Cortisol Testing Basics

Cortisol is the principal glucocorticoid released by the adrenal cortex, especially the zona fasciculata. Its production is directed by the hypothalamic-pituitary-adrenal axis: corticotropin-releasing hormone stimulates pituitary adrenocorticotropic hormone, which stimulates adrenal cortisol release. Cortisol then suppresses CRH and ACTH through negative feedback. Secretion is both pulsatile and diurnal. Concentrations rise overnight, peak shortly after waking, and decline toward a nadir near midnight. The collection time therefore changes the clinical meaning of the number. An early-morning cortisol and a late-night salivary cortisol are not interchangeable measurements. Most circulating cortisol is bound to corticosteroid-binding globulin and albumin. Routine serum assays measure total cortisol, meaning that a change in binding proteins can change the reported concentration without a corresponding change in biologically active free cortisol. Oral estrogen and pregnancy increase corticosteroid-binding globulin and can raise total serum cortisol; the result may look abnormal even when free cortisol has not increased.