American Journal of Pharmacogenomics

, Volume 4, Issue 1, pp 19–28

Molecular Mechanisms, Physiological Consequences and Pharmacological Implications of Estrogen Receptor Action

  • Tomas Barkhem
  • Stefan Nilsson
  • Jan-Åke Gustafsson
Genomics in Health and Disease

Abstract

The estrogen receptors (ERs), ERα and ERβ, play a central role in mediating the biological effects of estrogen. The transcription rate of estrogen target genes is determined by several parameters including the type of ligand, estrogen receptor subtype and isoform, as well as interactions with receptor-binding cofactor proteins.

The ERs regulate gene expression by binding to specific response element sequences in the promoters of estrogen target genes. Alternative pathways have also been described in which the ERs modulate transcription indirectly, via protein : protein interactions. In this regulatory mode, which has been traced to activator protein (AP)-1-, cyclic adenosine monophosphate (cAMP)-, and Sp1-response elements, the ERs appear to be tethered to target gene promoters via heterologous transcription factors. It has been found that ERα and ERβ have opposite effects on transcription mediated via the indirect mode of action. Moreover, recent studies suggest that ERβ may inhibit the stimulatory effects of ERα on cellular proliferation.

Estrogen is a key regulatory hormone that affects numerous physiological processes. Estrogen is required for female pubertal development and affects growth, differentiation and function of the female reproductive system. It has recently been suggested that estrogen also has an important role in the male urogenital tract. In addition, estrogens have profound effects in other tissues. For instance, in the skeleton estrogen prevents bone-resorption by inhibition of osteoclast function.

Numerous reports have suggested that estrogen has a beneficial effect in the cardiovascular system and in the CNS; however, this has not been confirmed in randomized clinical trials. In fact, a large randomized trial on healthy postmenopausal women receiving oral estrogen plus progestin showed an increased incidence of cardiovascular disease. In addition, this study revealed an increased risk for dementia and impaired cognitive function in the group receiving oral estrogen/progestin. Additional clinical trials are required to determine which hormonal component causes these health risks or whether the effects were due to the combination of estrogen and progestin.

References

  1. 1.
    Jensen E, Jacobsen H. Basic guides to the mechanism of estrogen action. Recent Prog Horm Res 1962; 18: 387–414Google Scholar
  2. 2.
    Green S, Walter P, Kumar V, et al. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature 1986; 320(6058): 134–9PubMedGoogle Scholar
  3. 3.
    Greene GL, Gilna P, Waterfield M, et al. Sequence and expression of human estrogen receptor complementary DNA. Science 1986; 231(4742): 1150–4PubMedGoogle Scholar
  4. 4.
    Kuiper GG, Enmark E, Pelto-Huikko M, et al. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A 1996; 93(12): 5925–30PubMedGoogle Scholar
  5. 5.
    Barkhem T, Carlsson B, Nilsson Y, et al. Differential response of estrogen receptora and estrogen receptorβ to partial agonists/antagonists. Mol Pharmacol 1998; 54: 105–12PubMedGoogle Scholar
  6. 6.
    Kumar V, Chambon P. The estrogen receptor binds tightly to its responsive element as a ligand-induced homodimer. Cell 1988; 55(1): 145–56PubMedGoogle Scholar
  7. 7.
    Tora L, White J, Brou C, et al. The human estrogen receptor has two independent nonacidic transcriptional activation functions. Cell 1989; 59(3): 477–87PubMedGoogle Scholar
  8. 8.
    Brzozowski AM, Pike AC, Dauter Z, et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997; 389(6652): 753–8PubMedGoogle Scholar
  9. 9.
    Pike AC, Brzozowski AM, Hubbard RE, et al. Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist. EMBO J 1999; 18(17): 4608–18PubMedGoogle Scholar
  10. 10.
    Shiau AK, Barstad D, Loria PM, et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 1998; 95(7): 927–37PubMedGoogle Scholar
  11. 11.
    Kuiper GG, Carlsson B, Grandien K, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 1997; 138(3): 863–70PubMedGoogle Scholar
  12. 12.
    Sun J, Meyers MJ, Fink BE, et al. Novel ligands that function as selective estrogens or antiestrogens for estrogen receptor-alpha or estrogen receptor-beta. Endocrinology 1999; 140(2): 800–4PubMedGoogle Scholar
  13. 13.
    Enmark E, Pelto-Huikko M, Grandien K, et al. Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern. J Clin Endocrinol Metab 1997; 82(12): 4258–65PubMedGoogle Scholar
  14. 14.
    Mosselman S, Polman J, Dijkema R. ER beta: identification and characterization of a novel human estrogen receptor. FEBS Lett 1996; 392: 49–53PubMedGoogle Scholar
  15. 15.
    Tremblay GB, Tremblay A, Copeland NG, et al. Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor beta. Mol Endocrinol 1997; 11(3): 353–65PubMedGoogle Scholar
  16. 16.
    Pettersson K, Grandien K, Kuiper GG, et al. Mouse estrogen receptor beta forms estrogen response element-binding heterodimers with estrogen receptor alpha. Mol Endocrinol 1997; 11(10): 1486–96PubMedGoogle Scholar
  17. 17.
    Fuqua SA, Schiff R, Parra I, et al. Expression of wild-type estrogen receptor beta and variant isoforms in human breast cancer. Cancer Res 1999; 59(21): 5425–8PubMedGoogle Scholar
  18. 18.
    Ogawa S, Inoue S, Watanabe T, et al. The complete primary structure of human estrogen receptor beta (hER beta) and its heterodimerization with ER alpha in vivo and in vitro. Biochem Biophys Res Commun 1998; 243(1): 122–6PubMedGoogle Scholar
  19. 19.
    Wilkinson HA, Dahllund J, Liu H, et al. Identification and characterization of a functionally distinct form of human estrogen receptor Beta. Endocrinology 2002; 143(4): 1558–61PubMedGoogle Scholar
  20. 20.
    Fuqua SA, Chamness GC, McGuire WL. Estrogen receptor mutations in breast cancer. J Cell Biochem 1993; 51(2): 135–9PubMedGoogle Scholar
  21. 21.
    Murphy LC, Dotzlaw H, Leygue E, et al. The pathophysiological role of estrogen receptor variants in human breast cancer. J Steroid Biochem Mol Biol 1998; 65(1–6): 175–80PubMedGoogle Scholar
  22. 22.
    Chu S, Fuller PJ. Identification of a splice variant of the rat estrogen receptor beta gene. Mol Cell Endocrinol 1997; 132(1–2): 195–9PubMedGoogle Scholar
  23. 23.
    Petersen DN, Tkalcevic GT, Koza-Taylor PH, et al. Identification of estrogen receptor beta2, a functional variant of estrogen receptor beta expressed in normal rat tissues. Endocrinology 1998; 139(3): 1082–92PubMedGoogle Scholar
  24. 24.
    Hanstein B, Liu H, Yancisin MC, et al. Functional analysis of a novel estrogen receptor-beta isoform. Mol Endocrinol 1999; 13(1): 129–37PubMedGoogle Scholar
  25. 25.
    Ogawa S, Inoue S, Watanabe T, et al. Molecular cloning and characterization of human estrogen receptor betacx: a potential inhibitor ofestrogen action in human. Nucleic Acids Res 1998; 26(15): 3505–12PubMedGoogle Scholar
  26. 26.
    Beekman JM, Allan GF, Tsai SY, et al. Transcriptional activation by the estrogen receptor requires a conformational change in the ligand binding domain. Mol Endocrinol 1993; 7(10): 1266–74PubMedGoogle Scholar
  27. 27.
    Love RR, Mazess RB, Barden HS, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992; 326(13): 852–6PubMedGoogle Scholar
  28. 28.
    Love RR, Newcomb PA, Wiebe DA, et al. Effects of tamoxifen therapy on lipid and lipoprotein levels in postmenopausal patients with node-negative breast cancer. J Natl Cancer Inst 1990; 82(16): 1327–32PubMedGoogle Scholar
  29. 29.
    Wolf DM, Jordan VC. Gynecologic complications associated with long-term adjuvant tamoxifen therapy for breast cancer. Gynecol Oncol 1992; 45(2): 118–28PubMedGoogle Scholar
  30. 30.
    Endoh H, Maruyama K, Masuhiro Y, et al. Purification and identification of p68 RNA helicase acting as a transcriptional coactivator specific for the activation function 1 of human estrogen receptor alpha. Mol Cell Biol 1999; 19(8): 5363–72PubMedGoogle Scholar
  31. 31.
    Webb P, Nguyen P, Shinsako J, et al. Estrogen receptor activation function 1 works by binding p160 coactivator proteins. Mol Endocrinol 1998; 12(10): 1605–18PubMedGoogle Scholar
  32. 32.
    Smith CL, Nawaz Z, O’Malley BW. Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol Endocrinol 1997; 11(6): 657–66PubMedGoogle Scholar
  33. 33.
    Lavinsky RM, Jepsen K, Heinzel T, et al. Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Proc Natl Acad Sci U S A 1998; 95(6): 2920–5PubMedGoogle Scholar
  34. 34.
    Norris JD, Paige LA, Christensen DJ, et al. Peptide antagonists of the human estrogen receptor. Science 1999; 285(5428): 744–6PubMedGoogle Scholar
  35. 35.
    Jackson TA, Richer JK, Bain DL, et al. The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT. Mol Endocrinol 1997; 11(6): 693–705PubMedGoogle Scholar
  36. 36.
    Shang Y, Brown M. Molecular determinants for the tissue specificity of SERMs. Science 2002; 295(5564): 2465–8PubMedGoogle Scholar
  37. 37.
    Webb P, Nguyen P, Kushner PJ. Differential SERM effects on corepressor binding dictate ERalpha activity in vivo. J Biol Chem 2003; 278(9): 6912–20PubMedGoogle Scholar
  38. 38.
    Taylor AH, Al-Azzawi F. Immunolocalisation of oestrogen receptor beta in human tissues. J Mol Endocrinol 2000; 24(1): 145–55PubMedGoogle Scholar
  39. 39.
    Paech K, Webb P, Kuiper GG, et al. Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites. Science 1997; 277: 1508–10PubMedGoogle Scholar
  40. 40.
    Zhu Y, Bian Z, Lu P, et al. Abnormal vascular function and hypertension in mice deficient in estrogen receptor beta. Science 2002; 295(5554): 505–8PubMedGoogle Scholar
  41. 41.
    Lefstin JA, Yamamoto KR. Allosteric effects of DNA on transcriptional regulators. Nature 1998; 392(6679): 885–8PubMedGoogle Scholar
  42. 42.
    Klinge CM, Jernigan SC, Smith SL, et al. Estrogen response element sequence impacts the conformation and transcriptional activity of estrogen receptor alpha. Mol Cell Endocrinol 2001; 174(1–2): 151–66PubMedGoogle Scholar
  43. 43.
    Wood JR, Greene GL, Nardulli AM. Estrogen response elements function as allosteric modulators of estrogen receptor conformation. Mol Cell Biol 1998; 18(4): 1927–34PubMedGoogle Scholar
  44. 44.
    Wood JR, Likhite VS, Loven MA, et al. Allosteric modulation of estrogen receptor conformation by different estrogen response elements. Mol Endocrinol 2001; 15(7): 1114–26PubMedGoogle Scholar
  45. 45.
    Hall JM, McDonnell DP, Korach KS. Allosteric regulation of estrogen receptor structure, function, and coactivator recruitment by different estrogen response elements. Mol Endocrinol 2002; 16(3): 469–86PubMedGoogle Scholar
  46. 46.
    Barkhem T, Haldosen LA, Gustafsson JA, et al. Transcriptional synergism on the pS2 gene promoter between a p160 coactivator and estrogen receptor-alpha depends on the coactivator subtype, the type of estrogen response element, and the promoter context. Mol Endocrinol 2002; 16(11): 2571–81PubMedGoogle Scholar
  47. 47.
    Galien R, Garcia T. Estrogen receptor impairs interleukin-6 expression by preventing protein binding on the NF-kappaB site. Nucleic Acids Res 1997; 25(12): 2424–9PubMedGoogle Scholar
  48. 48.
    Webb P, Lopez GN, Uht RM, et al. Tamoxifen activation of the estrogen receptor/AP-1 pathway: potential origin for the cell-specific estrogen-like effects of antiestrogens. Mol Endocrinol 1995; 9(4): 443–56PubMedGoogle Scholar
  49. 49.
    Kushner PJ, Agard DA, Greene GL, et al. Estrogen receptor pathways to AP-1. J Steroid Biochem Mol Biol 2000; 74(5): 311–7PubMedGoogle Scholar
  50. 50.
    Webb P, Nguyen P, Valentine C, et al. The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions. Mol Endocrinol 1999; 13(10): 1672–85PubMedGoogle Scholar
  51. 51.
    Batistuzzo de Medeiros S, Krey G, Hihi AK, et al. Functional interaction between the estrogen receptor and the transcription activator Sp1 regulate the estrogen-dependent transcriptional activity of the vitellogeninA1 io promoter. J Biol Chem 1997; 272: 18250–60PubMedGoogle Scholar
  52. 52.
    Porter W, Saville B, Hoivik D, et al. Functional synergy between the transcription factor Sp1 and the estrogen receptor. Mol Endocrinol 1997; 11: 1569–80PubMedGoogle Scholar
  53. 53.
    Zou A, Marschke KB, Arnold KE, et al. Estrogen receptor beta activates the human retinoic acid receptor alpha-1 promoter in response to tamoxifen and other estrogen receptor antagonists, but not in response to estrogen. Mol Endocrinol 1999; 13(3): 418–30PubMedGoogle Scholar
  54. 54.
    Liu MM, Albanese C, Anderson CM, et al. Opposing action of estrogen receptors alpha and beta on cyclin D1 gene expression. J Biol Chem 2002; 277(27): 24353–60PubMedGoogle Scholar
  55. 55.
    Planas-Silva MD, Weinberg RA. Estrogen-dependent cyclin E-cdk2 activation through p21 redistribution. Mol Cell Biol 1997; 17(7): 4059–69PubMedGoogle Scholar
  56. 56.
    Prall OW, Rogan EM, Musgrove EA, et al. c-Myc or cyclin D1 mimics estrogen effects on cyclin E-Cdk2 activation and cell cycle reentry. Mol Cell Biol 1998; 18(8): 4499–508PubMedGoogle Scholar
  57. 57.
    Couse JF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev 1999; 20(3): 358–417PubMedGoogle Scholar
  58. 58.
    Dechering K, Boersma C, Mosselman S. Estrogen receptors alpha and beta: two receptors of a kind? Curr Med Chem 2000; 7(5): 561–76PubMedGoogle Scholar
  59. 59.
    Nilsson S, Makela S, Treuter E, et al. Mechanisms of estrogen action. Physiol Rev 2001; 81(4): 1535–65PubMedGoogle Scholar
  60. 60.
    Fitzpatrick SL, Funkhouser JM, Sindoni DM, et al. Expression of estrogen receptor-beta protein in rodent ovary. Endocrinology 1999; 140(6): 2581–91PubMedGoogle Scholar
  61. 61.
    Nilsson S, Gustafsson JA. Biological role of estrogen and estrogen receptors. Crit Rev Biochem Mol Biol 2002; 37(1): 1–28PubMedGoogle Scholar
  62. 62.
    Bocchinfuso WP, Korach KS. Mammary gland development and tumorigenesis in estrogen receptor knockout mice. J Mammary Gland Biol Neoplasia 1997; 2: 323–34PubMedGoogle Scholar
  63. 63.
    Forster C, Makela S, Warri A, et al. Involvement of estrogen receptor beta in terminal differentiation of mammary gland epithelium. Proc Natl Acad Sci U S A 2002; 99(24): 15578–83PubMedGoogle Scholar
  64. 64.
    Korach KS, Couse JF, Curtis SW, et al. Estrogen receptor gene disruption: molecular characterization and experimental and clinical phenotypes. Recent Prog Horm Res 1996; 51: 159–86PubMedGoogle Scholar
  65. 65.
    Pendaries C, Darblade B, Rochaix P, et al. The AF-1 activation-function of ERalpha may be dispensable to mediate the effect of estradiol on endothelial NO production in mice. Proc Natl Acad Sci U S A 2002; 99(4): 2205–10PubMedGoogle Scholar
  66. 66.
    Scully KM, Gleiberman AS, Lindzey J, et al. Role of estrogen receptor-alpha in the anterior pituitary gland. Mol Endocrinol 1997; 11(6): 674–81PubMedGoogle Scholar
  67. 67.
    Couse JF, Bunch DO, Lindzey J, et al. Prevention of the polycystic ovarian phenotype and characterization of ovulatory capacity in the estrogen receptor-alpha knockout mouse. Endocrinology 1999; 140(12): 5855–65PubMedGoogle Scholar
  68. 68.
    Krege JH, Hodgin JB, Couse JF, et al. Generation and reproductive phenotypes of mice lacking estrogen receptor beta. Proc Natl Acad Sci U S A 1998; 95(26): 15677–82PubMedGoogle Scholar
  69. 69.
    Morishima A, Grumbach MM, Simpson ER, et al. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 1995; 80(12): 3689–98PubMedGoogle Scholar
  70. 70.
    Eddy EM, Washburn TF, Bunch DO, et al. Targeted disruption of the estrogen receptor gene in male mice causes alteration of spermatogenesis and infertility. Endocrinology 1996; 137(11): 4796–805PubMedGoogle Scholar
  71. 71.
    Weihua Z, Makela S, Andersson LC, et al. A role for estrogen receptor beta in the regulation of growth of the ventral prostate. Proc Natl Acad Sci U S A 2001; 98(11): 6330–5PubMedGoogle Scholar
  72. 72.
    Dupont S, Krust A, Gansmuller A, et al. Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes. Development 2000; 127(19): 4277–91PubMedGoogle Scholar
  73. 73.
    Jilka RL, Hangoc G, Girasole G, et al. Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science 1992; 257(5066): 88–91PubMedGoogle Scholar
  74. 74.
    Meema HE, Meema S. Prevention of postmenopausal osteoporosis by hormone treatment of the menopause. CMAJ 1968; 99(6): 248–51Google Scholar
  75. 75.
    Rossouw JE, Anderson GL, Prentice RL, et al. 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(3): 321–33PubMedGoogle Scholar
  76. 76.
    Smith EP, Boyd J, Frank GR, et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man (published erratum appears in N Engl J Med 1995 Jan 12; 332 (2): 131). N Engl J Med 1994; 331(16): 1056–61PubMedGoogle Scholar
  77. 77.
    Carani C, Qin K, Simoni M, et al. Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 1997; 337(2): 91–5PubMedGoogle Scholar
  78. 78.
    Arts J, Kuiper GG, Janssen JM, et al. Differential expression of estrogen receptors alpha and beta mRNA during differentiation of human osteoblast SV-HFO cells. Endocrinology 1997; 138(11): 5067–70PubMedGoogle Scholar
  79. 79.
    Onoe Y, Miyaura C, Ohta H, et al. Expression of estrogen receptor beta in rat bone. Endocrinology 1997; 138(10): 4509–12PubMedGoogle Scholar
  80. 80.
    Oreffo RO, Kusec V, Virdi AS, et al. Expression of estrogen receptor-alpha in cells of the osteoclastic lineage. Histochem Cell Biol 1999; 111(2): 125–33PubMedGoogle Scholar
  81. 81.
    Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 2000; 21(2): 115–37PubMedGoogle Scholar
  82. 82.
    Pacifici R. Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis. J Bone Miner Res 1996; 11(8): 1043–51PubMedGoogle Scholar
  83. 83.
    Hofbauer LC, Heufelder AE. Role of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in bone cell biology. J Mol Med 2001; 79(5–6): 243–53PubMedGoogle Scholar
  84. 84.
    Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology 2001; 142(12): 5050–5PubMedGoogle Scholar
  85. 85.
    Hofbauer LC, Khosla S, Dunstan CR, et al. The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 2000; 15(1): 2–12PubMedGoogle Scholar
  86. 86.
    Kousteni S, Bellido T, Plotkin LI, et al. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 2001; 104(5): 719–30PubMedGoogle Scholar
  87. 87.
    Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease: ten-year follow-up from the nurses’ health study. N Engl J Med 1991; 325(11): 756–62PubMedGoogle Scholar
  88. 88.
    Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992; 117(12): 1016–37PubMedGoogle Scholar
  89. 89.
    Sudhir K, Chou TM, Chatterjee K, et al. Premature coronary artery disease associated with a disruptive mutation in the estrogen receptor gene in a man. Circulation 1997; 96(10): 3774–7PubMedGoogle Scholar
  90. 90.
    Iafrati MD, Karas RH, Aronovitz M, et al. Estrogen inhibits the vascular injury response in estrogen receptor alpha-deficient mice. Nat Med 1997; 3(5): 545–8PubMedGoogle Scholar
  91. 91.
    Lindner V, Kim SK, Karas RH, et al. Increased expression of estrogen receptor-beta mRNA in male blood vessels after vascular injury. Circ Res 1998; 83(2): 224–9PubMedGoogle Scholar
  92. 92.
    Pare G, Krust A, Karas RH, et al. Estrogen receptor-alpha mediates the protective effects of estrogen against vascular injury. Circ Res 2002; 90(10): 1087–92PubMedGoogle Scholar
  93. 93.
    Nabulsi AA, Folsom AR, White A, et al. Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women: The Atherosclerosis Risk in Communities Study Investigators. N Engl J Med 1993; 328(15): 1069–75PubMedGoogle Scholar
  94. 94.
    Srivastava RA, Srivastava N, Averna M, et al. Estrogen up-regulates apolipoprotein E (ApoE) gene expression by increasing ApoE mRNA in the translating pool via the estrogen receptor alpha-mediated pathway. J Biol Chem 1997; 272(52): 33360–6PubMedGoogle Scholar
  95. 95.
    Croston GE, Milan LB, Marschke KB, et al. Androgen receptor-mediated antagonism of estrogen-dependent low density lipoprotein receptor transcription in cultured hepatocytes. Endocrinology 1997; 138(9): 3779–86PubMedGoogle Scholar
  96. 96.
    Ma PT, Yamamoto T, Goldstein JL, et al. Increased mRNA for low density lipoprotein receptor in livers of rabbits treated with 17 alpha-ethinyl estradiol. Proc Natl Acad Sci U S A 1986; 83(3): 792–6PubMedGoogle Scholar
  97. 97.
    Kovanen PT, Brown MS, Goldstein JL. Increased binding of low density lipoprotein to liver membranes from rats treated with 17 alpha-ethinyl estradiol. J Biol Chem 1979; 254(22): 11367–73PubMedGoogle Scholar
  98. 98.
    Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998; 280(7): 605–13PubMedGoogle Scholar
  99. 99.
    Foody JA. Preventive cardiology. Curr Opin Cardiol 1999; 14(5): 382–91PubMedGoogle Scholar
  100. 100.
    Kooistra T, Emeis JJ. Hormone replacement therapy. Curr Opin Chem Biol 1999; 3(4): 495–9PubMedGoogle Scholar
  101. 101.
    Shughrue PJ, Lubahn DB, Negro-Vilar A, et al. Responses in the brain of estrogen receptor alpha-disrupted mice. Proc Natl Acad Sci U S A 1997; 94(20): 11008–12PubMedGoogle Scholar
  102. 102.
    Birge SJ. Is there a role for estrogen replacement therapy in the prevention and treatment of dementia? J Am Geriatr Soc 1996; 44(7): 865–70PubMedGoogle Scholar
  103. 103.
    Lamberts SW, van den Beld AW, van der Lely AJ. The endocrinology of aging. Science 1997; 278(5337): 419–24PubMedGoogle Scholar
  104. 104.
    Fillit H. Estrogens in the pathogenesis and treatment of Alzheimer’s disease in postmenopausal women. Ann N Y Acad Sci 1994; 743: 233–8PubMedGoogle Scholar
  105. 105.
    Lichtman R. Perimenopausal and postmenopausal hormone replacement therapy: Pt 1. An update of the literature on benefits and risks. J Nurse Midwifery 1996; 41(1): 3–28PubMedGoogle Scholar
  106. 106.
    Shughrue PJ, Lane MV, Merchenthaler I. Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system. J Comp Neurol 1997; 388(4): 507–25PubMedGoogle Scholar
  107. 107.
    Osterlund M, Kuiper GG, Gustafsson JA, et al. Differential distribution and regulation of estrogen receptor-alpha and -beta mRNA within the female rat brain. Brain Res Mol Brain Res 1998; 54(1): 175–80PubMedGoogle Scholar
  108. 108.
    Rapp SR, Espeland MA, Shumaker SA, et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003; 289(20): 2663–72PubMedGoogle Scholar
  109. 109.
    Shumaker SA, Legault C, Thal L, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003; 289(20): 2651–62PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Tomas Barkhem
    • 1
  • Stefan Nilsson
    • 1
  • Jan-Åke Gustafsson
    • 2
  1. 1.Karo Bio ABHuddingeSweden
  2. 2.Department of Medical Nutrition and BioSciences at NovumKarolinska InstituteHuddingeSweden

Personalised recommendations