Primary Generalized Glucocorticoid Resistance

Primary Generalized Glucocorticoid Resistance

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In humans, glucocorticoids regulate a broad spectrum of physiologic functions essential for life, and they play an important role in the maintenance of basal and stress-related homeostasis. [1, 2, 3] Approximately 20% of the genes expressed in human leukocytes are regulated positively or negatively by glucocorticoids. [4] Glucocorticoids are involved in almost every cellular, molecular, and physiologic network of the organism and play a pivotal role in critical biologic processes, such as growth, reproduction, intermediary metabolism, immune and inflammatory reactions, and central nervous system and cardiovascular functions. [1, 4] Furthermore, glucocorticoids represent one of the most widely used therapeutic compounds, often used in the treatment of inflammatory, autoimmune, and lymphoproliferative disorders. [1]

At the cellular level, the actions of glucocorticoids are mediated by a 94-kd protein, the glucocorticoid receptor (GR). The human (h) GR belongs to the steroid/thyroid/retinoic acid superfamily of nuclear receptors and functions as a ligand-dependent transcription factor that regulates the expression of glucocorticoid-responsive genes positively or negatively. [5, 6, 7] See panel A in the image below.

The hGR cDNA was isolated by expression cloning in 1985. [8] The hGR gene is one locus on the long arm of chromosome 5 (q31.3) and consists of 9 exons. Alternative splicing of the hGR gene in exon 9 generates 2 highly homologous receptor isoforms, termed α and β. These are identical through amino acid 727, but then diverge, with hGRα having an additional 50 amino acids and hGRβ having an additional, nonhomologous 15 amino acids. [3, 5, 6, 7] See the image above.

The hGRα represents the classic GR that functions as a ligand-dependent transcription factor, while the hGRβ does not bind glucocorticoid agonists; has intrinsic, hGRα-independent, gene-specific transcriptional activity; and exerts a dominant negative effect on the transcriptional activity of hGRα. [9, 10]

The human GR is a modular protein composed of distinct regions illustrated in panel B in the image below, as follows: (1) The amino-terminal A/B region, also called immunogenic or N-terminal domain (NTD) and (2) the C, D, and E regions, which correspond to the DNA-binding domain, the hinge region, and the ligand-binding domain, respectively.

The NTD of the hGRα contains a major transactivation domain, termed activation function (AF)–1, which is located between amino acids 77 and 262 of the hGRα and is ligand-independent. The AF-1 plays an important role in the interaction of the receptor with molecules necessary for the initiation of transcription, such as coactivators, chromatin modulators, and basal transcription factors, including RNA polymerase II, TATA-binding protein (TBP), and a host of TBP-associated proteins (TAFIIs). [3, 5, 6]

The DNA-binding domain (DBD) of the hGRα corresponds to amino acids 420-480 and contains 2 zinc finger motifs through which the hGRα binds to specific DNA sequences, the glucocorticoid-response elements (GREs) in the promoter region(s) of target genes. [5, 6] The DBD is the most highly conserved domain throughout the steroid receptor family. The 2 zinc finger motifs are able to tetrahedrally coordinate a zinc atom and are held by 4 cysteine (Cys) residues (see the image below, panel C).

Only very few amino acids, termed the proximal (P)–box, within the first zinc finger are responsible for specific recognition of the cognate GREs. Another set of amino acids, called the distal (D)–box within the second zinc finger, forms the weak dimerization interface of the DBD. The DBD of the hGRα also contains sequences important for nuclear translocation. [5, 6]

The hinge region or region D is a flexible region located between the DNA- and ligand-binding domains. Its amino terminus is an integral part of the DBD and is involved in its dimerization. The hinge region confers structural flexibility in the receptor dimmers, thereby allowing a single receptor dimmer to interact with multiple GREs. [5, 6]

The ligand-binding domain (LBD) of the hGRα corresponds to amino acids 481-777, binds to glucocorticoids, and plays a critical role in the ligand-induced activation of hGRα. The LBD also contains a second transactivation domain, termed AF-2, which is ligand-dependent, as well as sequences important for receptor dimerization, nuclear translocation, binding to the heat shock proteins, and interaction with coactivators. [5, 6]

Expressed hGRα is a panel of 8 amino terminal translational isoforms of varying lengths, each of which consists of 3 subdomains, the N-terminal (NTD), the DNA-binding (DBD), and the ligand-binding (LBD) domains. These hGRα isoforms differ at their amino-termini and may differentially transduce the glucocorticoid signal to target tissues, depending on their selective relative expression and inherent activities. It is likely that similar differential cell-specific production and functional differences might also be present between the putative hGRβ translational isoforms. [5, 6] This marked complexity in the transcription/translation of the hGR gene enables target tissues to differentially respond to circulating glucocorticoid concentrations and accounts for the highly stochastic nature of the glucocorticoid signaling pathway. [11]

In the absence of ligand, hGRα resides mostly in the cytoplasm of cells as part of a hetero-oligomeric complex, which contains chaperon heat shock proteins (HSPs) 90, 70, and FKBP51, as well as other proteins. [7, 11] Upon ligand-induced activation, the hGRα dissociates from this multiprotein complex and translocates into the nucleus, where it binds as a homodimer to GREs in the promoter regions of target genes and regulates their expression positively or negatively, depending on GRE sequence and promoter context. [7, 11]  See the image below.

To initiate transcription, the hGRα uses its transcriptional activation domains, activation AF-1 and AF-2, located in the NTD and LBD, respectively, as surfaces to interact with nuclear receptor coactivators and chromatin-remodeling complexes. [12, 13, 14, 15] The ligand-activated hGRα can also modulate gene expression independently of DNA-binding, by interacting, possibly as a monomer, with other transcription factors, such as nuclear factor-kB, activator protein-1, p53, and signal transducers and activators of transcription. [7] Following transcriptional activation or inhibition of glucocorticoid-responsive genes, the hGRα dissociates from the ligand and has a lower affinity for binding to GREs. The unliganded hGRα remains within the nucleus for a considerable length of time and is then exported to the cytoplasm; both within the nucleus and within the cytoplasm, the hGRα may be recycled and/or degraded in the proteasome. [16] See the image above.

Alterations in the molecular mechanisms of hGRα action may lead to alterations in tissue sensitivity to glucocorticoids, which may take the form of glucocorticoid resistance or glucocorticoid hypersensitivity and may be associated with significant morbidity. [17, 18, 19] In the present review, the pathophysiology and molecular mechanisms underlying primary generalized glucocorticoid resistance, or Chrousos syndrome, are summarized.

Clinical manifestations

Primary generalized familial or sporadic glucocorticoid resistance, or Chrousos syndrome, is a rare, familial or sporadic condition, initially described and elucidated by Chrousos et al. This condition is characterized by generalized, mostly partial, target-tissue insensitivity to glucocorticoids, which leads to compensatory activation of the hypothalamic-pituitary-adrenal (HPA) axis and hypersecretion of corticotropin in the systemic circulation. [20, 21, 22] The latter results in adrenocortical hyperplasia, increased cortisol secretion as compensation for the reduced action of glucocorticoids at target tissues, and increased production of adrenal steroids with mineralocorticoid (cortisol, deoxycorticosterone [DOC], and corticosterone) and/or androgenic activity (androstenedione, dehydroepiandrosterone [DHEA], and DHEA-sulfate [DHEAS]). [20, 21, 22]

The clinical manifestations of primary generalized glucocorticoid resistance, or Chrousos syndrome, reflect the pathophysiologic alterations described above and primarily include those of mineralocorticoid and/or androgen excess. [20, 21, 22] Clinical manifestations of glucocorticoid deficiency might occur, but these are rare and have only been reported in a young child with hypoglycemic generalized tonic-clonic seizures during the course of a febrile illness [23] ; in a newborn baby with severe hypoglycemia, excessive fatigability with feeding, increased susceptibility to infections, and concurrent growth hormone deficiency [24] ; and in several adult patients with chronic fatigue. [20, 21, 22]

Clinical manifestations of mineralocorticoid excess include hypertension and hypokalemic alkalosis. Clinical manifestations of androgen excess include ambiguous genitalia in a karyotypic female at birth and gonadotropin-independent precocious puberty in children of either sex; acne, hirsutism, and hypofertility in both sexes; male-pattern hair loss, menstrual irregularities, and oligo-anovulation in females; and oligospermia in males. [20, 21, 22] The clinical spectrum of the condition is broad, ranging from most severe to mild forms, while a number of patients may be asymptomatic, displaying biochemical alterations only. [20, 21, 22]

This variable clinical phenotype is due to variations in the tissue sensitivity of the glucocorticoid, mineralocorticoid, and/or androgen receptor signaling pathways; variations in the activity of key hormone-inactivating or hormone-activating enzymes, such as the 11β-hydroxysteroid dehydrogenase [25] ; and other genetic or epigenetic factors, such as the presence of insulin resistance and visceral obesity. [21]

In recognition of Professor George P. Chrousos’ extensive and ground-breaking research work in this field, it has been proposed that the term Chrousos syndrome be used in place of primary generalized familial and sporadic glucocorticoid resistance. [26, 27]

hGR mutations

The molecular basis of Chrousos syndrome has been ascribed primarily to mutations in the hGR gene, which impair the molecular mechanisms of hGR action and decrease tissue sensitivity to glucocorticoids. [23, 24, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]  See the image below.

Most hGR mutations associated with primary generalized glucocorticoid resistance or Chrousos syndrome have been identified, and the molecular mechanisms through which these various natural hGR mutants affect glucocorticoid signal transduction have been systematically investigated in almost all reported cases of generalized glucocorticoid resistance. The following have been studied [22, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 42, 43, 44] :

The transcriptional activity of the mutant receptors

The ability of the mutant receptors to exert a dominant negative effect on the wild-type receptor

The affinity of the mutant receptors for the ligand

The subcellular localization of the mutant receptors and their nuclear translocation following exposure to the ligand

The ability of the mutant receptors to bind to GREs

The interaction of the mutant receptors with the glucocorticoid receptor–interacting protein-1 (GRIP1) coactivator, which belongs to the p160 family of nuclear receptor coactivators and plays an important role in the hGRα-mediated transactivation of glucocorticoid-responsive genes

Compared with the wild-type receptor, all mutant receptors demonstrate variable reduction in their ability to transactivate glucocorticoid-responsive genes in response to dexamethasone. [28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 42, 43, 44] The mutant receptors hGRaI559N, hGRaF737L, hGRaI747M, and hGRaL773P exert a dominant negative effect on the wild-type receptor, which may contribute to manifestations of the disease at the heterozygote state. [28, 32, 34, 36, 39] All mutant receptors in which the mutations are located in the LBD of the receptor show a variable reduction in their affinity for the ligand. [28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 42, 43, 44]

The only two mutant receptors that demonstrate normal affinity for the ligand are the hGRaR477H and the hGRαV423A, in which the mutations were located in the DBD. [38, 41] Most pathologic mutant receptors are observed primarily in the cytoplasm of cells in the absence of ligand, except for the hGRaV729I and hGRaF737L receptors, which are localized in both the cytoplasm and the nucleus of cells.

Exposure to dexamethasone induces a slow translocation of the mutant receptors into the nucleus, which ranges from 20-180 minutes, compared with the wild-type hGRα, which requires only 12 minutes for complete translocation. [28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 42, 43, 44] All mutant receptors in which the mutations are located in the LBD preserve their ability to bind to DNA and display an abnormal interaction with the GRIP1 coactivator in vitro. [28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 42, 43, 44] The only two mutant receptors that fail to bind to DNA but display a normal interaction with the GRIP1 coactivator are the hGRaR477H and the hGRαV423A, in which the mutations are located in the DBD. [38, 41]

United States

Glucocorticoid resistance is rare.


Primary generalized glucocorticoid resistance or Chrousos syndrome is rare internationally.

Cardiovascular morbidity and mortality is increased if primary generalized glucocorticoid resistance or Chrousos syndrome is not treated.

The syndrome should not be confused with essential hypertension.

Use of diuretics may lead to severe hypokalemia.

Hyperandrogenism primarily occurs in children and women.

Kino T, Chrousos GP. Glucocorticoid effects on gene expression. Steckler T, Kalin NH , Reul JMHM, eds. Handbook of Stress and the Brain. Amsterdam: Elsevier; 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, et al. 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 Jan. 14(1):40-51. [Medline].

Chrousos GP. Hormone resistance and hypersensitivity rtates. Chrousos GP, Olefsky JM, Samols E. (eds). Modern Endocrinology Series. Philadelphia, PA: Lippincott, Williams & Wilkins; 2002. 318(6047): 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, Vingerhoeds A, Brandon D, et al. Primary cortisol resistance in man. A glucocorticoid receptor-mediated disease. J Clin Invest. 1982 Jun. 69(6):1261-9. [Medline]. [Full Text].

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, et al. 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, et al. 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, et al. 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 Mar 23. 9:27. [Medline].

Karl M, Lamberts SW, Koper JW, et al. 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, et al. 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, et al. 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, et al. 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, et al. 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, et al. 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, et al. 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, et al. 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, et al. 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].

Roberts ML, Kino T, Nicolaides NC, et al. A novel point mutation in the DNA-binding domain (DBD) of the human glucocorticoid receptor causes primary generalized glucocorticoid resistance by disrupting the hydrophobic structure of its DBD. J Clin Endocrinol Metab. 2013 Apr. 98(4):E790-5. [Medline].

Nicolaides NC, Roberts ML, Kino T, et al. A novel point mutation of the human glucocorticoid receptor gene causes primary generalized glucocorticoid resistance through impaired interaction with the LXXLL motif of the p160 coactivators: dissociation of the transactivating and transreppressive activities. J Clin Endocrinol Metab. 2014 May. 99(5):E902-7. [Medline].

Nicolaides NC, Geer EB, Vlachakis D, et al. A novel mutation of the hGR gene causing Chrousos syndrome. Eur J Clin Invest. 2015 Aug. 45(8):782-91. [Medline].

Nicolaides NC, Skyrla E, Vlachakis D, et al. Functional characterization of the hGRαT556I causing Chrousos syndrome. Eur J Clin Invest. 2016 Jan. 46(1):42-9. [Medline].

Nicolaides NC, Charmandari E. Chrousos syndrome: from molecular pathogenesis to therapeutic management. Eur J Clin Invest. 2015 May. 45(5):504-14. [Medline].


Disclosure: Nothing to disclose.

Tomoshige Kino, MD, PhD Staff Scientist, Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health

Tomoshige Kino, MD, PhD is a member of the following medical societies: Endocrine Society

Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children’s Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, American College of Endocrinology

Disclosure: Nothing to disclose.

Evangelia Charmandari, MD, MSc, PhD, MRCP Associate Professor of Pediatric and Adolescent Endocrinology, Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, Greece

Evangelia Charmandari, MD, MSc, PhD, MRCP is a member of the following medical societies: British Medical Association, Endocrine Society

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Barry B Bercu, MD Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children’s Hospital

Barry B Bercu, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Pediatric Endocrine Society, Society for Pediatric Research, Southern Society for Pediatric Research, Society for the Study of Reproduction, American Federation for Clinical Research, Pituitary Society

Disclosure: Nothing to disclose.

Robert P Hoffman, MD Professor and Program Director, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Division of Pediatric, Endocrinology, Diabetes, and Metabolism, Nationwide Children’s Hospital

Robert P Hoffman, MD is a member of the following medical societies: American College of Pediatricians, American Diabetes Association, American Pediatric Society, Christian Medical and Dental Associations, Endocrine Society, Midwest Society for Pediatric Research, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Thomas A Wilson, MD Professor of Clinical Pediatrics, Chief and Program Director, Division of Pediatric Endocrinology, Department of Pediatrics, The School of Medicine at Stony Brook University Medical Center

Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Pediatric Endocrine Society, Phi Beta Kappa

Disclosure: Nothing to disclose.

Literary work of this article was funded by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health (Bethesda, Maryland), the EU-European Social Fund, and the Greek Ministry of Development-General Secretariat of Research and Technology (Athens, Greece).

Primary Generalized Glucocorticoid Resistance

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