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NEJM Editorial Volume 346:1017-1018 March 28, 2002 Number 13 Individualized Hormone-Replacement Therapy?For many years, the conventional wisdom, backed by observational epidemiologic studies, has held that "replacement" of estrogen after menopause would restore the relative protection from cardiovascular disease enjoyed by premenopausal women as compared with men of a similar age. This view was bolstered by a number of apparently beneficial effects of oral estrogen therapy on risk factors for cardiovascular disease, most notably reductions in the level of low-density lipoprotein (LDL) cholesterol and increases in the level of high-density lipoprotein (HDL) cholesterol. Recent clinical trials, however, have failed to support a benefit of hormone-replacement therapy in terms of clinical events1 and progression of narrowing of the coronary arteries2 in women with preexisting coronary heart disease, despite changes in LDL and HDL cholesterol levels that would be predictive of a considerable reduction in disease risk. An excess of early events in the Heart and Estrogen/Progestin Replacement Study (HERS)1 and other studies of hormone use3 has led to the suggestion that prothrombotic and proinflammatory effects of hormone therapy may supervene in women with existing atherosclerosis, whereas the presumed benefits of estrogen in terms of atherogenesis, which are as yet unproven, may take longer to become evident. The results of HERS have led to recommendations against starting hormone therapy in women with preexisting coronary heart disease,3 at least until further information is provided that makes possible the accurate weighing of the risks and the possible benefits for individual patients. Can such information be obtained, and if so, how? Ideally, a set of predictive markers would be developed that, with high probability, could be fitted into a comprehensive model for computing the likelihood of beneficial or adverse effects of hormone-replacement therapy with respect to the risk of coronary heart disease. An example of a quantitative model for an assessment of the risk of coronary heart disease based on predictive clinical and laboratory information is provided by the Framingham risk score, a tool that has been adapted for global risk assessment by Adult Treatment Panel III of the National Cholesterol Education Program.4 As it happens, the only laboratory measurement to date that has been related to a cardiovascular benefit of hormone-replacement therapy is the Lp(a) lipoprotein level, a risk factor that is not included in the Framingham score. In HERS, as in other studies, hormone-replacement therapy lowered Lp(a) lipoprotein levels, and the cardiovascular benefit of hormone-replacement therapy was significantly related to the initial Lp(a) lipoprotein level as well as the size of the reduction in the level.5 In this issue of the Journal, Herrington et al. introduce another approach to the challenge of predicting clinical responsiveness to hormone-replacement therapy: pharmacogenetics.6 They have determined that sequence variation in the intron 1 region of the gene encoding estrogen receptor is associated with the magnitude of the response of HDL cholesterol levels to estrogen or combination hormone-replacement therapy, though the underlying mechanism is not known. Although this observation will require confirmation by other studies, it is consistent with the finding of a relation between the same estrogen-receptor genotypes and changes in the level of sex hormone-binding globulin, another index of estrogen action.7 The authors state that their results point to the possibility of using genetic screening to guide the selection of appropriate candidates for postmenopausal hormone therapy. This suggestion has also arisen on the basis of the results of a case-control study of postmenopausal women with hypertension, in which the prothrombin G20210A mutation was associated with an increased risk of myocardial infarction in women receiving hormone-replacement therapy.8 However, as Herrington et al. acknowledge, the responsiveness of HDL cholesterol levels to hormone-replacement therapy has not yet been linked to variation in the risk or outcome of cardiovascular disease. Indeed, there is an inherent limitation to the use of intermediate phenotypes for assessment of the risks and benefits of therapy that is well illustrated by the case of HDL cholesterol. HDL metabolism is complex, with multiple determinants of plasma HDL cholesterol levels,8 numerous subpopulations of HDL particles,8,9 and a variety of postulated mechanisms whereby HDL cholesterol may modulate the risk of coronary heart disease.8,9,10 Although much attention has been paid to the role of HDL cholesterol and its constituent apolipoproteins in mediating the efflux of cholesterol from tissues and its delivery to the liver for oxidation and excretion,10 other antiatherogenic mechanisms have also been proposed, including attenuation of the effects of oxidative stress and inflammation in the arterial wall.11 In addition, variation in HDL cholesterol levels may reflect reciprocal changes in levels of lipoprotein particles containing apolipoprotein B.8 Estrogen therapy has been reported to increase levels of HDL cholesterol by mechanisms that include increased production of the HDL apolipoprotein A-I12 and reduced activity of hepatic lipase, an enzyme that is capable of promoting HDL catabolism.13 These two effects may operate differently, if at all, in modulating the risk of cardiovascular disease. The complexities of the actions of estrogen on genetic regulation of HDL metabolism are further illustrated by a report showing that the effects of estrogen on expression of the gene encoding apolipoprotein A-I are dependent on the intracellular balance of estrogen receptor and coactivators used by both this gene and the gene encoding the apolipoprotein A-I enhancer.14 Another study showed that estrogen mediates reciprocal changes in hepatocellular expression of alternatively spliced products of SR-BI (scavenger receptor, class B, type I), a gene encoding a receptor that mediates selective cellular uptake of cholesterol.15 An appreciation of the diverse structural and metabolic features of HDL cholesterol, which are influenced by multiple genes,10 highlights the many unanswered questions regarding the relation of any given change in the plasma HDL cholesterol level to the underlying mechanisms that influence the development of cardiovascular disease. The observation of Herrington et al. that the level of the HDL subfraction HDL3, but not the HDL2 subfraction, was increased by hormone-replacement therapy does not clearly point to an antiatherogenic effect, since HDL3 is itself heterogeneous and levels of the various HDL components may not be consistently related to the risk of cardiovascular disease.8,9,11 Moreover, as is the case with the entire spectrum of metabolic and cellular actions of estrogen, the specificity of the response of HDL cholesterol to different preparations of estrogen and different modes of delivery, as well as the interactions of estrogens with progestational agents in hormone-replacement therapy, is not well understood. It is conceivable that, ultimately, more comprehensive pharmacogenomic studies of hormone-replacement therapy, in conjunction with more detailed phenotypic markers of disease outcome - or, preferably, disease end points themselves - will lead to effective algorithms for individualizing recommendations for hormonal therapy for postmenopausal women. For maximal clinical usefulness, such algorithms should be based on markers of variation in biologic responsiveness (pharmacodynamics) as well as of the metabolism of exogenous hormones (pharmacokinetics). On the other hand, increased availability of other effective agents, such as statins, for the prevention and treatment of coronary heart disease,3,4 may obviate the need to deal with the complexities of hormone-replacement therapy for many women. Meanwhile, the findings of Herrington et al.6 reveal the potential for hormonal (or pharmacologic or dietary) perturbations to expose biologically important functions of genes that can teach us a great deal about the complex regulatory networks that underlie our individuality. Ronald M. Krauss, M.D. University of California Berkeley, CA 94720
References 1.Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-613.[Medline] 2.Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522-529.[Abstract/Full Text] 3.Mosca L, Collins P, Herrington DM, et al. Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 2001;104:499-503.[Full Text] 4.Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497.[Medline] 5.Shlipak MG, Simon JA, Vittinghoff E, et al. Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause. JAMA 2000;283:1845-1852.[Medline] 6.Herrington DM, Howard TD, Hawkins GA, et al. Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med 2002;346:967-975. 7.Psaty BM, Smith NL, Lemaitre RN, et al. Hormone replacement therapy, prothrombotic mutations, and the risk of incident nonfatal myocardial infarction in postmenopausal women. JAMA 2001;285:906-913.[Medline] 8.Tribble DL, Krauss RM. HDL and coronary artery disease. Adv Intern Med 1993;38:1-29.[Medline] 9.Tailleux A, Fruchart JC. HDL heterogeneity and atherosclerosis. Crit Rev Clin Lab Sci 1996;33:163-201.[Medline] 10.Kawashiri MA, Maugeais C, Rader DJ. High-density lipoprotein metabolism: molecular targets for new therapies for atherosclerosis. Curr Atheroscler Rep 2000;2:363-372.[Medline] 11.Van Lenten BJ, Navab M, Shih D, Fogelman AM, Lusis AJ. The role of high-density lipoproteins in oxidation and inflammation. Trends Cardiovasc Med 2001;11:155-161.[Medline] 12.Jin FY, Kamanna VS, Kashyap ML. Estradiol stimulates apolipoprotein A-I- but not A-II-containing particle synthesis and secretion by stimulating mRNA transcription rate in Hep G2 cells. Arterioscler Thromb Vasc Biol 1998;18:999-1006.[Abstract/Full Text] 13.Tikkanen MJ, Nikkila EA, Kuusi T, Sipinen SU. High density lipoprotein-2 and hepatic lipase: reciprocal changes produced by estrogen and norgestrel. J Clin Endocrinol Metab 1982;54:1113-1117.[Abstract] 14.Harnish DC, Evans MJ, Scicchitano MS, Bhat RA, Karathanasis SK. Estrogen regulation of the apolipoprotein AI gene promoter through transcription cofactor sharing. J Biol Chem 1998;273:9270-9278.[Abstract/Full Text] 15.Graf GA, Roswell KL, Smart EJ. 17beta-Estradiol promotes the up-regulation of SR-BII in HepG2 cells and in rat livers. J Lipid Res 2001;42:1444-1449.[Abstract/Full Text] |