Medical therapy for Cushing's disease: adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers.

Morbidity and mortality in Cushing's disease (CD) patients are increased if patients are not appropriately treated. Surgery remains the first line therapy, however the role of medical therapy has become more prominent in patients when biochemical remission is not achieved/or recurs after surgery, while waiting effects of radiation therapy or when surgery is contraindicated. Furthermore, use of preoperative medical therapy has been also recognized. In addition to centrally acting therapies (reviewed elsewhere in this special issue), adrenal steroidogenesis inhibitors, and glucocorticoid receptor antagonists are frequently used. A PubMed search of all original articles or abstracts detailing medical therapy in CD, published within 12 months (2013-2014), were identified and pertinent data extracted. Although not prospectively studied, ketoconazole and metyrapone have been the most frequently used medical therapies. A large retrospective ketoconazole study showed that almost half of patients who continued on ketoconazole therapy achieved biochemical control and clinical improvement; however almost 20% discontinued ketoconazole due to poor tolerability. Notably, hepatotoxicity was usually mild and resolved after drug withdrawal. Etomidate remains the only drug available for intravenous use. A new potent inhibitor of both aldosterone synthase and 11β-hydroxylase, following the completion of a phase II study LCI699 is being studied in a large phase III with promising results. Mifepristone, a glucocorticoid receptor antagonist, has been approved for hyperglycemia associated with Cushing's syndrome based on the results of a prospective study where it produced in the majority of patients' significant clinical and metabolic improvement. Absence of both a biochemical marker for remission and/or diagnosis of adrenal insufficiency remain, however, a limiting factor. Patient characteristics and preference should guide the choice between different medications in the absence of clinical trials comparing any of these therapies. Despite significant progress, there is still a need for a medical therapy that is more effective and with less adverse effects for patients with CD.