Changes in plasma ACTH levels and corticotroph tumor size in patients with Cushing's disease during long-term treatment with the glucocorticoid receptor antagonist mifepristone

Abstract

Context: Pituitary effects of long-term therapy with mifepristone, a glucocorticoid receptor antagonist, in Cushing's disease (CD) patients are not well understood.

Objective: Our objective was to report changes in ACTH and pituitary magnetic resonance imaging (MRI) findings during long-term use of mifepristone in CD patients.

Design and setting: The Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing's Syndrome (SEISMIC) was a 24-week, open-label study of mifepristone, and its long-term extension (LTE) is a multicenter U.S. study.

Patients: Forty-three CD patients (mean age 45.3 years) were enrolled in SEISMIC with 27 continuing into the LTE study.

Interventions: Mifepristone (300-1200 mg) was administered once daily.

Main outcome measures: ACTH and pituitary MRI were assessed at baseline and at regular intervals during treatment.

Results: A ≥2-fold increase in ACTH was observed in 72% of patients treated for a median duration of 11.3 months. The mean peak increase in ACTH was 2.76 ± 1.65-fold during SEISMIC, and mean ACTH concentrations remained stable during the LTE. ACTH was directly correlated with mifepristone dose and declined to near baseline levels after mifepristone discontinuation. Tumor regressed in 2 patients and progressed in 3 patients with macroadenomas. An additional microadenoma was identified after 25 months of treatment after a baseline tumor-negative MRI.

Conclusions: In the largest prospective study to date, long-term mifepristone treatment increased ACTH in approximately two-thirds of patients with CD. ACTH elevations were observed within the first few weeks of treatment, were dose-dependent, and generally remained stable over time. Corticotroph tumor progression and regression may occur over time, but patients may have significant increases in ACTH levels without evidence of tumor growth.

Trial registration: ClinicalTrials.gov NCT00569582 NCT00936741.

Figure 1.

Patient disposition.

Figure 2.

ACTH concentrations during the study. Study visits are shown on the x-axis: B, baseline; 6W FU, 6-week follow-up visit after 6 weeks after discontinuation of mifepristone; entry into LTE occurred at 6W FU after W24 visit. Visits labeled with M indicate visit time on LTE and do not represent cumulative time on mifepristone. M2/3 represents ACTH levels from month 3 or 2 for subjects not having a month-3 visit due to protocol amendment (see text). The small n at the 6W FU visit at the conclusion of the LTE is due to several patients transitioning to commercially available drug.

Figure 3.

A, Mifepristone dose and B, ACTH concentration. ACTH increase correlates with cortisol. *, Spearman correlation coefficient r.

Figure 4.

Central image analysis of MRIs that showed macroadenomas with progression or regression. Dates shown in bold indicate first detection of progression. A, Atypical macroadenoma, progression at 2.5 months of treatment; B, macroadenoma progression at 6 months of treatment; C, macroadenoma, progression at 19 months of treatment; D, macroadenoma, regression at 1 year.