Effectiveness of Metyrapone in Treating Cushing's Syndrome: A Retrospective Multicenter Study in 195 Patients

Abstract

Background: Cushing's syndrome (CS) is a severe condition with excess mortality and significant morbidity necessitating control of hypercortisolemia. There are few data documenting use of the steroidogenesis inhibitor metyrapone for this purpose.

Objective: The objective was to assess the effectiveness of metyrapone in controlling cortisol excess in a contemporary series of patients with CS.

Design: This was designed as a retrospective, multicenter study.

Setting: Thirteen University hospitals were studied.

Patients: We studied a total of 195 patients with proven CS: 115 Cushing's disease, 37 ectopic ACTH syndrome, 43 ACTH-independent disease (adrenocortical carcinoma 10, adrenal adenoma 30, and ACTH-independent adrenal hyperplasia 3).

Measurements: Measurements included biochemical parameters of activity of CS: mean serum cortisol "day-curve" (CDC) (target 150-300 nmol/L); 9 am serum cortisol; 24-hour urinary free cortisol (UFC).

Results: A total of 164/195 received metyrapone monotherapy. Mean age was 49.6 ± 15.7 years; mean duration of therapy 8 months (median 3 mo, range 3 d to 11.6 y). There were significant improvements on metyrapone, first evaluation to last review: CDC (91 patients, 722.9 nmol/L [26.2 μg/dL] vs 348.6 nmol/L [12.6 μg/dL]; P < .0001); 9 am cortisol (123 patients, 882.9 nmol/L [32.0 μg/dL] vs 491.1 nmol/L [17.8 μg/dL]; P < .0001); and UFC (37 patients, 1483 nmol/24 h [537 μg/24 h] vs 452.6 nmol/24 h [164 μg/24 h]; P = .003). Overall, control at last review: 55%, 43%, 46%, and 76% of patients who had CDCs, UFCs, 9 am cortisol less than 331 nmol/L (12.0 μg/dL), and 9 am cortisol less than upper limit of normal/600 nmol/L (21.7 μg/dL). Median final dose: Cushing's disease 1375 mg; ectopic ACTH syndrome 1500 mg; benign adrenal disease 750 mg; and adrenocortical carcinoma 1250 mg. Adverse events occurred in 25% of patients, mostly mild gastrointestinal upset and dizziness, usually within 2 weeks of initiation or dose increase, all reversible.

Conclusions: Metyrapone is effective therapy for short- and long-term control of hypercortisolemia in CS.

Figure 1

Age of patients at initiation of metyrapone therapy and diagnosis of CS.

Figure 2

Mean serum CDC and 9 am serum cortisol levels during treatment with metyrapone monotherapy. A, Change in mean CDC in 91 patients treated with metyrapone monotherapy between the first review after initiation of metyrapone and the last review on treatment: 52% (47/91) patients achieved biochemical normalization, 89% showed an improvement. B, Change in the pretreatment 9 am cortisol level in 123 patients treated with metyrapone monotherapy and the last review on treatment: 86% showed an improvement; 102 (83%) patients had a 9 am serum cortisol value below the ULN for the assay used or 600 nmol/L (whichever was lowest) and 69 (56%) had a 9 am level less than 331 nmol/L.

Figure 3

Potassium levels before and during metyrapone monotherapy in 138 patients.