Merits and pitfalls of mifepristone in Cushing's syndrome

Abstract

Objective: Mifepristone is the only available glucocorticoid receptor antagonist. Only few adult patients with hypercortisolism were treated to date by this drug. Our objective was to determine effectiveness and tolerability of mifepristone in Cushing's syndrome (CS). Design: Retrospective study of patients treated in seven European centers. Methods: Twenty patients with malignant (nZ15, 12 with adrenocortical carcinoma, three with ectopic ACTH secretion) or benign (nZ5, four with Cushing's disease, one with bilateral adrenal hyperplasia) CS were treated with mifepristone. Mifepristone was initiated with a median starting dose of 400 mg/day (200-1000). Median treatment duration was 2 months (0.25-21) for malignant CS, and 6 months (0.5-24) for benign CS. Clinical (signs of hypercortisolism, blood pressure, signs of adrenal insufficiency), and biochemical parameters (serum potassium and glucose) were evaluated. Results: Treatment was stopped in one patient after 1 week due to severe uncontrolled hypokalemia. Improvement of clinical signs was observed in 11/15 patients with malignant CS (73%), and 4/5 patients with benign CS (80%). Psychiatric symptoms improved in 4/5 patients within the first week. Blood glucose levels improved in 4/7 patients. Signs of adrenal insufficiency were observed in 3/20 patients. Moderate to severe hypokalemia was observed in 11/20 patients and increased blood pressure levels in 3/20 patients. Conclusion: Mifepristone is a rapidly effective treatment of hypercortisolism, but requires close monitoring of potentially severe hypokalemia, hypertension, and clinical signs of adrenal insufficiency. Mifepristone provides a valuable treatment option in patients with severe CS when surgery is unsuccessful or impossible.

New developments in the medical treatment of Cushing's syndrome

“…Most of these patients could be controlled with daily mifepristone dosages between 400 and 800 mg. An advantage of mifepristone is its rapid onset of action. Indeed, in this retrospective cohort, psychiatric symptoms improved within a week in 4/5 patients (Castinetti et al 2009). This paper also summarized earlier published case reports on mifepristone treatment showing clinical improvement in 9/9 patients with EAS.…”

“…A recently published retrospective study reported improvement of clinical signs in 15/20 patients with CS of different etiologies after treatment with mifepristone (Castinetti et al 2009). Most of these patients could be controlled with daily mifepristone dosages between 400 and 800 mg. An advantage of mifepristone is its rapid onset of action.…”

“…Mifepristone is the only glucocorticoid receptor (GR) antagonist that is currently available (Castinetti et al 2009) and counteracts the effect of cortisol at tissue level. It was initially developed as a compound with antiprogestin activity by blocking the progestin receptor.…”

“…Theoretically, long-term use of mifepristone could provoke NS in patients with CD. Dose titration of mifepristone should be performed according to clinical signs and serum potassium levels (Castinetti et al 2009). …”

“…This paper also summarized earlier published case reports on mifepristone treatment showing clinical improvement in 9/9 patients with EAS. Dosages higher than 1000 mg/day seem to be associated with more side effects, in particular hypokalemia and clinical adrenal insufficiency (Castinetti et al 2009). Glucocorticoid antagonizing therapy may also modulate sst 2 expression of ACTH-producing neuroendocrine tumors.…”