research Clinics Program
Follow-up Study. Circulation. 1987;75:1102-1109.
4. Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen therapy and cardiovascular disease: ten-year follow-up from the Nurses' Health Study. N Engl J Med. 1991;325:756-762. [Abstract]
5. Stampfer MJ, Colditz GA. Estrogen replacement and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med. 1991;20:47-63. [Medline] [Order article via Infotrieve]
6. American College of Physicians. Guidelines for counseling postmenopausal women about preventive hormone therapy. Ann Intern Med. 1992;117:1038-1041.
7.
Belchetz PE. Hormonal treatment of
postmenopausal women. N Engl J Med. 1994;330:1062-1071.
8.
Colditz GA, Hankinson SE, Hunter DJ, Willett WC,
Manson JE, Stampfer MJ, Hennekens C, Rosner B, Speizer FE. The
use of estrogens and progestins and the risk of breast cancer in
postmenopausal women. N Engl J Med. 1995;332:1589-1593.
9. Pilote L, Hlatky MA. Attitudes of women toward hormone replacement therapy and prevention of heart disease. Am Heart J. 1995;129:1237-1238.[Medline] [Order article via Infotrieve]
10.
Sullivan JM, VanderZwaag R, Hughes JP, Kroetz
FW, Ramanathan KB, Mirvis DM. Estrogen replacement and
coronary artery disease: effect on survival in postmenopausal
women. Arch Intern Med. 1990;150:2557-2562.
11. Stevenson JC, Crook D, Godsland IF. Influence of age and menopause on serum lipids and lipoproteins in healthy women. Atherosclerosis. 1993;98:83-90. [Medline] [Order article via Infotrieve]
12.
Campos H, McNarara SR, Wilson PWF, Ordovas JM,
Schaefer EJ. Differences in low density lipoprotein subfractions
and apolipoproteins in premenopausal and postmenopausal women.
J Clin Endocrinol Metab. 1988;67:30-35.
13.
Brown SA, Hutchinson R, Morrisett JD, Boerwinkle E,
Davis CE, Gotto AM, Patsch W. Plasma lipid, lipoprotein
cholesterol, and apoprotein distributions in selected US
communities: the Atherosclerosis Risk in Communities
(ARIC) study. Arterioscler Thromb. 1993;13:1139-1158.
14. Tikkanen MJ, Nikkila EA, Vartianen E. Natural oestrogen as an effective treatment for type-II hyperlipoproteinemia in postmenopausal women. Lancet. 1978;2:490-491. [Medline] [Order article via Infotrieve]
15. Granfone A, Campos H, McNamara JR, Schaefer MM, Lamon-Fava S, Ordovas JM, Schaefer EJ. Effects of estrogen replacement on plasma lipoproteins and apolipoproteins in postmenopausal, dyslipidemic women. Metabolism. 1992;41:1193-1198. [Medline] [Order article via Infotrieve]
16.
Lobo RA. Effects of hormonal replacement
on lipids and lipoproteins in postmenopausal women.
J Clin Endocrinol Metab. 1991;73:925-930.
17. Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar V, Sacks FM. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med. 1991;325:1196-1204. [Abstract]
18.
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.
19.
Kushwaha RS, Born KM. Effect of estrogen and
progesterone on the hepatic cholesterol
7-hydroxylase activity in ovariectomized baboons.
Biophys Acta. 1991;1084:300-302. [Medline]
[Order article via Infotrieve]
20. Windler E, Kovanen PT, Chao YS, Brown MS, Havel RJ, Goldstein JL. The estradiol-stimulated lipoprotein receptor of rat liver. J Biol Chem. 1980;225:10464-10471.
21.
Tikkanen MJ, Nikkila EA, Kussi T, Sipinens S.
High density lipoprotein-2 and hepatic lipase: reciprocal changes
produced by estrogen and norgestrel. J
Clin Endocrinol Metab. 1982;54:1113-1117.
22. Sacks FM, Walsh BW. Sex hormones and lipoprotein metabolism. Curr Opin Lipidol. 1994;5:236-240. [Medline] [Order article via Infotrieve]
23.
Soma MR, Osnago-Gadda I, Paoletti R, Fumagalli R,
Morrisett JD, Meschia M, Crosignani P. The lowering of
lipoprotein(a) induced by estrogen plus progesterone replacement
therapy in postmenopausal women. Arch Intern Med. 1993;153:1462-1468.
24.
Jenner JL, Orodovas JM, Lamon-Fava S, Schaefer MM,
Wilson PWF, Castelli WP, Schaefer EJ. Effects of age, sex, and
menopausal status on plasma lipoprotein(a) levels: the Framingham
Offspring Study. Circulation. 1993;87:1135-1141.
25.
Ridker PM, Hennekens CH, Stampfer MJ. A
prospective study of lipoprotein (a) and the risk of myocardial
infarction. JAMA. 1993;270:2195-2199.
26.
Schaefer EJ, Lamon-Fava S, Jenner JL, McNamara JR,
Ordovas JM, Davis E, Abolafia JM, Lippel K, Levy RI. Lipoprotein
(a) levels and risk of coronary heart disease in men: the Lipid
Research Clinics Coronary Primary Prevention Trial.
JAMA. 1994;271:999-1003.
27. Sacks FM. Is there anything to add to our lipid risk factors for coronary heart disease? Am J Cardiol. 1995;75:1263-1264. [Medline] [Order article via Infotrieve]
28.
Levine GN, Keaney JF, Vita JA.
Cholesterol reduction in cardiovascular
disease: clinical benefits and possible mechanisms.
N Engl J Med. 1995;332:512-521.
29.
Hough JL, Zilversmit DB. Effect of 17 beta
estradiol on aortic cholesterol content and
metabolism in cholesterol-fed
rabbits. Arteriosclerosis. 1986;6:57-63.
30. Clarkson TB, Shively CA, Morgan TM, Koritnik DR, Adams MR, Kaplan JR. Oral contraceptives and coronary artery atherosclerosis of cynomolgus monkeys. Obstet Gynecol. 1990;75:217-222. [Medline] [Order article via Infotrieve]
31.
Adams MR, Kaplan JR, Manuck SB, Koritnik DR, Parks
JS, Wolfe MS, Clarkson TB. Inhibition of coronary artery
atherosclerosis by 17-beta estradiol in ovariectomized
monkeys: lack of an effect of added progesterone.
Arteriosclerosis. 1990;10:1051-1057.
32. Furchgott RF, Zawadzki JV. The obligatory role of the endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373-376. [Medline] [Order article via Infotrieve]
33. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524-526. [Medline] [Order article via Infotrieve]
34. Vanhoutte PM. The endothelium: modulator of vascular smooth muscle tone. N Engl J Med. 1988;319:512-513. [Medline] [Order article via Infotrieve]
35.
Rubanyi GM, Romero JC, Vanhoutte PM.
Flow-induced release of endothelium-derived
relaxing factor. Am J Physiol. 1986;250:H1145-H1149.
36. Panza JA, Quyyumi AA, Brush JE, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990;323:22-27. [Abstract]
37. Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ, Coleman SM, Loscalzo J, Dzau VJ. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990;86:228-234.
38.
Zeiher AM, Drexler H, Wollschlager H, Just H.
Modulation of coronary vasomotor tone in humans: progressive
endothelial dysfunction with different early stages of
coronary atherosclerosis.
Circulation. 1991;83:391-401.
39. Egashira K, Inou T, Hirooka Y, Yamada A, Maruoka Y, Kai H, Sugimachi M, Suzuki S, Takeshita A. Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. J Clin Invest. 1993;91:29-37.
40.
Vita JA, Treasure CB, Nabel EG, McLenachan JM, Fish
RD, Yeung AC, Vekshtein VI, Selwyn AP, Ganz P. Coronary
vasomotor response to acetylcholine relates to risk factors for
coronary artery disease.
Circulation. 1990;81:491-497.
41.
Zeiher AM, Schachinger V, Minners J.
Long-term cigarette smoking impairs
endothelium-dependent coronary
arterial vasodilator function.
Circulation. 1995;92:1094-1100.
42. Chowienczyk PJ, Watts GF, Cockroft JR, Brett SE, Ritter JM. Sex differences in endothelial function in normal and hypercholesterolaemic subjects. Lancet. 1994;334:305-306.
43. Celermajer DS, Sorensen KE, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Deanfield JE. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol. 1994;24:471-476. [Abstract]
44.
Gisclard V, Miller VM, Vanhoutte PM. Effect of
17ß-estradiol on endothelium-dependent
responses in the rabbit. J Pharmacol Exp
Ther. 1988;244:19-22.
45.
Williams JK, Adams MR, Klopfenstein HS.
Estrogen modulates responses of atherosclerotic coronary
arteries. Circulation. 1990;81:1680-1687.
46. Williams JK, Adams MR, Herrington DM, Clarkson TB. Short-term administration of estrogen and vascular responses of atherosclerotic coronary arteries. J Am Coll Cardiol. 1992;20:452-457. [Abstract]
47. Jiang C, Sarrel PM, Lindsay DC, Poole-Wilson PA, Collins P. Endothelium-independent relaxation of rabbit coronary artery by 17ß-oestradiol in vitro. Br J Pharmacol. 1991;104:1033-1037. [Medline] [Order article via Infotrieve]
48. Jiang C, Sarrel PM, Poole-Wilson PA, Collins P. Acute effect of 17ß-estradiol on rabbit coronary artery contractile responses to endothelin-1. Am J Physiol. 1993;263:H271-H272.
49. Chester AH, Jiang C, Borland JA, Yacoub MH, Collins P. Oestrogen relaxes human epicardial coronary arteries through non-endothelium-dependent mechanisms. Coron Artery Dis. 1995;6:417-422. [Medline] [Order article via Infotrieve]
50.
Han S-Z, Karaki H, Ouchi Y, Akishita M, Orimo
H. 17ß-Estradiol inhibits Ca2+ influx and
Ca2+ release induced by thromboxane
A2 in porcine coronary artery.
Circulation. 1995;91:2619-2626.
51.
Reis SE, Gloth ST, Blumenthal RS, Resar JR, Zacur HA,
Gerstenblith G, Brinker JA. Ethinyl estradiol acutely attenuates
abnormal coronary vasomotor responses to acetylcholine in
postmenopausal women. Circulation. 1994;89:52-60.
52.
Gilligan DM, Quyyumi AA, Cannon RO. Effects of
physiological levels of estrogen on
coronary vasomotor function in postmenopausal women.
Circulation. 1994;89:2545-2551.
53. Herrington DM, Braden GA, Williams JK, Morgan TM. Endothelium-dependent coronary vasomotor responsiveness in postmenopausal women with and without estrogen therapy. Am J Cardiol. 1994;73:951-952. [Medline] [Order article via Infotrieve]
54.
Collins P, Rosano GMC, Sarrel PM, Ulrich L,
Adamopoulos S, Beale CM, McNeill JG, Poole-Wilson PA.
17ß-Estradiol attenuates acetylcholine-induced coronary
arterial constriction in women but not men with
coronary heart disease.
Circulation. 1995;92:24-30.
55.
Gilligan DM, Badar DM, Panza JA, Quyyumi AA, Cannon
RO. Acute vascular effects of estrogen in postmenopausal
women. Circulation. 1994;90:786-791.
56. Gilligan DM, Badar DM, Panza JA, Quyyumi AA, Cannon RO. Effects of estrogen therapy on peripheral vasomotor function in postmenopausal women. Am J Cardiol. 1995;75:264-268. [Medline] [Order article via Infotrieve]
57. Lip GYH, Beevers M, Churchill D, Beevers DG. Hormone replacement therapy and blood pressure in hypertensive women. J Hum Hypertens. 1994;8:491-494. [Medline] [Order article via Infotrieve]
58.
Lieberman EH, Gebhard MD, Uehata A, Walsh BW, Selwyn
AP, Ganz P, Yeung AC, Creager MA. Estrogen improves
endothelium-dependent, flow-mediated
vasodilation in postmenopausal women. Ann Intern
Med. 1994;121:936-941.
59. Harrison DG, Armstrong ML, Freiman PC, Heistad DD. Restoration of endothelium-dependent relaxation by dietary treatment of atherosclerosis. J Clin Invest. 1987;80:1808-1811.
60. Leung W-H, Lau C-P, Wong C-K. Beneficial effect of cholesterol-lowering therapy on coronary endothelium-dependent relaxation in hypercholesterolemic patients. Lancet. 1993;341:1496-1500. [Medline] [Order article via Infotrieve]
61.
Egashira K, Hirooka Y, Kai H, Sugimachi M, Suzuki S,
Inou T, Takeshita A. Reduction in serum cholesterol
with pravastatin improves
endothelium-dependent coronary vasomotion
in patients with hypercholesterolemia.
Circulation. 1994;89:2519-2524.
62.
Treasure CB, Klein JL, Weintraub WS, Talley JD,
Stillabower ME, Kosinski AS, Zhang J, Boccuzzi SJ, Cedarholm JC,
Alexander RW. Beneficial effects of cholesterol
lowering-therapy on the coronary
endothelium in patients with coronary artery
disease. N Engl J Med. 1995;332:481-487.
63.
Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn
AP, Ganz P. The effect of cholesterol-lowering
and antioxidant therapy on endothelium-dependent
coronary vasomotion. N Engl J Med. 1995;332:488-493.
64.
Goode GK, Heagerty AM. In vitro responses of
human peripheral small arteries in
hypercholesterolemia and effects of
therapy. Circulation. 1995;91:2898-2903.
65. Rosano GMC, Sarrel PM, Poole-Wilson PA, Collins P. Beneficial effect of oestrogen on exercise-induced myocardial ischaemia in women with coronary artery disease. Lancet. 1993;342:133-136. [Medline] [Order article via Infotrieve]
66.
Lerman A, Webster MWI, Chesebro JH, Edwards WD, Wei
C-M, Fuster V, Burnett JC. Circulating and tissue endothelin
immunoreactivity in hypercholesterolemic
pigs. Circulation. 1993;88:2923-2928.
67.
Polderman KH, Stehouwer CDA, van Kamp GJ, Dekker GA,
Verheugt FWA, Gooren LJG. Influence of sex hormones on plasma
endothelin levels. Ann Intern Med. 1993;118:429-432.
68.
Hayashi T, Fukuto JM, Ignarro LJ, Chaudhuri G.
Basal release of nitric oxide from aortic rings is greater in female
rabbits than male rabbits: implications for
atherosclerosis. Proc Natl Acad Sci
U S A. 1992;89:11259-11263.
69. Van Buren GA, Yang D, Clark KE. Estrogen-induced uterine vasodilatation is antagonized by L-nitroarginine methyl ester an inhibitor of nitric oxide synthesis. Am J Obstet Gynecol. 1992;167:828-833. [Medline] [Order article via Infotrieve]
70.
Weiner CP, Lizasoain I, Baylis SA, Knowles RG,
Charles IG, Moncada S. Induction of calcium-dependent nitric
oxide synthases by sex hormones. Proc Natl Acad Sci
U S A. 1994;91:5212-5216.
71. Schray-Utz B, Zeiher AM, Busse R. Expression of constitutive NO synthase in cultured endothelial cells is enhanced by 17ß-estradiol. Circulation. 1993;88(suppl I):I-80. Abstract.
72. Caulin-Glaser TL, Sessa W, Sarrel P, Bender J. The effect of 17ß-estradiol on human endothelial cell nitric oxide production. Circulation. 1994;90(suppl I):I-30. Abstract.
73. Sayegh HS, Ohara Y, Navas JP, Peterson TE, Dockery S, Harrison DG. Endothelial nitric oxide synthase regulation by estrogens. Circulation. 1993;88(suppl I):I-80. Abstract.
74.
Rosselli M, Imthurn B, Keller PJ, Jackson EK, Dubey
RK. Circulating nitric oxide (nitrite/nitrate) levels in
postmenopausal women substituted with 17ß-estradiol and
norethisterone acetate. Hypertension. 1995;25:848-853.
75.
Moncada S, Higgs A. The
L-arginine-nitric oxide pathway. N
Engl J Med. 1993;329:2002-2012.
76.
Cooke JP, Tsao PS. Cytoprotective effects of
nitric oxide. Circulation. 1993;88:2451-2454.
77. Steinberg D, Parasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989;320:915-924. [Medline] [Order article via Infotrieve]
78. Berliner JA, Territo MC, Savanian A, Ramin S, Kim JA, Bamshad B, Emerson M, Fogelman AM. Minimally modified low density lipoprotein stimulates monocyte endothelial interactions. J Clin Invest. 1990;85:1260-1266.
79.
Carew TE, Schwenke DC, Steinberg D.
Antiatherogenic effect of probucol unrelated to its
hypocholesterolemic effect: evidence that
antioxidants in vivo can selectively inhibit low density lipoprotein
degradation in macrophage-rich fatty streaks slowing the
progression of atherosclerosis in the WHHL
rabbit. Proc Natl Acad Sci U S A. 1987;84:7725-7729.
80.
Stampfer MJ, Hennekens CH, Manson JE, Colditz GA,
Rosner B, Willett WC. Vitamin E consumption and the risk of
coronary disease in women. N Engl J
Med. 1993;328:1444-1449.
81.
Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E,
Colditz GA, Willett WC. Vitamin E consumption and the risk of
coronary heart disease in men. N Engl J
Med. 1993;328:1450-1456.
82. Yagi K, Komura S. Inhibitory effect of female hormones on lipid peroxidation. Biochem Int. 1986;13:1051-1055. [Medline] [Order article via Infotrieve]
83. Sugioka K, Shimosegawa Y, Nakano M. Estrogens as natural antioxidants of membrane phospholipid peroxidation. FEBS Lett. 1987;210:37-39. [Medline] [Order article via Infotrieve]
84. Yoshino K, Komura S, Watanabe I, Nakagawa Y, Yagi K. Effect of estrogens on serum and liver lipid peroxide levels in mice. J Clin Biochem Nutr. 1987;3:233-240.
85. Nakano M, Sugioka K, Naito I, Takekoshi S, Niki E. Novel and potent biological antioxidants on membrane phospholipid peroxidation: 2-hydroxy estrone and 2-hydroxy estradiol. Biochem Biophys Res Commun. 1987;142:919-924. [Medline] [Order article via Infotrieve]
86. Mukai K, Daifuku K, Yokoyama S, Nakano M. Stopped-flow investigation of antioxidant activity of estrogens in solution. Biochim Biophys Acta. 1990;1035:348-352. [Medline] [Order article via Infotrieve]
87. Huber LA, Scheffler E, Poll T, Ziegler R, Dresel HA. 17ß-Estradiol inhibits LDL oxidation and cholesterol ester formation in cultured macrophages. Free Radic Res Commun. 1990;8:167-173. [Medline] [Order article via Infotrieve]
88. Maziere C, Auclair M, Ronveaux M-F, Salmon S, Santus R, Maziere J-C. Estrogens inhibit copper and cell-mediated modification of low density lipoprotein. Atherosclerosis. 1991;89:175-182. [Medline] [Order article via Infotrieve]
89. Rifici VA, Khachadurian AK. The inhibition of low-density lipoprotein oxidation by 17ß-estradiol. Metabolism. 1992;41:1110-1114. [Medline] [Order article via Infotrieve]
90. Negre-Salvayre A, Pieraggi M-T, Mabile L, Salvayre R. Protective effect of 17ß-estradiol against the cytotoxicity of minimally oxidized LDL to cultured bovine aortic endothelial cells. Atherosclerosis. 1993;99:207-217. [Medline] [Order article via Infotrieve]
91. Subbiah MTR, Kessel B, Agrawal M, Rajan R, Abplanalp W, Rymaszewski Z. Antioxidant potential of specific estrogens on lipid peroxidation. J Clin Endocrinol Metab. 1993;77:1095-1097. [Abstract]
92. Sack MN, Rader DJ, Cannon RO. Oestrogen and inhibition of oxidation of low-density lipoproteins in postmenopausal women. Lancet. 1994;343:269-270. [Medline] [Order article via Infotrieve]
93. Guetta V, Panza JA, Waclawiw MA, Cannon RO. Effect of combined 17ß-estradiol and vitamin E on low-density lipoprotein oxidation in postmenopausal women. Am J Cardiol. 1995;75:1274-1276. [Medline] [Order article via Infotrieve]
94.
Keaney JF, Shwaery GT, Xu A, Nicolosi RJ, Loscalzo J,
Foxall TL, Vita JA. 17ß-Estradiol preserves
endothelial vasodilator function and limits
low-density lipoprotein oxidation in
hypercholesterolemic swine.
Circulation. 1994;89:2251-2259.
95. Niki E. Antioxidants in relation to lipid peroxidation. Chem Phys Lipids. 1987;44:227-253. [Medline] [Order article via Infotrieve]
96.
Esterbauer H, Wag G, Puhl H. Lipid
peroxidation and its role in atherosclerosis.
Br Med Bull. 1993;49:566-576.
97.
Casino PR, Kilcoyne CM, Quyyumi AA, Hoeg JM, Panza
JA. Role of nitric oxide in the
endothelium-dependent vasodilation of
hypercholesterolemic patients.
Circulation. 1993;88:2541-2547.
98.
Mangin EL, Kugiyama K, Nguy JH, Kerns SA, Henry
PD. Effects of lysolipids and oxidatively modified low density
lipoprotein on endothelium-dependent relaxation of
rabbit aorta. Circ Res. 1993;72:161-166.
99.
Shimokawa H, Flavahan NA, Vanhoutte PM. Loss
of endothelial pertussis toxin-sensitive G protein
function in atherosclerotic porcine coronary arteries.
Circulation. 1991;83:652-660.
100. Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases superoxide anion production. J Clin Invest. 1993;91:2546-2551.
101. Minor RL, Myers PR, Guerra R, Bates JN, Harrison DG. Diet-induced atherosclerosis increases the release of nitrogen oxides from rabbit aorta. J Clin Invest. 1990;86:2109-2116.
102. Gilligan DG, Sack M, Guetta V, Casino PR, Quyyumi AA, Rader DJ, Panza JA, Cannon RO. Effect of antioxidant vitamins on low-density lipoprotein oxidation and impaired endothelium-dependent vasodilation in patients with hypercholesterolemia. J Am Coll Cardiol. 1994;24:1611-1617. [Abstract]
103.
The Coronary Drug Project Research Group.
The Coronary Drug Project: initial findings leading to
modifications of its research protocol. JAMA. 1970;214:1303-1313.
104.
Nabulsi AA, Folsom AR, White A, Patsch W, Heiss G, Wu
KK, Szklo M. Association of hormone-replacement therapy with
various cardiovascular risk factors in postmenopausal
women. N Engl J Med. 1993;328:1069-1075.
105.
Gebara OCE, Mittleman MA, Sutherland P, Lipinska I,
Matheney T, Xu P, Welty FK, Wilson PWF, Levy D, Muller JE, Tofler
GH. Association between increased estrogen status and increased
fibrinolytic potential in the Framingham Offspring Study.
Circulation. 1995;91:1952-1958.
106.
Kugiyama K, Sakamoto T, Misumi I, Sugiyama S, Ohgushi
M, Ogawa H, Horiguchi M, Yasue H. Transferable lipids in
oxidized low-density lipoprotein stimulate plasminogen
activator inhibitor-1 and inhibit
tissue-type plasminogen activator release
from endothelial cells. Circ
Res. 1993;73:335-343.
107.
Etingin OR, Hajjar DP, Hajjar KA, Harpel PC, Nachman
RL. Lipoprotein (a) regulates plasminogen
activator inhibitor-1 expression in
endothelial cells. J Biol
Chem. 1991;266:2459-2465.
108.
Fischer GM. In vivo effects of estradiol on
collagen and elastin dynamics in rat aorta.
Endocrinology. 1972;91:1227-1232.
109.
Wolinsky H. Effects of estrogen and
progesterone treatment on the response of the aorta of male rats to
hypertension: morphological and chemical studies.
Circ Res. 1972;30:341-349.
110. Fischer GM, Swain ML. Effect of sex hormones on blood pressure and vascular connective tissue in castrated and noncastrated male rats. Am J Physiol. 1977;232:H617-H621.
111. Beldekas JC, Smith B, Gerstenfeld LC, Sonenshein GE, Franzblau G. Effect of 17ß-estradiol on the biosynthesis of collagen in cultured bovine aortic smooth muscle cells. Biochemistry. 1981;20:2162-2167. [Medline] [Order article via Infotrieve]
112.
Fischer GM, Swain ML. In vivo effects of sex
hormones on aortic elastin and collagen dynamics in castrated and
intact rats. Endocrinology. 1978;102:92-97.
113. Fischer-Dzoga K, Wissler RW, Vesselinovitch D. The effect of estradiol on the proliferation of rabbit aortic medial tissue culture cells induced by hyperlipemic serum. Exp Mol Pathol. 1983;39:355-363. [Medline] [Order article via Infotrieve]
114. Vargas R, Wroblewska B, Rego A, Hatch J, Ramwell PW. Oestradiol inhibits smooth muscle proliferation of pig coronary artery. Br J Pharmacol. 1993;109:612-617. [Medline] [Order article via Infotrieve]
115. Mitchell HC. Effect of estrogens and a progestogen on platelet adhesiveness and aggregation in rabbits. J Lab Clin Med. 1974;83:79-89. [Medline] [Order article via Infotrieve]
116. Johnson M, Ramey E, Ramwell PW. Androgen-mediated sensitivity in platelet aggregation. Am J Physiol. 1977;232:H381-H385.
117.
Morales DE, McGowan KA, Grant DS, Maheshwari S,
Bhartiya D, Cid MC, Kleinman HK, Schnaper HW. Estrogen promotes
angiogenic activity in human umbilical vein endothelial
cells in vitro and in a murine model.
Circulation. 1995;91:755-763.
118.
Ylikorkala O, Kuusi T, Tikkanen MJ, Viinikka L.
Desogestrel- and levonorgestrel-containing oral
contraceptives have different effects on urinary excretion of
prostacyclin metabolites and serum high density lipoproteins.
J Clin Endocrinol Metab. 1987;65:1238-1242.
119.
Sylvester JT, Gordon JB, Malamet RL, Wetzel RC.
Prostaglandins and estradiol-induced attenuation of
hypoxic pulmonary vasoconstriction. Chest. 1985;88:252S-254S.
120. Chang W, Nakao J, Orimo H, Murota S. Stimulation of prostaglandin cyclooxygenase and prostaglandin synthase activities by estradiol in rat aortic smooth muscles. Biochim Biophys Acta. 1980;620:472-482. [Medline] [Order article via Infotrieve]
121. Fogelberg M, Vesterqvist O, Diczfalusy U, Henriksson P. Experimental atherosclerosis: effects of oestrogen and atherosclerosis on thromboxane and prostacyclin formation. Eur J Clin Invest. 1990;20:105-110. [Medline] [Order article via Infotrieve]
122. Nordo Berge L, Hansen J-B, Svensson B, Lyngmo V, Nordoy A. Female sex hormones and platelet/endothelial cell interactions. Haemostasis. 1990;20:313-320. [Medline] [Order article via Infotrieve]
123.
David M, Griesmacher A, Muller MM.
17-Ethinyloestradiol decreases production and release of
prostacyclin in cultured human umbilical vein
endothelial cells.
Prostaglandins. 1989;38:431-438. [Medline]
[Order article via Infotrieve]
124.
Redmond EM, Cherian MN, Wetzel RC.
17ß-Estradiol inhibits flow- and acute hypoxia–induced
prostacyclin release from perfused endocardial
endothelial cells.
Circulation. 1994;90:2519-2524.
125. Proudler AJ, Ahmed AIH, Crook D, Fogelman I, Rymer JM, Stevenson JC. Hormone replacement therapy and serum angiotensin-converting-enzyme activity in postmenopausal women. Lancet. 1995;346:89-90. [Medline] [Order article via Infotrieve]
126. Hamlet MA, Rorie DK, Tyce GM. Effects of estradiol on release and disposition of norepinephrine from nerve endings. Am J Physiol. 1980;239:H450-H456.
127.
Colucci WS, Gimbrone MA, McLaughlin MK, Halpern W,
Alexander RW. Increased vascular catecholamine
sensitivity and -adrenergic receptor affinity in female and
estrogen-treated male rats. Circ Res. 1982;50:805-811.
128.
Miller VM, Vanhoutte PM. 17ß-Estradiol
augments endothelium-dependent contractions to
arachidonic acid in rabbit aorta. Am J
Physiol. 1990;258:R1502-R1507.
129. Hunt K, Vessey M, McPherson K, Coleman M. Long-term surveillance of mortality and cancer incidence in women receiving hormone replacement therapy. Br J Obstet Gynaecol. 1987;94:620-635. [Medline] [Order article via Infotrieve]
130. Falkeborn M, Persson I, Adami H-O, Bergstrom R, Eaker E, Mohsen HLR, Naessen T. The risk of acute myocardial infarction after oestrogen and oestrogen-progestogen replacement. Br J Obstet Gynaecol. 1992;99:821-828. [Medline] [Order article via Infotrieve]
131.
Psaty BM, Heckbert SR, Atkins D, Lemaitre R, Koepsell
TD, Wahl PW, Siscovick DS, Wagner EH. The risk of myocardial
infarction associated with the combined use of estrogens and progestins
in postmenopausal women. Arch Intern Med. 1994;154:1333-1339.
132.
Miller VM, Vanhoutte PM. Progesterone and
modulation of endothelium-dependent responses in
canine coronary arteries. Am J Physiol. 1991;261:R1022-R1027.
133. Williams JK, Honore EK, Washburn SA, Clarkson TB. Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries in cynomolgus monkeys. J Am Coll Cardiol. 1994;24:1757-1761. [Abstract]
134.
Jacobs DR, Mebane IL, Bangdiwala SI, Criqui MH,
Tyroler HA. High density lipoprotein cholesterol as
a predictor of cardiovascular disease mortality in men
and women: the follow-up study of the Lipid Research Clinics
Prevalence Study. Am J Epidemiol. 1990;131:32-47.
135. Kleinveld HA, Demacker PNM, De Haan AFJ, Stalenhoff AFH. Decreased in vitro oxidizability of low-density lipoprotein in hypercholesterolemic patients treated with 3-hydroxy-3-methylglutaryl-COA reductase inhibitors. Eur J Clin Invest. 1993;23:289-295. [Medline] [Order article via Infotrieve]
136. Lavy A, Brook GJ, Danker G, Amotz AB, Aviram M. Enhanced in vitro oxidation of plasma lipoproteins derived from hypercholesterolemic patients. Metabolism. 1991;40:794-799. [Medline] [Order article via Infotrieve]
137. Giroux LM, Davignon J, Naruszewicz M. Simvastatin inhibits the oxidation of low-density lipoproteins by activated human monocyte-derived macrophages. Biochim Biophys Acta. 1993;1165:335-338. [Medline] [Order article via Infotrieve]
138.
Fujii S, Sobel BE. Direct effects of
gemfibrozil on the fibrinolytic system: diminution of synthesis of
plasminogen activator inhibitor
type I. Circulation. 1992;85:1888-1893.
139.
Brown SL, Sobel BE, Fujii S. Attenuation of the
synthesis of plasminogen activator
inhibitor type I by niacin: a potential link between
lipid-lowering and fibrinolysis.
Circulation. 1995;92:767-772.
140. Wada H, Mori Y, Kaneko T, Wakita Y, Nakase T, Minamikawa K, Ohiwa M, Tamaki S, Tanigawa M, Kageyama S, Deguchi K, Nakano T, Shirakawa S, Suzuki K. Elevated plasma levels of vascular endothelial cell markers in patients with hypercholesterolemia. Am J Hematol. 1993;44:112-116. [Medline] [Order article via Infotrieve]
141. Carlson LA, Hamsten A, Asplund A. Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects treated with nicotinic acid. J Intern Med. 1989;226:271-276. [Medline] [Order article via Infotrieve]
142.
Rich-Edwards JW, Manson JE, Hennekens CH, Buring
JE. The primary prevention of coronary heart disease in
women. N Engl J Med. 1995;332:1758-1766.
143.
Brensike JR, Levy RI, Kelsey SF, Passamani ER,
Richardson JM, Loh IK, Stone NJ, Aldrich RF, Battaglini JW,
Moriarty DJ, Fished MR, Friedman L, Friederwald W, Detre KM, Epstein
SE. Effects of therapy with cholestyramine on progression of
coronary atherosclerosis: results of the NHLBI,
Type II Coronary Intervention Study.
Circulation. 1984;69:313-324.
144. Ornish D, Brown SE, Scherwitz LW, Billings JH, Armstrong WT, Ports TA, McLanahan SM, Kirkeeide RL, Brand RJ, Gould KL. Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial. Lancet. 1990;336:129-133. [Medline] [Order article via Infotrieve]
145.
Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC,
Havel RJ. Regression of coronary
atherosclerosis during treatment of familial
hypercholesterolemia with combined drug
regimens. JAMA. 1990;264:3007-3012.
146.
Waters D, Higginson L, Gladstone P, Boccuzzi SJ, Cook
T, Lesperance J, for the CCAIT Study Group. Effects of
cholesterol lowering on the progression of coronary
atherosclerosis in women: a Canadian Coronary
Atherosclerosis Intervention Trial (CCAIT) substudy.
Circulation. 1995;92:2404-2410.
147. Trial of clofibrate in the treatment of ischaemic heart disease: five-year study by a group of physicians of the Newcastle-Upon-Tyne region. BMJ. 1971;790:767-775.
148. The Scottish Society of Physicians. Ischaemic heart disease: a secondary prevention trial using clofibrate. BMJ. 1971;790:775-784.
149. Rosenhamer G, Carlson LA. Effect of combined clofibrate-nicotinic acid treatment in ischemic heart disease. Atherosclerosis. 1980;37:129-138. [Medline] [Order article via Infotrieve]
150. Buchwald H, Varco RL, Matts JP, Long JM, Fitch LL, Campbell GS, Pearce MB, Yellin AE, Edmiston A, Smink RO, Sawin HS, Campos CT, Hansen BJ, Tuna N, Karnegis JN, Sanmarco ME, Amplatz K, Castaneda-Zuniga WR, Hunter DW, Bissett JK, Weber FJ, Stevenson JW, Leon AS, Chalmers TC, and the POSCH Group. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. N Engl J Med. 1990;323:946-955. [Abstract]
151. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389. [Medline] [Order article via Infotrieve]
152.
Gotto AM. Lipid-lowering, regression, and
coronary events: a review of the Interdisciplinary Council on
Lipids and Cardiovascular Risk Intervention, seventh
council meeting. Circulation. 1995;92:646-656.
153.
Expert Panel on Detection, Evaluation and Treatment of
High Blood Cholesterol in Adults. Summary of the second
report of the National Cholesterol Education Program (NCEP)
expert panel on detection, evaluation and treatment of high blood
cholesterol in adults (Adult Treatment Panel II).
JAMA. 1993;269:3015-3023.
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