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

  • J Clin Endocrinol Metab. 2015 Nov;100(11):4146-54. doi: 10.1210/jc.2015-2616.
Eleni Daniel  1 ,  Simon Aylwin  1 ,  Omar Mustafa  1 ,  Steve Ball  1 ,  Atif Munir  1 ,  Kristien Boelaert  1 ,  Vasileios Chortis  1 ,  Daniel J Cuthbertson  1 ,  Christina Daousi  1 ,  Surya P Rajeev  1 ,  Julian Davis  1 ,  Kelly Cheer  1 ,  William Drake  1 ,  Kirun Gunganah  1 ,  Ashley Grossman  1 ,  Mark Gurnell  1 ,  Andrew S Powlson  1 ,  Niki Karavitaki  1 ,  Isabel Huguet  1 ,  Tara Kearney  1 ,  Kumar Mohit  1 ,  Karim Meeran  1 ,  Neil Hill  1 ,  Aled Rees  1 ,  Andrew J Lansdown  1 ,  Peter J Trainer  1 ,  Anna-Elisabeth H Minder  1 ,  John Newell-Price  1
Affiliations
  • 1. The Medical School (E.D., J.N.-P.), University of Sheffield, S10 2RX Sheffield, United Kingdom; King's College Hospital NHS Foundation Trust (S.A., O.M.), B15 2TT London, United Kingdom; The Medical School (S.B.), Newcastle University, NE2 4HH Newcastle, United Kingdom; Royal Victoria Infirmary (S.B., A.M.), SE5 9RS Newcastle, United Kingdom; College of Medical and Dental Sciences (K.B., V.C., N.K.), Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, M13 9PT Birmingham, United Kingdom; Department of Obesity and Endocrinology (D.J.C., C.D., S.P.R.), University of Liverpool, NE1 4LP Liverpool, United Kingdom; Centre for Endocrinology and Diabetes (J.D.), University of Manchester, L69 3GA Manchester, United Kingdom; Manchester Royal Infirmary (K.C.), M13 9WL Manchester, United Kingdom; Department of Endocrinology (W.D., K.G.), St Bartholomew's Hospital, EC1A 7BE London, United Kingdom; Oxford Centre for Diabetes (A.G., N.K., I.H.), Endocrinology and Metabolism, Churchill Hospital, M6 8HD Oxford, United Kingdom; Wellcome Trust-MRC Institute of Metabolic Science (M.G., A.S.P.), University of Cambridge, Addenbrooke's Hospital, OX3 7LE Cambridge, United Kingdom; Salford Royal Foundation Trust (T.K., K.Mo.), CB2 0QQ Salford, United Kingdom; Imperial College (K.Me., N.H.), SW7 2AZ London, United Kingdom; School of Medicine (A.R., A.J.L.), Cardiff University, CF14 4XN Cardiff, United Kingdom; and The Christie NHS Foundation Trust (P.J.T., A.-E.H.M.), M20 4BX Manchester, United Kingdom.
PMID: 26353009 DOI: 10.1210/jc.2015-2616
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.

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