Cortisol is the most potent glucocorticoid produced by the human adrenal. It is synthesized from cholesterol and its production is stimulated by pituitary adrenocorticotropic hormone (ACTH) which is regulated by corticotrophin releasing factor (CRF). ACTH and CRF secretions are inhibited by high cortisol levels in a negative feedback loop. In plasma a majority of cortisol is bound with high affinity to corticosteroid binding globulin (CBG or transcotin). Cortisol acts through specific intracellular receptors and affects numerous physiologic systems including immune function, glucose counter regulation, vascular tone, and bone metabolism.

Cortisol production has an ACTH-dependent circadian rhythm with peak levels in the early morning and a nadir at night. The factor controlling this rhythm is not completely defined and can be disrupted by a number of physical and psychological conditions. ACTH and cortisol are secreted independent of circadian rhythm in response to physical and psychological stress.

Elevated cortisol levels and lack of diurnal variation have been identified with Cushing’s disease (ACTH hypersecretion). Elevated circulating cortisol levels have also been identified in patients with adrenal tumors. Low cortisol levels are found in primary adrenal insufficiency (e.g. adrenal hypoplasia, Addison’s disease) and in ACTH deficiency. Due to the normal circadian variation in cortisol levels, distinguishing normal from abnormally low cortisol levels can be difficult, therefore several daily collections are recommended.