Discovery medicine

Advances in medical therapies for Cushing's syndrome.

PMID 22369976


Cushing's syndrome (CS) is a heterogeneous disorder of diverse etiologies, leading to cortisol excess. Endogenous CS is caused by tumors secreting adrenocorticotropin (ACTH) (either eutopically or ectopically), cortisol, or very rarely corticotropin-releasing hormone (CRH). Definitive therapy of endogenous CS optimally involves tumor resection. Indications for medical therapy include acutely ill patients in preparation for surgery, those for whom surgery is not indicated (such as patients with unknown tumor location or unresectable lesions, and patients unfit for surgery for medical reasons), or patients who remain hypercortisolemic postoperatively. In the current article, the published literature has been reviewed to summarize data on medical therapies used in CS. Several agents are either used "off label" or being studied as potential therapies for CS. Medications suppressing adrenal steroidogenesis currently in use include ketoconazole, metyrapone, mitotane, or etomidate. In addition, the investigational agent LCI699 is under study. Centrally acting agents, which suppress ACTH secretion, include cabergoline, octreotide, as well as the investigational agents pasireotide, bexarotene, and lapatinib, which are being studied in patients with pituitary tumors. Mifepristone, a type 2 glucocorticoid receptor antagonist, was recently approved by the FDA as a new therapy for CS. Although not definitive at present, medical therapies have an important role in the management of CS patients. It is anticipated that understanding the pathogenesis of these tumors at a molecular level may spawn the development of rationally designed, highly efficacious medical therapies for CS in the future.