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Routine assessment of the hypothalamic-pituitary-adrenal axis relies on the measurement of total serum cortisol levels. However, most cortisol in serum is bound to corticosteroid-binding globulin (CBG) and albumin, and changes in the structure or circulating levels of binding proteins markedly affect measured total serum cortisol levels. Furthermore, high-affinity binding to CBG is predicted to affect the availability of cortisol for the glucocorticoid receptor. CBG is a substrate for activated neutrophil elastase, which cleaves the binding protein and results in the release of cortisol at sites of inflammation, enhancing its tissue-specific anti-inflammatory effects. Further tissue-specific modulation of cortisol availability is conferred by corticosteroid 11β-dehydrogenase. Direct assessment of tissue levels of bioavailable cortisol is not clinically practicable and measurement of total serum cortisol levels is of limited value in clinical conditions that alter prereceptor glucocorticoid bioavailability. Bioavailable cortisol can, however, be measured indirectly at systemic, extracellular tissue and cell levels, using novel techniques that have provided new insight into the transport, metabolism and biological action of glucocorticoids. A more physiologically informative approach is, therefore, now possible in the assessment of the hypothalamic-pituitary-adrenal axis, which could prove useful in clinical practice.

Original publication




Journal article


Nat Rev Endocrinol

Publication Date





717 - 727


Animals, Biological Availability, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Protein Binding, Receptors, Glucocorticoid, Transcortin