• Toshio HayashiEmail author


In all age groups from childhood to old age, women have a longer average life expectancy than men, suggesting that sex (specifically, sex hormones) is closely related to geriatric diseases and aging. Disease structure changes as people age, with cardiovascular disease increasing dramatically in late elderly (older than 75 years of age) females and arteriosclerotic diseases surpassing malignancies as the leading cause of death. After menopause, however, this number increases dramatically, thus reducing the gender gap. The prevalence of cardiovascular disease in women aged 75 years or older is thus equal to that of men of the same age. As this age group has a greater population of females than males, women account for a greater number of cardiovascular disease cases. We will discuss recent knowledge, including the gender differences apparent in risk factors such as dyslipidemia and hypertension. Cardiovascular disease is a typical geriatric disease, and pathological aging contributes to estrogen action and sex differences in atherosclerosis.

Women have a longer average life expectancy than men, and sex hormones, especially estrogen, is closely related to geriatric diseases and aging. Disease structure changes as people age, with cardiovascular disease increasing dramatically in late elderly females and arteriosclerotic diseases surpassing malignancies as the leading cause of death. Although hormone replacement therapy for all postmenopausal women as one same dose of agents failed to prevent cardiovascular disease in elderly female, recent advance of basic and clinical gender-specific medical research made clear the molecular mechanism on the gender differences in cardiovascular diseases and coronary risk factors such as dyslipidemia. Cardiovascular disease is a typical geriatric disease, and pathological aging contributes to estrogen action and sex differences in atherosclerosis, which form the main etiology of cardiovascular disease. These gender-dependent differences in risk are important for an individualized strategy to prevent atherosclerotic disease.


Estrogen Nitric oxide Selective estrogen receptor modulators (SERM) Gender-based medicine Hormone replacement therapy 


  1. Aronow WS (2002) Pharmacologic therapy of lipid disorders in the elderly. Am J Geriatr Cardiol 11:247–256PubMedCrossRefGoogle Scholar
  2. Battaglioli T, Martinelli I (2007) Hormone therapy and thromboembolic disease. Curr Opin Hematol 14:488–493PubMedGoogle Scholar
  3. Besdine RW, Wetle TF (2010) Improving health for elderly people: an international health promotion and disease prevention agenda. Aging Clin Exp Res 22:219–230PubMedGoogle Scholar
  4. Brinton EA (1996) Oral estrogen replacement therapy in postmenopausal women selectively raises levels and production rates of lipoprotein A-I and lowers hepatic lipase activity without lowering the fractional catabolic rate. Arterioscler Thromb Vasc Biol 16:431–440PubMedCrossRefGoogle Scholar
  5. Brown MS, Kovanen PT, Goldstein JL (1980) Evolution of the LDL receptor concept-from cultured cells to intact animals. Ann N Y Acad Sci 348:48–68PubMedCrossRefGoogle Scholar
  6. Castelli WP, Anderson K, Wilson PW, Levy D (1992) Lipids and risk of coronary heart disease. The Framingham Study. Ann Epidemiol 2(1–2):23–8PubMedCrossRefGoogle Scholar
  7. Dao HH, Essalihi R, Bouvet C, Moreau P (2005) Evolution and modulation of age-related medial elastocalcinosis: impact on large artery stiffness and isolated systolic hypertension. Cardiovasc Res 66:307–317PubMedCrossRefGoogle Scholar
  8. Engberding N, Wenger NK (2008) Cardiovascular disease prevention tailored for women. Expert Rev Cardiovasc Ther 6:1123–1134PubMedCrossRefGoogle Scholar
  9. Esaki T, Hayashi T, Muto E, Yamada K, Kuzuya M, Iguchi A (1997) Expression of inducible nitric oxide synthase in T lymphocytes and macrophages of cholesterol-fed rabbits. Atherosclerosis 128:39–46PubMedCrossRefGoogle Scholar
  10. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, Glüer CC, Krueger K, Cohen FJ, Eckert S, Ensrud KE, Avioli LV, Lips P, Cummings SR (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 282:637–646PubMedCrossRefGoogle Scholar
  11. Flavahan NA (1992) Atherosclerosis or lipoprotein-induced endothelial dysfunction. Potential mechanisms underlying reduction in EDRF/nitric oxide activity. Circulation 85:1927–1938PubMedCrossRefGoogle Scholar
  12. Goldstein JL, Brown MS (1982) Lipoprotein receptors: genetic defense against atherosclerosis. Clin Res 30:417–426Google Scholar
  13. Gregory NC, Ilan B, Osaki Y, Geoffrey FW (2011) The impact of menthol cigarettes on smoking initiation among non-smoking young females in Japan. Int J Environ Res Public Health 8:1–14Google Scholar
  14. Grodstein F, Manson JE, Stampfer MJ (2001) Postmenopausal hormone use and secondary prevention of coronary events in the nurses’ health study. A prospective, observational study. Ann Intern Med 135:1–8PubMedCrossRefGoogle Scholar
  15. Grundy SM, Balady GJ, Criqui MH, Fletcher G, Greenland P, Hiratzka LF, Houston-Miller N, Kris-Etherton P, Krumholz HM, LaRosa J, Ockene IS, Pearson TA, Reed J, Washington R, Smith SC Jr (1997) Guide to primary prevention of cardiovascular diseases. A statement for healthcare professionals from the Task Force on Risk Reduction. American Heart Association Science Advisory and Coordinating Committee. Circulation 95:2329–2331PubMedCrossRefGoogle Scholar
  16. Guideline for Diagnosis and Prevention of Atherosclerotic Cardiovascular Diseases (2007) Edition. Available at
  17. Hashimoto M, Akishita M, Eto M, Ishikawa M, Kozaki K, Toba K, Sagara Y, Taketani Y, Orimo H, Ouchi Y (1995) Modulation of endothelium-dependent flow-mediated dilatation of the brachial artery by sex and menstrual cycle. Circulation 92(12):3431–3435PubMedCrossRefGoogle Scholar
  18. Hayashi T, Naito M, Ishikawa T, Kuzuya M, Funaki C, Tateishi T, Asai K, Hidaka H, Kuzuya F (1989) Beta-migrating very low density lipoprotein attenuates endothelium-dependent relaxation in rabbit atherosclerotic aortas. Blood Vessels 26:290–299PubMedGoogle Scholar
  19. Hayashi T, Ignarro LJ, Chaudhuri G (1992) Basal release of nitric oxide from aortic rings is greater in female rabbits than in male rabbits: implications for atherosclerosis. Proc Natl Acad Sci USA 89:1125–1163Google Scholar
  20. Hayashi T, Yamada K, Esaki T, Kuzuya M, Satake S, Ishikawa T, Hidaka H, Iguchi A (1995a) Estrogen increases endothelial nitric oxide by a receptor-mediated system. Biochem Biophys Res Commun 213:915–919CrossRefGoogle Scholar
  21. Hayashi T, Fukuto JM, Ignarro LJ, Chaudhuri G (1995b) Gender differences in atherosclerosis: possible role of nitric oxide. J Cardiovasc Pharmacol 26:792–802PubMedCrossRefGoogle Scholar
  22. Hayashi T, Yamada K, Esaki T, Muto E, Chaudhuri G, Iguchi A (1998) Physiological concentrations of 17 beta-estradiol inhibit the synthesis of nitric oxide synthase in macrophages via a receptor-mediated system. J Cardiovasc Pharmacol 31:292–298PubMedCrossRefGoogle Scholar
  23. Hayashi T, Jayachandran M, Sumi D, Thakur NK, Esaki T, Muto E, Kano H, Asai Y, Iguchi A (2000a) Physiological concentration of 17 b estradiol retards the progression of severe atherosclerosis induced by cholesterol diet plus balloon injury via NO. Arterioscler Thromb Vasc Biol 20:1613–1621PubMedCrossRefGoogle Scholar
  24. Hayashi T, Esaki T, Muto E, Kano H, Asai Y, Thakur NK, Sumi D, Jayachandran M, Iguchi A (2000b) Dehydroepiandrosterone retards atherosclerosis formation through the conversion to estrogen: the possible role of nitric oxide. Arterioscler Thromb Vasc Biol 20:782–792PubMedCrossRefGoogle Scholar
  25. Hayashi T, Ito I, Kano H, Endo H, Iguchi A (2000c) Estriol (E3) replacement improves endothelial function and bone mineral density in very elderly women. J Gerontol A Biol Sci Med Sci 55:B183–B190PubMedCrossRefGoogle Scholar
  26. Hayashi T, Matsui-Hirai H, Miyazaki-Akita A, Fukatsu A, Funami J, Ding QF, Kamalanathan S, Hattori Y, Ignarro LJ, Iguchi A (2006a) Endothelial cellular senescence is inhibited by nitric oxide: implications in atherosclerosis associated with menopause and diabetes. Proc Natl Acad Sci USA 103:17018–17023PubMedCrossRefGoogle Scholar
  27. Hayashi T, Esaki T, Sumi D, Mukherjee T, Iguchi A, Chaudhuri G (2006b) Modulating role of estradiol on arginase II expression in hyperlipidemic rabbits as an atheroprotective mechanism. Proc Natl Acad Sci USA 103:10485–10490PubMedCrossRefGoogle Scholar
  28. Hayashi T, Kawashima S, Itoh H, Yamada N, Sone H, Watanabe H, Hattori Y, Ohrui T, Yoshizumi M, Yokote K, Kubota K, Nomura H, Umegaki H, Iguchi A, Japan CDM group (2008) Importance of lipid levels in elderly diabetic individuals: baseline characteristics and 1-year survey of cardiovascular events. Circ J 72:218–25PubMedCrossRefGoogle Scholar
  29. Hayashi T, Kawashima S, Itoh H, Yamada N, Sone H, Watanabe H, Hattori Y, Ohrui T, Yokote K, Nomura H, Umegaki H, Iguchi A, Japan CDM Group (2009) Low HDL cholesterol is associated with the risk of stroke in elderly diabetic individuals: changes in the risk for atherosclerotic diseases at various ages. Diabetes Care 32:1221–3PubMedCrossRefGoogle Scholar
  30. Hayashi T, Kawashima S, Nomura H, Itoh H, Watanabe H, Ohrui T, Yokote K, Sone H, Hattori Y, Yoshizumi M, Ina K, Kubota K, Japan Cholesterol and Diabetes Mellitus Investigation Group (2011) Age, gender, insulin and blood glucose control status alter the risk of ischemic heart disease and stroke among elderly diabetic patients. Cardiovasc Diabetol 10:86–91PubMedCrossRefGoogle Scholar
  31. Hayashi T, Araki A, Kawashima S, Sone H, Watanabe H, Ohrui T, Yokote K, Takemoto M, Kubota K, Noda M, Noto H, Ina K, Nomura H (2013) Metabolic predictors of ischemic heart disease and cerebrovascular attack in elderly diabetic individuals: difference in risk by age. Cardiovasc Diabetol 12:10–16PubMedCrossRefGoogle Scholar
  32. Haynes MP, Sinha D, Russell KS, Collinge M, Fulton D, Morales-Ruiz M, Sessa WC, Bender JR (2000) Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3-kinase-Akt pathway in human endothelial cells. Circ Res 87:677–682PubMedCrossRefGoogle Scholar
  33. Heart Protection Study Collaborative Group (2002) MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360(9326):7–22CrossRefGoogle Scholar
  34. Hinson JP, Brooke A, Raven PW (2003) Therapeutic uses of dehydroepiandrosterone. Curr Opin Investig Drugs 4:1205–1208PubMedGoogle Scholar
  35. Hisamoto K, Ohmichi M, Kurachi H, Hayakawa J, Kanda Y, Nishio Y, Adachi K, Tasaka K, Miyoshi E, Fujiwara N, Taniguchi N, Murata Y (2001) Estrogen induces the Akt-dependent activation of endothelial nitric-oxide synthase in vascular endothelial cells. J Biol Chem 276:3459–3467PubMedCrossRefGoogle Scholar
  36. Hlatky MA, Boothroyd D, HERS Research Group (2002) Quality of life and depressive symptoms in postmenopausal women after receiving hormone therapy: results from the Heart and Estrogen/Progestin Replacement Study (HERS) trial. JAMA 287:591–597PubMedCrossRefGoogle Scholar
  37. Holm P, Andersen HL, Andersen MR, Erhardtsen E, Stender S (1999) The direct antiatherogenic effect of estrogen is present, absent, or reversed, depending on the state of the arterial endothelium. A time course study in cholesterol-clamped rabbits. Circulation 100:1727–1733PubMedCrossRefGoogle Scholar
  38. Imazu M, Sumii K, Yamamoto H, Toyofuku M, Tadehara F, Okubo M, Yamakido M, Kohno N, Onaka AT, Hawaii-Los Angeles-Hiroshima Study (2002) Influence of type 2 diabetes mellitus on cardiovascular disease mortality: findings from the Hawaii-Los Angeles-Hiroshima study. Diabetes Res Clin Pract 57:61–9PubMedCrossRefGoogle Scholar
  39. Kuzuya M, Shimokata H (2002) Changes in serum lipid levels during a 10 year period in a large Japanese population. A cross-sectional and longitudinal study. Atherosclerosis 163:313–320PubMedCrossRefGoogle Scholar
  40. Manson JE, Allison MA, Rossouw JE, Carr JJ, Langer RD, Hsia J, Kuller LH, Cochrane BB, Hunt JR, Ludlam SE, Pettinger MB, Gass M, Margolis KL, Nathan L, Ockene JK, Prentice RL, Robbins J, Stefanick ML, WHI and WHI-CACS Investigators (2007) Estrogen therapy and coronary-artery calcification. N Engl J Med 356:2591–2602PubMedCrossRefGoogle Scholar
  41. Miyazaki-Akita A, Hayashi T, Ding QF, Shiraishi H, Nomura T, Hattori Y, Iguchi A (2007) 17beta-estradiol antagonizes the down-regulation of endothelial nitric-oxide synthase and GTP ­cyclohydrolase I by high glucose: relevance to postmenopausal diabetic cardiovascular disease. J Pharmacol Exp Ther 320:591–598PubMedCrossRefGoogle Scholar
  42. Mizuno K, Nakaya N, Ohashi Y, Tajima N, Kushiro T, Teramoto T, Uchiyama S, Nakamura H, MEGA Study Group (2008) Usefulness of pravastatin in primary prevention of cardiovascular events in women: analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA study). Circulation 117:494–502PubMedCrossRefGoogle Scholar
  43. Mosselman S, Polman J, Dijkema R (1996) ERβ: identification and characterization of a novel human estrogen receptor. FEBS Lett 392:49–55PubMedCrossRefGoogle Scholar
  44. Muramatsu N, Akiyama H (2011) Japan: super-aging society preparing for the future. Gerontologist 51:425–432PubMedCrossRefGoogle Scholar
  45. Nakao J, Chang WC, Murota SI, Orimo H (1991) Estradiol-binding sites in rat aortic smooth muscle cells in culture. Atherosclerosis 38:75–80CrossRefGoogle Scholar
  46. Nawate S, Fukao M, Sakuma I, Soma T, Nagai K, Takikawa O, Miwa S, Kitabatake A (2005) Reciprocal changes in endothelium-derived hyperpolarizing factor- and nitric oxide-system in the mesenteric artery of adult female rats following ovariectomy. Br J Pharmacol 144:178–189PubMedCrossRefGoogle Scholar
  47. Oosterveer DM, Versmissen J, Yazdanpanah M, Hamza TH, Sijbrands EJ (2009) Differences in characteristics and risk of cardiovascular disease in familial hypercholesterolemia patients with and without tendon xanthomas: a systematic review and meta-analysis. Atherosclerosis 207:311–317PubMedCrossRefGoogle Scholar
  48. Ridker PM, Miletich JP, Hennekens CH, Buring J (1997) Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. JAMA 277:1305–1307PubMedCrossRefGoogle Scholar
  49. Roy S (1999) Effects of smoking on prostacyclin formation and platelet aggregation in users of oral contraceptives. Am J Obstet Gynecol 180:S364–S368PubMedCrossRefGoogle Scholar
  50. Sakuma I, Liu MY, Sato A, Hayashi T, Iguchi A, Kitabatake A, Hattori Y (2002) Endothelium-dependent hyperpolarization and relaxation in mesenteric arteries of middle-aged rats: influence of oestrogen. Br J Pharmacol 135:48–54PubMedCrossRefGoogle Scholar
  51. Sekimoto H, Goto Y, Goto Y, Naito C, Yasugi T, Okido M, Kuzuya F, Takeda R, Yamamoto A, Fukuzaki H et al (1983) Changes of serum total cholesterol and triglyceride levels in normal subjects in Japan in the past twenty years. Research committee on familial hyperlipidemia in Japan. Jpn Circ J 47:1351–1358PubMedCrossRefGoogle Scholar
  52. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J, ASCOT Investigators (2003) Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 361:1149–1158PubMedCrossRefGoogle Scholar
  53. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp RG, PROSPER Study Group (2002) PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER). Lancet 360:1623–1630PubMedCrossRefGoogle Scholar
  54. Shulman LP (2011) The state of hormonal contraception today: benefits and risks of hormonal contraceptives: combined estrogen and progestin contraceptives. Am J Obstet Gynecol 205:S9–S13PubMedCrossRefGoogle Scholar
  55. Simoncini T, Varone G, Fornari L, Mannella P, Luisi M, Labrie F, Genazzani AR (2002) Genomic and nongenomic mechanisms of nitric oxide synthesis induction in human endothelial cells by a fourth-generation selective estrogen receptor modulator. Endocrinology 143:2052–2206PubMedCrossRefGoogle Scholar
  56. Su W, Campos H, Judge H, Walsh BW, Sacks FM (1998) Metabolism of Apo(a) and ApoB100 of lipoprotein(a) in women: effect of postmenopausal estrogen replacement. J Clin Endocrinol Metab 83:3267–3276PubMedCrossRefGoogle Scholar
  57. Sumi D, Hayashi T, Jayachandran M, Iguchi A (2001) Estrogen prevents destabilization of endothelial nitric oxide synthase mRNA induced by tumor necrosis factor alpha through estrogen receptor mediated system. Life Sci 69:1651–1660PubMedCrossRefGoogle Scholar
  58. Taddei S (2009) Blood pressure through aging and menopause. Climacteric 12(Suppl 1):36–40PubMedCrossRefGoogle Scholar
  59. The Lipid Research Clinics Program Epidemiology Committee (1979) Plasma lipid distributions in selected North American populations: the Lipid Research Clinics Program Prevalence Study. Circulation 60:427–434CrossRefGoogle Scholar
  60. Tse J, Martin-McNaulty B, Halks-Miller M, Kauser K, DelVecchio V, Vergona R, Sullivan ME, Rubanyi GM (1999) Accelerated atherosclerosis and premature calcified cartilaginous metaplasia in the aorta of diabetic male Apo E knockout mice can be prevented by chronic treatment with 17 beta-estradiol. Atherosclerosis 144:303–313PubMedCrossRefGoogle Scholar
  61. Watanabe T, Miyahara Y, Akishita M, Nakaoka T, Yamashita N, Iijima K, Kim H, Kozaki K, Ouchi Y (2004) Inhibitory effect of low-dose estrogen on neointimal formation after balloon injury of rat carotid artery. Eur J Pharmacol 502:265–270PubMedCrossRefGoogle Scholar
  62. Wenger NK, Barrett-Connor E, Collins P, Grady D, Kornitzer M, Mosca L, Sashegyi A, Baygani SK, Anderson PW, Moscarelli E (2002) Baseline characteristics of participants in the Raloxifene Use for The Heart (RUTH) trial. Am J Cardiol 90:1204–1210PubMedCrossRefGoogle Scholar
  63. Writing Group for the Women’s Health Initiative Investigators (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s health Initiative randomized controlled trial. JAMA 288:321–333CrossRefGoogle Scholar
  64. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K, Japan EPA lipid intervention study (JELIS) Investigators (2007) Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 369(9567):1090–8PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2013

Authors and Affiliations

  1. 1.Department of GeriatricsNagoya University Graduate School of MedicineNagoyaJapan

Personalised recommendations