Successful long-term treatment of refractory Cushing's disease with high-dose mifepristone (RU 486)

An extremely ill patient, with Cushing's syndrome caused by an ACTH-secreting pituitary macroadenoma, experienced complications of end-stage cardiomyopathy, profound psychosis, and multiple metabolic disturbances. Initially treated unsuccessfully by a combination of conventional surgical, medical, and radiotherapeutic approaches, he responded dramatically to high-dose long-term mifepristone therapy (up to 25 mg/kg x d). Treatment efficacy was confirmed by the normalization of all biochemical glucocorticoid-sensitive measurements, as well as by the significant reversal of the patient's heart failure, the resolution of his psychotic depression, and the eventual unusual return of his adrenal axis to normal. His 18-month-long mifepristone treatment course was notable for development of severe hypokalemia that was attributed to excessive cortisol activation of the mineralocorticoid receptor, which responded to spironolactone administration. This case illustrates the efficacy of high-dose long-term treatment with mifepristone in refractory Cushing's syndrome. The case also demonstrates the potential need for concomitant mineralocorticoid receptor blockade in mifepristone-treated Cushing's disease, because cortisol levels may rise markedly, reflecting corticotroph disinhibition, to cause manifestations of mineralocorticoid excess.