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Review
. 2010 Oct;40(10):932-42.
doi: 10.1111/j.1365-2362.2010.02336.x. Epub 2010 Aug 19.

Chrousos Syndrome: A Seminal Report, a Phylogenetic Enigma and the Clinical Implications of Glucocorticoid Signalling Changes

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Review

Chrousos Syndrome: A Seminal Report, a Phylogenetic Enigma and the Clinical Implications of Glucocorticoid Signalling Changes

Evangelia Charmandari et al. Eur J Clin Invest. .
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Abstract

Background: Glucocorticoids regulate a broad spectrum of physiologic functions and play important roles in resting and stress homeostasis. Their actions are mediated by the nuclear glucocorticoid receptor (GR).

Design: Using a patient as a stimulus, we reviewed briefly the area of Primary Generalized Glucocorticoid Resistance in man and nonhuman primates.

Results: In man, Primary Generalized Glucocorticoid Resistance is a rare sporadic or familial syndrome characterized by target-tissue insensitivity to glucocorticoids and compensatory elevations in adrenocorticotropic hormone (ACTH), leading to increased secretion of cortisol and adrenal steroids with mineralocorticoid and/or androgenic activity, and causing hypermineralocorticoidism and hyperandrogenism without Cushing stigmata. The presentation, diagnosis and therapy of this condition are summarized. Many or, most likely, all New World primates have markedly elevated cortisol and ACTH, and resistance to dexamethasone suppression, without any pathology. These primates in fact have 'pan-steroid/sterol' resistance, including all five steroid hormones and 1,25-dihydroxy-vitamin D. In humans, the molecular basis of Primary Generalized Glucocorticoid Resistance has been mainly ascribed to recent mutations in the GR gene, which impair glucocorticoid signal transduction. In contrast, in the primates, steroid/sterol signalling systems have adapted under yet unknown selective pressures or genetic drift over many million years. Of course, other molecules of the signaling pathways may also be involved in both states. There are now a host of human states associated with tissue-specific pathologic glucocorticoid target tissue changes. These include allergic, autoimmune, inflammatory and lymphoproliferative disorders.

Conclusions: In recognition of Professor George P. Chrousos' extensive ground-breaking research in this field, and for the sake of brevity, we propose that 'Chrousos syndrome' is used instead of 'Primary Generalized Familial or Sporadic Glucocorticoid Resistance'.

Figures

Figure 1
Figure 1
Heuristic, simplified representation of the glucocorticoid signaling system and gene and pathologic mutations of the GR gene causing Chrousos syndrome. (A) 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-κB (NF-κB) and signal transducer and activator of transcription-5 (STAT5), ultimately modulating the transcriptional activity of respectively GRE- or TFRE-containing genes. (B) Location of the known mutations of the glucocorticoid receptor (hGR) gene causing Chrousos syndrome. 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.
Figure 1
Figure 1
Heuristic, simplified representation of the glucocorticoid signaling system and gene and pathologic mutations of the GR gene causing Chrousos syndrome. (A) 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-κB (NF-κB) and signal transducer and activator of transcription-5 (STAT5), ultimately modulating the transcriptional activity of respectively GRE- or TFRE-containing genes. (B) Location of the known mutations of the glucocorticoid receptor (hGR) gene causing Chrousos syndrome. 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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