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Effectiveness of Metyrapone in Treating Cushing's Syndrome: A Retrospective Multicenter Study in 195 Patients
Open accessAbstract
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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“Mean UFC is routinely used in clinical practice and research to monitor disease control and treatment response in patients with CS treated with medical therapy (129-137).”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [131]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“In clinical trials, the efficacy of steroidogenesis inhibitors and pituitary-directed therapies in patients with CS was primarily evaluated by the normalization of cortisol secretion per UFC (129-137).”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [131]
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“The restoration of cortisol circadian rhythm following medical therapy has not been investigated or established for most medications used to treat CS, and it is not routinely measured to determine treatment response (129-137).”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [131]
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Citations
Cites
Lacroix, A., Feelders, R. A., Stratakis, C. A., & Nieman, L. K. (2015) · The Lancet · doi:10.1016/s0140-6736(14)61375-1 · Cited by 1,777
Newell-Price, J. D. C., BERTAGNA, X. Y., Grossman, A. B., & Nieman, L. K. (2006) · The Lancet · doi:10.1016/s0140-6736(06)68699-6 · Cited by 1,258 · cited 1×
“ing effective biochemical control (1).”
Self-citationCANDIA, S. D. (1951) · PubMed · Cited by 365
Verhelst, J. A., Trainer, P. J., Howlett, T. A., Perry, L., Rees, L. H., Grossman, A. B., Wass, J. A. H., & Sesser, G. M. (1991) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1991.tb03517.x · Cited by 308 · cited 13×
“The main indication for metyrapone therapy was the control of severe symptoms of CS (CD 58%, EAS 77%, benign adrenal disease 44% and ACC 80%).”
BackgroundInfluentialSelf-citationKetoconazole in Cushing's disease: is it worth a try?
Castinetti, F., Guignat, L., Giraud, P., Muller, M., Kamenicky, P., Drui, D., Caron, P., Luca, F., Donadille, B., Vantyghem, M. C., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-3628 · Cited by 285 · cited 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).”
BackgroundInfluentialPasireotide Alone or with Cabergoline and Ketoconazole in Cushing's Disease
Feelders, R. A., de Bruin, C., Pereira, A. M., Romijn, J. A., Netea-Maier, R. T., Hermus, A. R., ZELISSEN, P. M. J., van Heerebeek, R., de Jong, F. H., van der Lely, A. J., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmc1000094 · Cited by 262 · cited 2×
“Nine out of 17 patients normalized with pasireotide/cabergoline and ketoconazole induced biochemical control in 6/8 remaining patients (75%) within 20 days of treatment (23).”
BackgroundMethodLiddle, G. W., Island, D. P., Lance, E. M., & Harris, A. P. (1958) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-18-8-906 · Cited by 249 · cited 2×
“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 11 -hydroxylase (8, 9).”
BackgroundKamenický, P., Droumaguet, C., Salenave, S., Blanchard, A., Jublanc, C., Gautier, J., Brailly‐Tabard, S., Leboulleux, S., Schlumberger, M. J., Baudin, É., et al. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-0536 · Cited by 218 · cited 3×
“Kamenický et al (21) used a triplemedication protocol with simultaneous administration of ketoconazole, metyrapone and mitotane in 11 patients with hypercortisolism and life-threatening complications as an alternative to bilateral adrenalectomy; all patients showed rapid clinical and biochemical improvement.”
BackgroundMethodMedical Therapy of Cushing's Disease
Nieman, L. K. (2002) · Pituitary · doi:10.1023/a:1022308429992 · Cited by 184 · cited 1×
“glucocorticoid receptor antagonist, mifepristone (2, 3).”
Metyrapone in long-term management of Cushing's disease.
Jeffcoate, W. J., REES, L. H., Tomlin, S., Jones, A. E., Edwards, C., & BESSER, G. M. (1977) · BMJ · doi:10.1136/bmj.2.6081.215 · Cited by 164 · cited 2×
“reported the efficacy of metyrapone in patients with CD undergoing radiotherapy (13-15) and EAS (17).”
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Diagnosis and Treatment of Pituitary Adenomas: A Review
Molitch, M. E. (2017) · JAMA · doi:10.1001/jama.2016.19699 · Cited by 933
Consensus on diagnosis and management of Cushing's disease: a guideline update
Fleseriu, M., Auchus, R., Bancos, I., Ben-Shlomo, A., Bertherat, J., Biermasz, N. R., Boguszewski, C. L., Bronstein, M. D., Buchfelder, M., Carmichael, J. D., et al. (2021) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(21)00235-7 · Cited by 953
Self-citationThe Functional and Clinical Significance of the 24-Hour Rhythm of Circulating Glucocorticoids
Oster, H., Challet, E., Ott, V., Arvat, E., de Kloet, E. R., Dijk, D.-J., Lightman, S., Vgontzas, A., & Van Cauter, E. (2017) · Endocrine Reviews · doi:10.1210/er.2015-1080 · Cited by 548
Diagnosis and Management of Pituitary Adenomas: A Review
Tritos, N. A., & Miller, K. K. (2023) · JAMA · doi:10.1001/jama.2023.5444 · Cited by 331
Pivonello, R., Fleseriu, M., Newell-Price, J., Bertagna, X., Findling, J., Shimatsu, A., Gu, F., Auchus, R., Leelawattana, R., Lee, E. J., et al. (2020) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(20)30240-0 · Cited by 222
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Metadata
- Authors
- Daniel, E., Aylwin, S., Mustafa, O., Ball, S., Munir, A., Boelaert, K., Chortis, V., Cuthbertson, D. J., Daousi, C., Rajeev, S. P., Davis, J., Cheer, K., Drake, W., Gunganah, K., Grossman, A., Gurnell, M., Powlson, A. S., Karavitaki, N., Huguet, I., Kearney, T., Mohit, K., Meeran, K., Hill, N., Rees, A., Lansdown, A. J., Trainer, P. J., Minder, A.-E. H., & Newell-Price, J.
- Affiliations
- University of Liverpool (GB)
- St Bartholomew's Hospital (GB)
- Corresponding author
- Newell-Price, John
- ORCID
- Daniel, Eleni
- Aylwin, Simon
- Mustafa, Omar
- Boelaert, Kristien
- Chortis, Vasileios
- Cuthbertson, Daniel J.
- Davis, Julian
- Drake, William
- Grossman, Ashley
- Gurnell, Mark
- Powlson, Andrew S.
- Karavitaki, Niki
- Huguet, Isabel
- Kearney, Tara
- Meeran, Karim
- Hill, Neil
- Rees, Aled
- Lansdown, Andrew J.
- Trainer, Peter J.
- Minder, Anna-Elisabeth H.
- Newell-Price, John
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2015-11
- Volume
- 100
- Issue
- 11
- Pages
- 4146-4154
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC5393433
- OpenAlex
- W2145652401
- Semantic Scholar
- be0aef20802f4f370e4b64b56cf53c0bf9ace992
- Cited by
- 231
- References
- 31
- Citations by year
- 2026: 14 · 2025: 22 · 2024: 19 · 2023: 17 · 2022: 36 · 2021: 24 · 2020: 14 · 2019: 24 · 2018: 21 · 2017: 19 · 2016: 18 · 2015: 2
- FWCI
- 17.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- National Institute for Health and Care Research (ACF-2011-04-005)
- Society for Endocrinology
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Keywords
- metyrapone, Cushing's syndrome, hypercortisolism, Cushing's disease, ectopic ACTH syndrome, adrenocortical carcinoma, steroidogenesis inhibition, urinary free cortisol, treatment effectiveness, adverse effects, drug discontinuation, adrenal insufficiency
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Cushing Syndrome, Dose-Response Relationship, Drug, Drug Therapy, Combination, Enzyme Inhibitors, Humans, Hydrocortisone, Infant, Male, Metyrapone, Middle Aged, Pituitary Neoplasms, Retrospective Studies, Treatment Outcome, ACTH-Secreting Pituitary Adenoma, Young Adult
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