Estrogens ,homocysteine ,vasodilatation and menopause: basic mechanisms ,interactions and clinical implications

References

• Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet 1997;349:1269–76
   PubMed Web of Science ®Google Scholar
• Lloyd-Jones DM, Larson MG, Beiser A, et al. Life-time risk of developing coronary heart disease. Lancet 1999;353:89–92
   Google Scholar
• Wenger NK, Speroff L, Packard B. Cardiovascular health and disease in women. N Engl J Med 1993; 329:247–56
   PubMed Web of Science ®Google Scholar
• Van der Schouw YT, van der Graaf Y, Teyerberg EW, et al. Age at menopause as a risk factor for cardiovascular mortality. Lancet 1996;347:714–18
   PubMed Web of Science ®Google Scholar
• Ross ouw JE. Hormones, genetic factors, and gender differences in cardiovascular disease. Cardiovasc Res 2002;53:550–7
   Google Scholar
• Van Baal WM, Kooistra T, Stehouwer CDA. Cardiovascular disease risk and hormone replace-ment therapy (hrt): a review based on randomised, controlled studies in postmenopausal women. Curr Med Chem 2000;7:499–517
   Google Scholar
• Roeters van Lennep JE, Westerveld HT, Erkelens DW, et al. Risk factors for coronary heart disease: implications of gender. Cardiovasc Res 2002;53: 538–49
   Google Scholar
• Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in post-menopausal women. J Am Med Assoc 1998;280: 605–13
   PubMed Web of Science ®Google Scholar
• Folkow B. Myogenic mechanisms in the control of systemic resistance. Introduction and historical background.J Hypertens Suppl 1989;7:S1–4
   Google Scholar
• Davis MJ. Microvascular control of capillary pressure during increases in local arterial and venous pressure. Am J Physiol 1988;254:H772–84
   Google Scholar
• Mulvany MJ, Aalkjaer C. Structure and function of small arteries. Physiol Rev 1990;70:921–61
   PubMed Web of Science ®Google Scholar
• Faraci FM, Heistad DD. Regulation oflarge cerebral arteries and cerebral microvascular pressure. Circ Res 1990;66:8–17
   PubMed Web of Science ®Google Scholar
• Iida N. Different flow regulation mechanisms between celiac and mesenteric vascular beds in conscious rats. Hypertension 1995;25:260–5
   Google Scholar
• Welsh DG, Morielli AD, Nelson MT, et al. Transient receptor potential channels regulate myogenic tone of resistance arteries. Circ Res 2002;90:248–50
   PubMed Web of Science ®Google Scholar
• Ignarro U, Buga GM, Wood KS, et al. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 1987;84:9265–9
   PubMed Web of Science ®Google Scholar
• Ignarro U. Nitric oxide. A novel signal transduction mechanism for transcellular communication. Hypertension 1990;16:477–83
   Google Scholar
• Somlyo AV, Somlyo AP. Electromechanical and pharmacological coupling in vascular smooth muscle. J Pharmacol Exp Ther 1968;159:129–45
   PubMed Web of Science ®Google Scholar
• Somlyo AP, Bond M, Somlyo AV. Calcium content of mitochondria and endoplasmic reticulum in liver frozen rapidly in vivo. Nature 1985;314:622–5
   Google Scholar
• Somlyo AP, Somlyo AV. Signal transduction and regulation in smooth muscle. Nature 1994;372: 231–6
   PubMed Web of Science ®Google Scholar
• Walsh MP, Kargacin GJ, Kendrick-Jones J, et al. Intracellular mechanisms involved in the regulation of vascular smooth muscle tone. Can J Physiol Pharmacol 1995;73:565–73
   Google Scholar
• Ignarro IT Biosynthesis and metabolism of endothelium-derived nitric oxide. Annu Rev Pharmacol Toxicol 1990;30:535–60
   PubMed Web of Science ®Google Scholar
• Ignarro U, Cirino G, Casini A, et al. Nitric oxide as a signaling molecule in the vascular system: an over-view. J Cardiovasc Pharmacol 1999;34:879–86
   PubMed Web of Science ®Google Scholar
• Davis MJ, Hill MA. Signaling mechanisms under-lying the vascular myogenic response. Physiol Rev 1999;79:387–423
   PubMed Web of Science ®Google Scholar
• Ross R. Atherosclerosis — an inflammatory disease. N Engl J Med 1999;340:115–26
   PubMed Web of Science ®Google Scholar
• Napoli C, Ignarro IT Nitric oxide and athero-sclerosis. Nitric Oxide 2001;5:88–97
   PubMed Web of Science ®Google Scholar
• Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999;340:1801–11
   PubMed Web of Science ®Google Scholar
• Mendelsohn ME. Mechanisms of estrogen action in the cardiovascular system. J Steroid Biochem Mol Biol 2000;74:337–43
   PubMed Web of Science ®Google Scholar
• Adams MR, Kaplan JR, Manuck SB, et al. Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomised monkeys: lack of an effect of added progesterone. Atherosclerosis 1990; 10:1051–7
   Google Scholar
• Wagner JD, St Clair RW, Schwenke DC, et al. Regional differences in arterial low density lipo-protein metabolism in surgically postmenopausal cynomolgus monkeys. Effects of estrogen and pro-gesterone replacement therapy. Arteriosder Thromb 1992;12:717–26
   Google Scholar
• Williams JK, Shively CA, Clarkson TB. Determi-nants of coronary artery reactivity in premenopausal female cynomolgus monkeys with diet-induced atherosclerosis. Circulation 1994;90:983–7
   Google Scholar
• Williams JK, Honore EK, Washburn SA, et al. Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries in cynomolgus monkeys. J Am Coll Cardiol 1994;24: 1757–61
   PubMed Web of Science ®Google Scholar
• Register TC, Adams MR, Golden DL, et al. Con-jugated equine estrogens alone, but not in combina-tion with medroxyprogesterone acetate, inhibit aortic connective tissue remodeling after plasma lipid lowering in female monkeys. Arterioscler Thromb Vasc Biol 1998;18:1164–71
   PubMed Web of Science ®Google Scholar
• Williams JK, Adams MR, Herrington DM, et al. Short-term administration of estrogen and vascular responses of atherosclerotic coronary arteries. J Am Coll Cardiol 1992;20:452–7
   PubMed Web of Science ®Google Scholar
• Collins P, Rosano GM, Sarrel PM, et al. 17 beta-Estradiolattenuatesacetylcholine-inducedcoronary arterial constriction in women but not men with coronary heart disease. Circulation 1995;92: 24–30
   PubMed Web of Science ®Google Scholar
• Gilligan DM, Badar DM, Panza JA, et al. Acute vascular effects of estrogen in postmenopausal women. Circulation 1994;90:786–91
   PubMed Web of Science ®Google Scholar
• Gilligan DM, Quyyumi AA, Cannon RO III. Effects of physiological levels of estrogen on coronary vasomotor function in postmenopausal women. Circulation 1994;89:2545–51
   Google Scholar
• Reis SE, Gloth ST, Blumenthal RS, et al. Ethinyl estradiol acutely attenuates abnormal coronary vaso-motor responses to acetylcholine in postmenopausal women. Circulation 1994;89:52–60
   PubMed Web of Science ®Google Scholar
• Volterrani M, Rosano G, Coats A, et al. Estrogen acutely increases peripheral blood flow in post-menopausal women. Am J Med 1995;99:119–22
   PubMed Web of Science ®Google Scholar
• Guetta V, Quyyumi AA, Prasad A, et al. The role of nitric oxide in coronary vascular effects of estrogen in postmenopausal women. Circulation 1997;96: 2795–801
   PubMed Web of Science ®Google Scholar
• Al Khdili F, Eriksson M, Landgren BM, et al. Effect of conjugated estrogen on peripheral flow-mediated vasodilation in postmenopausal women. Am J Cardiol 1998;82:215–18
   Google Scholar
• Roque M, Heras M, Roig E, et al. Short-term effects of transdermal estrogen replacement therapy on coronary vascular reactivity in postmenopausal women with angina pectoris and normal results on coronary angio grams. J Am Coll Cardiol 1998;31: 139–43
   PubMed Web of Science ®Google Scholar
• Giltay EJ, Lambert J, Gooren 14, et al. Sex steroids, insulin, and arterial stiffness in women and men. Hypertension 1999;34:590–7
   Google Scholar
• Pirhonen JP, Vuento MH, Makinen JI, et al. Long-term effects of hormone replacement therapy on the uterus and on uterine circulation. AmJ Obstet Gynecol 1993;168:620–30
   Google Scholar
• Zalud I, Conway C, Schulman H, et al. Endometrial and myometrial thickness and uterine blood flow in postmenopausal women: the influence of hormonal replacement therapy and age [see comments] .J Ultrasound Med 1993;12:737–41
   Google Scholar
• Belfort MA, Saade GR, Snabes M, et al. Hormonal status affects the reactivity of the cerebral vasculature. Am J Obstet Gynecol 1995;172:1273–8
   PubMed Web of Science ®Google Scholar
• Bonilla-Musoles F, Ballester MJ, Marti MC, et al. Transvaginal color Doppler assessment of endo-metrial status in normal postmenopausalwomen: the effect of hormone replacement therapy. J Ultrasound Med 1995;14:503–7
   Google Scholar
• Penotti M, Farina M, Castiglioni E, et al. Alteration in the pulsatility index values of the internal carotid and middle cerebral arteries after suspension of postmenopausal hormone replacement therapy: a randomized crossover study. Am J Obstet Gynecol 1996;175:606–11
   PubMed Web of Science ®Google Scholar
• Hata K, Hata T. Effects of oophorectomy and hormone replacement therapy on ophthalmic artery blood flow velocity waveforms. J Ultrasound Med 1997;16:737–41
   PubMed Web of Science ®Google Scholar
• Jackson S, Vyas S. A double-blind, placebo con-trolled study of postmenopausal oestrogen replace-ment therapy and carotid artery pulsatility index. BrJ Obstet Gynaecol 1998;105:408–12
   PubMedGoogle Scholar
• Van Baal WM, Kenemans P, Stehouwer CDA, et al. Sequentially combined hormone replacement therapy reduces impedance to flow within the uterine and central retinal arteries in healthy post-menopausal women. Am J Obstet Gynecol 1999;181: 1365–73
   PubMed Web of Science ®Google Scholar
• Post MS, van der Mooren MJ, van Baal WM, et al. Raloxifene reduces impedance to flow within the uterine artery in early postmenopausal women: a 2-year randomized, placebo-controlled, compara-tive study. Am J Obstet Gynecol 2001;185:557–62
   Google Scholar
• Jiang CW, Sarrel PM, Lindsay DC, et al. Endothelium-independent relaxation of rabbit coronary artery by 17 beta-oestradiol in vitro. Br J Pharmacol 1991;104:1033–7
   PubMed Web of Science ®Google Scholar
• Jiang C, Sarrel PM, Poole-Wilson PA, et al. Acute effect of 17 beta-estradiol on rabbit coronary artery contractile responses to endothelin-1. Am J Physiol 1992;263:H271–5
   Google Scholar
• Kitazawa T, Hamada E, Kitazawa K, et al. Non-geno mic mechanism of 17 beta-oestradiol-induced inhibition of contraction in mammalian vascular smooth muscle. J Physiol 1997;499:497–511
   PubMed Web of Science ®Google Scholar
• Teoh H, Leung SW, Man RY. Short-term exposure to physiological levels of 17 beta-estradiol enhances endothelium-independent relaxation in porcine coronary artery. Cardiovasc Res 1999;42: 224–31
   Google Scholar
• Vedernikov YP, Liao QP, Jam V, et al. Effect of chronic treatment with 17beta-estradiol and progesterone on endothelium-dependentand endo-thelium-independent relaxation in isolated aortic rings from ovariectomized rats. Am J Obstet Gynecol 1997;176:603–8
   Google Scholar
• Caulin-Glaser T, Garcia-Cardena G, Sarrel P, et al. 17 beta-estradiol regulation of human endothelial cell basal nitric oxide release, independent of cyto-solic Ca2+ mobilization. Circ Res 1997;81:885–92
   PubMed Web of Science ®Google Scholar
• MacRitchie AN, Jun SS, Chen Z, et al. Estrogen upregulates endothelial nitric oxide synthase gene expression in fetal pulmonary artery endothelium. Circ Res 1997;81:335–62
   Google Scholar
• Lantin-Hermoso RL, Rosenfeld CR, Yuhanna IS, et al. Estrogen acutely stimulates nitric oxide synthase activity in fetal pulmonary artery endothe-lium. Am J Physiol 1997;2731119–26
   Google Scholar
• Stefano GB, Prevot V, Beauvillain JC, et al. Cell-surface estrogen receptors mediate calcium-dependent nitric oxide release in human endothelia. Circulation 2000;101:1594–7
   PubMed Web of Science ®Google Scholar
• Huang A, Sun D, Kaley G, et al. Estrogen preserves regulation of shear stress by nitric oxide in arterioles of female hypertensive rats. Hypertension 1998;31: 309–14
   PubMedGoogle Scholar
• Huang A, Sun D, Koller A, et al. Gender difference in flow-induced dilation and regulation of shear stress: role of estrogen and nitric oxide. Am J Physiol 1998;275:R1571–7
   PubMed Web of Science ®Google Scholar
• Huang A, Sun D, Kaley G, et al. Estrogen maintains nitric oxide synthesis in arterioles of female hyper-tensive rats. Hypertension 1997;29:1351–6
   PubMedGoogle Scholar
• Huang A, Sun D, Koller A, et al. Gender difference in myogenic tone of rat arterioles is due to estrogen-induced, enhanced release of NO. Am J Physiol 1997;272:H1804–9
   Google Scholar
• Smolders RGV, van der Mooren MJ, Kenemans P, et al. 17-beta estradiol induces a rapid, endothelium-dependent, sex-specific, vasodilatation in spontaneous constricted rat arterioles. Am J Obstet Gynecol 2002;187:375–81
   Google Scholar
• Han SZ, Karaki H, Ouchi Y, et al. 17-beta estradiol inhibits influx and Ca2+ release induced by thromboxane A2 in porcine coronary artery. Circulation 1995;91:2619–26
   PubMed Web of Science ®Google Scholar
• Dantas AP, Tostes RC, Fortes ZB, et al. In vivo evidence for antioxidant potential of estrogen in microvessels of female spontaneously hypertensive rats. Hypertension 2002;39:405–11
   PubMed Web of Science ®Google Scholar
• Jiang C, Poole-Wilson PA, Sarrel PM, et al. Effect of 17 beta-oestradiol on contraction, Ca2+ current and intracellular free Ca2+ in guinea-pig isolated cardiac myocytes. Br J Pharmacol 1992;106:739–45
   PubMed Web of Science ®Google Scholar
• Collins P, Beale CM, Rosano GM. Oestrogen as a calcium channel blocker. Eur Heart J 1996;17 (Suppl D):27–31
   Google Scholar
• White RE, Darkow DJ, Lang JL. Estrogen relaxes coronary arteries by opening BKCa channels through a cGMP-dependent mechanism. Circ Res 1995;77:936–42
   Google Scholar
• Wellman GC, Bonev AD, Nelson MT, et al. Gender differences in coronary artery diameter involve estrogen, nitric oxide, and Ca(2+)-dependent K+ channels. Circ Res 1996;79:1024–30
   PubMed Web of Science ®Google Scholar
• White RE, Han G, Maunz M, et al. Endothelium-independent effect of estrogen on Ca(2+)-activated K(+) channels in human coronary artery smooth muscle cells. Cardiovasc Res 2002;53:650–61
   PubMed Web of Science ®Google Scholar
• Razandi M, Pedram A, Greene GL, et al. Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells. Mol Endocrinol 1999;13:307–19
   PubMed Web of Science ®Google Scholar
• Russell KS, Haynes MP, Sinha D, et al. Human vascular endothelial cells contain membrane binding sites for estradiol, which mediate rapid intracellular signaling. Proc Natl Acad Sci USA 2000;97:5930–5
   PubMed Web of Science ®Google Scholar
• Haynes MP, Sinha D, Russell KS, et al. Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the P13-kinase-akt pathway in human endothelial cells. Circ Res 2000;87:677–82
   PubMed Web of Science ®Google Scholar
• Simoncini T, Hafezi-Moghadam A, Brazil DP, et al. Interaction of oestrogen receptor with the regula-tory subunit of phosphatidylinosito1-3-0H kinase. Nature 2000;407:538–41
   PubMed Web of Science ®Google Scholar
• Chambliss KL, Yuhanna IS, Mineo C, et al. Estrogen receptor alpha and endothelial nitric oxide synthase are organized into a functional signaling module in caveolae. Circ Res 2000;87:E44–52
   PubMed Web of Science ®Google Scholar
• Chen Z, Yuhanna IS, Galcheva-Gargova Z, et al. Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest 1999;103:401–6
   Google Scholar
• Simoncini T, Genazzani AR, Liao JK. Nongenomic mechanisms of endothelial nitric oxide synthase activation by the selective estrogen receptor modu-lator raloxifene. Circulation 2002;105:1368–73
   Google Scholar
• Weiner CP, Lizasoain I, Baylis SA, et al. Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc Natl Acad Sci USA 1994;91:5212–16
   PubMed Web of Science ®Google Scholar
• Sudhir K, Jennings GL, Funder JW, et al. Estrogen enhances basal nitric oxide release in the forearm vasculature in perimenopausal women. Hypertension 1996;28:330–4
   PubMed Web of Science ®Google Scholar
• Rubanyi GM, Freay AD, Kauser K, et al. Vascular estrogen receptors and endothelium-derived nitric oxide production in the mouse aorta. Gender differ-ence and effect of estrogen receptor gene disrup-tion. J Clin Invest 1997;99:2429–37
   Google Scholar
• Finkelstein JD. The metabolism of homocysteine: pathways and regulation. Eur J Pediatr 1998;157 (Suppl 2): S40–4
   PubMed Web of Science ®Google Scholar
• Verhoef P, Stampfer MJ, Buring JE, et al. Homo-cysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate. Am J Epidemiol 1996;143:845–59
   PubMed Web of Science ®Google Scholar
• Siri PW, VerhoefP, Kok FJ. Vitamins B6, B12, and folate: association with plasma total homocysteine and risk of coronary atherosclerosis.J Am Coll Nutr 1998;17: 435–41
   Google Scholar
• Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genet 1995;10:111–13
   PubMed Web of Science ®Google Scholar
• Kang SS, Passen EL, Ruggie N, et al. Thermolabile defect of methylenetetrahydrofolate reductase in coronary artery disease. Circulation 1993;88:1463–9
   PubMed Web of Science ®Google Scholar
• Fohr IP, Prinz-Langenohl R, Bronstrup A, et al. 5,10-Methylenetetrahydrofolate reductase geno-type determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetra-hydrofolate or folic acid in healthy young women. Am J Clin Nutr 2002;75:275–82
   PubMed Web of Science ®Google Scholar
• Carey MC, Donovan DE, FitzGerald O, et al. Homocystinuria. I. A clinical and pathological study of nine subjects in six families. Am J Med 1968;45:7–25
   Google Scholar
• McCully KS. Vascular pathology of homocysteine-mia: implications for the pathogenesis of arterio-sclerosis. Am J Pathol 1969;56:111–28
   PubMed Web of Science ®Google Scholar
• Finkelstein JD, Kyle WE, Harris BJ. Methionine metabolism in mammals: regulatory effects of S-adenosylhomocysteine. Arch Biochem Biophys 1974;165:774–9
   Google Scholar
• Finkelstein JD. Pathways and regulation of homo-cysteine metabolism in mammals. Semin Thromb Hemost 2000;26:219–25
   PubMed Web of Science ®Google Scholar
• Upchurch GR Jr, Welch GN, Fabian AJ, et al. Homo cyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem 1997;272:17012–17
   Google Scholar
• Tyagi SC, Smiley LM, Mujumdar VS. Homo-cyst(e)ine impairs endocardial endothelial function. Can J Physiol Pharmacol 1999;77:950–7
   PubMed Web of Science ®Google Scholar
• Ungvari Z, Pacher P, Rischak K, et al. Dysfunction of nitric oxide mediation in isolated rat arterioles with methionine diet-induced hyp erhomo - cysteinemia. Arteriosder Thromb Vasc Biol 1999;19: 1899–904
   PubMed Web of Science ®Google Scholar
• Ungvari Z, Koller A. Ho mocysteine reduces smooth muscle [Ca2+]i and constrictor responses of isolated arterioles. J Cardiovasc Pharmacol 2001;37:705–12
   Google Scholar
• Van Guldener C, Stehouwer CDA. Hyperhomo-cysteinemia, vascular pathology, and endothelial dysfunction. Semin Thromb Hemost 2000;26:281–9
   PubMed Web of Science ®Google Scholar
• Raghuveer G, Sinkey CA, Chenard C, et al. Effect of vitamin E on resistance vessel endothelial dysfunc-tion induced by methionine. Am J Cardiol 2001;88: 285–90
   Google Scholar
• Heinecke JW, Rosen H, Suzuki LA, et al. The role of sulfur-containing amino acids in superoxide production and modification of low density lipoprotein by arterial smooth muscle cells. J Biol Chem 1987; 262:10098–103
   PubMed Web of Science ®Google Scholar
• Elliott SJ, Koliwad SK. Redox control of ion channel activity in vascular endothelial cells by glutathione. Microcirculation 1997;4:341–7
   Web of Science ®Google Scholar
• Weiss N, Heydrick S, Zhang YY, et al. Cellular redox state and endothelial dysfunction in mildly hyperhomocysteinemic cystathionine beta-synthase-deficient mice. Arteriosder Thromb Vasc Biol 2002;22:34–41
   PubMed Web of Science ®Google Scholar
• Weiss N, Zhang YY, Heydrick S, et al. Over-expression of cellular glutathione peroxidase rescues homocyst(e)ine-induced endothelial dysfunction. Proc Natl Acad Sci USA 2001;98:12503–8
   PubMed Web of Science ®Google Scholar
• Tawakol A, Omland T, Gerhard M, et al. Hyper-homocyst(e)inemia is associated with impaired endothelium-dependent vaso dilation in humans. Circulation 1997;95:1119–21
   PubMed Web of Science ®Google Scholar
• Chambers JC, McGregor A, Jean-Marie J, et al. Acute hyperhomocysteinaemia and endothelial dysfunction. Lancet 1998;351:36–7
   Google Scholar
• Bellamy MF, McDowell IF, Ramsey MW, et al. Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. Circulation 1998;98:1848–52
   PubMed Web of Science ®Google Scholar
• Boger RH, Bode-Boger SM, Sydow K, et al. Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in monkeys with hyperhomocyst(e)inemia or hypercholesterolemia. Arterioscler Thromb Vasc Biol 2000;20:1557–64
   PubMed Web of Science ®Google Scholar
• Boger RH, Lentz SR, Bode-Boger SM, et al. Eleva-tion of asymmetrical dimethylarginine may mediate endothelial dysfunction during experimental hyperhomocyst(e)inaemia in humans. Clin Sci (Lond) 2001;100:161–7
   Google Scholar
• Stuhlinger MC, Tsao PS, Her JH, et al. Homo-cysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation 2001;104:2569–75
   PubMed Web of Science ®Google Scholar
• Boushey CJ, Beresford SA, Omenn GS. A quantita-tive assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. J Am Med Assoc 1995; 274:1049–57
   Google Scholar
• Stampfer MJ, Malinow MR, Willett WC, et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. J Am Med Assoc 1992;268:877–81
   PubMed Web of Science ®Google Scholar
• Graham IM, Daly LE, Refium HM, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Proj ect. J Am Med Assoc 1997;277:1775–81
   PubMed Web of Science ®Google Scholar
• Nygard O, Nordrehaug JE, Refium H, et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997; 337:230–6
   PubMed Web of Science ®Google Scholar
• Refium H, Ueland PM, Nygard O, et al. Homo-cysteine and cardiovascular disease. Annu Rev Med 1998;49:31–62
   Google Scholar
• Steegers-Theunissen RP, Boers GH, Trijbels FJ, et al. Maternal hyperhomocysteinemia: a risk factor for neural-tube defects? Metabolism 1994;43: 1475–80
   Google Scholar
• Steegers-Theunissen RP, Boers GH, Blom HJ, et al. Hyperhomocysteinemia and recurrent spontaneous abortion or abruptio placentae. Lancet 1992;339: 1122–3
   Google Scholar
• Nelen WL, Blom HJ, Steegers EA, et al. Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. Fertil Steril 2000; 74:1196–9
   PubMed Web of Science ®Google Scholar
• Goddijn-Wessel TA, Wouters MG, van de Molen EF, et al. Hyperhomocysteinemia: a risk factor for placental abruption or infarction. Eur J Obstet Gynecol Reprod Biol 1996;66:23–9
   Google Scholar
• De Vries JI, Dekker GA, Huijgens PC, et al. Hyper-homocysteinaemia and protein S deficiency in complicated pregnancies. Br J Obstet Gynaecol 1997; 104:1248–54
   PubMedGoogle Scholar
• Dimitrova KR, DeGroot K, Myers AK, et al. Estrogen and homocysteine. Cardiovasc Res 2002;53: 577–88
   PubMed Web of Science ®Google Scholar
• Stehouwer CDA. Heterogeneity of the association between plasma homocysteine and atherothrom-botic disease: insights from studies of vascular structure and function. Clin Chem Lab Med 2001;39:705–9
   Google Scholar
• Blundell G, Jones BG, Rose FA, et al. Homocysteine mediated endothelial cell toxicity and its ameliora-tion. Atherosclerosis 1996;122:163–72
   PubMed Web of Science ®Google Scholar
• Majors A, Ehrhart LA, Pezacka EH. Homocysteine as a risk factor for vascular disease. Enhanced collagen production and accumulation by smooth muscle cells. Arterioscler Thromb Vasc Biol 1997;17: 2074–81
   Google Scholar
• Tyagi SC. Homocysteine redox receptor and regu-lation of extracellular matrix components in vascular cells. Am J Physiol 2001;274:C396–405
   Google Scholar
• Hultberg B, Andersson A, Isaksson A. Hypo-methylation as a cause of homo cysteine-induced cell damage in human cell lines. Toxicology 2000;147: 69–75
   Google Scholar
• Harrington EO, Smeglin A, Newton J, et al. Protein tyrosine phosphatase-dependent proteolysis of focal adhesion complexes in endothelial cell apoptosis. Am J Physiol 2001;280:L342–53
   Google Scholar
• Mijatovic V, van der Mooren MJ. Homo cysteine in postmenopausal women and the importance of hormone replacement therapy. Clin Chem Lab Med 2001;39:764–7
   PubMed Web of Science ®Google Scholar
• Giltay EJ, Ho ogeveen EK, Elbers JH, et al. Effects of sex steroids on plasma total homocysteine levels — a study in transsexual males and females. J Clin Endocrinol Metab 1998;83:550–3
   PubMedGoogle Scholar
• De Bree A, Verschuren WM, Blom HJ, et al. Associ-ation between B vitamin intake and plasma homocysteine concentration in the general Dutch population aged 20-65 y. Am J Clin Nutr 2001; 73:1027–33
   PubMedGoogle Scholar
• Carmel R, Howard JM, Green R, et al. Hormone replacement therapy and cobalamin status in elderly women. Am J Clin Nutr 1996;64:856–9
   PubMedGoogle Scholar
• Steegers-Theunissen RP, Boers GH, Steegers EA, et al. Effects of sub-50 oral contraceptives on homo-cysteine metabolism: a preliminary study. Contra-ception 1992;45: 129–39
   Google Scholar
• O'Connor DL, Green T, Picciano MF. Maternal folate status and lactation. J Mammary Gland Biol Neoplasia 1997;2:279–89
   PubMed Web of Science ®Google Scholar
• Steegers-Theunissen RP, Wathen NC, Eskes TK, et al. Maternal and fetal levels of methionine and homocysteine in early human pregnancy. BrJ Obstet Gynaecol 1997;104:20–4
   Google Scholar
• Olszewski AJ, McCully KS. Homocysteine content of lipoproteins in hypercholesterolaemia. Athero-sclerosis 1991;88:61–8
   PubMed Web of Science ®Google Scholar
• Windier EE, Kovanen PT, Chao YS, et al. The estradiol-stimulated lipoprotein receptor of rat liver. A binding site that membrane mediates the uptake of rat lipoproteins containing apoproteins B and E. J Biol Chem 1980;255:10464–71
   Google Scholar
• Brown CA, McKinney KQ, Young KB, et al. The C677T methylenetetrahydrofolate reductase poly-morphism influences the homocysteine-lowering effect of hormone replacement therapy. Mol Genet Metab 1999;67:43–8
   PubMed Web of Science ®Google Scholar
• Blom HJ, van der Mooren MJ. Hyperhomo-cysteinemia: a risk factor for cardiovascular disease — influence of sex hormones on homocysteine metabolism. Gynecol Endocrinol 1996;10:75–9
   PubMed Web of Science ®Google Scholar
• Boers GH, Smals AG, Trijbels FJ, et al. Unique effi-ciency of methionine metabolism in premenopausal women may protect against vascular disease in the reproductive years. J Clin Invest 1983;72:1971–6
   PubMedGoogle Scholar
• Wouters MG, Moorrees MT, van der Mooren MJ, et al. Plasma homocysteine and menopausal status. Eur J Clin Invest 1995;25:801–5
   PubMed Web of Science ®Google Scholar
• Hak AE, Polderman KH, Westendorp IC, et al. Increased plasma homocysteine after menopause. Atherosclerosis 2000;149:163–8
   PubMed Web of Science ®Google Scholar
• Van der Mooren MJ, Wouters MG, Blom HJ, et al. Hormone replacement therapy may reduce high serum homocysteine in postmenopausal women. Eur J Clin Invest 1994;24:733–6
   PubMed Web of Science ®Google Scholar
• Van der Mooren MJ, Demacker PN, Blom HJ, et al. The effect of sequential three-monthly hormone replacement therapy on several cardiovascular risk estimators in postmenopausal women. Fertil Steril 1997;67:67–73
   PubMed Web of Science ®Google Scholar
• Mijatovic V, Kenemans P, Netelenbos C, et al. Postmenopausal oral 17beta-estradiol continuously combined with dydrogesterone reduces fasting serum homocysteine levels. Fertil Steril 1998;69: 876–82
   PubMed Web of Science ®Google Scholar
• Mijatovic V, Kenemans P, Jakobs C, et al. A randomized controlled study of the effects of 17beta-estradiol—dydrogesterone on plasma homo-cysteine in postmenopausal women. Obstet Gynecol 1998;91:432–6
   PubMed Web of Science ®Google Scholar
• Mijatovic V, Netelenbos C, van der Mooren MJ, et al. Randomized, double-blind, placebo-controlled study of the effects of raloxifene and conjugated equine estrogen on plasma homo-cysteine levels in healthy postmenopausal women. Fertil Steril 1998;70:1085–9
   Google Scholar
• Van Baal WM, Smolders RGV, van der Mooren MJ, et al. Hormone replacement therapy and plasma homocysteine levels. Obstet Gynecol1999;94:485–91
   PubMed Web of Science ®Google Scholar
• Barnabei VM, Phillips TM Hsia J. Plasma homo-cysteine in women taking hormone replacement therapy: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. J Womens Health Gend Based Med 1999;8:1167–72
   PubMedGoogle Scholar
• Walsh BW, Paul S, Wild RA, et al. The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women; a randomized, controlled trial. J Clin Endocrinol Metab 2000;85:214–18
   PubMed Web of Science ®Google Scholar
• Ventura P, Cagnacci A, Malmusi S, et al. Con-tinuous combined hormone replacement therapy with oral 17 beta-estradiol and norethisterone ace-tate improves homocysteine metabolism in postmenopausal women. Menopause 2001;8:252–8
   PubMed Web of Science ®Google Scholar
• Hak AE, Bak AA, Lindemans J, et al. The effect of hormone replacement therapy on serum homo-cysteine levels in perimenopausal women: a randomized controlled trial. Atherosclerosis 2001;158: 437–43
   PubMed Web of Science ®Google Scholar
• Somekawa Y, Kobayashi K, Tomura S, et al. Effects of hormone replacement therapy and methylene-tetrahydrofolate reductase polymorphism on plasma folate and homocysteine levels in postmenopausal Japanese women. Fertil Steril 2002;77:481–6
   PubMed Web of Science ®Google Scholar
• Yildirir A, Aybar F, Tokgozoglu L, et al. Effects of hormone replacement therapy on plasma homocysteine and C-reactive protein levels. Gynecol Obstet Invest 2002;53:54–8
   PubMed Web of Science ®Google Scholar
• Smolders RGV, Vogelvang TE, Mijatovic V, et al. A 2-year, randomized, comparative, placebo-controlled study on the effects of raloxifene on lipoprotein(a) and homocysteine. Maturitas 2002; 41:105–14
   PubMed Web of Science ®Google Scholar
• Bush TL, Barrett-Connor E, Cowan LD, et al. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation 1987;75:1102–9
   PubMed Web of Science ®Google Scholar
• Grodstein F, Stampfer MJ, Manson JE, et al. Post-menopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996; 335:453–61
   PubMed Web of Science ®Google Scholar
• Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other considerations. Annu Rev Public Health 1998;19:55–72
   PubMed Web of Science ®Google Scholar
• Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. J Am Med Assoc 1998;279:359–64
   PubMed Web of Science ®Google Scholar
• Peterson JC, Spence JD. Vitamins and progression of atherosclerosis in hyperhomocyst(e)inaemia. Lancet 1998;351:263
   PubMed Web of Science ®Google Scholar
• Vermeulen EG, Stehouwer CDA, Twisk JW, et al. Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of sub-clinical atherosclerosis: a randomised, placebo-controlled trial. Lancet 2000;355:517–22
   PubMed Web of Science ®Google Scholar
• Thakur MK, Kanungo MS. Methylation of chromosomal proteins and DNA of rat brain and its modulation by estradiol and calcium during aging. Exp Gerontol 1981;16:331–6
   Google Scholar
• Wilks AF, Cozens PJ, Mattaj IW, et al. Estrogen induces a demethylation at the 5' end region of the chicken vitellogenin gene. Proc Natl Acad Sci USA 1982;79:4252–5
   PubMed Web of Science ®Google Scholar
• Wilks A, Seldran M, Jost JP. An estrogen-dependent demethylation at the 5' end of the chicken vitellogenin gene is independent of DNA synthesis. Nucleic Acids Res 1984;12: 1163–77
   Google Scholar
• Lu 14, Liehr JG, Sirbasku DA, et al. Hypo-methylation of DNA in estrogen-induced and -dependent hamster kidney tumors. Carcinogenesis 1988;9:925–9
   Google Scholar
• Thakur MK, Kaur J. Methylation of DNA and its modulation by estrogen in the uterus of aging rats. Cell Mol Biol 1992;38:525–32
   Google Scholar
• Li S, Washburn KA, Moore R, et al. Develop-mental exposure to diethylstilbestrol elicits demethylation of estrogen-responsive lactoferrin gene in mouse uterus. Cancer Res 1997;57:4356–9
   PubMed Web of Science ®Google Scholar
• Lyons AS, Petrucelli RJ. Hippocrates. In Medicine: an Illustrated History. New York: Abradale Press, 1990:207–19
   Google Scholar
• Evio S, Tiitinen A, Turpeinen U, et al. Failure of the combination of sequential oral and transdermal estradiol plus norethisterone acetate to affect plasma homocysteine levels. Fertil Steril 2000; 74:1080–3
   PubMed Web of Science ®Google Scholar