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Effectiveness of metyrapone in treating Cushing's Syndrome: a retrospective multicenter study in 195 patients

Daniel, Eleni, Aylwin, Simon, Mustafa, Omar, Ball, Steve, Munir, Atif, Boelaert, Kristien, Chortis, Vasileios, Cuthbertson, Daniel J., Daousi, Christina, Rajeev, Surya P., Davis, Julian, Cheer, Kelly, Drake, William, Gunganah, Kirun, Grossman, Ashley, Gurnell, Mark, Powlson, Andrew S., Karavitaki, Niki, Huguet, Isabel, Kearney, Tara, Mohit, Kumar, Meeran, Karim, Hill, Neil, Rees, Dafydd Aled ORCID:, Lansdown, Andrew J., Trainer, Peter J., Minder, Anna-Elisabeth H. and Newell-Price, John 2015. Effectiveness of metyrapone in treating Cushing's Syndrome: a retrospective multicenter study in 195 patients. Journal of Clinical Endocrinology & Metabolism 100 (11) , p. 4146. 10.1210/jc.2015-2616

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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. Cushing's syndrome (CS) is a severe condition with excess mortality and significant morbidity necessitating effective biochemical control (1). Where a cause amenable to surgical intervention is identified, surgery at a center with appropriate expertise is the optimum management. Nevertheless, many patients need urgent control of severe or persisting hypercortisolemia. Options for medical treatment include steroidogenesis enzyme inhibitors suitable for all causes of CS (ketoconazole, metyrapone, mitotane), agents to suppress ACTH in Cushing's disease (CD), such as dopamine agonists and pasireotide, and the glucocorticoid receptor antagonist, mifepristone (2, 3). The modern use of ketoconazole has recently been reported in a multicenter French Study (4), although its availability in the United States has been restricted after an Food and Drug Administration safety warning for hepatotoxicity in 2013 (5, 6), but it is widely available in Europe in 2015 (7).The cortisol-lowering effect of metyrapone was described as early as 1958 by Liddle et al (8), with later reports confirming metyrapone as a potent inhibitor of the steroidogenesis enzyme 11β-hydroxylase (8, 9). Since then, it has been used as a diagnostic test of adrenal reserve and to treat the hypercortisolism of CS. Despite its widespread use, data on metyrapone are scarce, with the largest study to date (including 91 patients) being published over 25 years ago (10). Here, we have assessed the effectiveness of metyrapone therapy in a contemporary series of patients with CS, by performing a retrospective study of patients treated in the United Kingdom.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: The Endocrine Society
ISSN: 0021-972X
Date of Acceptance: 2 September 2015
Last Modified: 31 Oct 2022 10:55

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