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From the Division of Cardiology (K.K.K.), Gil Medical Center, Gachon Medical School, Incheon, Korea; and the Division of Cardiovascular Medicine (I.S.), Hokkaido University Graduate School of Medicine, Sapporo, Japan.
ABSTRACT
Many observational studies and experimental and animal studies have demonstrated that estrogen replacement therapy (ERT) or hormone replacement therapy (HRT) (estrogen plus progestin) significantly reduces the risk of coronary heart disease. Nonetheless, recent randomized controlled trials demonstrated some trends toward an increased risk of cardiovascular events rather than a reduction of risk. Recently, both the HRT and ERT arms of the Women’s Health Initiative (WHI) study were terminated early because of an increased/no incidence of invasive breast cancer, increased incidence of stroke, and increased trend/no protective effects of cardiovascular disease. We discuss the controversial effects of HRT and ERT on cardiovascular system and provide a hypothesis that the failure of HRT and ERT in reducing the risk of cardiovascular events in postmenopausal women might be because of the stage of their atherosclerosis at the time of initiation of HRT or ERT.
Recent randomized controlled trials have caused many people to suggest that the inclusion of the progestin in the HRT portion of this study is responsible for the adverse cardiovascular outcomes observed. Discussion of this issue is the focus of this review article.
Key Words: progestin ? estrogen ? women ? cardiovascular disease
Introduction
Generally, postmenopausal women who choose to use hormone replacement therapy (HRT) use a progestin combined with estrogen to prevent uterine hyperplasia and malignancy. In the United States, 90% of postmenopausal women have not undergone hysterectomy. Many observational studies and experimental and animal studies have demonstrated that estrogen replacement therapy (ERT) or HRT (estrogen plus progestin) significantly reduces the risk of coronary heart disease. Nonetheless, recent randomized controlled trials demonstrated some trends toward an increased risk of cardiovascular events rather than a reduction of risk.1,2 Recently, the HRT arm of the Women’s Health Initiative (WHI) study3 was terminated in July 2002, earlier than the original date, because of an increased incidence of invasive breast cancer and trends toward worse cardiovascular outcomes. In contrast, the parallel ERT arm of the WHI had been allowed to continue; however, very recently, this study was also terminated on March 2, 2004, earlier than the original date, because ERT did not increase or decrease the risk of coronary heart disease and increased the risk of stroke similar to HRT arm of the WHI study.4 This had caused many people to suggest that the inclusion of the progestin in the HRT portion of this study is responsible for the adverse cardiovascular outcomes observed. Discussion of this issue is the focus of this review article.
Biological Effects of ERT and HRT
The vascular endothelium plays a pivotal role in the pathogenesis of atherosclerosis, which contributes to the development of coronary heart disease. We review studies to compare the effects of ERT and HRT on endothelial function.
Effects on Lipoprotein
Orally administered estrogens lower serum levels of low-density lipoprotein (LDL) cholesterol and raise levels of high-density lipoprotein (HDL) cholesterol, each by 15%, and raise levels of triglyceride by 20% to 25% in postmenopausal women.5 The route of administration of estrogen influences its effects on serum lipids. Transdermally administered 17? estradiol (E2) has less of an effect on serum lipid concentrations than do orally administered estrogens. Coadministration of a progestin can blunt the changes in serum lipids caused by estrogen.5–7 The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial reported that medroxyprogesterone acetate (MPA) attenuated the effects of conjugated equine estrogen (CEE) in increasing HDL cholesterol levels.5 We observed that CEE 0.625 mg alone or in combination with MPA 2.5 mg changed total cholesterol and LDL cholesterol levels to a similar extent; however, HRT did not increase triglyceride levels and increased HDL cholesterol levels less than did ERT, which was consistent with PEPI Trial.6 ERT and HRT have also been shown to reduce serum levels of lipoprotein(a) to a similar extent.8–10
Effects on LDL Oxidation
Wilcox et al11 found significant inhibition in vivo of LDL oxidation by CEE in postmenopausal women. Both CEE alone and MPA combined with CEE significantly inhibited LDL oxidation in postmenopausal women.12,13 However, we observed that MPA combined with CEE or E2 did not inhibit the effects of CEE or E2 on LDL oxidation.6 CEE may conceivably lack an antioxidant effect, because it primarily comprises equine estrogens (EEs): the 1 human-like estrogen contained in this preparation (estrone) is a weaker antioxidant than E2.14 Interestingly, oral CEE significantly increased plasma triglyceride and decreased LDL particle size, which counteracted antioxidant effect of estrogen.15,16 MPA neither increased plasma triglyceride nor attenuated antioxidant effect of estrogen.16
Effects on Vasomotion
We found that CEE 0.625 mg administered to 28 hypercholesterolemic postmenopausal women improved flow-mediated dilation comparable to the effect of simvastatin 10 mg daily, despite greater reduction in LDL cholesterol levels with simvastatin.8 Lieberman et al17 reported that oral E2 resulted in significant improvement in flow-mediated brachial artery dilation compared with placebo. Of interest, Vehkavaara et al18 reported that oral E2-induced increase in endothelium-dependent vasodilation could be explained not by acute estradiol effects but by several antiatherogenic changes in lipoproteins, in contrast to transdermal estradiol showing no effects on both endothelium-dependent vasodilation and lipoproteins.
With regard to the effects of progestin, there have been inconsistent observations, with some groups demonstrating adverse effects of MPA19 and others20–22 reporting no adverse effects of MPA. Gerhard et al23 observed that intravaginal micronized progesterone (MP) added to E2 did not significantly attenuate the improvement in flow-mediated dilation that was observed with E2 alone. In contrast, Sorensen et al24 reported that cyclical E2 and norethisterone did not improve endothelial function. This study has several problems. First, this study was an open-labeled design. Second, the fact that HRT users had significantly higher total cholesterol levels and similar HDL cholesterol levels than nonusers gives suspicion regarding compliance of participants. Investigators did not measure serum estradiol concentration. Third, HRT users and nonusers had very low flow-mediated dilation (2.5% and 2.2%, respectively) compared with others’ reports, despite healthy postmenopausal women. Under these conditions, it is very difficult to observe differences after any therapy. Fourth, because there were no ERT users and baseline vascular study as controls, we do not know whether HRT impaired or did not change flow-mediated dilation. Recently, 2 articles demonstrated that MPA inhibited the beneficial effects of E225 or CEE12 on endothelium-dependent vasodilation. However, we and others observed that MPA 2.5 mg combined with CEE 0.625 mg significantly improved flow-mediated brachial artery dilator response to hyperemia in postmenopausal women.20,21
There are some technical issues related to ultrasound imaging using high-frequency linear transducer that may limit the interpretation of the studies noted. For example, this technique can be greatly affected by operator’s skill. At this point, 1 study using cardiovascular magnetic resonance demonstrated that contraceptive depot MPA-impaired endothelium-dependent vasodilation and hypoestrogenism may be the mechanism of action.19 There are some problems in this study. First, the serum estradiol concentration 64.6 pmol/L in MPA users is much lower than 250 pmol/L in postmenopausal women using conventional HRT,6 and postmenopausal women who reached this concentration with HRT improved endothelium-dependent vasodilation, as reported by us and others.20–22 Furthermore, in the same estradiol concentration, 57.6 pmol/L and 65.3 pmol/L, respectively, CEE and CEE plus MPA both reduced coronary atherosclerosis by 62% in postmenopausal cynomolgus monkeys.26 Second, MPA users had significantly lower HDL cholesterol levels than controls, which can affect endothelium-dependent vasodilation. Third, the number of subjects, 12, was too small, as authors declared in the limitation. Indeed, a recent study using radioisotope (objective measurement) demonstrated that MPA did not affect the effects of estrogen.27
Effects on Inflammation
Cell Adhesion Molecules
The selectin family of cell adhesion molecules (CAM), which includes L-selectin and E-selectin, binds to carbohydrate ligands on leukocytes and promotes "rolling" of these cells—the first step in adhesion—on activated endothelium before the firm adherence of intercellular CAM-1 (ICAM-1) and vascular CAM-1 (VCAM-1), with subsequent incorporation into the vessel wall. The pathophysiological relevance of CAM in humans has been suggested by its localization in atherosclerotic plaques. Serum concentrations of VCAM-1, ICAM-1, and L-selectin have been reported to be higher in patients with coronary artery disease than in healthy controls.28,29
Koh et al30 first reported that either transdermal E2 or transdermal E2 and oral MPA lowered inflammatory CAM expression in postmenopausal women. In this study, we observed MPA did not negate the effects of estrogen on reducing soluble CAM levels. In a randomized, double-blind, crossover study, 6 or 8 weeks of treatment with CEE alone or combined with MP or MPA significantly diminished E-selectin, ICAM-1, and VCAM-1 expression as compared with baseline (Figure 1).8,9,20 These findings have since been confirmed by others.31 The PEPI trial confirmed the reduction of E-selectin by HRT.32
Figure 1. Soluble E-selectin (A), vascular cell adhesion molecule (VCAM-1) (B), intercellular adhesion molecule (ICAM-1) levels (C), and monocyte chemoattractant protein (MCP)-1 levels before therapy (baseline) and after micronized progesterone (CEE+MP) or medroxyprogesterone acetate (CEE+MPA) combined with conjugated equine estrogen (CEE). Both therapies significantly decreased E-selectin, VCAM-1, ICAM-1, and MCP-1 levels from baseline values (P<0.001, P=0.016, P=0.048, and P<0.005 by ANOVA, respectively) by a similar degree. Used with permission from Koh et al.20
Chemokine and Cytokines
There was a significant correlation between the mean maximum intimal medial thickness and monocyte chemoattractant protein (MCP)-1 levels at baseline in postmenopausal women. In this study, E2 significantly reduced MCP-1 levels.33 We recently observed that CEE with MP or MPA significantly decreased MCP-1 levels from baseline values in healthy postmenopausal women (Figure 1).20,34 Tumor necrosis factor (TNF)- is a multifunctional circulating cytokine derived from endothelial and smooth muscle cells as well as macrophages associated with coronary atheroma. Further, TNF- enhances the rate of monocyte recruitment into developing atherosclerotic lesions.35 TNF- is involved in several cardiovascular processes. We observed that CEE with MP or MPA significantly reduced TNF- levels from the baseline in hypertensive or overweight postmenopausal women, and, furthermore, patients with the highest baseline of TNF- levels showed the greatest extent of reductions.36 Our observation was consistent with the findings of Walsh et al.37 The effects of ERT or HRT on soluble IL-6 levels in postmenopausal women are inconsistent. Some studies observed the increase of IL-6 levels,38,39 whereas we in our study and studies of others observed no significant changes.37,40
C-Reactive Protein
C-reactive protein (CRP) may induce the synthesis of cytokines, CAMs, tissue factor, and angiotensin II type I receptor in monocytes, endothelial cells, and smooth muscle cells.41–44 Tissue factor activates the extrinsic coagulation cascade, providing a link between inflammation and thrombosis. In addition, CRP may contribute to atherogenesis by facilitating uptake of LDL by macrophages and decreasing endothelial nitric oxide synthase expression and activity.45,46
Ridker et al47 reported the predictive value of CRP in determining the risk of future cardiovascular events in 122 apparently healthy participants in the Women’s Health Study who subsequently had a first cardiovascular event during a 3-year follow-up period. They found that women who had cardiovascular events had higher baseline CRP levels than control subjects. The PEPI Study showed that both ERT and HRT regimens resulted in a large sustained increase in levels of CRP with a decrease in E-selectin levels.32 Others have reported the same observations with oral HRT.18,37–40 In contrast, transdermal administration of ERT significantly lowered CRP levels48 or did not change CRP levels49,50 in postmenopausal women. Therefore, this paradoxical effect in the inflammatory marker CRP is caused by a first pass effect in the liver as documented by the differences in transdermal and oral administration, and this increase of CRP may be not a biologically meaningful. However, this controversy over whether there are proinflammatory effects of estrogen persists. Indeed, a recent article observed that increased CRP levels for 3 years of ERT and HRT treatment in the WHI trial did not cause cardiovascular events;51 however, in viewing that CRP has several important atherogenic properties as well as inflammation marker, oral estrogen-induced CRP increase over years may result in atherogenesis progression. Interestingly, MPA attenuated the increase of CRP and serum amyloid A protein concentration with oral CEE in women.31,52 Both ERT and HRT significantly decreased plasma homocysteine levels.52
Estrogen Receptor Polymorphisms
Estrogen receptor polymorphisms may modify the effects of ERT and HRT on lipids levels and other outcomes related to treatment in postmenopausal women. In this regard, postmenopausal women who have the estrogen receptor polymorphisms had an augmented response of HDL cholesterol and E-selectin to HRT. However, these responses were evident in both ERT and HRT.53,54
Effects on Arterial Compliance and Stiffness
Twenty-six postmenopausal women using HRT had a significantly increased total systemic arterial compliance and lower pulse wave velocity than those not using HRT.55 Of interest, 11 postmenopausal women had HRT withdrawn for 4 weeks, resulting in a significant decrease in total systemic arterial compliance and significant increase in pulse wave velocity. Other studies observed that the carotid arterial stiffness index was similar in ERT users with and without MPA or MP who had no evidence of coronary artery disease and was significantly lower than in nonusers.56,57
Effects on Hemostasis and Fibrinolysis
The clinical manifestation of atherosclerotic disease hinges on thrombogenic as well as inflammatory cellular and molecular pathways. After plaque disruption, platelets and circulating factors that mediate thrombosis are exposed to the lesional lipid core, which is thrombogenic. Therefore, the effects on thrombosis, fibrinolysis, and overall coagulation status of endogenous estrogen in women of childbearing status, as well as ERT and HRT in postmenopausal women, bear directly on endothelial function.58
The relationship between thrombosis, estrogen status, and endothelial dysfunction is supported by the fact that soluble thrombomodulin—a key regulator of activated thrombin—and tissue-plasminogen activator (t-PA), which promotes fibrinolysis, are considered markers of endothelial damage and were elevated in a study of prematurely menopausal women.59 Six weeks of HRT resulted in a significant reduction in mean soluble thrombomodulin, t-PA, and von Willebrand factor (vWF) compared with premenopausal levels, suggesting beneficial effects on endothelial injury and hemostasis.59 Indeed, findings on coagulation status reported in the PEPI trial may partly explain the higher risk of thromboembolism in the HERS placebo group.32 Among control patients in the PEPI trial, factor VIIIc and fibrinogen increased over time. The vWF antigen concentration also increased to 34% after 12 months, and then returned to baseline at month 36.
Significantly enhanced systemic fibrinolysis resulted from 1 month of treatment with oral CEE, either alone or combined with MPA, in 30 postmenopausal women in a randomized crossover trial.6 Both CEE and CEE/MPA decreased plasma plasminogen activator inhibitor-1 (PAI-1) levels from baseline by >50%. MPA did not negate the effects of CEE on the improvement of fibrinolysis potential. These findings are surprising because MPA stimulated PAI-1 release from bovine aortic60 and human umbilical endothelial cells.61 These effects were more pronounced in women with higher levels of PAI-1 at baseline. In addition, levels of D-dimer exhibited a significant inverse correlation with PAI-1 levels, suggesting enhanced fibrinolysis potential (Figure 2). Six months of HRT with oral cyclic E2 combined with MP also increased global fibrinolytic capacity by 63% versus baseline and reduced both PAI-1 antigen and PAI activity in 45 healthy postmenopausal women.62 However, such treatment was also associated with an activation in coagulant function. This hypercoagulable state was reflected by significant increases in prothrombin fragment (F1+2) and decreased antithrombin activity among HRT users as compared with women who received no HRT.
Figure 2. Scatter plots showing the correlation between the percent change in plasminogen activator inhibitor type-1 (PAI-1) antigen and percent change in D-dimer after oral conjugated estrogen (CEE) alone and after combined treatment of conjugated estrogen and medroxyprogesterone acetate (CEE/MPA). Reproduced with permission from Koh et al.6
However, because activation of coagulation pathways has been detected dose-dependently in postmenopausal women treated with CEE 0.625 and 1.25 mg,63 potentiation of fibrinolysis could be a consequence of activation of coagulation pathways as a primary response to estrogen administration. However, Winkler et al64 speculated that small doses of estrogen/progestogen induce increases in fibrinolytic capacity via a marked reduction of PAI-1. In this regard, Koh et al65 observed that the increase in fibrinolytic potential was independent of any effect on coagulation of CEE at conventional dosages. Other groups62,66 also reported no correlation between fibrinolytic potential and coagulation activation using HRT regimens. Cushman et al39 found that hemostasis markers and evidence of procoagulation were not associated and fibrinolytic potential increased. However, in contrast to healthy postmenopausal women,6,20,62,65 we recently reported that HRT did not significantly decrease PAI-1 antigen levels and, rather, increased tissue factor activity and F1+2 levels from baseline in hypertensive or overweight postmenopausal women,67 consistent with the HERS.
Lp(a) increases in serum concentration after menopause.68 Although Lp(a) is usually construed as an independent risk factor for coronary artery disease, it is structurally homologous with plasminogen. Through competition with this molecule as a substrate for fibrinolytic enzymes, Lp(a) can exert prothrombotic effects. In this regard, both ERT and HRT significantly decreased Lp(a) levels.69 Indeed, a recent study from HERS reported that CEE plus MPA appeared to have a more favorable effect in women with high initial Lp(a) levels than in women with low levels.70 However, activation of coagulation after ERT or HRT may not be balanced by activation of fibrinolysis in some postmenopausal women.6,58,67 Thus, ERT or HRT should not be initiated in women with coronary artery disease or the coexistence of other risk factors for hypercoagulability.
Experimental and Animal Studies
Experimental studies reported that synthetic, not natural, progestins interfered with estrogen protection against vasoconstriction.71,72 MPA attenuated estrogen-mediated inhibition of neointima formation after balloon injury of the rat carotid artery73 and coronary artery atherosclerosis in female monkeys.74 Contrary to these studies, some studies demonstrated that HRT (17?-estradiol and cyclic progesterone or norethisterone acetate, or levonorgestrel) reduced LDL or cholesterol accumulation in the coronary arteries or the aorta in surgically postmenopausal rabbits75 or monkeys.76 The latter effect of HRT was similar to the effect of unopposed 17?-estradiol. A recent article from Clarkson’s group demonstrated that CEE and CEE plus MPA significantly, and to a similar extent, reduced coronary atherosclerosis measured by coronary artery intimal area by 62% in postmenopausal cynomolgus monkeys (Figure 3).26 This study confirms that synthetic MPA did not attenuate the effects of CEE to reduce coronary atherosclerosis.
Figure 3. Comparison of effects of CEE and CEE+MPA on coronary artery atherosclerosis. Both CEE and CEE+MPA reduced coronary atherosclerosis by 62% (similar extent) in postmenopausal cynomolgus monkeys. Modified from Clarkson et al.26
Clinical Studies
Nonetheless, observational studies of HRT report no differences in risk for clinical cardiovascular events between users of unopposed estrogen and users of estrogen combined with progestins (Figure 4).77–83 The Nurses’ Health Study observed a similar reduction in risk for coronary heart disease among women using oral CEE alone (relative risk: 0.55; CI: 0.45 to 0.68) and those using HRT (relative risk: 0.64; CI: 0.49 to 0.85).84 Of interest, some observational studies observed that users of estrogen combined with progestins had less cardiovascular events than users of unopposed estrogen. The Coumadin Aspirin Reinfarction Study (CARS) investigators analyzed the data from postmenopausal women with a recent myocardial infarction.85 They reported that users of estrogen/progestin had a lower incidence of death/myocardial infarction/unstable angina during follow-up than users of estrogen only (relative risk: 0.56; CI: 0.37 to 0.85). Northern California Kaiser Permanente Diabetes Registry observed that the relative hazard for myocardial infarction associated with current estrogen plus progestin use was 0.77 (95% CI: 0.61 to 0.97); in contrast, the relative hazard for myocardial infarction associated with current unopposed estrogen use was 0.88 (95% CI: 0.73 to 1.05).86
Figure 4. Shown here are the results from observational studies published over a 7-year period between 1993 and 2000 that examined whether the risk of cardiovascular disease (CVD) developing is different for women who use ERT versus those who use HRT.77–83 Risk estimates that are significantly <1.0 indicate a reduction in CVD risk with hormone replacement. As is seen here, findings from observational studies have consistently shown that there is little or no difference between ERT and HRT users in terms of relative risk for CVD. Thus, the addition of progestogen does not appear to offset the CVD risk benefit associated with the use of unopposed estrogen.
Angiographic Studies
Women’s Angiographic Vitamin and Estrogen (WAVE) Trial used quantitative angiographic end points to determine whether HRT or antioxidant supplements, alone or in combination, influenced the progression of coronary artery disease in postmenopausal women.87 Participants in WAVE were on average 65 years old and had at least 1 15% to 75% coronary stenosis at baseline coronary angiography. Participants were randomly assigned in a 2x2 factorial design to receive either 0.625 mg CEE plus 2.5 mg MPA daily or matching placebo, and 400 IU of vitamin E twice daily plus 500 mg vitamin C twice daily, or placebo. The WAVE trial demonstrated that HRT failed to slow the angiographic progression of coronary artery disease in postmenopausal women with established coronary disease, speculating the possible adverse effects of MPA in the favorable effects of estrogen. However, the Estrogen Replacement and Atherosclerosis (ERA) Trial showed the lack of difference in atherosclerosis progression between the estrogen-only arm and the combined HRT arm, suggesting that potential beneficial effects of estrogen itself were not likely reduced by the addition of MPA.1
Clinical Implications
The fact that ERT and HRT did not confer cardioprotective effects in the recent randomized controlled trials can be assimilated readily according to the "healthy endothelium" concept.88–90 In short, the favorable vascular effects of estrogen on atherosclerosis, inflammation, hemostasis, and coronary flow reserve are dependent on the integrity of the endothelium and estrogen receptor populations in endothelial cells and vascular smooth muscle cells,91 and these conditions were probably not met by most women in these trials because of their advanced age, multiple risk factors, and coronary atherosclerosis. Optimization of estrogen’s cardioprotective properties may depend on maintenance of a healthy endothelium. The importance of timing of intervention on the effect of estrogens on atherogenesis has been previously observed in nonhuman primates.74,92–94 When monkeys with little or no atherosclerosis were made menopausal and ERT was immediately initiated along with an atherogenic diet, CEE for 2 years was associated with a substantial 70% reduction in atherosclerosis.74,92 However, when monkeys were allowed to have more atherosclerosis in the premenopausal period and CEE was immediately initiated along with an atherogenic diet, there was a 50% reduction in atherosclerosis.93 Interestingly, when CEE was delayed for 2 years while an atherogenic diet was administered in an estrogen-deficient state, even though CEE and a healthy diet were instituted for another 2 years, there was no effect of CEE on atherosclerotic progression.94 In this regard, recent data related to the timing of estrogen initiation were reported.95 In a rat model, E2 did not cause regression or alter progression of established lesions in the carotid arteries, aortic arch, or thoracic aorta. However, E2 prevented initiation of new lesions in the iliac, femoral, and popliteal arteries, and in the abdominal aorta. We and others observed these findings in postmenopausal women (Figure 5).20,96–98 Based on these views, the subjects enrolled in HERS may have received no benefit from HRT because of the advanced stage of their atherosclerosis at the time HRT was initiated. Similarly, although the majority of the women enrolled in the WHI had not yet had a clinically apparent cardiovascular event, based on their advanced age, high body mass index, and a relatively high prevalence of smoking, diabetes, and hyperlipidemia, they too may not have been able to manifest the atheroprotective effects of the HRT (Table). Accordingly, this may have caused the failure of CEE plus MPA to demonstrate cardioprotective effects in these randomized controlled trials. We may explain why 2 recent randomized controlled trials showed different results even though these studies were performed by the same investigators with the same medications and the same study protocols.99,100 In Estrogen in the Prevention of Atherosclerosis Trial (EPAT), the rate of change in intima-media thickness was significantly reduced in the E2 group compared with placebo.99 In contrast, in Women’s Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial (WELL-HART), the rate of change in intima-media thickness was not significantly reduced in the E2 group compared with placebo.100 The only differences of these 2 studies are participants’ characteristics: women with established coronary artery disease (>30% stenosis) and 5 years longer duration of menopause to randomization for the WELL-HART study. Again, there were no differences of ERT and HRT effects on the rate of change in intima-media thickness in WELL-HART study. A recent report from WHI study observed that CEE plus MPA reduced the risk of coronary heart disease differently according to the year since menopause and the presence of hot flashes.101 Postmenopausal women <10, 10 to 19, and >20 years since menopause had hazard ratios for coronary heart disease of 0.89, 1.22, and 1.71, respectively, and women with hot flashes had a hazard ratio for coronary heart disease of 0.95, compared with women without hot flashes having a hazard ratio of 1.98, although the difference did not reach statistical significance. Of interest, a very recent report from the ERT arm of the WHI also observed that the subgroup of women in the youngest decade appeared to respond to estrogen more favorably than did older women for many of the outcomes, including the coronary heart disease and global index.4 Postmenopausal women aged 50 to 59, 60 to 69, and 70 to 79 years had hazard ratios for coronary heart disease of 0.56, 0.92, and 1.04, respectively, (P for interaction=0.14) and women aged 50 to 59, 60 to 69, and 70 to 79 years had a hazard ratio for global index of 0.80, 0.98, and 1.16 (P for interaction=0.08), although the difference did not reach statistical significance.
Figure 5. A, Flow-mediated dilatation before therapy (baseline) and after micronized progesterone (CEE+MP) or medroxyprogesterone acetate (CEE+MPA) combined with conjugated equine estrogen (CEE). In healthy postmenopausal women, CEE+MP or CEE+MPA significantly improved the percent flow-mediated dilator response to hyperemia relative to baseline measurements (P=0.004 by ANOVA) by a similar degree. Standard error of the mean is identified by the bars. Reproduced with permission from Koh et al.20 B, Flow-mediated dilation after placebo and conjugated equine estrogen. In type 2 diabetic postmenopausal women, CEE improved, but not significantly, the percent flow-mediated dilator response to hyperemia compared with placebo (P=0.501). Standard error of the mean is identified by the bars. Reproduced with permission from Koh et al.97
Comparison of Baseline Characteristics Between Nurses’ Health Study and WHI
However, the early increment in coronary event rates in the recent randomized controlled trials might have been precipitated by procoagulant effects of estrogen in a susceptible cohort. Thrombogenic events are considered more likely in patients with certain heritable conditions, such as platelet antigen-2 (PIA-2) polymorphisms.102 Further, factor V Leiden mutation increases the risk of primary and recurrent venous thromboembolic events by 3- to 6-fold103 and the risk of myocardial infarction.104 Indeed, ERT and HRT may decrease or increase atherothrombosis risk depending on the presence of factor V Leiden mutation.105,106 Consistent with these facts, the ERT arm of the WHI study increased the risk of stroke similar to that in the findings reported from the HRT arm of the WHI study.4
In conclusion, with biological views, that added progestin negates the beneficial effects of estrogen to prevent coronary heart disease is correct only in the effect of HDL cholesterol levels and inconsistent in the effect of vasomotion in postmenopausal women. However, animal, clinical, and angiographic studies have demonstrated that added progestin does not negate the beneficial effects of estrogen. The main reasons why recent randomized studies reported failure of HRT in reducing the risk of cardiovascular events may be caused by other factors, such as long postmenopause state (not healthy endothelium) or thromboembolism risk and proinflammation after ERT.
Acknowledgments
We greatly appreciate Richard H. Karas, MD, PhD (Molecular Cardiology Research Institute, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, Mass) for his critical review and comments regarding the manuscript.
References
Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE, Furberg CD, Kowalchuk GJ, Stuckey TD, Rogers WJ, Givens DH, Waters D. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med. 2000; 343: 522–529.
Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. For the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998; 280: 605–613.
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002; 288: 321–333.
Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women’s Health Initiative randomized controlled trial. The Women’s Health Initiative steering committee. JAMA. 2004; 291: 1701–1712.
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.
Koh KK, Mincemoyer R, Bui MN, Csako G, Pucino F, Guetta V, Waclawiw M, Cannon RO III. Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women. N Engl J Med. 1997; 336: 683–690.
Davidson MH, Maki KC, Marx P, Maki AC, Cyrowski MS, Nanavati N, Arce JC. Effects of continuous estrogen and estrogen-progestin replacement regimens on cardiovascular risk markers in postmenopausal women. Arch Intern Med. 2000; 160: 3315–3325.
Koh KK, Cardillo C, Bui MN, Hathaway L, Csako G, Waclawiw MA, Panza JA, Cannon RO III. Vascular effects of estrogen and cholesterol-lowering therapies in hypercholesterolemic postmenopausal women. Circulation. 1999; 99: 354–360.
Koh KK, Blum A, Hathaway L, Mincemoyer R, Csako G, Waclawiw MA, Panza JA, Cannon RO III. Vascular effects of estrogen and vitamin E therapies in postmenopausal women. Circulation. 1999; 100: 1851–1857.
Soma MR, Osnago-Gadda I, Paoletti R, Fumagalli R, Morrisett JD, Meschia M, Crosignani P. The lowering of lipoprotein induced by estrogen plus progesterone replacement therapy in postmenopausal women. Arch Intern Med. 1993; 153: 1462–1468.
Wilcox JG, Hwang J, Hodis HN, Sevanian A, Stanczyk FZ, Lobo RA. Cardioprotective effects of individual conjugated equine estrogens through their possible modulation of insulin resistance and oxidation of low-density lipoprotein. Fertil Steril. 1997; 67: 57–62.
Wakatsuki A, Okatani Y, Ikenoue N, Fukaya T. Effect of medroxyprogesterone acetate on endothelium-dependent vasodilation in postmenopausal women receiving estrogen. Circulation. 2001; 104: 1773–1778.
Bhavnani BR, Cecutti A, Gerulath A, Woolever AC, Berco M. Comparison of the antioxidant effects of equine estrogens, red wine components, vitamin E, and probucol on low-density lipoprotein oxidation in postmenopausal women. Menopause. 2001; 8: 408–419.
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.
Wakatsuki A, Ikenoue N, Okatani Y, Fukaya T. Estrogen-induced small low density lipoprotein particles may be atherogenic in postmenopausal women. J Am Coll Cardiol. 2001; 37: 425–430.
Wakatsuki A, Okatani Y, Ikenoue N, Fukaya T. Different effects of oral conjugated equine estrogen and transdermal estrogen replacement therapy on size and oxidative susceptibility of low-density lipoprotein particles in postmenopausal women. Circulation. 2002; 106: 1771–1776.
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.
Vehkavaara S, Hakala-Ala-Pietila T, Virkamaki A, Bergholm R, Ehnholm C, Hovatta O, Taskinen MR, Yki-Jarvinen H. Differential effects of oral and transdermal estrogen replacement therapy on endothelial function in postmenopausal women. Circulation. 2000; 102: 2687–2693.
Sorensen MB, Collins P, Ong PJ, Webb CM, Hayward CS, Asbury EA, Gatehouse PD, Elkington AG, Yang GZ, Kubba A, Pennell DJ. Long-term use of contraceptive depot medroxyprogesterone acetate in young women impairs arterial endothelial function assessed by cardiovascular magnetic resonance. Circulation. 2002; 106: 1646–1651.
Koh KK, Jin DK, Yang SH, Lee SK, Hwang HY, Kang MH, Kim W, Kim DS, Choi IS, Shin EK. Vascular effects of synthetic or natural progestogen combined with conjugated equine estrogen in healthy postmenopausal women. Circulation. 2001; 103: 1961–1966.
Herrington DM, Werbel BL, Riley WA, Pusser BE, Morgan TM. Individual and combined effects of estrogen/progestin therapy and lovastatin on lipids and flow-mediated vasodilation in postmenopausal women with coronary artery disease. J Am Coll Cardiol. 1999; 33: 2030–2037.
McCrohon JA, Adams MR, McCredie RJ, Robinson J, Pike A, Abbey M, Keech AC, Celermajer DS. Hormone replacement therapy is associated with improved arterial physiology in healthy post-menopausal women. Clin Endocrinol (Oxf). 1996; 45: 435–441.
Gerhard M, Walsh BW, Tawakol A, Haley EA, Creager SJ, Seely EW, Ganz P, Creager MA. Estradiol therapy combined with progesterone and endothelium-dependent vasodilation in postmenopausal women. Circulation. 1998; 98: 1158–1163.
Sorensen KE, Dorup I, Hermann AP, Mosekilde L. Combined hormone replacement therapy does not protect women against the age-related decline in endothelium-dependent vasomotor function. Circulation. 1998; 97: 1234–1238.
Kawano H, Motoyama T, Hirai N, Yoshimura T, Kugiyama K, Ogawa H, Okamura H, Yasue H. Effect of medroxyprogesterone acetate plus estradiol on endothelium-dependent vasodilation in postmenopausal women. Am J Cardiol. 2001; 87: 238–240.
Clarkson TB, Anthony MS, Wagner JD. A comparison of tibolone and conjugated equine estrogens effects on coronary artery atherosclerosis and bone density of postmenopausal monkeys. J Clin Endocrinol Metab. 2001; 86: 5396–5404.
Campisi R, Nathan L, Pampaloni MH, Schoder H, Sayre JW, Chaudhuri G, Schelbert HR. Noninvasive assessment of coronary microcirculatory function in postmenopausal women and effects of short-term and long-term estrogen administration. Circulation. 2002; 105: 425–430.
Nakai K, Itoh C, Kawazoe K, Miura Y, Sotoyanagi H, Hotta K, Itoh T, Kamata J, Hiramori K. Concentration of soluble vascular cell adhesion molecule-1 (VCAM-1) correlated with expression of VCAM-1 mRNA in the human atherosclerotic aorta. Coron Artery Dis. 1995; 6: 497–502.
Haught WH, Mansour M, Rothlein R, Kishimoto TK, Mainolfi EA, Hendricks JB, Hendricks C, Mehta JL. Alterations in circulating intercellular adhesion molecule-1 and L-selectin: further evidence for chronic inflammation in ischemic heart disease. Am Heart J. 1996; 132: 1–8.
Koh KK, Bui MN, Mincemoyer R, Cannon RO III. Effects of hormone therapy on inflammatory cell adhesion molecules in postmenopausal healthy women. Am J Cardiol. 1997; 80: 1505–1507.
Wakatsuki A, Okatani Y, Ikenoue N, Fukaya T. Effect of medroxyprogesterone acetate on vascular inflammatory markers in postmenopausal women receiving estrogen. Circulation. 2002; 105: 1436–1439.
Cushman M, Legault C, Barrett-Connor E, Stefanick ML, Kessler C, Judd HL, Sakkinen PA, Tracy RP. Effect of postmenopausal hormones on inflammation-sensitive proteins. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Study. Circulation. 1999; 100: 717–722.
Stork S, Baumann K, von Schacky C, Angerer P. The effect of 17 ?-estradiol on MCP-1 serum levels in postmenopausal women. Cardiovasc Res. 2002; 53: 642–649.
Koh KK, Son JW, Jin DK, Ahn JY, Lee S-K, Hwang HY, Ahn TH, Shin EK. Effect of hormone replacement therapy on nitric oxide bioactivity and monocyte chemoattractant protein-1 levels. Int J Cardiol. 2001; 81: 43–50.
Barath P, Fishbein MC, Cao J, Berenson J, Helfant RH, Forrester JS. Detection and localization of tumor necrosis factor in human atheroma. Am J Cardiol. 1990; 65: 297–302.
Koh KK, Ahn JY, Kang MH, Kim DS, Jin DK, Sohn MS, Park GS, Choi IS, Shin EK. Effects of hormone replacement therapy on plaque stability, inflammation, and fibrinolysis in hypertensive or overweight postmenopausal women. Am J Cardiol. 2001; 88: 1423–1426.
Walsh BW, Cox DA, Sashegyi A, Dean RA, Tracy RP, Anderson PW. Role of tumor necrosis factor- and interleukin-6 in the effects of hormone replacement therapy and raloxifene on C-reactive protein in postmenopausal women. Am J Cardiol. 2001; 88: 825–828.
Herrington DM, Brosnihan KB, Pusser BE, Seely EW, Ridker PM, Rifai N, MacLean DB. Differential effects of estrogen and droloxifene on C-reactive protein and other markers of inflammation in healthy postmenopausal women. J Clin Endocrinol Metab. 2001; 86: 4216–4222.
Cushman M, Meilahn EN, Psaty BM, Kuller LH, Dobs AS, Tracy RP. Hormone replacement therapy, inflammation, and hemostasis in elderly women. Arterioscler Thromb Vasc Biol. 1999; 19: 893–899.
Koh KK, Schenke WH, Waclawiw M, Csako G, Cannon RO III. Statin attenuates increase in C-reactive protein during estrogen replacement therapy in postmenopausal women. Circulation. 2002; 105: 1531–1533.
Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999; 340: 448–454.
Cermak J, Key NS, Bach RR, Balla J, Jacob HS, Vercellotti GM. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood. 1993; 82: 513–520.
Pasceri V, Willerson JT, Yeh ETH. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000; 102: 2165–2168.
Wang CH, Li SH, Weisel RD, Fedak PW, Dumont AS, Szmitko P, Li RK, Mickle DA, Verma S. C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle. Circulation. 2003; 107: 1783–1790.
Zwaka TP, Hombach V, Torzewski J. C-reactive protein-mediated low density lipoprotein uptake by macrophages : implications for atherosclerosis. Circulation. 2001; 103: 1194–1197.
Venugopal SK, Devaraj S, Yuhanna I, Shaul P, Jialal I. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation. 2002; 106: 1439–1441.
Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation. 1998; 98: 731–733.
Sattar N, Perera M, Small M, Lumsden M-A. Hormone replacement therapy and sensitive C-reactive protein concentrations in women with type-2 diabetes. Lancet. 1999; 354: 487–488.
Decensi A, Omodei U, Robertson C, Bonanni B, Guerrieri-Gonzaga A, Ramazzotto F, Johansson H, Mora S, Sandri MT, Cazzaniga M, Franchi M, Pecorelli S. Effect of transdermal estradiol and oral conjugated estrogen on C-reactive protein in retinoid-placebo trial in healthy women. Circulation. 2002; 106: 1224–1228.
Vongpatanasin W, Tuncel M, Wang Z, Arbique D, Mehrad B, Jialal I. Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women. J Am Coll Cardiol. 2003; 41: 1358–1363.
Pradhan AD, Manson JE, Rossouw JE, Siscovick DS, Mouton CP, Rifai N, Wallace RB, Jackson RD, Pettinger MB, Ridker PM. Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women’s Health Initiative observational study. JAMA. 2002; 288: 980–987.
Yildirir A, Aybar F, Tokgozoglu L, Yarali H, Kabakci G, Bukulmez O, Sinici I, Oto A. Effects of hormone replacement therapy on plasma homocysteine and C-reactive protein levels. Gynecol Obstet Invest. 2002; 53: 54–58.
Herrington DM, Howard TD, Hawkins GA, Reboussin DM, Xu J, Zheng SL, Brosnihan KB, Meyers DA, Bleecker. Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med. 2002; 346: 967–974.
Herrington DM, Howard TD, Brosnihan KB, McDonnell DP, Li X, Hawkins GA, Reboussin DM, Xu J, Zheng SL, Meyers DA, Bleecker ER. Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein. Circulation. 2002; 105: 1879–1882.
Rajkumar C, Kingwell BA, Cameron JD, Waddell T, Mehra R, Christophidis N, Komesaroff PA, McGrath B, Jennings GL, Sudhir K, Dart AM. Hormonal therapy increases arterial compliance in postmenopausal women. J Am Coll Cardiol. 1997; 30: 350–356.
Nagai Y, Earley CJ, Kemper MK, Bacal CS, Metter EJ. Influence of age and postmenopausal estrogen replacement therapy on carotid arterial stiffness in women. Cardiovasc Res. 1999; 41: 307–311.
Bui MN, Arai AE, Hathaway L, Waclawiw MA, Csako G, Cannon RO III. Effect of hormone replacement therapy on carotid arterial compliance in healthy postmenopausal women. Am J Cardiol. 2002; 90: 82–85.
Koh KK, Horne MKI, Cannon RO III. Effects of hormone replacement therapy on coagulation, fibrinolysis, and thrombosis risk in postmenopausal women. Thromb Haemost. 1999; 82: 626–633.
Lip GYH, Blann AD, Jones AF, Beevers DG. Effects of hormone-replacement therapy on hemostatic factors, lipid factors, and endothelial function in women undergoing surgical menopause: Implications for prevention of atherosclerosis. Am Heart J. 1997; 134: 764–771.
Blei F, Wilson EL, Mignatti P, Rifkin DB. Mechanism of action of angiostatic steroids: suppression of plasminogen activator activity via stimulation of plasminogen activator inhibitor synthesis. J Cell Physiol. 1993; 155: 568–578.
Takada A, Takada Y, Urano T. The physiological aspects of fibrinolysis. Thromb Res. 1994; 76: 1–31.
Scarabin P-Y, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol. 1997; 17: 3071–3078.
Caine YG, Bauer KA, Barzzegar S, ten Cate H, Sacks FM, Walsh BW, Schiff I, Rosenberg RD. Coagulation activation following estrogen administration to postmenopausal women. Thromb Haemost. 1992; 68: 392–395.
Winkler UH, Schindler AE, Endrikat J, Dusterberg B. A comparative study of the effects of the hemostatic system of two monophasic gestodene oral contraceptives containing 20 μg and 30 μg ethinylestradiol. Contraception. 1996; 53: 75–84.
Koh KK, Horne MK III, Csako G, Waclawiw MA, Cannon RO III. Relation of fibrinolytic potentiation by estrogen to coagulation pathway activation in postmenopausal women. Am J Cardiol. 1999; 83: 466–469.
Teede HJ, McGrath BP, Smolich JJ, Malan E, Kotsopoulos D, Liang YL, Peverill RE. Postmenopausal hormone replacement therapy increases coagulation activity and fibrinolysis. Arterioscler Thromb Vasc Biol. 2000; 20: 1404–1409.
Koh KK, Ahn JY, Kim DS, Ryu WS, Shin M-S, Ahn TH, Choi IS, Shin EK. Effect of hormone replacement therapy on tissue factor activity, C-reactive protein and tissue factor pathway inhibitor. Am J Cardiol. 2003; 91: 371–373.
Jenner JL, Ordovas JM, Lamon-Fava S, Schaefer MM, Wilson PW, 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.
Godsland IF. Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein, and apolipoprotein (a) concentrations: analysis of studies published from 1974–2000. Fertil Steril. 2001; 75: 898–915.
Shlipak MG, Simon JA, Vittinghoff E, Lin F, Barrett-Connor E, Knopp RH, Levy RI, Hulley SB. Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause. JAMA. 2000; 283: 1845–1852.
Miyagawa K, Rosch J, Stanczyk F, Hermsmeyer K. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nature Med. 1997; 3: 324–327.
Miller VM, Vanhoutte PM. Progesterone and modulation of endothelium-dependent responses in canine coronary arteries. Am J Physiol. 1991; 261: R1022–R1027.
Levine RL, Chen S-J, Durand J, Chen Y-F, Oparil S. Medroxyprogesterone attenuates estrogen-mediated inhibition of neointima formation after balloon injury of the rat carotid artery. Circulation. 1996; 94: 2221–2227.
Adams MR, Register TC, Golden DL, Wagner JD, Williams JK. Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary aretery atherosclerosis. Arterioscler Thromb Vasc Biol. 1997; 17: 217–221.
Wagner JD, Clarkson TB, St Clair RW, Schwenke DC, Shively CA, Adams MR. Estrogen and progesterone replacement therapy reduces low density lipoprotein accumulation in the coronary arteries of surgically postmenopausal cynomolgus monkeys. J Clin Invest. 1991; 88: 1995–2002.
Haarbo J, Leth-Espensen P, Stender S, Christiansen C. Estrogen monotherapy and combined estrogen-progestogen replacement therapy attenuate aortic accumulation of cholesterol in ovariectomized cholesterol-fed rabbits. J Clin Invest. 1991; 87: 1274–1279.
Rosenberg L. Hormone replacement therapy: the need for reconsideration. Am J Public Health. 1993; 83: 1670–1673.
Mann RD, Lis Y, Chukwujindu J, Chanter DO. A study of the association between hormone replacement therapy, smoking and the occurrence of myocardial infarction in women. J Clin Epidemiol. 1994; 47: 307–312.
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.
Sidney S, Petitti DB, Quesenberry CP Jr. Myocardial infarction and the use of estrogen and estrogen-progestogen in postmenopausal women. Ann Intern Med. 1997; 127: 501–508.
Grodstein F, Stampfer MJ, Falkeborn M, Naessen T, Persson I. Postmenopausal hormone therapy and risk of cardiovascular disease and hip fracture in a cohort of Swedish women. Epidemiology. 1999; 10: 476–480.
Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med. 2000; 133: 933–941.
Varas-Lorenzo C, Garcia-Rodriguez LA, Perez-Gutthann S, Duque-Oliart A. Hormone replacement therapy and incidence of acute myocardial infarction. A population-based nested case-control study. Circulation. 2000; 101: 2572–2578.
Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Willett WC, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med. 1996; 335: 453–461.
Alexander KP, Newby LK, Hellkamp AS, Harrington RA, Peterson ED, Kopecky S, Langer A, O’Gara P, O’Connor CM, Daly RN, Califf RM, Khan S, Fuster V. Initiation of hormone replacement therapy after acute myocardial infarction is associated with more cardiac events during follow-up. J Am Coll Cardiol. 2001; 38: 1–7.
Ferrara A, Quesenberry CP, Karter AJ, Njoroge CW, Jacobson AS, Selby JV. Northern California Kaiser Permanente Diabetes Registry. Current use of unopposed estrogen and estrogen plus progestin and the risk of acute myocardial infarction among women with diabetes: the Northern California Kaiser Permanente Diabetes Registry, 1995–1998. Circulation. 2003; 107: 43–48.
Waters DD, Alderman EL, Hsia J, Howard BV, Cobb FR, Rogers WJ, Ouyang P, Thompson P, Tardif JC, Higginson L, Bittner V, Steffes M, Gordon DJ, Proschan M, Younes N, Verter JI. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA. 2002; 288: 2432–2440.
Koh KK. Effects of estrogen on vascular wall: vasomotor function and inflammation. Cardiovas Res. 2002; 55: 714–726.
Koh KK. Can a healthy endothelium influence the cardiovascular effects of hormone replacement therapy? Int J Cardiol. 2003; 87: 1–8.
Mendelsohn ME, Karas RH. The time has come to stop letting the HERS tale wag the dogma. Circulation. 2001; 104: 2256–2259.
Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med. 1999; 340: 1801–1811.
Clarkson TB, Anthony MS, Jerome CP. Lack of effect of raloxifene on coronary artery atherosclerosis of postmenopausal monkeys. J Clin Endocrinol Metab. 1998; 83: 721–726.
Clarkson TB, Anthony MS, Morgan TM. Inhibition of postmenopausal atherosclerosis progression: a comparison of the effects of conjugated equine estrogens and soy phytoestrogens. J Clin Endocrinol Metab. 2001; 86: 41–47.
Williams JK, Anthony MS, Honore EK, Herrington DM, Morgan TM, Register TC, Clarkson TB. Regression of atherosclerosis in female monkeys. Arterioscler Thromb Vasc Biol. 1995; 15: 827–836.
Rosenfeld ME, Kauser K, Martin-McNulty B, Polinsky P, Schwartz SM, Rubanyi GM. Estrogen inhibits the initiation of fatty streaks throughout the vasculature but does not inhibit intra-plaque hemorrhage and the progression of established lesions in apolipoprotein E deficient mice. Atherosclerosis. 2002; 164: 251–259.
Koh KK, Ahn JY, Jin DK, Yoon BK, Kim HS, Kim DS, Shin MS, Son JW, Choi IS, Shin EK. Effects of continuous combined hormone replacement therapy on inflammation in hypertensive and/or overweight postmenopausal women. Arterioscler Thromb Vasc Biol. 2002; 22: 1459–1464.
Koh KK, Kang MH, Jin DK, Lee SK, Ahn JY, Hwang HY, Yang SH, Kim DS, Ahn TH, Shin EK. Vascular effects of estrogen in type 2 diabetic postmenopausal women. J Am Coll Cardiol. 2001; 38: 1409–1415.
Herrington DM, Espeland MA, Crouse JR 3rd, Robertson J, Riley WA, McBurnie MA, Burke GL. Estrogen replacement and brachial artery flow-mediated vasodilation in older women. Arterioscler Thromb Vasc Biol. 2001; 21: 1955–1961.
Hodis HN, Mack WJ, Lobo RA, Shoupe D, Sevanian A, Mahrer PR, Selzer RH, Liu Cr CR, Liu Ch CH, Azen SP. Estrogen in the Prevention of Atherosclerosis Trial Research Group. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001; 135: 939–953.
Hodis HN, Mack WJ, Azen SP, Lobo RA, Shoupe D, Mahrer PR, Faxon DP, Cashin-Hemphill L, Sanmarco ME, French WJ, Shook TL, Gaarder TD, Mehra AO, Rabbani R, Sevanian A, Shil AB, Torres M, Vogelbach KH, Selzer RH. Women’s Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial Research Group. Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women. N Engl J Med. 2003; 349: 535–545.
Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, Trevisan M, Black HR, Heckbert SR, Detrano R, Strickland OL, Wong ND, Crouse JR, Stein E, Cushman M. Women’s Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003; 349: 523–534.
Weiss EJ, Bray PF, Tayback M, Schulman SP, Kickler TS, Becker LC, Weiss JL, Gerstenblith G, Goldschmidt-Clermont PJ. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med. 1996; 334: 1090–1094.
Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Ann Intern Med. 1997; 127: 895–903.
Rosendaal FR, Siscovick DS, Schwartz SM, Beverly RK, Psaty BM, Longstreth WT Jr., Raghunathan TE, Koepsell TD, Reitsma PH. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood. 1997; 89: 2817–2821.
Glueck CJ, Wang P, Fontaine RN, Tracy T, Sieve-Smith L, Lang JE. Effect of exogenous estrogen on atherothrombotic vascular disease risk related to the presence or absence of the Factor V Leiden mutation (resistance to activated protein C). Am J Cardiol. 1999; 84: 549–554.
Herrington DM, Vittinghoff E, Howard TD, Major DA, Owen J, Reboussin DM, Bowden D, Bittner V, Simon JA, Grady D, Hulley SB. Factor V Leiden, hormone replacement therapy, and risk of venous thromboembolic events in women with coronary disease. Arterioscler Thromb Vasc Biol. 2002; 22: 1012–1017.