Primary Generalized Glucocorticoid Resistance Workup
- Author: Evangelia Charmandari, MD, MSc, PhD, MRCP; Chief Editor: Stephen Kemp, MD, PhD more...
The concentrations of plasma corticotropin, plasma renin activity (recumbent and upright), and aldosterone, as well as those of serum cortisol, testosterone, androstenedione, DHEA, DHEAS, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and fasting glucose and insulin should be recorded in the morning.
Determination of the 24-hour urinary free cortisol (UFC) excretion on 2 or 3 consecutive days is central to the diagnosis, given that patients with Chrousos syndrome demonstrate increased 24-hour UFC excretion in the absence of clinical manifestations suggestive of hypercortisolism. In patients with Chrousos syndrome, the rise in serum cortisol and androgen concentrations, as well as in the 24-hour UFC excretion, varies considerably depending on the severity of impairment of glucocorticoid signal transduction. In most severe cases, serum cortisol and 24-hour UFC concentrations may be, respectively, up to 7- and 50-fold higher than the upper limit of normal range.
Plasma corticotropin concentrations may be normal or high in patients with Chrousos syndrome and normal or low in primary generalized glucocorticoid resistance.
The responsiveness of the HPA axis to exogenous glucocorticoids should also be tested with dexamethasone in patients suspected of having Chrousos syndrome. Increasing doses of dexamethasone (0.3 mg, 0.6 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg) should be given orally at midnight every other day, and a serum sample should be drawn at 8:00 am the following morning for determination of serum cortisol and dexamethasone concentrations. The concurrent measurement of serum dexamethasone concentrations is suggested in order to exclude the possibility of nonadherence to treatment, increased metabolic clearance, or decreased absorption of this medication. Affected subjects demonstrate resistance of the HPA axis to dexamethasone suppression, which varies depending on the severity of the condition. The dose of dexamethasone required to suppress serum cortisol concentrations by 50% may be up to 7.5-fold higher than that required to achieve the same degree of HPA axis suppression in healthy subjects.
Thymidine incorporation assays and dexamethasone-binding assays on peripheral blood mononuclear cells in association with sequencing of the hGR gene are necessary to confirm the diagnosis.[28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39] In Chrousos syndrome, the thymidine incorporation assays reveal resistance to dexamethasone-induced suppression of phytohemagglutinin-stimulated thymidine incorporation, while the dexamethasone-binding assays often show decreased affinity of the hGR receptor for the ligand compared with control subjects.[22, 27] The opposite is true for patients with primary generalized glucocorticoid resistance.
Sequencing of the coding region of the hGR gene, including the intron/exon junctions, reveals mutations or deletions in most but not all patients with Chrousos syndrome.[27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39] Once a structural defect is determined, it is suggested that functional characterization of the mutant receptor should be undertaken in order to determine the molecular mechanisms through which the mutant hGR impairs glucocorticoid signal transduction.
Kino T, Chrousos GP. Glucocorticoid effects on gene expression. Handbook of Stress and the Brain, T. Steckler NH. Kalin, J. M. H. M. Reul, Eds. Elsevier, Amsterdam. 2005. 5(1): 295–311.
Chrousos GP, Charmandari E, Kino T. Glucocorticoid action networks--an introduction to systems biology. J Clin Endocrinol Metab. 2004 Feb. 89(2):563-4. [Medline].
Chrousos GP. The glucocorticoid receptor gene, longevity, and the complex disorders of Western societies. Am J Med. 2004 Aug 1. 117(3):204-7. [Medline].
Galon J, Franchimont D, Hiroi N, et al. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J. 2002 Jan. 16(1):61-71. [Medline].
Zhou J, Cidlowski JA. The human glucocorticoid receptor: one gene, multiple proteins and diverse responses. Steroids. 2005 May-Jun. 70(5-7):407-17. [Medline].
Duma D, Jewell CM, Cidlowski JA. Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modification. J Steroid Biochem Mol Biol. 2006 Dec. 102(1-5):11-21. [Medline].
Nicolaides NC, Galata Z, Kino T, Chrousos GP, Charmandari E. The human glucocorticoid receptor: molecular basis of biologic function. Steroids. 2010 Jan. 75(1):1-12. [Medline].
Hollenberg SM, Weinberger C, Ong ES, Cerelli G, Oro A, Lebo R. Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature. 1985 Dec 19-1986 Jan 1. 318(6047):635-41. [Medline].
Kino T, Manoli I, Kelkar S, Wang Y, Su YA, Chrousos GP. Glucocorticoid receptor (GR) beta has intrinsic, GRalpha-independent transcriptional activity. Biochem Biophys Res Commun. 2009 Apr 17. 381(4):671-5. [Medline].
Oakley RH, Jewell CM, Yudt MR, Bofetiado DM, Cidlowski JA. The dominant negative activity of the human glucocorticoid receptor beta isoform. Specificity and mechanisms of action. J Biol Chem. 1999 Sep 24. 274(39):27857-66. [Medline].
Chrousos GP, Kino T. Intracellular glucocorticoid signaling: a formerly simple system turns stochastic. Sci STKE. 2005 Oct 4. 2005(304):pe48. [Medline].
McKenna NJ, Lanz RB, O'Malley BW. Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev. 1999 Jun. 20(3):321-44. [Medline].
McKenna NJ, O'Malley BW. Combinatorial control of gene expression by nuclear receptors and coregulators. Cell. 2002 Feb 22. 108(4):465-74. [Medline].
Auboeuf D, Honig A, Berget SM, O'Malley BW. Coordinate regulation of transcription and splicing by steroid receptor coregulators. Science. 2002 Oct 11. 298(5592):416-9. [Medline].
Hittelman AB, Burakov D, Iniguez-Lluhi JA, Freedman LP, Garabedian MJ. Differential regulation of glucocorticoid receptor transcriptional activation via AF-1-associated proteins. EMBO J. 1999 Oct 1. 18(19):5380-8. [Medline].
Liu J, DeFranco DB. Protracted nuclear export of glucocorticoid receptor limits its turnover and does not require the exportin 1/CRM1-directed nuclear export pathway. Mol Endocrinol. 2000. 14(1):40-51.
Chrousos GP. Hormone Resistance and Hypersensitivity States. Chrousos GP, Olefsky JM, Samols E. (eds). Modern Endocrinology Series. Lippincott, Williams & Wilkins: Philadelphia, PA; 2002. 318(6047): page 542.
Kino T, De Martino MU, Charmandari E, Mirani M, Chrousos GP. Tissue glucocorticoid resistance/hypersensitivity syndromes. J Steroid Biochem Mol Biol. 2003 Jun. 85(2-5):457-67. [Medline].
Chrousos GP, Kino T. Glucocorticoid signaling in the cell. Expanding clinical implications to complex human behavioral and somatic disorders. Ann N Y Acad Sci. 2009 Oct. 1179:153-66. [Medline].
Chrousos GP, Detera-Wadleigh SD, Karl M. Syndromes of glucocorticoid resistance. Ann Intern Med. 1993 Dec 1. 119(11):1113-24. [Medline].
Charmandari E, Kino T, Ichijo T, Chrousos GP. Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder. J Clin Endocrinol Metab. 2008 May. 93(5):1563-72. [Medline].
Nader N, Bachrach BE, Hurt DE, Gajula S, Pittman A, Lescher R. A novel point mutation in helix 10 of the human glucocorticoid receptor causes generalized glucocorticoid resistance by disrupting the structure of the ligand-binding domain. J Clin Endocrinol Metab. 2010 May. 95(5):2281-5. [Medline].
McMahon SK, Pretorius CJ, Ungerer JP, Salmon NJ, Conwell LS, Pearen MA. Neonatal complete generalized glucocorticoid resistance and growth hormone deficiency caused by a novel homozygous mutation in Helix 12 of the ligand binding domain of the glucocorticoid receptor gene (NR3C1). J Clin Endocrinol Metab. 2010 Jan. 95(1):297-302. [Medline].
Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev. 2004 Oct. 25(5):831-66. [Medline].
Charmandari E, Kino T. Chrousos syndrome: a seminal report, a phylogenetic enigma and the clinical implications of glucocorticoid signalling changes. Eur J Clin Invest. 2010 Oct. 40(10):932-42. [Medline].
Chrousos G. Q&A: primary generalized glucocorticoid resistance. BMC Med. 2011. 9:27.
Karl M, Lamberts SW, Koper JW, Katz DA, Huizenga NE, Kino T. Cushing's disease preceded by generalized glucocorticoid resistance: clinical consequences of a novel, dominant-negative glucocorticoid receptor mutation. Proc Assoc Am Physicians. 1996 Jul. 108(4):296-307. [Medline].
Hurley DM, Accili D, Stratakis CA, Karl M, Vamvakopoulos N, Rorer E. Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance. J Clin Invest. 1991 Feb. 87(2):680-6. [Medline].
Karl M, Lamberts SW, Detera-Wadleigh SD, Encio IJ, Stratakis CA, Hurley DM. Familial glucocorticoid resistance caused by a splice site deletion in the human glucocorticoid receptor gene. J Clin Endocrinol Metab. 1993 Mar. 76(3):683-9. [Medline].
Malchoff DM, Brufsky A, Reardon G, McDermott P, Javier EC, Bergh CH. A mutation of the glucocorticoid receptor in primary cortisol resistance. J Clin Invest. 1993 May. 91(5):1918-25. [Medline].
Kino T, Stauber RH, Resau JH, Pavlakis GN, Chrousos GP. Pathologic human GR mutant has a transdominant negative effect on the wild-type GR by inhibiting its translocation into the nucleus: importance of the ligand-binding domain for intracellular GR trafficking. J Clin Endocrinol Metab. 2001 Nov. 86(11):5600-8. [Medline].
Ruiz M, Lind U, Gafvels M, Eggertsen G, Carlstedt-Duke J, Nilsson L. Characterization of two novel mutations in the glucocorticoid receptor gene in patients with primary cortisol resistance. Clin Endocrinol (Oxf). 2001 Sep. 55(3):363-71. [Medline].
Mendonca BB, Leite MV, de Castro M, Kino T, Elias LL, Bachega TA. Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene. J Clin Endocrinol Metab. 2002 Apr. 87(4):1805-9. [Medline].
Vottero A, Kino T, Combe H, Lecomte P, Chrousos GP. A novel, C-terminal dominant negative mutation of the GR causes familial glucocorticoid resistance through abnormal interactions with p160 steroid receptor coactivators. J Clin Endocrinol Metab. 2002 Jun. 87(6):2658-67. [Medline].
Charmandari E, Kino T, Souvatzoglou E, Vottero A, Bhattacharyya N, Chrousos GP. Natural glucocorticoid receptor mutants causing generalized glucocorticoid resistance: molecular genotype, genetic transmission, and clinical phenotype. J Clin Endocrinol Metab. 2004 Apr. 89(4):1939-49. [Medline].
Charmandari E, Raji A, Kino T, Ichijo T, Tiulpakov A, Zachman K. A novel point mutation in the ligand-binding domain (LBD) of the human glucocorticoid receptor (hGR) causing generalized glucocorticoid resistance: the importance of the C terminus of hGR LBD in conferring transactivational activity. J Clin Endocrinol Metab. 2005 Jun. 90(6):3696-705. [Medline].
Charmandari E, Kino T, Ichijo T, Zachman K, Alatsatianos A, Chrousos GP. Functional characterization of the natural human glucocorticoid receptor (hGR) mutants hGRalphaR477H and hGRalphaG679S associated with generalized glucocorticoid resistance. J Clin Endocrinol Metab. 2006 Apr. 91(4):1535-43. [Medline].
Charmandari E, Kino T, Ichijo T, Jubiz W, Mejia L, Zachman K. A novel point mutation in helix 11 of the ligand-binding domain of the human glucocorticoid receptor gene causing generalized glucocorticoid resistance. J Clin Endocrinol Metab. 2007 Oct. 92(10):3986-90. [Medline].
Zhu HJ, Dai YF, Wang O, Li M, Lu L, Zhao WG. Generalized glucocorticoid resistance accompanied with an adrenocortical adenoma and caused by a novel point mutation of human glucocorticoid receptor gene. Chin Med J (Engl). 2011 Feb. 124(4):551-5. [Medline].