Corticosteroid-binding Globulin Gene Polymorphisms: Clinical Implications and Links to Idiopathic Chronic Fatigue Disorders

D. J. Torpy; J. T. Ho


Clin Endocrinol. 2007;67(2):161-167. 

In This Article

Summary and Introduction

Corticosteroid-binding globulin (CBG) binds cortisol with high affinity, facilitating transport of cortisol in blood, although tissue-specific CBG–cortisol interactions have long been postulated. There are three heritable, human CBG gene mutations that can reduce CBG–cortisol binding affinity and/or reduce circulating CBG levels. In some families, fatigue and low blood pressure have been associated with affinity altering or CBG level reducing mutations. The limited numbers of reports raise the possibility of ascertainment bias as many cases presented with features suggesting cortisol deficiency. The recent description of a genetically CBG-deficient mouse listed fatigue, manifest as reduced activity levels, as part of the phenotype, which also included immune aberrations. Severe CBG mutations may produce fatigue, but one study suggests that these are a rare cause of idiopathic fatigue. A mechanism for the effect of CBG mutations on fatigue is not readily apparent because free cortisol levels are normal, although we speculate that CBG may have an effect on cortisol–brain transport.

CBG is the 50–60-kDa high-affinity plasma transport glycoprotein for cortisol.[1] It is secreted from hepatocytes as a 383-amino-acid peptide after cleavage of a 22-amino-acid signal peptide and circulates at concentrations ranging from 30 to 52 pg/ml. Each CBG molecule contains five active glycosylation sites. Variable bi- and triantennary glycosylation leads to CBG size (neutral sugars) and charge (sialic acid) heterogeneity. Glycosylation at Asp238 appears to be necessary for the adoption of a tertiary structure and creation of an active steroid binding site.[2] However, near-complete deglycosylation does not alter steroid binding.[1] Each CBG molecule has a single steroid binding site involving the Trp371 residue as demonstrated by photoaffinity-labelling and site-directed mutagenesis (Fig. 1).[3] CBG glycosylation shifts to a predominantly triantennary pattern in pregnancy with increased sialic acid groups, slowing clearance through the liver sialo-glycoprotein receptor, contributing to the two- to threefold rise in circulating CBG of pregnancy.[4] It has been proposed that nonlectin binding pregnancy-specific CBG glycoforms may facilitate transplacental cortisol transport based on glycoform-specific enhanced syncytiotrophoblast membrane binding.[5] It is not known whether the glycosylation changes in pregnancy are equivalent to those resulting from exogenous oestrogen.

A protein model for CBG was developed by Dr Christopher J. Bagley (Hanson Institute) using the Homology module of the InsightII software suite (Accelrys, San Diego, CA). The structures of antichymotrypsin (PDB code) and antitrypsin (PDB code) were used as templates for the model, which was refined by energy minimization using the Discover module. The cartoon was prepared using MOLSCRIPT.[54] The backbone trace of the structure is shown with the ribbon form used to denote helices and beta strands. The site of cleavage of the activation loop is shown as an arrowhead. Residues that are mutated in natural human variants (Ser224, Asp376 and Leu93) or thought to participate in binding steroids (Trp371 and Cys228) are shown as CPK spheres. A ring denotes the approximate region of cortisol binding.

CBG is a member of the serine protease inhibitor (SERPIN) structural family although it lacks intrinsic serine protease inhibitor activity. The 19-kb five-exon (four-coding) gene is located at 14q32•1, among several contiguous highly homologous genes that are thought to be derived from a common ancestor gene.[6,7] The gene is also expressed in the kidney, placenta and pancreas.[1,8] Levels of CBG are increased by oestrogen and pregnancy and decreased by insulin, or by glucocorticoids, such as prednisolone, or in Cushing's syndrome.[1,10] The effects of glucocorticoids on CBG synthesis are glucocorticoid receptor dependent and those of oestradiol (and mitotane) are oestrogen receptor α dependent.[11,12] High-affinity CBG–cortisol binding is saturated beyond cortisol levels of 400–500 nmol/l, hence the free cortisol levels rise exponentially at high cortisol concentrations.[13] Under normal circadian conditions approximately 80% of cortisol is bound to CBG, 10–15% is bound to low-affinity albumin and 5–8% of circulating cortisol is unbound or free.[14] Currently, only the free or unbound cortisol fraction is thought to be biologically active. Under conditions of stress, elevated cortisol levels saturate available CBG and increase the free cortisol fraction to above 20%.[15]

CBG is traditionally considered to have a transport role, distributing water-insoluble cortisol throughout the circulation, a buffer role perhaps blunting elevations of free cortisol during a secretory surge, or a reservoir function acting as a pool of cortisol during times of reduced cortisol secretion. Two lines of evidence have suggested a specific-tissue cortisol delivery role for CBG. These include the finding of a specific CBG interaction with human leucocyte elastase (HLE) and evidence for the presence of CBG receptors. HLE specifically cleaves CBG at the 344–345 residue leading to loss of a 39-amino-acid C-terminal fragment and almost complete loss of CBG–cortisol binding affinity.[16] Hence, CBG may play a role in delivering cortisol specifically to inflammatory sites.[17] One report of specific, saturable, high-affinity CBG binding sites in prostate tissue suggested the presence of a cell-surface CBG receptor, but no CBG receptor has been cloned.[18] Recently, endocytic uptake of SHBG–sex steroid complexes by megalin, a low density lipoprotein (LDL) receptor analogue, has been described.[19] It is not known whether a similar mechanism applies to CBG–cortisol. If present, such a receptor may play a role in tissue-specific CBG–cortisol delivery. Immunocytochemical detection of CBG has been reported in pituicytes and costaining with ACTH suggests that CBG is present selectively in corticotrophs.[20] Reports of intracellular localization of CBG and differential expression of CBG mRNA according to gestational stage in various tissues have led to the proposition that CBG may play a role in modulating access of cortisol to the glucocorticoid receptor, thereby altering tissue glucocorticoid sensitivity.[20,21]

CBG participates actively in the stress response. Immune activation liberates interleukin-6 (IL-6), which stimulates cortisol secretion through activation of the hypothalamic CRH neurone.[22] Concomitant direct inhibition of CBG gene transcription by IL-6 augments the stress response by increasing the free cortisol fraction, thereby increasing circulating glucocorticoid activity.[23,24] In vivo, exogenous IL-6 reduces CBG concentrations by 50% in humans, and specific illnesses such as burns, sepsis and cardiac surgery are associated with similar drops in CBG levels, which correlate with the extent of IL-6 elevation.[15,24,25,26] In post-traumatic stress disorder, a condition associated with low cortisol levels and elevated catecholamines, CBG levels have been shown to be elevated.[27]


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.