"To gain an overview of the impact of HRT and lipid-lowering therapy on serum lipoproteins and CAD risk in women "

"To understand the mechanism of action of SERMs and phytoestrogens in modifying biochemical markers of cardiovascular disease in women "

": Cardiovascular disease may be a hormone-responsive disorder, as evidenced by the age-adjusted lower incidence of the disease in women than in men and the decrease in cardiovascular risk with hormone replacement therapy (HRT) found in observational studies. Also, evidence indicates that the incidence of cardiovascular disease rises sharply in the absence of estrogen after menopause. This response is accompanied by an increase in cardiovascular risk factors, including lipid levels. In this article, Drs Ariyo and Villablanca review the effect of HRT and its analogues on lipoprotein metabolism and discuss the influence of conventional HRT, selective estrogen receptor modulators (SERMs, sometimes called designer estrogens), and phytoestrogens on lipid parameters in women."

"Ariyo AA, Villablanca AC. Estrogens and lipids: Can HRT, designer estrogens, and phytoestrogens reduce cardiovascular risk markers after menopause? Postgrad Med 2002;111(1):23-30"

"ardiovascular disease remains the leading cause of death in women in Western societies. Annually in the United States, more than 500,000 women die of cardiovascular disease. About half of these deaths are caused by coronary artery disease (CAD) (1). Currently, postmenopausal women account for more than 30% of the female population at risk for CAD. In addition, nearly 40% of women in the United States are older than 45. According to life-expectancy projections, many of these women will spend as much as 30 years of their life in the postmenopausal state. These figures underscore the potentially enormous medical and public health impact of CAD risk associated with menopause and the possible benefits of intervention. "

" Data from large, population-based observational studies demonstrate a reduction in cardiovascular risk among HRT users (2). Confirmation from ongoing prospective studies is not yet available. Results of observational primary prevention studies suggest a nearly 50% reduction in CAD risk and a 30% to 40% reduction in deaths from all causes in women taking estrogen (3). For example, the Lipid Research Clinics Program Follow-up Study (4) demonstrated an age-adjusted 66% lower relative risk of death from cardiovascular disease in HRT users compared with nonusers. "

" Similarly, during up to 10 years of follow-up in the Nurses' Health Study (5), the overall risk of fatal and nonfatal cardiovascular events in women taking estrogen, after adjustment for age and other cardiovascular risk factors, was 44% lower than that in women who had never received estrogen therapy. Observational studies have not yet clarified whether a similar reduction in CAD risk occurs in women taking estrogen plus progesterone as in women taking unopposed estrogen. "

" Several biologically plausible mechanisms have been proposed for the estrogen-mediated cardioprotection seen in these trials, including estrogen-associated changes in lipid metabolism. Additional mechanisms include favorable hemostatic and fibrinolytic activity, improved vasomotor tone and vascular cell growth, reduced myocardial ischemia, and significant antioxidant effects (6,7). "

" One of the most attractive and important mechanisms is the favorable effect of HRT on lipoproteins. Up to half of the apparent cardiovascular benefit observed in estrogen-treated women may be due to favorable effects of HRT on lipoproteins--specifically, decreases in low-density lipoprotein cholesterol (LDL-C) and increases in high-density lipoprotein cholesterol (HDL-C) (8). "

" CAD is relatively rare in premenopausal women. After menopause, however, the risk of CAD in women rapidly increases and gradually approaches that in men at older ages. The annual incidence of CAD in women aged 55 to 64 is seven times higher than that in women aged 35 to 44 (9). Although CAD is more age-dependent in women than in men, a number of well-established risk factors contribute to CAD in women as they do in men. These include smoking, diabetes, hypertension, obesity, and physical inactivity. In addition, hyperlipidemia plays a significant role in the development of atherosclerotic heart disease in men and women. "

" According to the Framingham data, for every 1% increase in total cholesterol level there is a 2% increase in risk of CAD (10). Therefore, in women, elevations in lipid levels contribute significantly to cardiovascular morbidity and mortality from CAD. "

" Hyperlipidemia (total cholesterol, >240 mg/dL [6.21 mmol/L]) is exceedingly common and occurs in about 25% to 33% of women in the United States. Furthermore, the relative CAD risk associated with elevated lipid levels is different in men than in women. For example, relative risk from elevated triglyceride levels is greater in women than in men (11), and the threshold for increased risk from low levels of HDL-C is higher (12). HDL-C is atheroprotective as evidenced by a strong inverse association between HDL-C levels and cardiovascular risk (11). "

" Low HDL-C values may be a stronger predictor of CAD risk in women than in men. It has been estimated that for every 1 mg/dL (0.026 mmol/L) increase in HDL-C, there is a 3% decrease in risk of CAD and a 4.7% decrease in risk of mortality from cardiovascular disease (13). Furthermore, HDL-C levels greater than 60 mg/dL (1.55 mmol/L), which are more commonly found in women than in men, are so protective as to essentially negate the effect of one other cardiovascular risk factor (14). "

" A number of changes that occur in the lipid profile after menopause are associated with increased cardiovascular risk. Lipid parameters gradually change to effect a 25% increase in LDL-C and apolipoprotein B and a 15% increase in total cholesterol (15). Although lipid levels in men also gradually increase with age, the elevations in total cholesterol and LDL-C are not of the same magnitude as those in women. Additionally, modest elevations in triglyceride and lipoprotein(a) [Lp(a)] levels also occur in postmenopausal women (16). In contrast, levels of HDL-C and its subclass HDL"

" remain unchanged or decline only slightly after menopause. Overall, postmenopausal lipoprotein changes result in a significant increase in cardiovascular risk for women. "

" HRT is widely used among postmenopausal women around the world. In the United States, the most commonly used preparations are oral conjugated equine estrogens (CEE) (Premarin, 0.625 mg per day), transdermal estrogen patches, and combination preparations of CEE and the progestin medroxyprogesterone acetate (Premphase, 5 mg per day given cyclically; Prempro, 2.5 or 5 mg per day given continuously). Accumulating evidence indicates that orally administered HRT in postmenopausal women confers cardioprotective effects mediated to a large extent by a reduction in LDL-C and an increase in HDL-C concentrations (8). "

" Transdermally administered estradiol-17beta has minimal or no effect on lipoprotein levels, suggesting that the hepatic effects of estrogen are important for changes in lipoprotein levels. In general, the beneficial effects of combined estrogen and progesterone therapy are similar to those of therapy with unopposed estrogen. However, important differences in the action of HRT on the various components of lipoproteins may be related to cardiovascular risk (table 1). "

"Table 1. Effect of HRT and its analogues on lipid parameters and other biochemical markers of cardiovascular risk"

" HDL-C, high-density lipoprotein cholesterol; HRT, hormone replacement therapy; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); SERM, selective estrogen receptor modulator. "

" Prospective studies suggest that HDL-C is more closely related to cardiovascular disease in women than LDL-C (17) and is the best predictor of CAD risk in women (18). Epidemiologic studies suggest that a substantial proportion of the cardiovascular benefit from HRT may be specifically mediated by the higher HDL-C levels in HRT-treated women (4). It is worth noting that as the level of endogenous estrogen falls shortly after menopause, lipid levels rise, with the exception of HDL-C concentration. "

" Repeatedly, HRT has been demonstrated to result in a significant increase in levels of HDL-C. In the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial (19), women taking oral CEE were shown to have HDL-C levels 9% higher than those taking placebo. Substantial evidence from the PEPI trial and other smaller, shorter clinical trials suggests that unopposed estrogen has a more favorable effect on HDL-C than estrogen given with continuous or cyclic synthetic progestin (20). However, the PEPI trial also demonstrated that, compared with medroxyprogesterone acetate, micronized progesterone preserves most of oral estrogen's favorable effect on HDL-C. The increase in HDL-C levels in response to HRT is caused by increased production of apolipoprotein A-I, the major apolipoprotein of HDL-C, and by decreased hepatic lipase activity--effects that enhance the uptake of HDL-C and the catabolism of HDL"

" (21), the HDL subparticle considered the most active in reverse cholesterol transport. Despite the strong inverse association between HDL-C levels and CAD risk, no clinical trial has been performed to demonstrate that increasing HDL-C levels reduces CAD risk in women. "

" The oxidation and subsequent phagocytosis of LDL-C by macrophages result in the formation of foam cells, which are key to the development of atherosclerosis (22). Recent data indicate that HRT is associated with a 10% to 15% reduction in LDL-C levels (19). Estrogen lowers LDL-C levels when taken with or without a progestin, although progestin blunts the estrogen-related increase in HDL-C levels. "

" Metabolic studies suggest that the reduction in LDL-C levels with HRT is a result of enhanced hepatic lipoprotein uptake, accelerated conversion of hepatic cholesterol to bile acids, and increased expression of LDL-C receptors on hepatocytes (23). The result is augmented clearance of LDL-C particles from plasma. This process, incidentally, is also the mechanism for enhanced cholelithiasis seen in women taking HRT. Unfortunately, there are few observational data, and no clinical data, to show that LDL-C is as important a heart disease risk factor in women as in men. Nevertheless, the average decrease in LDL-C with HRT is large and might be expected to reduce CAD risk. "

" Mild elevation in levels of serum triglycerides is seen in women using HRT, regardless of whether they are given unopposed estrogen or a combination of estrogen and progesterone. Some studies have reported higher triglyceride levels with estrogen therapy alone than with combined HRT (20). Very low-density lipoprotein (VLDL) levels increase in response to HRT because of enhanced production, not impaired clearance, of hepatic VLDL and apolipoprotein B (24). "

" In response to HRT, triglyceride levels can change substantially in certain persons. Therefore, women with a baseline triglyceride level greater than 500 mg/dL (5.65 mmol/L) should be considered for exclusion from HRT. It is not known whether estrogen-stimulated VLDL production has the same atherogenic effect as impaired lipolysis caused by intrinsically high levels of triglycerides. Experts suspect that hypertriglyceridemia secondary to HRT may not be atherogenic (24). "

" Lp(a) is structurally similar to LDL-C and plasminogen and is believed to be proatherogenic and antithrombolytic. Whether Lp(a) constitutes an independent risk factor for CAD is controversial, because so far, results of studies are contradictory (25). Lp(a) may be a risk factor for CAD in some patients, including those with hereditary hyperlipidemia. Levels of Lp(a) rise after menopause (24), but it is unclear whether higher levels of Lp(a) in older women are primarily a result of age or of menopause. "

" Estrogen is among the few pharmacologic agents that have been shown to lower Lp(a) levels. In fact, reductions of up to 50% in Lp(a) concentration have been reported with estrogen use (26). However, whether the plasma level reduction of Lp(a) translates into reduced cardiovascular risk is not clear. So far, this relationship has not been convincingly demonstrated by any clinical study. "

" According to the 1994 National Cholesterol Education Program (NCEP) guidelines (14), HRT alone or in combination with conventional lipid-lowering therapy was recommended for the treatment of hyperlipidemia in women. However, recently revised NCEP guidelines (27) indicate that for women aged 45 to 75, the favorable effects of therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") in clinical trials make a cholesterol-lowering drug preferable to HRT for CAD risk reduction. "

" Separate and combined effects of treatment with low doses of a hypolipidemic agent (ie, simvastatin, 10 mg per day) and continuous combined HRT (CEE plus medroxyprogesterone acetate) on serum lipids were investigated in a recent study of postmenopausal women with hypercholesterolemia to determine the agents' relative effectiveness in lowering serum lipid levels (28). The most effective therapy in this well-controlled 6-month trial was combined therapy. Significant reductions in LDL-C occurred in women receiving combined therapy compared with those receiving hypolipidemic drug treatment alone (23% versus 16%). Combination therapy also increased HDL-C levels more than statin therapy alone (21% for combination therapy versus 11% for simvastatin at 6 months). "

" Aggressive lipid-lowering therapy may have a greater impact on secondary prevention of CAD events in women than in men. For example, for a similar reduction in serum lipoproteins, hyperlipidemic women in both the Scandinavian Simvastatin Survival Study (29) (4S) and Cholesterol and Recurrent Events (30) (CARE) secondary prevention trial achieved greater risk reduction in cardiovascular end points than men from aggressive lipid lowering. This effect was observed in women with severe hyperlipidemia (in 4S) and those with milder elevations of cholesterol (in the CARE trial). Despite significant reductions in LDL-C and increases in HDL-C levels, the Heart and Estrogen/progestin Replacement Study (31) (HERS) failed to show a reduction in cardiovascular events in women with CAD, suggesting that lipid lowering alone is not sufficient for CAD risk modification in women with established cardiovascular disease. "

" SERMs are a new class of pharmacologic agents now available to women who cannot tolerate or are unwilling to use conventional HRT. Because of the growing number of SERMs and their importance in a wide array of organ systems, it is becoming increasingly important for physicians to understand not only the tissue-specific actions of SERMs but also their clinical practice applications and anticipated role for patient care. Perhaps nowhere is the interest keener than in cardiovascular protection. "

" SERMs were formerly referred to as antiestrogens, a description that is now known to be inappropriate. The term SERM has been coined to describe compounds that, in contrast to pure estrogen agonists or antagonists, have a mixed and selective pattern of estrogen agonist-antagonist activity, which largely depends on the tissue targeted (32). The most actively studied SERMs currently are tamoxifen citrate (Nolvadex) and raloxifene (Evista). "

" Although the data are incomplete regarding the effect of SERMs on cardiovascular morbidity and mortality, early experience with the prototypic first-generation SERM, tamoxifen, has demonstrated reduction in the risk of cardiovascular disease (2). Clinical trials are in progress to assess the efficacy of raloxifene (approved by the US Food and Drug Administration for prevention of osteoporosis) on cardiovascular risk in postmenopausal women. As a class, SERMs are also known to have significant lipid-reducing properties, which may help explain their emerging potential role in cardiovascular protection. "

" SERMs have been shown to favorably affect a number of clinical markers of cardiovascular risk, including lipid parameters. However, the effects of these agents on lipids differ from those of HRT in a number of important ways. Raloxifene, a nonsteroidal benzothiophene derivative, has effects equal to those of CEE in lowering total cholesterol and LDL-C levels and is at least as potent as CEE in its LDL-C antioxidant effect. However, unlike CEE and tamoxifen, raloxifene use does not raise HDL-C levels. A potential advantage of raloxifene over HRT is that serum triglyceride levels are not increased with its use (33). Reductions in Lp(a) levels, though of lesser magnitude than those with CEE, have also been demonstrated with raloxifene (32). "

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