George P. Chrousos, MD; Sevilla D. Detera-Wadleigh, PhD; Michael Karl, MD
Glucocorticoid resistance results from the partial, albeit apparently generalized, inability of glucocorticoids to exert their effects on target tissues. The condition is associated with compensatory increases in circulating pituitary corticotropin and cortisol, with the former causing excess secretion of both adrenal androgens and adrenal steroid biosynthesis intermediates with salt-retaining activity. The manifestations of glucocorticoid resistance vary from chronic fatigue (perhaps a result of glucocorticoid deficiency in the central nervous system) to various degrees of hypertension with or without hypokalemic alkalosis or hyperandrogenism, or both, caused by increased cortisol and other salt-retaining steroids and adrenal androgens, respectively. In women, hyperandrogenism can result in acne, hirsutism, menstrual irregularities, oligoanovulation, and infertility; in men, it may lead to infertility and in children, to precocious puberty. Different molecular defects, such as point mutations or a microdeletion of the highly conserved glucocorticoid receptor gene, alter the functional characteristics or concentrations of the intracellular receptor and appear to cause glucocorticoid resistance.
The extreme variability in the clinical manifestations of glucocorticoid resistance and its mimicry of many common diseases can be explained by the overall degree of glucocorticoid resistance, differing sensitivity of target tissues to mineralocorticoids or androgens or both, and perhaps different biochemical defects of the glucocorticoid receptor, with selective resistance of certain glucocorticoid responses in specific tissues. The various different symptoms of classic glucocorticoid resistance and the theoretical potential of this condition to appear surreptitiously emphasize the importance of the glucocorticoid receptor in the pathogenesis of human disease.
The elaborate negative feedback mechanisms responsible for maintaining glucocorticoid homeostasis compensate for the insensitivity of tissues to glucocorticoids by resetting the hypothalamic-pituitary-adrenal axis at a higher level. Thus, corticotropin-releasing hormone (CRH), adrenocorticotropin (ACTH), and cortisol secretion are increased. The compensatory increase in ACTH production causes increased secretion of glucocorticoid precursors with mineralocorticoid activity (DOC, deoxycorticosterone; B, corticosterone) and increased secretion of several adrenal androgens.
indicates the position of the pathogenetic mutation in the first kindred from the National Institutes of Health (NIH) ; indicates the 4-basepair deletion and conservative mutation in the second NIH family ; and the black arrowhead indicates the pathogenetic mutation in the family reported by McDermott and colleagues . The gene consists of 10 exons of variable lengths numbered 1 to 8, and 9 and 9 . Exon 2 codes for the amino terminal domain; exons 3 and 4 code for the DNA-binding domain; and exons 5 to 9 code for the ligand-binding domain. The steroid-binding glucocorticoid receptor is glucocorticoid receptor (GR ). Glucocorticoid receptor (GR ) is produced by alternative splicing and does not bind glucocorticoids, and its functional importance is obscure. The three main domains of the human glucocorticoid receptor are represented in a linear model, as originally defined. Subsequent in vitro mutagenesis studies have assigned these and other functions to various regions of the receptor protein, as indicated underneath the schematic representation of the receptor. Numbers correspond to amino acids in the primary sequence of the receptor. HSP = heat-shock protein; NLS = nuclear localization sequences. Homologies of the five other classes of steroid and sterol receptors to the glucocorticoid receptor expressed as percent identity in primary sequence (AR = androgen receptor; ER = estrogen receptor; MR = mineralocorticoid receptor; PR = progesterone receptor; and VDR = 1,25[OH] vitamin D receptor).
Family 1 pedigree showing autosomal codominant transmission of the glucocorticoid resistance (black symbol indicates symptomatic; half-black symbol indicates biochemically affected only). Nucleotide sequence of the glucocorticoid receptor cDNA from the propositus and his asymptomatic but biochemically affected son. The propositus has T in place of A at nucleotide 2054, changing the aspartate codon GAC normally present at position 641 to the valine codon, GTC. Both A and T are present in the son's sequence, suggesting heterozygosity. The cDNA sequence of the asymptomatic but biochemically affected brother was identical to that of the son. From Hurley and colleagues ; reproduced with permission. Family 2 pedigree showing autosomal-dominant segregation of patients with glucocorticoid resistance (black symbols, affected; white symbols, unaffected). Sequences of the glucocorticoid receptor alleles at the 3-donor splice junction of exon 6 in the proposita and her glucocorticoid-resistant brothers. The boxed nucleotides depict the 4-basepair sequence deleted in one allele. The arrow on the right indicates the exon-intron boundary in the normal allele. The autoradiogram shows the sequence of the normal and the affected allele: the 4-basepair deletion in one allele, including the last bases of the exon and the first nucleotides of the intron, results in double bands. Nucleotide sequences of glucocorticoid receptor-exon 2 genomic DNA of the proposita and her affected brothers. On the left side, the proposita and one of her affected brothers were heterozygous for a mutation at codon 363 (cDNA position 1220) with a guanine (G) replacing the wild-type adenine (A) in one allele. On the right side, the second affected brother was homozygous for the wild-type sequence. Analysis of glucocorticoid receptor gene transcripts by direct sequencing of PCR-amplified cDNA obtained by reverse transcription of total RNA. On the left side, analysis of the proposita's cDNA showed only the sequence bearing G at position 1220, whereas transcripts with the wild-type sequence were not detectable. The base substitution results in a conservative amino acid substitution from asparagine to serine. On the right side, in contrast, the second affected brother had only the wild-type sequence. From Karl and colleagues ; reproduced with permission.
Appendix Table 1.
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George P. Chrousos, Sevilla D. Detera-Wadleigh, Michael Karl. Syndromes of Glucocorticoid Resistance. Ann Intern Med. 1993;119:1113–1124. doi: 10.7326/0003-4819-119-11-199312010-00009
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Published: Ann Intern Med. 1993;119(11):1113-1124.
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