Cortisol Resistance in Conditions such as Asthma and the Involvement of 11β-HSD-2: A Hypothesis

Abstract

The two types of corticosteroid hormones, the mineralocorticoids and glucocorticoids, act in a complementary manner and are functionally closely linked. Aldosterone and glucocorticoids express their functions through the glucocorticoid receptors (GRs; GRα and GRβ) and the mineralocorticoid receptors (MRs). Commercially available steroidal drugs used in conditions such as asthma may act on both GR and MR receptors; although glucocorticoid-receptor agonists play a fundamental role in the treatment of inflammatory conditions, prolonged exposure may have adverse effects such as the development of resistance. Glucocorticoid resistance in such conditions has been observed to be accompanied by a downregulation of GRα, a twofold decrease in GR protein half-life, downregulation of GRα mRNA expression, and enhanced expression of GRβ. Other suggestions for glucocorticoid resistance include alternative splicing of the GR gene with subsequent expression of the GRβ protein isoform, defective regulation of gene transcription of the GR gene or GR mutations, defective DNA binding and transactivating domains of the GR. In addition, we would like to suggest that dysregulation of the MR enzyme 11β-HSD-2 may be one of the causes of resistance. When expressed in cells with MRs, this enzyme’s major role is to prevent permanent occupancy of MR by glucocorticoid hormones, allowing concentration-dependent binding of aldosterone to MR. However, deficiency of the 11β-HSD isoforms (particularly 11β-HSD-2) leads to the activation of MRs by glucocorticoids rather than the glucocorticoids interacting with its “normal” receptors, the GRs. We will substantiate on support for our hypothesis in the dysregulation of this enzyme, which is typically associated with significantly higher levels of circulating plasma cortisol and elevated levels of cholesterol, little or no response to systemic glucocorticoids, and problems associated with homeostasis primarily in the distal nephron and distal colon. These are some of the symptoms typically noted in cortisol resistance.

Key words

Glucocorticoid receptors - mineralocorticoid receptors - cortisol resistance - 11β-HSD enzyme isoforms

References

• 1 Farman N, Rafestin-Oblin M E. Multiple aspects of mineralocorticoid selectivity.  Am J Physiol Renal Physiol. 2001;  280 (2) F181-F192
• 2 Arriza J L, Weinberger C, Cerelli G, Glaser T M, Handelin B L, Housman D E, Evans R M. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor.  Science. 1987;  237 268-275
• 3 Tsai M J, Omalley B W. Molecular mechanisms of action of steroid/thyroid receptor superfamily members.  Annu Rev Biochem. 1994;  63 451-486
• 4 Rogerson F M, Brennan F E, Fuller P J. Mineralocorticoid receptor binding, structure and function.  Mol Cell Endocrinol. 2004;  217 (1 - 2) 203-212
• 5 Garcia A, Steiner B, Kronenberg G, Bick-Sander A, Kempermann G. Age-dependent expression of glucocorticoid- and mineralocorticoid receptors on neural precursor cell populations in the adult murine hippocampus.  Aging Cell. 2004;  3 (6) 363-371
• 6 Sapolsky R M, Romero L M, Munck A U. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.  Endocr Rev. 2000;  21 (1) 55-89
• 7 Simpson S A, Tait J F, Wettstein A, Neher R, von Euw J, Reichstein T. Isolierung eines neuen kristallisierten Hormons aus Nebennieren mit besonders hoher Wirksamkeit auf den Mineralstoffwechsel.  Experientia. 1953;  9 333-335
• 8 Stockand J D. New ideas about aldosterone signalling in epithelia.  Am J Physiol. 2002;  282 F559-F576
• 9 Vanderbilt J N, Miesfeld R, Maler B A, Yamamoto K R. Intracellular receptor concentration limits glucocorticoid-dependent enhancer activity.  Mol Endocrinol. 1987;  1 68-74
• 10 Pujols L, Mullol J, Torrego A, Picado C. Glucocorticoid receptors in human airways.  Allergy. 2004;  59 (10) 1042-1052
• 11 Burnstein K L, Cidlowski J A. At the cutting edge. The down side of glucocorticoid receptor regulation.  Mol Cell Endocrinol. 1992;  83 C1-C8
• 12 Knutsson P U, Brönnegård M, Marcus C, Stierna P. Regulation of glucocorticoid receptor mRNA in nasal mucosa by local administration of fluticasone and budesonide.  J Allergy Clin Immunol. 1996;  97 655-661
• 13 Korn S H, Wouters E FM, Wesseling G, Arends J-W, Thunnissen F BJM. In vitro and in vivo modulation of a- and b-glucocorticoid receptor mRNA in human bronchial epithelium.  Am J Respir Crit Care Med. 1997;  155 1117-1122
• 14 Chikanza I C, Petrou P, Kingsley G, Chrousos G, Panayi G S. Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis.  Arthritis Rheum. 1992;  35 1281-1288
• 15 Schlaghecke R, Kornely E, Wollenhaupt J, Specker C. Glucocorticoid receptors in rheumatoid arthritis.  Arthritis Rheum. 1992;  35 740-744
• 16 Tanaka H, Akama H, Ichikawa Y. et al . Glucocorticoid receptor in patients with lupus nephritis: relationship between receptor levels in mononuclear leukocytes and effect of glucocorticoid therapy.  J Rheumatol. 1992;  19 878-883
• 17 Wilkinson J R, Crea A E, Clark T J, Lee T H. Identification and characterization of a monocyte-derived neutrophilactivating factor in corticosteroid-resistant bronchial asthma.  J Clin Investig. 1989;  84 1930-1941
• 18 Oakley R H, Sar M, Cidlowski J A. The human glucocorticoid receptor isoform. Expression, biochemical properties, and putative function.  J Biol Chem. 1996;  271 9550-9559
• 19 Necela B M, Cidlowski J A. Crystallization of the human glucocorticoid receptor ligand binding domain: a step towards selective glucocorticoids.  Trends Pharmacol Sci. 2003;  24 58-61
• 20 Pelaia G, Vatrella A, Cuda G, Maselli R, Marsico S A. Molecular mechanisms of corticosteroid actions in chronic inflammatory airway diseases.  Life Sci. 2003;  72 1549-1561
• 21 Hamid Q A, Wenzel S E, Hauk P J, Tsicopoulos A, Wallaert B, Lafitte J J, Chrousos G P, Szefler S J, Leung D Y. Increased glucocorticoid receptor b in airway cells of glucocorticoid- insensitive asthma.  Am J Respir Crit Care Med. 1999;  159 1600-1604
• 22 Christodoulopoulos P, Leung D Y, Elliott M W, Hogg J C, Muro S, Toda M, Laberge S, Hamid Q A. Increased number of glucocorticoid receptor-beta-expressing cells in the airways in fatal asthma.  J Allergy Clin Immunol. 2000;  106 (3) 479-484
• 23 Hamilos D L, Leung D Y, Muro S, Kahn A M, Hamilos S S, Thawley  S E, Hamid Q A. GRβ expression in nasal polyp inflammatory cells and its relationship to the anti-inflammatory effects of intranasal fluticasone.  J Allergy Clin Immunol. 2001;  108 59-68
• 24 Honda M, Orii F, Ayabe T, Imai S, Ashida T, Obara T, Kohgo Y. Expression of glucocorticoid receptor b in lymphocytes of patients with glucocorticoidresistant ulcerative colitis.  Gastroenterology. 2000;  118 859-866
• 25 Orii F, Ashida T, Nomura M, Maemoto A, Fujiki T, Ayabe T, Imai S, Saitoh Y, Kohgo Y. Quantitative analysis for human glucocorticoid receptor alpha/beta mRNA in IBD.  Biochem Biophys Res Commun. 2002;  296 (5) 1286-1294
• 26 Werner S, Bronnegard M. Molecular basis of glucocorticoid-resistant syndromes.  Steroids. 1996;  61 (4) 216-221
• 27 Adcock I M, Brown C R, Gelder C M, Shirasaki H, Peters M J, Barnes P J. The effects of glucocorticoids on transcription factor activation in human peripheral blood mononuclear cells.  Am J Physiol. 1995;  37 C331-C338
• 28 Adcock I M, Lane S J, Brown C R, Peters M J, Lee T H, Barnes P J. Differences in binding of glucocorticoid receptor to DNA in steroid-resistant asthma.  J Immunol. 1995;  54 3500-3505
• 29 Powers J H, Hillmann A G, Tang D C, Harmon J M. Cloning and expression of mutant glucocorticoid receptors from glucocorticoid-sensitive and resistant human leukemic cells.  Cancer Res. 1993;  53 4059-4065
• 30 Leung D Y, de Castro M, Szefler S J, Chrousos G P. Mechanisms of glucocorticoid-resistant asthma.  Ann N Y Acad Sci. 1998;  840 735-746
• 31 O’Connor T M, O’Halloran D J, Shanahan F. The stress response and the hypothalamic-pituitary-adrenal axis: from molecule to melancholia.  Q J Med. 2000;  93 323-333
• 32 Rohleder N, Joksimovic L, Wolf J M, Kirschbaum C. Hypocortisolism and increased glucocorticoid sensitivity of pro-inflammatory cytokine production in Bosnian war refugees with posttraumatic stress disorder.  Biol Psychiatry. 2004;  55 (7) 745-751
• 33 Hollenberg S M, Weinberger C, Ong E S, Cerelli G, Oro A, Lebo R, Thompson E B, Rosenfeld M G, Evans R M. Primary structure and expression of a functional human glucocorticoid receptor cDNA.  Nature. 1985;  318 635- 641
• 34 Adcock I M, Gilbey T, Gelder C M, Chung K F, Barnes P J. Glucocorticoid receptor localization in normal and asthmatic lung.  Am J Respir Crit Care Med. 1996;  154 771-782
• 35 Yun C-B, Lee B-H, Jang T-J. Expression of glucocorticoid receptors and cyclooxygenase-2 in nasal polyps from nonallergic patients.  Ann Otol Rhinol Laryngol. 2002;  111 61-67
• 36 Dahia P L, Honegger J, Reincke M, Jacobs R A, Mirtella A, Fahlbusch R, Besser G M, Chew S L, Grossman A B. Expression of glucocorticoid receptor gene isoforms in corticotropin-secreting tumors.  J Clin Endocrinol Metab. 1997;  82 1088-1093
• 37 Pedersen K B, Vedeckis W V. Quantification and glucocorticoid regulation of glucocorticoid receptor transcripts in two human leukemic cell lines.  Biochemistry. 2003;  42 (37) 10978-10990
• 38 Pedersen K B, Geng C D, Vedeckis W V. Three mechanisms are involved in glucocorticoid receptor autoregulation in a human T-lymphoblast cell line.  Biochemistry. 2004;  43 (34) 10851-10858
• 39 Kumar R, Thompson E B. The structure of the nuclear hormone receptors.  Steroids. 1999;  64 310-319
• 40 Rohleder N, Wolf J M, Kirschbaum C. Glucocorticoid sensitivity in humans - interindividual differences and acute stress effects.  Stress. 2003;  6 (3) 207-222
• 41 Melo M R, Faria C D, Melo K C, Reboucas N A, Longui C A. Real-time PCR quantitation of glucocorticoid receptor alpha isoform.  . BMC molecular biology [electronic resource] 2004;  5 (1) 19
• 42 Pratt W B, Toft D O. Regulation of signaling protein function and trafficking by the Hsp90/Hsp70-based chaperone machinery.  Exp Biol Med (Maywood). 2003;  228 (2) 111-133
• 43 Pratt W B, Toft D O. Steroid receptor interactions with heat shock protein and immunophilin chaperones.  Endocr Rev. 1997;  18 (3) 306-60
• 44 Capepond F, Schweizer-Groyer G, Segard-Maurel I, Jibard N, Hollenberg S M, Giguere V, Evans R M, Baulieu E E. Heat shock protein 90 as a critical factor in maintaining glucocorticosteroid receptor in a nonfunctional state.  J Biol Chem. 1991;  266 5834-5841
• 45 Morishima Y, Kanelakis K C, Murphy P JM, Schewach D S, Pratt W B. Evidence for iterative ratcheting of receptor-bound Hsp70 between its ATP and ADP conformations during assembly of glucocorticoid receptor Hsp90 heterocomplexes.  Biochemistry. 2001;  40 1109-1116
• 46 Czar M J, Galigniana M D, Silverstein A M, Pratt W B. Geldanamycin, a heat shock protein 90-binding benzoquinone ansamycin, inhibits steroid-dependent translocation of the glucocorticoid receptor from the cytoplasm to the nucleus.  Biochemistry. 1997;  36 (25) 7776-7785
• 47 Elbi C, Walker D A, Romere G, Sullivan W P, Toft D O, Hagen G L, DeFranco D B. Molecular chaperones function as steroid receptor nuclear mobility factors.  Proceedings of the National Academy of Sciences of the United States of America. 2004;  101 (9) 2876-2881
• 48 Harell J M, Murphy P J, Morishima Y, Chen H, Mansfield J F, Galigniana M D, Pratt W B. Evidence for glucocorticoid receptor transport on microtubules by dynein.  J Biol Chem. 2004;  279 (52) 54647-54654
• 49 Bamberger C M, Schulte H M, Chrousos G P. Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids.  Endocr Rev. 1996;  17 245-261
• 50 Yudt M R, Cidlowski J A. The glucocorticoid receptor: coding a diversity of proteins and responses through a single gene.  Mol Endocrinol. 2002;  16 1719-1726
• 51 Bray P J, Cotton R G. Variations of the human glucocorticoid receptor gene (NR3C1): pathological and in vitro mutations and polymorphisms.  Hum Mutat. 2003;  21 557-568
• 52 De Castro M, Elliot S, Kino T, Bamberger C, Karl M, Webster E, Chrousos G P. The non-ligand binding b-isoform of the human glucocorticoid receptor (hGRβ): Tissue levels, mechanism of action, and potential physiologic role.  Mol Med. 1996;  2 597-607
• 53 Gougat C, Jaffuel D, Gagliardo R, Henriquet C, Bousquet J, Demoly P, Mathieu M. Overexpression of the human glucocorticoid receptor a and b isoforms inhibits AP-1 and NF-κB activities hormone independently.  J Mol Med. 2002;  80 309-318
• 54 Oakley R H, Webster J C, Sar M, Parker C R, Cidlowski J A. Expression and subcellular distribution of the b-isoform of the human glucocorticoid receptor.  Endocrinology. 1997;  138 5028-5038
• 55 Webster J C, Oakley R H, Jewell C M, Cidlowski J A. Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative beta isoform: a mechanism for the generation of glucocorticoid resistance.  Proc Natl Acad Sci USA. 2001;  98 6865-6870
• 56 De Lange P, Koper J W, Huizenga N A, Brinkmann A O, de Jong F H, Karl M, Chrousos G P, Lamberts S W. Differential hormone dependent transcriptional activation and repression by naturally occurring human glucocorticoid receptor variants.  Mol Endocrinol. 1997;  11 1156- 1164
• 57 Brogan I J, Murray I A, Cerillo G, Needham M, White A, Davis J RE. Interaction of glucocorticoid receptor isoform with transcription factors AP-1 and NF-kB: lack of effect of glucocorticoid receptor b.  Mol Cell Endocrinol. 1999;  157 95-104
• 58 De Lange P, Koper J W, Brinkmann A O, de Jong F H, Lamberts S WJ. Natural variants of the b isoform of the human glucocorticoid receptor do not alter sensitivity to glucocorticoids.  Mol Cell Endocrinol. 1999;  153 163-168
• 59 Yudt M R, Jewell C M, Bienstock R J, Cidlowski J A. Molecular origins for the dominant negative function of human glucocorticoid receptor beta.  Mol Cell Biol. 2003;  23 (12) 4319-4330
• 60 Rohleder N, Schommer N C, Hellhammer D H, Engel R, Kirschbaum C. Sex differences in glucocorticoid sensitivity of proinflammatory cytokine production after psychosocial stress.  Psychosocial Stress Psychosom Med. 2001;  63 (6) 966-972
• 61 Scheinman R I, Cogswell P C, Lofquist A K, Baldwin A S. Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids.  Science. 1995;  270 (5234) 283-286
• 62 Scheinman R I, Gualberto A, Jewell C M, Cidlowski J A, Baldwin A S. Characterization of mechanisms involved in transrepression of NF-κB by activated glucocorticoid receptors.  Mol Cell Biol. 1995;  15 (2) 943-953
• 63 Schule R, Rangarajan P, Kliewer S, Ransone L J, Bolado J, Yang N, Verma I M, Evans R M. Functional antagonism between oncoprotein c-Jun and the glucocorticoid receptor.  Cell. 1990;  62 1217-1226
• 64 Jonat C, Rahmsdorf H J, Park K K, Cato A C, Gebel S, Ponta H, Herrlich P. Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone.  Cell. 1990;  62 1189-1204
• 65 Yang-Yen H F, Chambard J C, Sun Y L, Schmidt T J, Drouin J, Karin M. Transcriptional interference between c-Jun and the glucocorticoid receptor: mutual inhibition of DNA binding due to direct protein-protein interaction.  Cell. 1990;  62 1205-1215
• 66 Ray A, Prefontaine K E. Physical association and functional antagonism between the p65 subunit of transcription factor NF-κB and the glucocorticosteroid receptor.  Proc Natl Acad Sci USA. 1994;  91 752-756
• 67 Caldenhoven E, Liden J, Wissink S, van de Stolpe A, Raaijimakers J, Koenderman L, Okret S, Gustafsson J A, van der Saag P T. Negative cross-talk between RelA and the glucocorticoid receptor: a possible mechanism for the anti-inflammatory action of glucocorticoids.  Mol Endocrinol. 1995;  9 401-412
• 68 McKay L I, Cidlowski J A. Cross-talk between nuclear factor-kappa B and the steroid hormone receptors: mechanisms of mutual antagonism.  Mol Endocrinol. 1998;  12 (1) 45-56
• 69 Auphan N, DiDonato J A, Rosette C, Helmberg A, Karin M. Immunosuppression by glucocorticoids: inhibition of NF-κB activity through induction of I kappa B synthesis.  Science. 1995;  270 286-290
• 70 Nissen R M, Yamamoto K R. The glucocorticoid receptor inhibits NF-κB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain.  Genes Dev. 2000;  14 2314-2329
• 71 Ito K, Barnes P J, Adcock I M. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1b-induced histone H4 acetylation on lysines 8 and 12.  Mol Cell Biol. 2000;  20 6891-6903
• 72 Kagoshima M, Ito K, Cosio B, Adcock I M. Glucocorticoid suppression of nuclear factor-jB: a role for histone modifications.  Biochem Soc Trans. 2003;  31 60-65
• 73 Bosscher K D, van den Berghe W, Haegeman G. The interplay between the glucocorticoid receptor and nuclear factor-jB or activator protein-1: molecular mechanisms for gene repression.  Endocrine Rev. 2003;  24 488-522
• 74 Caelles C, GonzaŽlez-Sancho J M, Mun˜oz A. Nuclear hormone receptor antagonism with AP-1 by inhibition of the JNK pathway.  Genes Dev. 1997;  11 3351-3364
• 75 Rogerson F M, Fuller P J. Interdomain interactions in the mineralocorticoid receptor.  Mol Cell Endocrinol. 2003;  200 45-55
• 76 Fuse H, Kitagawa H, Kato S. Characterization of transactivational property and coactivator mediation of rat mineralocorticoid receptor activation function-1 (AF-1).  Mol Endocrinol. 2000;  14 889-899
• 77 Liu W, Wang J, Yu G, Pearce D. Steroid receptor transcriptional synergy is potentiated by disruption of the DNA-binding domain dimer interface.  Mol Endocrinol. 1996;  10 1399-1406
• 78 Fagart J, Wurtz J-M, Souque A, Hellal-Levy C, Moras D, Rafestin-Oblin M-E. Antagonism in the human mineralocorticoid receptor.  The EMBO J. 1998;  17 3317-3325
• 79 Rupprecht R, Arriza J L, Spengler D, Reul J MHM, Evans R M, Holsboer F, Damm K. Transactivation and synergistic properties of the mineralocorticoid receptor: relationship to the glucocorticoid receptor.  Mol Endocrinol. 1993;  7 597-603
• 80 Nemoto T, Ohara-Nemoto Y, Sato N, Ota M. Dual role of 90-kDa heat shock protein in the function of the mineralocorticoid receptor.  J Biochem. 1993;  113 769-775
• 81 Farman N, Oblin M E, Lombes M, Delahaye F, Westphal H M, Bonvalet J P, Gasc J M. Immunolocalization of gluco- and mineralocorticoid receptors in the rabbit kidney.  Am J Physiol Cell Physiol. 1991;  260 C226-C233
• 82 Edwards C RW, Stewart P M, Burt D, Bret L, Mc Intyre M A, Sutanto W S, de Kloet E R, Monder C. Localisation of 11β-hydroxysteroid dehydrogenase-tissue specific protector of the mineralocorticoid receptor.  Lancet. 1988;  2 (8618) 986-989
• 83 Funder J W, Pearce P T, Smith R, Smith A I. Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated.  Science. 1988;  242 583-585
• 84 Takeda Y. Pathophysiological roles of vascular 11beta-hydroxysteroid dehydrogenase and aldosterone.  J Steroid Biochem Mol Biol. 2003;  85 (2 - 5) 443-447
• 85 Roland B L, Funder J W. Localization of 11β-hydroxysteroid dehydrogenase type 2 in rat tissues: in situ studies.  Endocrinology. 1996;  137 1123-1128
• 86 Seckl J R, Chapman K E. The 11-beta-hydroxysteroid dehydrogenase system, a determinant of glucocorticoid and mineralocorticoid action-medical and physiological aspects of the 11-beta-hydroxysteroid dehydrogenase system.  Eur J Biochem. 1997;  249 361-364
• 87 Rusvai E, Naray-Fejes-Toth A. A new isoform of 11-beta-hydroxysteroid dehydrogenase in aldosterone target cells.  J Biol Chem. 1993;  268 10717-10720
• 88 Kotelvtsev Y, Holmes M C, Burchell A, Houston P M, Schmoll D, Jamieson P, Best R, Brown R, Edwards C R, Seckl J R, Mullins J J. 11β-Hydroxysteorid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress.  Proc Natl Acad Sci USA. 1997;  94 14924-14929
• 89 White P C, Mune T, Agarwal A K. 11 Beta-hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid excess.  Endocr Rev. 1997;  18 135-156
• 90 Kannisto K, Pietilainen K H, Ehrenborg E, Rissanen A, Kaprio J, Hamsten A, Yki-Jarvinen H. Overexpression of 11beta-hydroxysteroid dehydrogenase-1 in adipose tissue is associated with acquired obesity and features of insulin resistance: studies in young adult monozygotic twins.  J Clin Endocrinol Metab. 2004;  89 (9) 4414-4421
• 91 Bujalska I J, Kumar S, Stewart P M. Does central obesity reflect “Cushing's disease of the omentum”?.  Lancet. 1997;  349 1210-1213
• 92 Stewart P M, Krozowski Z S. 11β-Hydroxysteroid dehydrogenase.  Vitam Horm. 1999;  57 249-324
• 93 Ricketts M L, Verhaeg J M, Bujalska I, Howie A J, Rainey W E, Stewart P M. Immunohistochemical localization of type 1 11β-hydroxysteroid dehydrogenase in human tissues.  J Clin Endocrinol Metab. 1998;  83 1325-1335
• 94 DeRijk R H, Eskandari F, Sternberg E M. Corticosteroid resistance in a subpopulation of multiple sclerosis patients as measured by ex vivo dexamethasone inhibition of LPS induced IL-6 production.  J Neuroimmunol. 2004;  151 (1 - 2) 180-188
• 95 Michelson D, Stone L, Galliven E, Magiakou M A, Chrousos G P, Sternberg E M, Gold P W. Multiple sclerosis is associated with alterations in hypothalamic-pituitary-adrenal axis function.  J Clin Endocrinol Metab. 1994;  79 848-853
• 96 Fraser R, Ingram M C, Anderson N H, Morrison C, Davies E, Connell J M. Cortisol effects on body mass, blood pressure, and cholesterol in the general population.  Hypertension. 1999;  33 1364-1368
• 97 Sapolsky R M. Stress, the aging brain, and the mechanisms of neuron death. Cambridge; MIT Press 1992
• 98 Szemeredi K, Bagdy G, Kopin I J, Goldstein D S. Neurocirculatory regulation in cortisol-induced hypertension.  Clin Exp Hypertens A. 1989;  11 1425-1439
• 99 Sundin O, Ohman A, Palm T, Strom G. Cardiovascular reactivity, Type A behavior, and coronary heart disease: comparisons between myocardial infarction patients and controls during laboratory-induced stress.  Psychophysiology. 1995;  32 28-35
• 100 LeBlanc J, Ducharme M B. Influence of personality traits on plasma levels of cortisol and cholesterol.  Physiol Behav. 2005;  84 677-680
• 101 Friedman M, Rosenman R H. Type A behavior and your heart. New York; Knopp 1974
• 102 Lobel T E. Personality correlates of type A coronary-prone behavior.  J Pers Assess. 1988;  52 434-440
• 103 LeBlanc J, Ducharme M B, Thompson M. Study on the correlation of the autonomic nervous system responses to a stressor of high discomfort with personality traits.  Physiol Behav. 2004;  82 647-652
• 104 Van Rossum E F, Koper J W, Huizenga N A, Uitterlinden A G, Janssen J A, Brinkmann A O, Grobbee D E, de Jong F H, van Duyn C M, Pols H A, Lamberts S W. Polymorphism in the glucocorticoid receptor gene, which decreases sensitivity to glucocorticoids in vivo, is associated with low insulin and cholesterol levels.  Diabetes. 2002;  51 3128-3134
• 105 Charmandari E, Kino T, Souvatzoglou E, Vottero A, Bhattacharyya N, Chrousos G P. Natural glucocorticoid receptor mutants causing generalized glucocorticoid resistance: molecular genotype, genetic transmission, and clinical phenotype.  J Clin Endocrinol Metab. 2004;  89 1939-1949
• 106 Van Oosten B W, Truyen L, Barkhof F, Polman C H. Multiple sclerosis therapy. A practical guide.  Drugs. 1995;  49 200-212
• 107 Kabra S K, Lodha R. Management of unresponsive asthma.  Indian J Pediatr. 2004;  71 (8) 729-732
• 108 Zennaro M C, Lombes M. Mineralocorticoid resistance.  Trends Endocrinol Metab. 2004;  15 (6) 264-270
• 109 Shamim W, Yousufuddin M, Francis D P, Gualdiero P, Honour J W, Anker S D, Coats A J. Raised urinary glucocorticoid and adrenal androgen precursors in the urine of young hypertensive patients: possible evidence for partial glucocorticoid resistance.  Heart. 2001;  86 (2) 139-144
• 110 Iida S, Fujii H, Moriwaki K. Disorders caused by abnormalities of glucocorticoid receptors.  Nippon Rinsho. 2002;  60 (2) 356-360
• 111 Chrousos G P. The stress response and immune function: clinical implications: The 1999 Novera H. Spector Lecture.  Ann NY Acad Sci. 2000;  917 38-67
• 112 Mastorakos G, Chrousos G P, Weber J S. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans.  J Clin Endocrinol Metab. 1993;  77 1690-1694
• 113 Mastorakos G, Weber J S, Magiakou M A, Gunn H, Chrousos G P. Hypothalamic-pituitary-adrenal axis activation and stimulation of systemic vasopressin secretion by recombinant interleukin 6 in humans: potential implications for the syndrome of inappropriate vasopressin secretion.  J Clin Endocrinol Metab. 1994;  79 934-939
• 114 Sher E R, Leung D YM, Surs W, Kam J C, Zieg G, Kamada A K, Szefler S J. Steroid-resistant asthma: cellular mechanisms contributing to inadequate response to glucocorticoid therapy.  J Clin Invest. 1994;  93 33-39
• 115 Fehm H L, Born J, Peters A. Glucocorticoids and melanocortins in the regulation of body weight in humans.  Horm Metab Res. 2004;  36 360-364
• 116 Dutta D, Sharma R. Regulation of hepatic glucocorticoid receptors in mice dietary restriction.  Horm Metab Res. 2003;  35 415-420