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(Circulation. 1996;93:1928-1937.)
© 1996 American Heart Association, Inc.

Articles

Cardiovascular Effects of Estrogen and Lipid-Lowering Therapies in Postmenopausal Women

Victor Guetta, MD; Richard O. Cannon, III, MD

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

	Introduction

Top Introduction Lipoprotein Effects of Estrogen Coronary Vasomotor Effects of... Systemic Vasomotor Effects of... Estrogen and Nitric Oxide Antioxidant Effects of Estrogen Oxidized LDL and Vasomotor... Hemostatic Effects of Estrogen Other 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... Conclusions References

 
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 mortality^{3 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.

	Lipoprotein Effects of Estrogen

Top Introduction Lipoprotein Effects of Estrogen Coronary Vasomotor Effects of... Systemic Vasomotor Effects of... Estrogen and Nitric Oxide Antioxidant Effects of Estrogen Oxidized LDL and Vasomotor... Hemostatic Effects of Estrogen Other 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... Conclusions References

 
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.

	Coronary Vasomotor Effects of Estrogen

Top Introduction Lipoprotein Effects of Estrogen Coronary Vasomotor Effects of... Systemic Vasomotor Effects of... Estrogen and Nitric Oxide Antioxidant Effects of Estrogen Oxidized LDL and Vasomotor... Hemostatic Effects of Estrogen Other 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... Conclusions References

 
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.

	Systemic Vasomotor Effects of Estrogen

Top Introduction Lipoprotein Effects of Estrogen Coronary Vasomotor Effects of... Systemic Vasomotor Effects of... Estrogen and Nitric Oxide Antioxidant Effects of Estrogen Oxidized LDL and Vasomotor... Hemostatic Effects of Estrogen Other 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... Conclusions References

 
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.

	Estrogen and Nitric Oxide

Top Introduction Lipoprotein Effects of Estrogen Coronary Vasomotor Effects of... Systemic Vasomotor Effects of... Estrogen and Nitric Oxide Antioxidant Effects of Estrogen Oxidized LDL and Vasomotor... Hemostatic Effects of Estrogen Other 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... Conclusions References

 
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 factors^{66 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}

	Antioxidant Effects of Estrogen

Top Introduction Lipoprotein Effects of Estrogen Coronary Vasomotor Effects of... Systemic Vasomotor Effects of... Estrogen and Nitric Oxide Antioxidant Effects of Estrogen Oxidized LDL and Vasomotor... Hemostatic Effects of Estrogen Other 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... Conclusions References

 
Over the past decade, evidence has accumulated indicating that oxidative modification of LDL greatly increases its atherogenicity^{77 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.

	Oxidized LDL and Vasomotor Function

Top Introduction Lipoprotein Effects of Estrogen Coronary Vasomotor Effects of... Systemic Vasomotor Effects of... Estrogen and Nitric Oxide Antioxidant Effects of Estrogen Oxidized LDL and Vasomotor... Hemostatic Effects of Estrogen Other 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... Conclusions References

 
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

	Hemostatic Effects of Estrogen

Top Introduction Lipoprotein Effects of Estrogen Coronary Vasomotor Effects of... Systemic Vasomotor Effects of... Estrogen and Nitric Oxide Antioxidant Effects of Estrogen Oxidized LDL and Vasomotor... Hemostatic Effects of Estrogen Other 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... Conclusions References

 
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.

	Other Potential Cardiovascular Effects of Estrogen

Top Introduction Lipoprotein Effects of Estrogen Coronary Vasomotor Effects of... Systemic Vasomotor Effects of... Estrogen and Nitric Oxide Antioxidant Effects of Estrogen Oxidized LDL and Vasomotor... Hemostatic Effects of Estrogen Other 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... Conclusions References

 
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 synthesis^{108 109 110 111} 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.

	Combined Effects of Progestin and Estrogen in Postmenopausal Women

Top Introduction Lipoprotein Effects of Estrogen Coronary Vasomotor Effects of... Systemic Vasomotor Effects of... Estrogen and Nitric Oxide Antioxidant Effects of Estrogen Oxidized LDL and Vasomotor... Hemostatic Effects of Estrogen Other 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... Conclusions References

 
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.

	Lipid-Lowering Therapy as an Alternative to Estrogen Therapy

Top Introduction Lipoprotein Effects of Estrogen Coronary Vasomotor Effects of... Systemic Vasomotor Effects of... Estrogen and Nitric Oxide Antioxidant Effects of Estrogen Oxidized LDL and Vasomotor... Hemostatic Effects of Estrogen Other 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... Conclusions References

 
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.

	Systemic Vasomotor Effects of Lipid-Lowering Therapy

Top Introduction Lipoprotein Effects of Estrogen Coronary Vasomotor Effects of... Systemic Vasomotor Effects of... Estrogen and Nitric Oxide Antioxidant Effects of Estrogen Oxidized LDL and Vasomotor... Hemostatic Effects of Estrogen Other 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... Conclusions References

 
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}

	Antioxidant Effects of Cholesterol Reduction Therapy

Top Introduction Lipoprotein Effects of Estrogen Coronary Vasomotor Effects of... Systemic Vasomotor Effects of... Estrogen and Nitric Oxide Antioxidant Effects of Estrogen Oxidized LDL and Vasomotor... Hemostatic Effects of Estrogen Other 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... Conclusions References

 
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}

	Lipid-Lowering Therapy and Thrombosis

Top Introduction Lipoprotein Effects of Estrogen Coronary Vasomotor Effects of... Systemic Vasomotor Effects of... Estrogen and Nitric Oxide Antioxidant Effects of Estrogen Oxidized LDL and Vasomotor... Hemostatic Effects of Estrogen Other 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... Conclusions References

 
Several lipid-lowering agents may potentiate fibrinolysis independent of alterations in plasma lipoproteins. Thus, Fujii's group^{138 139} 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

	Cholesterol Reduction Therapy and Prevention of Cardiovascular Events

Top Introduction Lipoprotein Effects of Estrogen Coronary Vasomotor Effects of... Systemic Vasomotor Effects of... Estrogen and Nitric Oxide Antioxidant Effects of Estrogen Oxidized LDL and Vasomotor... Hemostatic Effects of Estrogen Other 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... Conclusions References

 
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 progression^{143 144 145 146} or reduction in cardiovascular events^{147 148 149 150 151} 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]).

	Conclusions

Top Introduction Lipoprotein Effects of Estrogen Coronary Vasomotor Effects of... Systemic Vasomotor Effects of... Estrogen and Nitric Oxide Antioxidant Effects of Estrogen Oxidized LDL and Vasomotor... Hemostatic Effects of Estrogen Other 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... Conclusions References

 
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.

	Selected Abbreviations and Acronyms

 

HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A PAI-1 = plasminogen activator inhibitor-1 TPA = tissue-type plasminogen activator

	Acknowledgments

 
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.

	References

Top Introduction Lipoprotein Effects of Estrogen Coronary Vasomotor Effects of... Systemic Vasomotor Effects of... Estrogen and Nitric Oxide Antioxidant Effects of Estrogen Oxidized LDL and Vasomotor... Hemostatic Effects of Estrogen Other 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... Conclusions References

 

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