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Syndromes of Glucocorticoid Resistance

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The Acth Axis: Pathogenesis, Diagnosis and Treatment

Part of the book series: Endocrine Updates ((ENDO,volume 21))

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Abstract

There exists variability in the sensitivity to glucocorticoids within the normal population. These differences are probably minor as the majority of our knowledge about variability in glucocorticoid sensitivity has been collected by observations in patients, who received pharmacological amounts of glucocorticoid in order to treat non-endocrine diseases. Exogenous glucocorticoids play a major role in the acute and chronic therapy of a number of immune diseases such as asthma and rheumatoid arthritis, and contribute considerably to the prevention of allograft rejection after organ transplantation (1). Nevertheless, some disadvantages of glucocorticoid therapy have reduced the enthusiasm to use these agents. The first disadvantage is the unpredictable occurrence of side effects during (chronic) therapy (2-4). Although plasma concentrations can be measured, it is currently impossible to define a safe glucocorticoid dose for a given patient which provides a maximal beneficial effect with as little side effects as possible. Another disadvantage is the unpredictable efficacy of glucocorticoid therapy in chronic immune disease. There is clinical and laboratory evidence that patients can be divided into steroid sensitive and steroid resistant groups (4). These differences have been documented in the treatment of asthma and rheumatoid arthritis as well as in renal grafts recipients, and can be observed every day in clinical settings.

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References

  1. Boumpas DT, Chrousos GP, Wilder RL etal 1993 Glucocorticoid therapy for immune mediated diseases: Basic and clinical correlates. Ann Intern Med 119:1198–1208

    PubMed  CAS  Google Scholar 

  2. Bollet AJ, Black R, Bunim JJ 1955 Major undesirable side effects resulting from prednisolone and prednisone. JAMA 158:459–463

    Article  CAS  Google Scholar 

  3. Saag KG, Oehnke R, Caldwell JR etal 1994 Low dose long term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse effects. Am J Med 96:115–123

    Article  PubMed  CAS  Google Scholar 

  4. Lamberts SWJ, Huizenga NATM, de Lange P et al 1996 Clinical aspects of glucocorticoid sensitivity. Steroids 61:157–160

    Article  PubMed  CAS  Google Scholar 

  5. Vingerhoeds AC, Thijssen JH, Schwarz F 1976 Spontaneous hypercortisolism without Cushing’s syndrome. J Clin Endocrinol Metab 43:1128–1133

    Article  PubMed  CAS  Google Scholar 

  6. Evans ME 1988 The steroid and thyroid hormone receptor superfamily. Science 40:889–895

    Article  Google Scholar 

  7. Giguere V, Hollenberg SM, Rosenfeld MG et al 1986 Functional domains of the human glucocorticoid receptor. Cell. 46:645–652

    Article  PubMed  CAS  Google Scholar 

  8. Fredman LP, Luisi BF, Korszun ZN et at 1988 The function and structure of the metal coordination sites within the glucocorticoid receptor DNA binding domain. Nature 334:543–546

    Article  Google Scholar 

  9. Zilliacus J, Wright APH, Calrstedt-Dule J et at 1995 Structural determinants of DNA binding specificity by steroid receptors. Mol Endocrinol 9:389–400

    Article  PubMed  CAS  Google Scholar 

  10. Bamberger CM, Schulte HM, Chrousos GP 1996 Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocrine Rev 17:245–261

    CAS  Google Scholar 

  11. Tsai SY, Carlstedt-Duke J, Weigel NL et al 1988 Molecular interactions of steroid hormone receptor with its enhancer element: Evidence for receptor dimer formation. Cell 55:361–369

    Article  PubMed  CAS  Google Scholar 

  12. Hollenberg SM, Weinberger C, Ong ES et al 1985 Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature 318:635–641

    Article  PubMed  CAS  Google Scholar 

  13. Lefstin JA, Thomas JR, Yamamoto KR 1994 Influence of a steroid receptor DNA binding domain on transcriptional regulatory functions. Genes Dev 8:2842–2856

    Article  PubMed  CAS  Google Scholar 

  14. Dalman FC, Scherrer IC, Taylor LP et al 1991 Localization of the 90 kDa heat shock protein binding site within the hormone binding domain of the glucocorticoid receptor by peptide competition. J Biol Chem 266:3482–3490

    PubMed  CAS  Google Scholar 

  15. Hutchkinson KA, Scherre LC, Czar MJ et at 1993 Regulation of glucocorticoid receptor function through assembly of a receptor heat shock protein complex. Ann NY Acad SCI 648:35–48

    Article  Google Scholar 

  16. Pratt WB 1993 The role of heat shock proteins in the regulation of the function, folding and trafficing of the glucocorticoid receptor. J Biol Chem 268:21455–21458

    PubMed  CAS  Google Scholar 

  17. Picard D, Yamamoto KT 1987 Two signals mediate hormone dependent nuclear localization of the glucocorticoid receptor. EMBO 6:3333–3340

    CAS  Google Scholar 

  18. Dahlman-Wright K, Wright APH, Gustafsson J-A 1992 Determinants of high-affinity DNA binding by the glucocorticoid receptor: Evaluation of receptor domains outside the DNA-binding domain. Biochemistry 31:9040–9044

    Article  PubMed  CAS  Google Scholar 

  19. Hollenberg S, Evans RM 1988 Multiple cooperative transactivation domains in the human glucocorticoid receptor. Cell 55:899–906

    Article  PubMed  CAS  Google Scholar 

  20. Webster NJG, Green S, Jin JR et al 1988 The hormone binding domain of estrogen and glucocorticoid receptors contain an inducable transcription activation function. Cell 54:199–207

    Article  PubMed  CAS  Google Scholar 

  21. Danielian PS, White R, Lees JA et al 1992 Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors. EMBO 11:1025–1033

    CAS  Google Scholar 

  22. Lanz RB, Rusconi S 1994 A conserved carboxy terminal subdomain is important for ligand interpretation and transactivation by nuclear receptors. Endocrinology 135:2183–2195

    Article  PubMed  CAS  Google Scholar 

  23. Vedeckis WV 1983 Biochemistry 22:1983–1984

    Article  PubMed  CAS  Google Scholar 

  24. Harrison RW, Fairfield S, Orth DN 1974 Evidence for glucocorticoid transport through the target cell membrane. Biochem Biophys Res Commun 61:1262–1267

    Article  PubMed  CAS  Google Scholar 

  25. Hu L-M, Bodwell J, Hu J-M et al 1994 Glucocorticoid receptors in ATP depleted cells. J Biol Chem 269:6571–6577

    PubMed  CAS  Google Scholar 

  26. Orti E, Bodwell JE, Munck A 1992 Phosphorilation of steroid hormone receptors. Endocrine Rev 13:105–128

    CAS  Google Scholar 

  27. Bodwell JE, Hu L-M, Hu J-m et al 1993 Glucocorticoid receptors: ATP dependent cycling and hormone dependent hyperphosphorilation J Steroid Biochem Mol Biol 47:31–38

    CAS  Google Scholar 

  28. Nigg EA, Bauerle PA, Luhrmann R 1991 Cell 66:15–22

    Article  PubMed  CAS  Google Scholar 

  29. Wright AP, Zilliacus J, McEwan IJ et al 1993 Structure and function of the glucocorticoid receptor. J Steroid Biochem Mol Biol 47:11–19

    Article  PubMed  CAS  Google Scholar 

  30. Muller M, Renkawitz R 1990 Biochim Biophys Acta 1088:171–182

    Google Scholar 

  31. Bresnick EH, John S, Berard DS et al 1990 Glucocorticoid dependent receptor disruption of a specific nucleosome on the MMTV promotor is prevented by sodium butyrate. Proc Natl Acad Sci USA 87:3977–3981

    Article  PubMed  CAS  Google Scholar 

  32. Ranson LJ, Verma IM 1990 Nuclear proto oncogenes fos and jun. Annu Rev Cell Biol 6:539–557

    Article  Google Scholar 

  33. Angel P, Karin M 1991 The role of jun, fos and AP-1 complex in cell proliferation and transformation. Biochim Biophys Acta 1072:129–157

    PubMed  CAS  Google Scholar 

  34. Lee W, Mitchell P, Tjian R 1987 Purified AP-1 interacts with TPA-inducible enhancer elements. Cell 49:741–752

    Article  PubMed  CAS  Google Scholar 

  35. Barnes PJ, Karin M 1997 Nuclear factor kB - A pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 336:1066–1071

    Article  PubMed  CAS  Google Scholar 

  36. Lamberts SWJ, Poldermans D, Zweens M et al 1986 Familial cortisol resistance: differential diagnostic and therapeutic aspects. J Clin Endocrinol Metab 63:1328–1333

    Article  PubMed  CAS  Google Scholar 

  37. Lamberts SWJ, Koper JW, Biemond Pet al 1992 Cortisol receptor resistance: the variability of its clinical presentation and response to treatment. J Clin Endocrinol Metab 74:313–321

    Article  PubMed  CAS  Google Scholar 

  38. Chrousos GP 1993 Syndromes of glucocorticoid resistance. Ann Internal Med 119:1113–1124

    CAS  Google Scholar 

  39. Chrousos GP, Vingerhoeds AC, Brandon D et al 1982 Primary cortisol resistance in man: a glucocorticoid receptor mediated disease. J Clin Invest 69:1261–1268

    Article  PubMed  CAS  Google Scholar 

  40. Lida S, Moriwaki K, Itoh Y et al 1985 Primary cortisol resistance accompanied by a reduction in glucocorticoid receptors in two members of the same family. J Clin Endocrinol Metab 60:967–971

    Article  Google Scholar 

  41. Bronnegard M, Werner S, Gustafsson JA 1989 Primary cortisol resistance associated with a thermolabile glucocorticoid receptor in a patient with fatigue as the only symptom. 78:1270–1278

    Google Scholar 

  42. Nawata H, Sekiya K, Higuchi K et al 1987 Decreased DNA binding of glucocorticoid receptor complex in cultured skin fibroblasts from a patient with the glucocorticoid resistance syndrome. J Clin Endocrinol Metab 65:219–226

    Article  PubMed  CAS  Google Scholar 

  43. Jaursch-Hancke C, Allolio B, Reinke M et al 1989 Primary cortisol resistance as a differential diagnosis of Cushing’s syndrome. Acta Endocrinol Copenh 120 (supp) 113

    Google Scholar 

  44. Vercei P, Frank K, Haack D et al 1989 Primary glucocorticoid receptor defect with likely familial involvement. Cancer Res 49 (supp) 2220s-2221s

    Google Scholar 

  45. Malchoff CD, Javier EC, Malchoff DM et al 1990 Primary cortisol resistance presnting as isosexual precocity. J Clin Endocrinol Metab 70:503–507

    Article  PubMed  CAS  Google Scholar 

  46. Werner S, Thoreu M, Gustafsson JA et al 1992 Glucocorticoid recptor abnormalities in fibroblasts from patients with idiopathic resistance to dexamethasone diagnosed when evaluated for adrenocortical disorders. J Clin Endocrinol Metab 75:1005–1009

    Article  PubMed  CAS  Google Scholar 

  47. Karl M, Lamberts SWJ, Koper FJW et al 1996 Cushing’s disease preceded by generalized glucocorticoid resistance: clinical consequences of a novel, dominant negative glucocorticoid receptor variant. Proc Assoc Am Physic 108:296–307

    CAS  Google Scholar 

  48. Mendonca BB, Leite MV, Bachea TA et al 1999 Familial glucocorticoid resistance due to a novel mutation in the glucocorticoid receptor gene associated with a heterozygous large conversion of 21-hydroxylase gene causing female pseudohermafroditism. The Endocrine society, San Diego, p 273 (Abstr)

    Google Scholar 

  49. Ruiz M, Lind U, Gafvels M et al 2001 Characterization of two novel mutations in the glucocorticoid receptor gene in patients with primary cortisol resistance. Clin Endocrinol 55: 363–371

    Article  CAS  Google Scholar 

  50. Vottero A, Combe H, Lecomte P, Longui CA, Chrousos GP 1999 A novel mutation of the glucocorticoid receptor in familial glucocorticoid resistance. The Endocrine society, San Diego, p 90 (Abstr)

    Google Scholar 

  51. Enico IJ, Detero-Wadleigh SD 1991 The genomic structure of the human glucocrticoid receptor. J Biol Chem 266:7182–7188

    Google Scholar 

  52. Karl M, Lamberts SWJ, Detera-Wadleigh SD et al 1993 Familial glucocorticoid resistance caused by a splice site deletion in the human glucocorticoid receptor gene. J Clin Endocrinol Metab 76:683–689

    Article  PubMed  CAS  Google Scholar 

  53. Hurley DM, Accili D, Stratakis CA et al 1991 Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance. J Clin Invest 87:680–686

    Article  PubMed  CAS  Google Scholar 

  54. Malchoff DM, Brufsky A, Reardon G et al 1993 A mutation of the glucocorticoid receptor in primary cortisol resistance. J Clin Invest 91:1918–1925

    Article  PubMed  CAS  Google Scholar 

  55. Scheithauer BW, Kovacs K, Randall RV 1983 The pituitary gland in untreated Addison’s disease. Arch Pathol Lab Med 107:484–487

    PubMed  CAS  Google Scholar 

  56. Huizenga NATM, De Lange P, Koper FJW et al 2000 Five patients with clinical and/or biochemical cortisol resistance without alterations in the glucocorticoid receptor gene. J Clin Endocrinol Metab 85(5):2076–2081

    Article  PubMed  CAS  Google Scholar 

  57. Koper FJW, Stolk RP, Huizenga NATM et al 1997 Lack of association between five polymorphisms in the glucocorticoid receptor gene and glucocorticoid resistance. Hum Genet 99: 663–668

    Article  PubMed  CAS  Google Scholar 

  58. De Lange P, Koper FJW, Huizenga NATM et al 1997 Different hormone dependent transcriptional activation and -repression by naturally occuring human glucocorticoid receptor variants. Mol Endocrinol 11(8): 1156–1164

    Article  PubMed  Google Scholar 

  59. New MI, Nimkarn S, Brandon DD et al 1999 Resistance to several steroids in two sisters. J Clin Endocrinol Metab 84:4454–4464

    Article  PubMed  CAS  Google Scholar 

  60. Sher ER, Leung DYM, Surs W et al 1994 Steroid resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy. J Clin Invest 93:33–39

    Article  PubMed  CAS  Google Scholar 

  61. Norbiato G, Bevilaqua M, Vago T et al 1992 Cortisol resistance in acquired immunodeficiency syndrome. J Clin Endocrinol Metab 74:608–613

    Article  PubMed  CAS  Google Scholar 

  62. Chikanza IC, Panayi GS 1993 The effects of hydrocortisone on in vitro lymphocyte proliferation and interleukin-2 and -4 production in corticosteroid sensitive and resistant subjects. Eur J Clin Invest 23:845–850

    Article  PubMed  CAS  Google Scholar 

  63. Munck A, Guyre PM, Holbrook NJ 1984 Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocrine Rev. 5:25–44

    Article  CAS  Google Scholar 

  64. Almawi WY, Lipman ML, Stevens AC et al 1991 Abrogation of glucocorticoid mediated inhibition of T cell proliferation by the synergistic action of IL-1, IL-6 and IFN gamma. J Immunol 146:3523–3537

    PubMed  CAS  Google Scholar 

  65. Gilles S, Crabtree CR, Smith KA 1979 Glucocorticoid induced inhibition of T cell growth factor production. J Immunol 123:1624–1631

    Google Scholar 

  66. Boumpas DT, Anastassiou ED, Older SA et al 1991 Dexamethasone inhibits human IL-2 but not IL-2 receptor gene expression in vitro at the level of nuclear transcription. J Clin Invest 87:1739–1747

    Article  PubMed  CAS  Google Scholar 

  67. Molijn GJ, Spek JJ, van Uffelen JCJ et al 1995 Differential adaptation of glucocorticoid sensitivity of peripheral blood mononuclear leukocytes in patients with sepsis or septic shock J Clin Endocrinol Metab 80:1799–1803

    PubMed  CAS  Google Scholar 

  68. Corrigan CJ, Brown JPH, Barnes NC et al 1991 Glucocorticoid resitance in chronic asthma: glucocorticoid pharmacokinetics, glucocorticoid receptor characteristics and inhibition of peripheral blood T cell proliferation by glucocorticoid in vitro. Am Rev Respir Dis 144:1016–1025

    Article  PubMed  CAS  Google Scholar 

  69. Corrigan CJ, Brown JPH, Barnes NC et al 1991 Glucocorticoid resistance in chronic asthma: peripheral blood T lymphocyte activation and comparison of the T lymphocyte inhibitory effects of glucocorticoids and cyclosporin A. Am Rev Respir Dis 144:1026–1032

    Article  PubMed  CAS  Google Scholar 

  70. Bamberger M, Bamberger AM, de Castro M et al 1995 Glucocorticoid receptor p, a potential endogenous inhibitor of glucocorticoid action in humans. J Clin Invest 95: 2435–2441

    Article  PubMed  CAS  Google Scholar 

  71. Hecht K, Carlstedt-Duke J, Stierna P et al 1997 Evidence that the p-isoform human glucocorticoid receptor does not act as a physiologically significant repressor. J Biol Chem 272:26659–26664

    Article  PubMed  CAS  Google Scholar 

  72. Honda M, Fumika 0, Tokiyoshi A et al 2000 Expression of the glucocorticoid receptor p in lymphocytes of patients with glucocorticoid resistant ulcerative colitis. Gastroenterology 118:859–866

    Article  PubMed  CAS  Google Scholar 

  73. Lippman ME, Halterman RH, Leventhal BG et al 1973 Glucocorticoid binding proteins in human acute lymphoblastic leukemic blast cells. J Clin Invest 52:1715–1726

    Article  PubMed  CAS  Google Scholar 

  74. Moalli P, Rosen S 1994 Glucocorticoid receptors and resistance to glucocorticoids in hematologic malignancies. Leukemia Lymphoma 15:363–374

    Article  PubMed  CAS  Google Scholar 

  75. Strasser Wozak E, Hattmann-Storfer R, Hala M et al 1995 Splice site mutations in the glucocortiod receptor gene cause resistance to glucocorticoid induced apaptosis in a human acute leukemic cell line. Cancer Res 55:348–353

    PubMed  CAS  Google Scholar 

  76. de Lange P, Segeren CM, Koper JW et al 2001Expression in hematologic malignancies of a glucocorticoid receptor splice variant that augments glucocorticoid mediated effects in transfected cells. Cancer Res 61(10):3937–3941

    PubMed  Google Scholar 

  77. Liddle GW 1960 Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing’s syndrome. J Clin Enocrinol and Metab. 20:1539–1560

    Article  CAS  Google Scholar 

  78. James VHT, Landon J, Wynn V 1965 Oral and intravenous suppression tests in the diagnosis of Cushing’s syndrome. J Clin Endocrinol and Metab. 33:515–524

    CAS  Google Scholar 

  79. Drouin J, Trifiro MA, Plante RK et al 1989 Glucocorticoid receptor binding to a specific DNA sequence is required for hormone-dependent repression of proopiomelanocortin gene transcription. Mol Cell Biol 9:5305–5314

    PubMed  CAS  Google Scholar 

  80. Ray DW, Littlewood AC, Clark AJL et al 1994 Human small cell lung cancer cell lines expressing the proopiomelanocortin gene have aberrant glucocorticoid receptor function. J Clin Invest 93:1625–1630

    Article  PubMed  CAS  Google Scholar 

  81. Karl M, Von Wichert G, Kempter E et al 1996 Nelson’s syndrome associated with a somatic frame shift mutation in the glucocorticoid receptor gene. J Clin Endocrinol Metab 81:124–129

    Article  PubMed  CAS  Google Scholar 

  82. Dahia PLM, Honneger J, Reinke M et al 1997 Expression of glucocorticoid receptor gene isoforms in corticotropin secreting tumors. J Clin Endocrinol Metab. 82:1088–1093

    Article  PubMed  CAS  Google Scholar 

  83. Huizenga NATM, de Lange P, Koper JW et al 1998 Human ACTH secreting pituitary adenomas show frequent loss of heterozygosity at the glucocorticoid receptor gene locus. J Clin Endocrinol and Metab 83:917–921

    Article  CAS  Google Scholar 

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  1. Department of Internal Medicine, University Hospital Dijkzigt, Dr Molewaterplein 40, Rotterdam, 3015, GD, The Netherlands

    Nannette A. T. M. Huizenga & Steven W. J. Steven

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  1. Nannette A. T. M. Huizenga
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  2. Steven W. J. Steven
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  1. Division of Endocrinology, Diabetology & Metabolism, University Hospital (CHUV), Lausanne, Switzerland

    Rolf C. Gaillard M.D.

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Huizenga, N.A.T.M., Steven, S.W.J. (2003). Syndromes of Glucocorticoid Resistance. In: Gaillard, R.C. (eds) The Acth Axis: Pathogenesis, Diagnosis and Treatment. Endocrine Updates, vol 21. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0501-3_15

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  • DOI: https://doi.org/10.1007/978-1-4615-0501-3_15

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