Cortisol (hydrocortisone), the predominant glucocorticoid, is secreted in response to stimulation by ACTH. Ninety percent of cortisol is bound to cortisol-binding globulin (CBG) and albumin; the free portion is responsible for its physiological effects. Cortisol stimulates gluconeogenesis, mobilizes fats and proteins, antagonizes insulin, and suppresses inflammation. Cortisol secretion varies diurnally, with the highest levels seen upon awakening and the lowest levels occurring late in the day. Bursts of cortisol excretion also may occur at night.

Elevated cortisol levels occur in Cushing's syndrome, in which there is excessive production of adrenocorticosteroids. Cushing's syndrome may be caused by pituitary adenoma, adrenal hyperplasia, benign or malignant adrenal tumors, and nonendocrine malignant tumors that secrete ectopic ACTH. Therapy with adrenocorticosteroids also may produce cushingoid signs and symptoms. Elevated cortisol levels are additionally associated with stress, hyperthyroidism, obesity, and diabetic ketoacidosis.

Decreased cortisol levels occur with Addison's disease, in which there is deficient production of adrenocorticosteroids. Addison's disease is usually caused by idiopathic adrenal hypofunction, although it may also be seen in pituitary hypofunction, hypothyroidism, tuberculosis, metastatic cancer involving the adrenal glands, amyloidosis, and hemochromatosis. Addison's disease may occur after withdrawal of corticosteroid therapy because of drug-induced atrophy of the adrenal glands.