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Primary Generalized Glucocorticoid Resistance Workup

  • Author: Evangelia Charmandari, MD, MSc, PhD, MRCP; Chief Editor: Stephen Kemp, MD, PhD  more...
 
Updated: Dec 04, 2013
 

Laboratory Studies

Endocrinologic evaluation

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.

Molecular studies

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.

 
 
Contributor Information and Disclosures
Author

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.

Coauthor(s)

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.

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.

Specialty Editor Board

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.

Chief Editor

Stephen Kemp, MD, PhD Former Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

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.

Acknowledgements

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).

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(A) Schematic representation of the structure of the human glucocorticoid receptor (hGR) gene. Alternative splicing of the primary transcript gives rise to the 2 mRNA and protein isoforms, hGR-alpha and hGR-beta. (B) Functional domains of the hGR-alpha. The functional domains and subdomains are indicated beneath the linearized protein structures. AF, activation function; DBD, DNA-binding domain; LBD, ligand-binding domain; NLS, nuclear localization signal. (C) Enlargement of part of the DBD showing the amino acid sequence (single letter codes) of the 2 zinc fingers and the dimerization loop (in bold). The A to T mutation at position 458 that could produce a dimerization defective receptor is shown.
Nucleocytoplasmic shuttling of the glucocorticoid receptor. Upon binding to the ligand, the activated hGRα dissociates from heat shock proteins (HSPs) and translocates into the nucleus, where it homodimerizes and binds to glucocorticoid response elements (GREs) in the promoter region of target genes or interacts with other transcription factors (TFs), such as activator protein-1 (AP-1), nuclear factor-kappaκB (NF-kappaκB), and signal transducer and activator of transcription-5 (STAT5), ultimately modulating the transcriptional activity of, respectively, GRE- or TFRE-containing genes.
Location of the known mutations of the hGR gene causing primary generalized glucocorticoid resistance. DBD: DNA-binding domain. GR, glucocorticoid receptor; GREs, glucocorticoid response element; HSP, heat shock protein; LBD, ligand-binding domain; NTD, amino terminal domain; TF, transcription factor; TFRE, transcription factor response element.
 
 
 
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