Cortisol is a glucocorticoid, or a corticosteroid hormone, produced by the adrenal glands in response to the production of adrenocortiotropic hormone (ACTH) in the pituitary gland. Cortisol is essential for the regulation of many physiological functions, including immune regulation and the release of glucose and amino acids for cellular metabolism. The production of cortisol is normally a highly regulated process, thus elevated levels of cortisol are indicative of diseases such as Cushing's disease or adrenal or pituitary tumors. Steroidogenesis inhibitors, neuromodulatory agents and cortisol receptor antagonists are pharmacological agents useful in lowering high cortisol levels.
Steroidogenesis inhibitor medications such as mitotane, cytadren and ketoconazole decrease the production of cortisol by directly inhibiting one or more enzymatic steps. Cytadren is an anti-steroid drug that inhibits the enzymatic conversion of cholesterol to delta-5-pregnenolone. By inhibiting this first step in the biosynthesis of cortisol, cytadren directly inhibits the production of cortisol from cholesterol, notes Drugs.com. Mitotane is another steroidogenesis inhibitor; it directly alters the peripheral metabolism of cortisol. Mitotane inhibits the activity of the cells of the adrenal gland, thereby inhibiting the production of cortisol. Cushing's disorder is characterized by excess production of cortisol by the adrenal glands and according to the Congress of Neurological Surgeons, 83 percent of patients with Cushing's disease achieved an 83 percent remission on mitotane alone.
Cortisol secretion is modulated by the release of ACTH from the pituitary, which in turn is controlled by the hypothalamic release of Corticotropin-releasing hormone, CRH. Neuromodulatory drugs such as octreotide, bromocriptine and cyproheptadine modulate the release of ACTH from the pituitary gland, thereby moderating the levels of cortisol in the body. Octreotide is a somatostatin analog, effective in combination with ketoconazole in lowering cortisol levels. Octreotide and ketoconazole have a synergistic, additive effect and normalize urinary cortisol levels in three out of four patients with ACTH-dependent hypercortisolism. Bromocriptine is a dopamine receptor agonist that likely modulates ACTH levels by inhibiting the release of CRH at the hypothalamus. In individuals with Cushing's disease, about 40 percent had normalized cortisol levels after treatment with bromocriptine.
Cortisol Receptor Antagonists
Mifepristone is a cortisol receptor antagonist sometimes used in the treatment of elevated levels of cortisol due to ectopic adrenocorticotrophin (ACTH)-producing tumors. Mifepristone competitively binds glucocorticoid receptors and suppresses the peripheral features of hypercortisolism in Cushing's syndromes. According to Cushing's Support and Research Foundation, Jennifer Kirkland, a clinical neuropsychologist, notes trial studies in which mifepristone has been found to be effective in reducing the effects of elevated cortisol, such as depression and mood disorders, without inhibiting the production of natural hormones.