Corticosteroid-Binding Globulin: A Review of Basic and Clinical Advances

Abstract

Corticosteroid-binding globulin (CBG, transcortin) is the primary cortisol binding protein. It is a non-inhibitory serine protease inhibitor, capable of conformational change from a high cortisol-binding affinity form to a low affinity form upon cleavage of its reactive centre loop by various proteases, such as neutrophil elastase. The burgeoning inflammatory role of CBG applies to acute, severe inflammation where depletion is associated with mortality, and to chronic inflammation where defects in cortisol delivery may perpetuate inflammation. Naturally occurring human mutations influence a wide range of CBG properties and point toward a role in hitherto unexplained chronic musculoskeletal pain and fatigue disorders as well as potentially affecting fertility outcomes including offspring gender. In vitro and knock-out animal models of CBG propose a role for CBG in cortisol transport to the brain, providing a foundation for understanding the human observations in those with CBG mutations and sex differences in stress-related mood and behaviour. Finally, CBG measurement has a practical role in the estimation of free cortisol, useful in clinical circumstances where CBG levels or cortisol binding affinity is reduced. Taken together, novel data suggest a role for cortisol in targeted cortisol delivery, with implications in acute and chronic inflammation, as well as roles in metabolism and neurocognitive function, implying that CBG is a multifaceted component in the mechanisms of hypothalamic-pituitary-adrenal axis related homeostasis.

Adrenal Crises in Children: Perspectives and Research Directions

“…As has been described previously [15], augmentation of the delivery of cortisol to inflamed tissue is believed to be as a result of a combination of inflammatory cytokine induced HPA axis activation, in combination with rapid cleavage of corticosteroid-binding globulin (CBG) by tissue elastases [70]. An increase in the secretion of cortisol and a diminution in CBG production occur early in this process [71]. The consequent depletion of circulating CBG may contribute to an insufficient supply of cortisol to inflamed tissues, leading to increased tissue damage, as cellular processes become overwhelmed by unrestrained activation of NF-κB [70].…”

Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity

“…CBG, or transcortin, is synthesized mainly by hepatocytes and binds CORT with high affinity to transport CORT in blood. This interaction regulates bioavailability during high CORT secretion (Meyer, Nenke, Rankin, Lewis, & Torpy, 2016). Of note, CBG also binds other hormones, including androgens and progesterone, which in humans are thought to displace cortisol from CBG (Dunn, Nisula, & Rodbard, 1981).…”

Endocrine disruption: In silico interactions between phthalate plasticizers and corticosteroid binding globulin

“…Recently, based on the CBG knock‐out mice models, CBG and cortisol have been reported to be associated with neurocognitive functions (Meyer et al, ). Children exposed to an imbalance of cortisol in‐utero have cerebellar developmental problems (Koning et al, ).…”

“…Corticosteroid‐binding globulin (CBG) is one of the two main steroid binding proteins (other being sex hormone‐binding globulin) and is the primary binding and transport protein for cortisol and other corticosteroids in the blood circulation (Bae & Kratzsch, ; Gardill, Vogl, Lin, Hammond, & Muller, ; Henley & Lightman, ; Meyer, Nenke, Rankin, Lewis, & Torpy, ). The main source of CBG in the body is liver (Khan, Aden, & Rosner, ).…”