Abstract
Mifepristone is the only glucocorticoid receptor antagonist currently approved for the treatment of Cushing's syndrome. Although originally developed as an abortifacient due to its blockade of the progesterone receptor, a number of case reports documented its efficacy as a glucocorticoid receptor blocker going back to 1985. The SEISMIC trial, published in 2012, provided sufficient data on efficacy and adverse effects for regulatory approval. Mifepristone provides clear benefits on glycemia, blood pressure, muscle weakness, body weight and the other myriad clinical manifestations of Cushing's syndrome. However, because it blocks the glucocorticoid receptor, blood cortisol and ACTH levels actually rise, rather than fall; this complicates patient management. Doses are adjusted based on clinical manifestations rather than hormone levels. Adverse effects include adrenal insufficiency due to overdosage, hypokalemia, and menorrhagia. Treatment of severe adrenal insufficiency requires high doses of dexamethasone. Other glucocorticoid receptor blockers without effects on the progesterone receptor are being developed. Because mifepristone inhibits CYP3A and CYP2C8/2C9, drug-drug interactions can occur. These potential adverse effects can largely be avoided with careful attention to detail. My opinion is that its current place in therapy is in patients with severe disease and in those not responding to other treatments.
Published Version
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