Advertisement

Treatments in Endocrinology

, Volume 5, Issue 1, pp 37–51 | Cite as

Effects of Transdermal Estrogen Replacement Therapy on Cardiovascular Risk Factors

Review Article

Abstract

The prevalence of hypertension and cardiovascular disease increases dramatically after menopause in women, implicating estrogen as having a protective role in the cardiovascular system. However, recent large clinical trials have failed to show cardiovascular benefit, and have even demonstrated possible harmful effects, of opposed and unopposed estrogen in postmenopausal women. While these findings have led to a revision of guidelines such that they discourage the use of estrogen for primary or secondary prevention of heart disease in postmenopausal women, many investigators have attributed the negative results in clinical trials to several flaws in study design, including the older age of study participants and the initiation of estrogen late after menopause.

Because almost all clinical trials use oral estrogen as the primary form of hormone supplementation, another question that has arisen is the importance of the route of estrogen administration with regards to the cardiovascular outcomes. During oral estrogen administration, the concentration of estradiol in the liver sinusoids is four to five times higher than that in the systemic circulation. This supraphysiologic concentration of estrogen in the liver can modulate the expression of many hepatic-derived proteins, which are not observed in premenopausal women. In contrast, transdermal estrogen delivers the hormone directly into the systemic circulation and, thus, avoids the first-pass hepatic effect.

Although oral estrogen exerts a more favorable influence than transdermal estrogen on traditional cardiovascular risk factors such as high- and low-density lipoprotein-cholesterol levels, recent studies have indicated that oral estrogen adversely influences many emerging risk factors in ways that are not seen with transdermal estrogen. Oral estrogen significantly increases levels of acute-phase proteins such as C-reactive protein and serum amyloid A; procoagulant factors such as prothrombin fragments 1+2; and several key enzymes involved in plaque disruption, while transdermal estrogen does not have these adverse effects.

Whether the advantages of transdermal estrogen with regards to these risk factors will translate into improved clinical outcomes remains to be determined. Two ongoing clinical trials, KEEPS (Kronos Early Estrogen Prevention Study) and ELITE (Early versus Late Intervention Trial with Estradiol) are likely to provide invaluable information regarding the role of oral versus transdermal estrogen in younger postmenopausal women.

Keywords

Estrogen Postmenopausal Woman Medroxyprogesterone Oral Estrogen Estrogen Administration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Vina J, Borras C, Gambini J, et al. Why females live longer than males? Importance of the upregulation of longevity-associated genes by oestrogenic compounds. FEBS Lett 2005; 579(12): 2541–5PubMedCrossRefGoogle Scholar
  2. 2.
    American Heart Association. Heart disease and stroke statistics: 2005 update. Dallas (TX): American Heart Association, 2005Google Scholar
  3. 3.
    The Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004; 291: 1701–12CrossRefGoogle Scholar
  4. 4.
    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: 321–33CrossRefGoogle Scholar
  5. 5.
    Mendelsohn ME, Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science 2005; 308(5728): 1583–7PubMedCrossRefGoogle Scholar
  6. 6.
    Clarkson TB, Appt SE. Controversies about HRT: lessons from monkey models. Maturitas 2005; 51(1): 64–74PubMedCrossRefGoogle Scholar
  7. 7.
    Kuhl H. Pharmacokinetics of oestrogens and progestogens. Maturitas 1990; 12(3): 171–97PubMedCrossRefGoogle Scholar
  8. 8.
    Sacks F, Walsh B. Sex hormones and lipoprotein metabolism. Curr Opin Lipidol 1994; 5: 236–40PubMedCrossRefGoogle Scholar
  9. 9.
    Acs N, Vajo Z, Miklos Z, et al. The effects of postmenopausal women replacement therapy on hemostatic variables: a meta-analysis of 46 studies. Gynecol Endocrinol 2002; 16: 335–46PubMedGoogle Scholar
  10. 10.
    Srivastava RAK, Baumann D, Schonfield G. In vivo regulation of low-density lipoprotein receptors by estrogen differs at the post-transcriptional level in rats and mouse. Eur J Biochem 1993; 216: 527–38PubMedCrossRefGoogle Scholar
  11. 11.
    Wakatsuki A, Okatani Y, Ikenoue N, et al. 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: 1771–6PubMedCrossRefGoogle Scholar
  12. 12.
    Hermenegildo C, Garcia-Martinez MC, Valldecabres C, et al. Transdermal estradiol reduces plasma myeloperoxidase levels without affecting the LDL resistance to oxidation or the LDL particle size. Menopause 2002; 9(2): 102–9PubMedCrossRefGoogle Scholar
  13. 13.
    Kawano H, Yasue H, Hirai N, et al. Effects of transdermal and oral estrogen supplementation on endothelial function, inflammation and cellular redox state. Int J Clin Pharmacol Ther 2003; 41(8): 346–53PubMedGoogle Scholar
  14. 14.
    Tikkanen MJ, Nikkila EA, Kuusi T, et al. High-density lipoprotein-2 and hepatic lipase: reciprocal changes produced by estrogen and norgestrel. J Clin Endocrinol Metab 1982; 54: 1113–7PubMedCrossRefGoogle Scholar
  15. 15.
    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: 898–915PubMedCrossRefGoogle Scholar
  16. 16.
    Hemelaar M, van der Mooren MJ, Mijatovic V, et al. Oral, more than transdermal, estrogen therapy improves lipids and lipoprotein (a) in postmenopausal women: a randomized, placebo-controlled study. Menopause 2003; 10(6): 550–8PubMedCrossRefGoogle Scholar
  17. 17.
    Abbas A, Fadel PJ, Wang Z, et al. Contrasting effects of oral versus transdermal estrogen on serum amyloid A (SAA) and high-density lipoprotein: SAA in postmenopausal women. Arterioscler Thromb Vasc Biol 2004; 24: e164–7PubMedCrossRefGoogle Scholar
  18. 18.
    Nanda S, Gupta N, Mehta HC, et al. Effect of oestrogen replacement therapy on serum lipid profile. Aust N Z J Obstet Gynaecol 2003; 43(3): 213–6PubMedCrossRefGoogle Scholar
  19. 19.
    Vihma V, Vehkavaara S, Yki-Jarvinen H, et al. Differential effects of oral and transdermal estradiol treatment on circulating estradiol fatty acid ester concentrations in postmenopausal women. J Clin Endocrinol Metab 2003; 88(2): 588–93PubMedCrossRefGoogle Scholar
  20. 20.
    Lasco A, Alvaro S, Frisina N, et al. Long-term transdermal estrogen therapy improves lipid profile but not insulin resistance in healthy postmenopausal women. Diabetes Care 2000; 23(3): 422–4PubMedCrossRefGoogle Scholar
  21. 21.
    Balci H, Altunyurt S, Acar B, et al. Effects of transdermal estrogen replacement therapy on plasma levels of nitric oxide and plasma lipids in postmenopausal women. Maturitas 2005; 50(4): 289–93PubMedCrossRefGoogle Scholar
  22. 22.
    Schindler AE, Campagnoli C, Druckmann R, et al. Classification and pharmacology of progestins. Maturitas 2003; 46 Suppl. 1: S7–16CrossRefGoogle Scholar
  23. 23.
    Kumar N, Koide SS, Tsong YY, et al. Nesterone: a progestin with a unique pharmacological profile. Steroids 2000; 65: 629–36PubMedCrossRefGoogle Scholar
  24. 24.
    Kwok S, Selby PL, McElduff P, et al. Progestogens of varying androgenicity and cardiovascular risk factors in postmenopausal women receiving oestrogen replacement therapy. Clin Endocrinol (Oxf) 2004; 61(6): 760–7CrossRefGoogle Scholar
  25. 25.
    Nugent AG, Leung KC, Sullivan D, et al. Modulation by progestogens of the effects of oestrogen on hepatic endocrine function in postmenopausal women. Clin Endocrinol (Oxf) 2003; 59(6): 690–8CrossRefGoogle Scholar
  26. 26.
    Sitruk-Ware R. Progestins in hormonal replacement therapy and cardiovascular risk. In: Sitruk-Ware R, Mishell Jr DR, editors. Progestins and antiprogestins in clinical practice. New York: Marcel Dekker Inc., 2000: 289–304Google Scholar
  27. 27.
    White WB, Pitt B, Preston RA, et al. Antihypertensive effects of drospirenone with 17beta-estradiol, a novel hormone treatment in postmenopausal women with stage 1 hypertension. Circulation 2005; 112(13): 1979–84PubMedCrossRefGoogle Scholar
  28. 28.
    Wolfe BM, Huff MW. Effects of combined estrogen and progestins administration on plasma lipoprotein metabolism in postmenopausal women. J Clin Invest 1989; 83: 40–5PubMedCrossRefGoogle Scholar
  29. 29.
    Wolfe BM, Grace DM. Norethindrone acetate inhibition of splanchnic triglyceride secretion in conscious glucose-fed swine. J Lipid Res 1979; 20: 175–82PubMedGoogle Scholar
  30. 30.
    Ehnholm C, Huttunen JK, Kinnunen PJ, et al. Effect of oxandrolone treatment on the activity of lipoprotein lipase, hepatic lipase and phospholipase A1 of human postheparin plasma. N Engl J Med 1975; 292(25): 1314–7PubMedCrossRefGoogle Scholar
  31. 31.
    Graff-Iversen S, Stensvold I, Lund-Larsen PG, et al. Serum lipids in postmenopausal or perimenopausal women using estrogen alone, estrogen with levonorgestrel, or estrogen with norethisterone, compared with nonusers: results from a cross-sectional study in two Norwegian counties 1985–1988. J Clin Epidemiol 1998; 51(12): 1311–6PubMedCrossRefGoogle Scholar
  32. 32.
    Hirvonen E, Malkonen M, Manninen V. Effects or different progestogens on lipoproteins during postmenopausal replacement therapy. N Engl J Med 1981; 304: 560–3PubMedCrossRefGoogle Scholar
  33. 33.
    The Writing Group of the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995; 273: 199–208CrossRefGoogle Scholar
  34. 34.
    Campagnoli C, Colombo P, De Aloysio D, et al. Positive effects on cardiovascular and breast metabolic markers of oral estradiol and dydrogesterone in comparison with transdermal estradiol and norethisterone acetate. Maturitas 2002; 41(4): 299–311PubMedCrossRefGoogle Scholar
  35. 35.
    Sendag F, Karadadas N, Ozsener S, et al. Effects of sequential combined transdermal and oral hormone replacement therapies on serum lipid and lipoproteins in postmenopausal women. Arch Gynecol Obstet 2002; 266(1): 38–43PubMedCrossRefGoogle Scholar
  36. 36.
    Stevenson JC, Oladipo A, Manassiev N, et al. Randomized trial of effect of transdermal continuous combined hormone replacement therapy on cardiovascular risk markers. Br J Haematol 2004; 124: 802–8PubMedCrossRefGoogle Scholar
  37. 37.
    Brynhildsen J, Hammar M. Lipids and clotting factors during low dose transdermal estradiol/norethisterone use. Maturitas 2005; 50(4): 344–52PubMedCrossRefGoogle Scholar
  38. 38.
    Melo NR, Latrilha MC, Santos RD, et al. Effects in post-menopausal women of transdermal estrogen associated with progestin upon the removal from the plasma of a microemulsion that resembles low-density lipoprotein (LDL). Maturitas 2005; 50(4): 275–81PubMedCrossRefGoogle Scholar
  39. 39.
    Cano A, Calaf J, Molina J. The lipid and clinical effects of sequential transdermal estradiol and estradiol/norethisterone acetate in 674 women. Arch Gynecol Obstet 2003; 268(4): 317–22PubMedCrossRefGoogle Scholar
  40. 40.
    Fenkci S, Fenkci V, Yilmazer M, et al. Effects of short-term transdermal hormone replacement therapy on glycaemic control, lipid metabolism, C-reactive protein and proteinuria in postmenopausal women with type 2 diabetes or hypertension. Hum Reprod 2003; 18(4): 866–70PubMedCrossRefGoogle Scholar
  41. 41.
    Ranta V, Oksanen H, Arrenbrecht S, et al. National differences in lipid response to postmenopausal hormone replacement therapy. Maturitas 2002; 42(4): 259–65PubMedCrossRefGoogle Scholar
  42. 42.
    Loscalzo J. Lipoprotein (a): a unique risk factor for atherothrombotic disease. Arterioscelerosis 1990; 10(5): 672–9CrossRefGoogle Scholar
  43. 43.
    Vehkavaara S, Hakala-Ala-Pietila T, Virkamaki A, et al. Differential effects of oral and transdermal estrogen replacement therapy on endothelial function in postmenopausal women. Circulation 2000; 102: 2687–93PubMedCrossRefGoogle Scholar
  44. 44.
    Ariyo AA, Thach C, Tracy R. Lp (a) lipoprotein, vascular disease, and mortality in the elderly. N Engl J Med 2003; 349(22): 2108–15PubMedCrossRefGoogle Scholar
  45. 45.
    Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999; 340: 115–26PubMedCrossRefGoogle Scholar
  46. 46.
    Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105(9): 1135–43PubMedCrossRefGoogle Scholar
  47. 47.
    Torzewski M, Rist C, Mortensen RF, et al. C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis. Arterioscler Thromb Vasc Biol 2000; 29: 2094–9CrossRefGoogle Scholar
  48. 48.
    Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 2000; 102: 2165–8PubMedCrossRefGoogle Scholar
  49. 49.
    Liang JS, Schreiber BM, Salmona M, et al. Amino terminal region of acute phase, but not constitutive, serum amyloid A (apoSAA) specifically binds and transports cholesterol into aortic smooth muscle and HepG2 cells. J Lipid Res 1996; 37: 2109–16PubMedGoogle Scholar
  50. 50.
    Patel H, Fellowes R, Coade S, et al. Human serum amyloid A has cytokine-like properties. Scand J Immunol 1998; 48: 410–8PubMedCrossRefGoogle Scholar
  51. 51.
    Kisilevsky R, Subrahmanyan L. Serum amyloid A changes high density lipoprotein’s cellular affinity: a clue to serum amyloid A’s principal function. Lab Invest 1992; 66: 778–85PubMedGoogle Scholar
  52. 52.
    Navab M, Berliner JA, Subbanagounder G, et al. HDL and the inflammatory response induced by LDL-derived oxidized phospholipids. Arterioscler Thromb Vasc Biol 2001; 21: 481–8PubMedCrossRefGoogle Scholar
  53. 53.
    Van Lenten BJ, Hama SY, de Beer FC, et al. Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response: loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures. J Clin Invest 1995; 96: 2758–67PubMedCrossRefGoogle Scholar
  54. 54.
    Ridker PM, Hennekens CH, Roitman-Johnson B, et al. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet 1998; 351: 88–92PubMedCrossRefGoogle Scholar
  55. 55.
    Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342: 836–43PubMedCrossRefGoogle Scholar
  56. 56.
    Ridker PM, Buring JE, Rifai N. Soluble P-selectin and the risk of future cardiovascular events. Circulation 2001; 103: 491–5PubMedCrossRefGoogle Scholar
  57. 57.
    Ridker PM, Rifai N, Stampfer MJ, et al. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101: 1767–72PubMedCrossRefGoogle Scholar
  58. 58.
    Pradhan AD, Manson JE, Rossouw JE, et al. Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women’s Health Initiative observational study. JAMA 2002; 288: 980–7PubMedCrossRefGoogle Scholar
  59. 59.
    Smith Jr SC, Anderson JL, Cannon III RO, et al. CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: application to clinical and public health practice: report from the clinical practice discussion group. Circulation 2004; 110: e550–3PubMedCrossRefGoogle Scholar
  60. 60.
    Khera A, McGuire DK, Murphy SA, et al. Race and gender differences in C-reactive protein levels. J Am Coll Cardiol 2005; 46(3): 464–9PubMedCrossRefGoogle Scholar
  61. 61.
    Xing D, Miller A, Novak L, et al. Estradiol and progestins differentially modulate leukocyte infiltration after vascular injury. Circulation 2004; 109(2): 234–41PubMedCrossRefGoogle Scholar
  62. 62.
    Lou H, Kodama T, Zhao YJ, et al. Inhibition of transplant coronary arteriosclerosis in rabbits by chronic estradiol treatment is associated with abolition of MHC class II antigen expression. Circulation 1996; 94: 3355–61PubMedCrossRefGoogle Scholar
  63. 63.
    Garidou L, Laffont S, Douin-Echinard V, et al. Estrogen receptor alpha signaling in inflammatory leukocytes is dispensable for 17beta-estradiol-mediated inhibition of experimental autoimmune encephalomyelitis. J Immunol 2004; 173: 2435–42PubMedGoogle Scholar
  64. 64.
    Morishita M, Miyagi M, Iwamoto Y. Effects of sex hormones on production of interleukin-1 by human peripheral monocytes. J Periodontol 1999; 70: 757–60PubMedCrossRefGoogle Scholar
  65. 65.
    Seli E, Kayisli UA, Selam B, et al. Estradiol suppresses vascular monocyte chemotactic protein-1 expression during early atherogenesis. Am J Obstet Gynecol 2002; 187: 1544–9PubMedCrossRefGoogle Scholar
  66. 66.
    Stupka N, Tiidus PM. Effects of ovariectomy and estrogen on ischemia reperfusion injury in hind limbs of female rats. J Appl Physiol 2001; 91: 1828–35PubMedGoogle Scholar
  67. 67.
    Cassidy RA. Influence of steroids on oxidant generation in activated human granulocytes and mononuclear leukocytes. Shock 2003; 20: 85–90PubMedCrossRefGoogle Scholar
  68. 68.
    Alvarez A, Hermenegildo C, Issekutz AC, et al. Estrogens inhibit angiotensin II-induced leukocyte-endothelial cell interactions in vivo via rapid endothelial nitric oxide synthase and cyclooxygenase activation. Circ Res 2002; 91: 1142–50PubMedCrossRefGoogle Scholar
  69. 69.
    Mueck AO, Seeger H, Wallwiener D. Medroxyprogesterone acetate versus norethisterone: effect on estradiol-induced changes of markers for endothelial function and atherosclerotic plaque characteristics in human female coronary endothelial cell cultures. Menopause 2002; 9: 273–81PubMedCrossRefGoogle Scholar
  70. 70.
    Wingrove CS, Garr E, Godsland IF, et al. 17beta-oestradiol enhances release of matrix metalloproteinase-2 from human vascular smooth muscle cells. Biochim Biophys Acta 1998; 1406: 169–74PubMedCrossRefGoogle Scholar
  71. 71.
    Thomas T, Rhodin J, Clark L, et al. Progestins initiate adverse events of menopausal estrogen therapy. Climacteric 2003; 6: 293–301PubMedGoogle Scholar
  72. 72.
    Seeger H, Wallwiener D, Mueck AO. Effect of medroxyprogesterone acetate and norethisterone on serum-stimulated and estradiol-inhibited proliferation of human coronary artery smooth muscle cells. Menopause 2001; 8: 5–9PubMedCrossRefGoogle Scholar
  73. 73.
    Cheng W, Lau OD, Abumrad NA. Two antiatherogenic effects of progesterone on human macrophages; inhibition of cholesteryl ester synthesis and block of its enhancement by glucocorticoids. J Clin Endocrinol Metab 1999; 84: 265–71PubMedCrossRefGoogle Scholar
  74. 74.
    McCrohon JA, Nakhla S, Jessup W, et al. Estrogen and progesterone reduce lipid accumulation in human monocyte-derived macrophages: a sex-specific effect. Circulation 1999; 100: 2319–25PubMedCrossRefGoogle Scholar
  75. 75.
    Adams MR, Register TC, Golden DL, et al. Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis. Arterioscler Thromb Vasc Biol 1997; 17: 217–21PubMedCrossRefGoogle Scholar
  76. 76.
    Adams MR, Kaplan JR, Manuck SB, et al. Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys: lack of an effect of added progesterone. Arteriosclerosis 1990; 10: 1051–7PubMedCrossRefGoogle Scholar
  77. 77.
    Clarkson TB, Appt SE. MPA and postmenopausal coronary artery atherosclerosis revisited. Steroids 2003; 68: 941–51PubMedCrossRefGoogle Scholar
  78. 78.
    Farzati A, Esposito K, Colacurci N, et al. Effects of transdermal hormone replacement therapy on levels of soluble P- and E-selectin in postmenopausal healthy women. Fertil Steril 2002; 77(3): 476–80PubMedCrossRefGoogle Scholar
  79. 79.
    Oger E, Alhenc-Gelas M, Plu-Bureau G, et al. Association of circulating cellular adhesion molecules with menopausal status and hormone replacement therapy: time-dependent change in transdermal, but not oral estrogen users. Thromb Res 2001; 101(2): 35–43PubMedCrossRefGoogle Scholar
  80. 80.
    Sites CK, Toth MJ, Cushman M, et al. Menopause-related differences in inflammation markers and their relationship to body fat distribution and insulin-stimulated glucose disposal. Fertil Steril 2002; 77(1): 128–35PubMedCrossRefGoogle Scholar
  81. 81.
    Silvestri A, Gebara O, Vitale C, et al. Increased levels of C-reactive protein after oral hormone replacement therapy may not be related to an increased inflammatory response. Circulation 2003; 107(25): 3165–9PubMedCrossRefGoogle Scholar
  82. 82.
    Zanger D, Yang BK, Ardans J, et al. Divergent effects of hormone therapy on serum markers of inflammation in postmenopausal women with coronary artery disease on appropriate medical management. J Am Coll Cardiol 2000; 36: 1797–802PubMedCrossRefGoogle Scholar
  83. 83.
    van Baal WM, Emeis JJ, Kenemans P, et al. Short-term hormone replacement therapy: reduced plasma levels of soluble adhesion molecules. Eur J Clin Invest 1999; 29(11): 913–21PubMedCrossRefGoogle Scholar
  84. 84.
    Stork S, von Schacky C, Angerer P. The effect of 17beta-estradiol on endothelial and inflammatory markers in postmenopausal women: a randomized, controlled trial. Atherosclerosis 2002; 165: 301–7PubMedCrossRefGoogle Scholar
  85. 85.
    Goudev A, Georgiev DB, Koycheva N, et al. Effects of low dose hormone replacement therapy on markers of inflammation in postmenopausal women. Maturitas 2002; 43: 49–53PubMedCrossRefGoogle Scholar
  86. 86.
    Koh KK, Son JY, Ahn JY, et al. Effect of hormone replacement therapy on nitric oxide bioactivity and monocyte chemoattractant protein-1 levels. Int J Cardiol 2001; 81: 43–50PubMedCrossRefGoogle Scholar
  87. 87.
    Stork S, Baumann K, von Schacky C, et al. The effect of 17beta-estradiol on MCP-1 serum levels in postmenopausal women. Cardiovasc Res 2002; 53: 642–9PubMedCrossRefGoogle Scholar
  88. 88.
    Sumino H, Ichikawa S, Ohyama Y, et al. Effect of transdermal hormone replacement therapy on the monocyte chemoattractant protein-1 concentrations and other vascular inflammatory markers and on endothelial function in postmenopausal women. Am J Cardiol 2005; 96(1): 148–53PubMedCrossRefGoogle Scholar
  89. 89.
    Bui MN, Arai AE, Hathaway L, et al. Effect of hormone replacement therapy on carotid arterial compliance in healthy postmenopausal women. Am J Cardiol 2002; 90: 82–5PubMedCrossRefGoogle Scholar
  90. 90.
    Koh KK, Ahn JY, Kang MH, et al. Effects of hormone replacement on plaque stability, inflammation, and fibrinolysis in hypertensive or overweight postmenopausal women. Am J Cardiol 2001; 88: 1423–6PubMedCrossRefGoogle Scholar
  91. 91.
    Wakatsuki A, Ikenoue N, Shinohara K, et al. Different effects of oral and transdermal estrogen replacement therapy on matrix metalloproteinase and their inhibitor in postmenopausal women. Circulation 2003; 23: 1948–9Google Scholar
  92. 92.
    Christodoulakos GE, Panoulis CP, Lambrinoudaki IV, et al. The effect of hormone therapy and raloxifene on serum matrix metalloproteinase-2 and -9 in postmenopausal women. Menopause 2004; 11(3): 299–305PubMedCrossRefGoogle Scholar
  93. 93.
    Cushman M, Legault C, Barrett-Connor E, et al. Effect of postmenopausal hormones on inflammation-sensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) study. Circulation 1999; 100: 717–22PubMedCrossRefGoogle Scholar
  94. 94.
    Ridker PM, Hennekens CH, Rifai N, et al. Hormone replacement therapy and increased plasma concentration of C-reactive protein. Circulation 1999; 100: 713–6PubMedCrossRefGoogle Scholar
  95. 95.
    van Baal WM, Kenemans P, van der Mooren MJ, et al. Increased C-reactive protein levels during short-term hormone replacement therapy in healthy postmenopausal women. Thromb Haemost 1999; 81(6): 925–8PubMedGoogle Scholar
  96. 96.
    Wakatsuki A, Okatani Y, Ikenoue N, et al. Effect of medroxyprogesterone acetate on vascular inflammatory markers in postmenopausal women receiving estrogen. Circulation 2002; 105: 1436–9PubMedCrossRefGoogle Scholar
  97. 97.
    Wakatsuki A, Ikenoue N, Shinohara K, et al. Effect of lower dosage of oral conjugated equine estrogen on inflammatory markers and endothelial function in healthy postmenopausal women. Arterioscler Thromb Vasc Biol 2004; 24(3): 571–6PubMedCrossRefGoogle Scholar
  98. 98.
    Skouby SO, Gram J, Anderson LF, et al. Hormone replacement therapy: estrogen and progestin effects on plasma C-reactive protein concentrations. Am J Obstet Gynecol 2002; 186: 969–77PubMedCrossRefGoogle Scholar
  99. 99.
    Koh KK, Shin MS, Sakuma I, et al. Effects of conventional or lower doses of hormone replacement therapy in postmenopausal women. Arterioscler Thromb Vasc Biol 2004; 24: 1516–21PubMedCrossRefGoogle Scholar
  100. 100.
    Giltay EJ, Gooren LJ, Emeis JJ, et al. Oral ethinyl estradiol, but not transdermal 17beta-estradiol, increases plasma C-reactive protein levels in men. Thromb Haemost 2000; 84: 359–60PubMedGoogle Scholar
  101. 101.
    Decensi A, Omodei U, Robertson C, et al. Effect of transdermal estradiol and oral conjugated estrogens on C-reactive protein in retinoid-placebo trial in healthy women. Circulation 2002; 106: 1224–8PubMedCrossRefGoogle Scholar
  102. 102.
    Strandberg TE, Ylikorkala O, Tikkanen MJ. Differing effects of oral and transdermal hormone replacement therapy on cardiovascular risk factors in healthy postmenopausal women. Am J Cardiol 2003; 92(2): 212–4PubMedCrossRefGoogle Scholar
  103. 103.
    Lacut K, Oger E, Le Gal G, et al. Differential effects of oral and transdermal postmenopausal estrogen replacement therapies on C-reactive protein. Thromb Haemost 2003; 90: 124–31PubMedGoogle Scholar
  104. 104.
    Sattar N, Perera M, Small M, et al. Hormone replacement therapy and sensitive C-reactive protein concentrations in women with type-2 diabetes. Lancet 1999; 354(9177): 487–8PubMedCrossRefGoogle Scholar
  105. 105.
    Vongpatanasin W, Tuncel M, Wang Z, et al. Differential effects of oral vs transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women. J Am Coll Cardiol 2003; 41: 1358–63PubMedCrossRefGoogle Scholar
  106. 106.
    Zegura B, Keber I, Sebestjen M, et al. Double blind, randomized study of estradiol replacement therapy on markers of inflammation, coagulation, and fibrinolysis. Atherosclerosis 2003; 168: 123–9PubMedCrossRefGoogle Scholar
  107. 107.
    Gol M, Akan P, Dogan E, et al. Effects of estrogen, raloxifene, and hormone replacement therapy on serum C-reactive protein and homocysteine levels. Maturitas. Epub 2005 Jun 27Google Scholar
  108. 108.
    de Valk-de Roo GW, Stehouwer CD, Meijer P, et al. Both raloxifene and estrogen reduce major cardiovascular risk factors in healthy postmenopausal women: a 2-year, placebo-controlled study. Arterioscler Thromb Vasc Biol 1999; 19(12): 2993–3000PubMedCrossRefGoogle Scholar
  109. 109.
    Prestwood KM, Unson C, Kulldorff M, et al. The effect of different doses of micronized 17beta-estradiol on C-reactive protein, interleukin-6, and lipids in older women. J Gerontol A Biol Sci Med Sci 2004; 59(8): 827–32PubMedCrossRefGoogle Scholar
  110. 110.
    Rossi R, Bursi F, Veronesi B, et al. Effects of progestins on estrogen-induced increase in C-reactive protein in postmenopausal women. Maturitas 2004; 49(4): 315–20PubMedCrossRefGoogle Scholar
  111. 111.
    Kiran H, Kiran G, Ekerbicer HC, et al. Effects of oestrogen replacement therapy on serum C-reactive protein levels in hysterectomised women. Aust N Z J Obstet Gynaecol 2004; 44(2): 131–4PubMedCrossRefGoogle Scholar
  112. 112.
    Herrington DM, Howard TD, Brosnihan KB, et al. Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein. Circulation 2002; 105(16): 1879–82PubMedCrossRefGoogle Scholar
  113. 113.
    Walsh B, Cox D, Sashegyi A, et al. Role of tumor necrosis factor-alpha and interleukin-6 in the effects of hormone replacement therapy and raloxifene on C-reactive protein in postmenopausal women. Am J Cardiol 2001; 88: 825–8PubMedCrossRefGoogle Scholar
  114. 114.
    Weissberger AJ, Ho KKY, Lazarus L. Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women. J Clin Endocrinol Metab 1991; 72: 374–81PubMedCrossRefGoogle Scholar
  115. 115.
    Sesmilo G, Biller BM, Llevadot J, et al. Effects of growth hormone administration on inflammatory and other cardiovascular risk markers in men with growth hormone deficiency: a randomized, controlled clinical trial. Ann Intern Med 2000; 133: 111–22PubMedGoogle Scholar
  116. 116.
    Jeschke MG, Barrow RE, Herndon DN. Insulin-like growth factor I plus insulin-like growth factor binding protein 3 attenuates the proinflammatory acute phase response in severely burned children. Ann Surg 2000; 231: 246–52PubMedCrossRefGoogle Scholar
  117. 117.
    Koh KK, Jin DK, Yang SH, et al. Vascular effects of synthetic or natural progestogen combined with conjugated equine estrogen in healthy postmenopausal women. Circulation 2001; 103: 1961–6PubMedCrossRefGoogle Scholar
  118. 118.
    Koh KK, Ahn JY, Jin DK, et al. Effects of continuous combined hormone replacement therapy on inflammation in hypertensive and/or overweight postmenopausal women. Arteriolscler Thromb Vasc Biol 2002; 22: 1459–64CrossRefGoogle Scholar
  119. 119.
    Ropponen A, Aittomaki K, Tikkanen MJ, et al. Levels of serum C-reactive protein during oral and transdermal estradiol in postmenopausal women with and without a history of intrahepatic cholestasis of pregnancy. J Clin Endocrinol Metab 2005; 90(1): 142–6PubMedCrossRefGoogle Scholar
  120. 120.
    Burt VL, Cutler JA, Higgins M, et al. Prevalence of hypertension in the US adult population: results from the Third National Health and Nutrition Examination Survey, 1988–1991. Hypertens 1995; 25: 305–13CrossRefGoogle Scholar
  121. 121.
    Cagnacci A, Arangino S, Angiolucci M, et al. Oral contraceptives and vascular reactivity of great vessels in women. Eur J Contracept Reprod Health Care 1999; 4: 61–5PubMedCrossRefGoogle Scholar
  122. 122.
    Seely E, Walsh B, Gerhard M, et al. Estradiol with or without progesterone and ambulatory blood pressure in postmenopausal women. Hypertension 1999; 33: 1190–4PubMedCrossRefGoogle Scholar
  123. 123.
    Manhem K, Ahlm H, Milsom I, et al. Transdermal oestrogen reduces daytime blood pressure in hypertensive women. J Hum Hypertens 1998; 12: 323–7PubMedCrossRefGoogle Scholar
  124. 124.
    Mercuro G, Zoncu S, Piano D, et al. Estradiol-17B reduces blood pressure and restores the normal amplitude of the circadian blood pressure rhythm in postmenopausal hypertension. Am J Hypertens 1998; 11: 909–13PubMedCrossRefGoogle Scholar
  125. 125.
    Akkad A, Halligan A, Abrams K, et al. Differing responses in blood pressure over 24 hours in normotensive women receiving oral or transdermal estrogen replacement therapy. Obstet Gynecol 1997; 89: 97–103PubMedCrossRefGoogle Scholar
  126. 126.
    Harvey P, Wing L, Savage J, et al. The effects of different types and doses of oestrogen replacement therapy on clinic and ambulatory blood pressure postmenopausal women. J Hypertens 1999; 17: 405–11PubMedCrossRefGoogle Scholar
  127. 127.
    van Ittersum FJ, van Baal WM, Kenemans P, et al. Ambulatory — not office — blood pressures decline during hormone replacement therapy in healthy postmenopausal women. Am J Hypertens 1998; 11: 1147–52PubMedCrossRefGoogle Scholar
  128. 128.
    Mueck AO, Seeger H. Effect of hormone therapy on BP in normotensive and hypertensive postmenopausal women. Maturitas 2004; 49: 189–203PubMedCrossRefGoogle Scholar
  129. 129.
    Affinito P, Palomba S, Bonifacio M, et al. Effects of hormonal replacement therapy in postmenopausal hypertensive patients. Maturitas 2001; 40: 75–83PubMedCrossRefGoogle Scholar
  130. 130.
    Girdler SS, Hinderliter AL, Wells EC, et al. Transdermal versus oral estrogen therapy in postmenopausal smokers: hemodynamic and endothelial effects. Obstet Gynecol 2004; 103: 169–80PubMedCrossRefGoogle Scholar
  131. 131.
    Schunkert H, Danser AH, Hense H, et al. Effects of estrogen replacement therapy on the renin-angiotensin system in postmenopausal women. Circulation 1997; 95: 39–45PubMedCrossRefGoogle Scholar
  132. 132.
    Seely E, Broshinan B, Jeunemaitre X, et al. Effects of conjugated estrogen and droloxifene on the renin-angiotensin system, blood pressure, and renal blood flow in postmenopausal women. Clin Endocrinol 2004; 60: 315–21CrossRefGoogle Scholar
  133. 133.
    Harvey PJ, Morris BL, Miller JA, et al. Estradiol induces discordant angiotensin and blood pressure responses to orthostasis in healthy postmenopausal women. Hypertension 2005; 45: 399–405PubMedCrossRefGoogle Scholar
  134. 134.
    Del Rio G, Velardo A, Menozzi R, et al. Acute estradiol and progesterone administration reduced cardiovascular and catecholamine responses to mental stress in menopausal women. Neuroendocrinology 1998; 67: 269–74PubMedCrossRefGoogle Scholar
  135. 135.
    Vongpatanasin W, Tuncel M, Mansour Y, et al. Estrogen replacement therapy decreases sympathetic vasoconstrictor activity in postmenopausal women. Circulation 2001; 103: 2903–8PubMedCrossRefGoogle Scholar
  136. 136.
    Weitz G, Elam M, Born J, et al. Postmenopausal estrogen administration suppresses muscle sympathetic nerve activity. J Clin Endocrinol Metab 2001; 86: 344–8PubMedCrossRefGoogle Scholar
  137. 137.
    Hunt BE, Taylor JA, Hamner JW, et al. Estrogen replacement therapy improves baroreflex regulation of vascular sympathetic outflow in postmenopausal women. Circulation 2001; 103(24): 2909–14PubMedCrossRefGoogle Scholar
  138. 138.
    O’Sullivan AJ, Crampton LJ, Freund J, et al. The route of estrogen replacement confers divergent effects on substrate oxidation and body composition in postmenopausal women. J Clin Invest 1998; 102: 1035–40PubMedCrossRefGoogle Scholar
  139. 139.
    Duanmu Z, Lapanowski K, Dunbar JC. Insulin-like growth factor-I decreases sympathetic nerve activity: the effect is modulated by glycemic status. Proc Soc Exp Biol Med 1997; 216: 93–7PubMedGoogle Scholar
  140. 140.
    Sverrisdottir YB, Elam M, Herlitz H, et al. Intense sympathetic nerve activity in adults with hypopituitarism and untreated growth hormone deficiency. J Clin Endocrinol Metab 1998; 83: 1881–5PubMedCrossRefGoogle Scholar
  141. 141.
    Scherrer U, Randin D, Tappy L, et al. Body fat and sympathetic nerve activity in healthy subjects. Circulation 1994; 89: 240–63CrossRefGoogle Scholar
  142. 142.
    Reckelhoff JF. Sex steroids, cardiovascular diseases, and hypertension. Hypertension 2005; 45: 170–4PubMedCrossRefGoogle Scholar
  143. 143.
    Christ M, Seyffart K, Hanns-Christian T, et al. Hormone replacement in postmenopausal women: impact of progestogens on autonomic tone and blood pressure regulation. Menopause 2002; 9: 127–36PubMedCrossRefGoogle Scholar
  144. 144.
    Sorensen MB, Rasmussen V, Jensen G, et al. Temporal changes in clinic and ambulatory blood pressure during cyclic post-menopausal hormone replacement therapy. J Hypertens 2000; 18(10): 1387–91PubMedCrossRefGoogle Scholar
  145. 145.
    Harvey PJ, Molloy D, Upton J, et al. Dose response effect of cyclical medroxyprogesterone on blood pressure in postmenopausal women. J Hum Hypertens 2001; 15(5): 313–21PubMedCrossRefGoogle Scholar
  146. 146.
    Manwaring P, Morfis L, Diamond T, et al. Effects of hormone replacement therapy on ambulatory blood pressure and vascular responses in normotensive women. Blood Press 2000; 9(1): 22–7PubMedCrossRefGoogle Scholar
  147. 147.
    Stojanovic ND, Kwong P, Byrne DJ, et al. The effects of transdermal estradiol alone or with cyclical dydrogesterone on markers of cardiovascular disease risk in postmenopausal women with type 2 diabetes: a pilot study. Angiology 2003; 54(4): 391–9PubMedCrossRefGoogle Scholar
  148. 148.
    Preston RA, White WB, Pitt B, et al. Effects of drospirenone/17-β estradiol on blood pressure and potassium balance in hypertensive postmenopausal women. Am J Hypertens 2005; 18: 797–804PubMedCrossRefGoogle Scholar
  149. 149.
    Daly E, Vessey MP, Hawkins MM, et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348: 977–80PubMedCrossRefGoogle Scholar
  150. 150.
    Jick H, Derby LE, Myers MW, et al. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet 1996; 348: 981–3PubMedCrossRefGoogle Scholar
  151. 151.
    Scarabin P, Oger E, Plu-Bureau G. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2004; 362: 428–32CrossRefGoogle Scholar
  152. 152.
    Clarke SC, Kelleher J, Lloyd-Jones H, et al. A study of hormone replacement therapy in postmenopausal women with ischemic heart disease: the Papworth HRT Atherosclerosis Study. BJOG 2002; 109: 1056–62PubMedCrossRefGoogle Scholar
  153. 153.
    Bland LB, Garzotto M, DeLoughery TG, et al. Phase II study of transdermal estradiol in androgen-independent prostate carcinoma. Cancer 2005; 103: 717–23PubMedCrossRefGoogle Scholar
  154. 154.
    van Kesteren PJ, Asscheman H, Megens JA, et al. Mortality and morbidity in transsexual subjects treated with cross-sex hormones. Clin Endocrinol (Oxf) 1997; 47: 337–42CrossRefGoogle Scholar
  155. 155.
    The Writing Group of the Estradiol Clotting Factors Study. Effects on haemostasis of hormone replacement therapy with transdermal estradiol and oral sequential medroxyprogesterone acetate: a 1-year, double-blind, placebo-controlled study. Thromb Haemost 1996; 75: 476–80Google Scholar
  156. 156.
    Chen FP, Lee N, Soong YK, et al. Comparison of transdermal and oral estrogenprogestin replacement therapy: effects on cardiovascular risk factors. Menopause 2001; 8: 347–52PubMedCrossRefGoogle Scholar
  157. 157.
    Perera M, Sattar N, Petrie JR, et al. The effects of transdermal estradiol in combination with oral norethisterone on lipoproteins, coagulation, and endothelial markers in postmenopausal women with type 2 diabetes: a randomized, placebo-controlled study. J Clin Endocrinol Metab 2001; 86: 1140–3PubMedCrossRefGoogle Scholar
  158. 158.
    Scarabin PY, Alhenc-Gelas M, Plu-Bureau G. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women: a randomized controlled trial. Arteriolscler Thromb Vasc Biol 1997; 17: 3071–8CrossRefGoogle Scholar
  159. 159.
    DeMitrio V, Marino R, Cicinelli E. Beneficial effects of postmenopausal hormone replacement therapy with transdermal estradiol on sensitivity to activated protein C. Blood Coagul Fibrinolysis 2000; 11: 175–82Google Scholar
  160. 160.
    Rabbani LE, Seminario NA, Sciacca RR, et al. Oral conjugated equine estrogen increases plasma von Willebrand factor in postmenopausal women. J Am Coll Cardiol 2002; 40: 1991–9PubMedCrossRefGoogle Scholar
  161. 161.
    Oger E, Alhenc-Gelas M, Lacut K, et al. Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial. Arteriolscler Thromb Vasc Biol 2003; 23: 1671–6CrossRefGoogle Scholar
  162. 162.
    Caine YG, Bauer KA, Barzegar S, et al. Coagulation activation following estrogen administration to postmenopausal women. Thromb Haemost 1992; 68: 392–5PubMedGoogle Scholar
  163. 163.
    Toorians AWFT, Thomassen MCLGD, Zweegman S, et al. Venous thrombosis and changes of hemostatic variables during cross-sex hormone treatment in transsexual people. J Clin Endocrinol Metab 2003; 88: 5723–9PubMedCrossRefGoogle Scholar
  164. 164.
    Post MS, Thomassen CLGD, van der Mooren MJW, et al. Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis: a randomized, placebo-controlled study in postmenopausal women. Arteriolscler Thromb Vasc Biol 2003; 23: 1116–21CrossRefGoogle Scholar
  165. 165.
    Viinikka L, Orpana A, Puolakka J, et al. Different effects of oral and transdermal hormonal replacement on prostacyclin and thromboxane A2. Obstet Gynecol 1997; 89(1): 104–7PubMedCrossRefGoogle Scholar
  166. 166.
    Hoibraaten E, Os I, Seljeflot I, et al. The effects of hormone replacement therapy on hemostatic variables in women with angiographically verified coronary artery disease: results from the Estrogen in Women with Atherosclerosis Study. Thromb Res 2000; 98: 19–27PubMedCrossRefGoogle Scholar
  167. 167.
    Vehkavavaara S, Silveira A, Hakala-Ala-Pietila T, et al. Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thromb Haemost 2001; 85(4): 619–25Google Scholar
  168. 168.
    Andersen L, Gram J, Skouby S, et al. Effects of hormone replacement therapy on hemostatic cardiovascular risk factors. Am J Obstet Gynecol 1999; 180: 283–9PubMedCrossRefGoogle Scholar
  169. 169.
    Gottsater A, Rendell M, Hulthen UL, et al. Hormone replacement therapy in healthy postmenopausal women: a randomized, placebo-controlled study of effects on coagulation and fibrinolytic factors. J Intern Med 2001; 249: 237–46PubMedCrossRefGoogle Scholar
  170. 170.
    Shahar E, Folsom A, Salomaa V. Relation of hormone replacement therapy to measures of plasma fibrinolytic activity. Circulation 1996; 93: 1970–5PubMedCrossRefGoogle Scholar
  171. 171.
    Teede HJ, McGrath BP, Smolich JJ, et al. Postmenopausal hormone replacement therapy increases coagulation activity and fibrinolysis. Arteriolscler Thromb Vasc Biol 2000; 20: 1404–9CrossRefGoogle Scholar
  172. 172.
    Brussaard HE, Leuven JA, Krans HM, et al. The effect of 17 beta-oestradiol on variables of coagulation and fibrinolysis in postmenopausal women with type 2 diabetes mellitus. Vascul Pharmacol 2002; 39(3): 141–7PubMedCrossRefGoogle Scholar
  173. 173.
    Koh KK, Ahn JY, Jin DK, et al. Significant differential effects of hormone therapy or tibolone on markers of cardiovascular disease in postmenopausal women: a randomized, double-blind, placebo-controlled, crossover study. Arterioscler Thromb Vasc Biol 2003; 23(10): 1889–94PubMedCrossRefGoogle Scholar
  174. 174.
    McKenzie J, Jaap AJ, Gallacher S, et al. Metabolie, inflammatory and haemostatic effects of a low-dose continuous combined HRT in women with type 2 diabetes: potentially safer with respect to vascular risk? Clin Endocrinol 2003; 59(6): 682–9CrossRefGoogle Scholar
  175. 175.
    Hall G, Blomback M, Landgren BM, et al. Effects of vaginally administered high estradiol doses on hormonal pharmacokinetics and hemostasis in postmenopausal women. Fertil Steril 2002; 78(6): 1172–7PubMedCrossRefGoogle Scholar
  176. 176.
    Lindoff C, Peterson F, Lecander I, et al. Transdermal estrogen replacement therapy: beneficial effects on hemostatic risk factors for cardiovascular disease. Maturitas 1996; 24: 43–50PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  1. 1.Department of Internal Medicine, Divisions of Hypertension and Cardiology, Department of Internal MedicineUniversity of Texas Southwestern Medical CenterDallasUSA

Personalised recommendations