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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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In the citing paper
“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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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
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“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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Items 201–231 of 231
More than the Genes: The Tumor Microenvironment in Adrenal Gland Carcinoma
Petrelli, F., Rocca, B. J., Arganini, M., & Ambrosio, M. R. (2022) · Interdisciplinary cancer research · doi:10.1007/16833_2022_81
Case 1-2023: A 49-Year-Old Man with Hypokalemia and Paranoia
Vokoun, C. W., Murphy, M. C., Reynolds, K. L., & Haines, M. S. (2023) · New England Journal of Medicine · doi:10.1056/nejmcpc2211366
Steroidogenesis inhibitors in the treatment of nonoperative Cushing’s syndrome – a literature review
Kamińska, M., Strzoda, A. J., Strzoda, A., Strzoda, A., Sowiński, W., Zdybel, M., Agata, J. U. D. A., Rojek, K., & Polak, A. (2023) · Family Medicine & Primary Care Review · doi:10.5114/fmpcr.2023.127682
Honour, J. W. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-818124-9.00019-x
Quarde, A. (2023) · doi:10.1002/9781119863564.ch1
Perspectivas atuais sobre síndrome de cushing: bases diagnósticas e terapêuticas
Nobre, P. V. C., Rosa, A. W., Malta, M. F. D. B., Florentino, H. S., de Oliveira, M. A. G., Vidal, M. R. G., Cordeiro, K. I. C., da Silva, C. L. L., Reis, T. D. L. A., Ribeiro, N. F. A. M., et al. (2024) · Brazilian Journal of Implantology and Health Sciences · doi:10.36557/2674-8169.2024v6n4p614-624 · Cited by 2
Wade, S. D., Sawicki, C. M., Smiley, M. K., Cuddy, M. A., Vukas, S., & Schwartz, P. J. (2024) · Wiley eBooks · doi:10.1002/9781394164929.ch6
From Nelson’s Syndrome to Corticotroph Tumor Progression Speed: An Update
Bessiène, L., Villa, C., BERTAGNA, X. Y., Baussart, B., & Assié, G. (2024) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/a-2359-8649
Bilateral adrenalectomy for Cushing disease
Castinetti, F. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-13825-6.00110-2
Medical therapy of pituitary adenomas
Molitch, M. E. (2024) · Brain medicine : · doi:10.61373/bm024i.0127
Clinicopathologic Features of the Adrenal Cortex
(2024) · American Registry of PathologyArlington, Virginia eBooks · doi:10.55418/9781933477473-03
Advances in pharmacological treatment of Cushing's disease.
Chai, J., Tang, Y. J., Liu, Y., Tan, H., & Li, J. (2024) · PubMed Central · doi:10.11817/j.issn.1672-7347.2024.240306
“…(NCT03277690) 纳入 44 名受试者，但 结果尚未公布 [38] 。 2012 年 7 月 4 日 EMA 授予左旋酮 康唑作为治疗 CS 的孤儿药 [39] 。 2021 年 12 月 FDA 批 准左旋酮康唑用于治疗不能手术或术后尚未生化缓 解的成人 CS [40] 。 [41] 。 一项纳入 195 例 CS 患者 ( 其中库欣病患者 115 例 ) 的多 中心回顾性研究 [42] 结果显示， 164 名接受美替拉酮单 药治疗的患者，平均治疗期 8 个月，平均血清皮质醇 日曲线 ( P <0.0001) 、 24 h 尿游离皮质醇 ( P <0.001) 或清 [15] 。”
InfluentialCushing’s syndrome: Guidance on thromboprophylaxis at last
Grossman, A. B. (2025) · Pituitary · doi:10.1007/s11102-025-01529-w
Self-citationXia, C., Hu, L., Fan, Y., Liu, J., & Gan, Y. (2025) · Hormone and Metabolic Research · doi:10.1055/a-2685-7512
“The observed results aligned with established AEs data from both approved labeling and clinical trial evidence for these two drugs [19–22].”
Kumar, S., Rawat, A., Sanapala, K., Alisha, K. A., Dhall, S., Prajapati, S. D., Patel, M. K., Das, A., Ramteke, H. D., & Khan, R. (2025) · medRxiv · doi:10.1101/2025.09.01.25334840
Liang, Z., Wang, S., Lan, X., Wei, Z., & Hou, E. (2025) · Cureus · doi:10.7759/cureus.92367
“In a retrospective multicenter study of 195 patients with Cushing’s syndrome, including those with adrenal adenoma, metyrapone monotherapy led to significant improvements in biochemical parameters, such as mean serum cortisol day-curve, 9 am serum cortisol, and 24-hour urinary free cortisol [41].”
Castro, M. A., García-Centeno, R., Aller, J., Marazuela, M., Soto, A., Gálvez, M. A., Cámara, R., Valassi, E., Bernabéu, I., Villar‐Taibo, R., et al. (2025) · Endocrinología Diabetes y Nutrición (English ed ) · doi:10.1016/j.endien.2025.501654
Ling, F., Wu, M., GuoYu, Zhou, R., Han, L., Wang, J., Ma, L., & Jia, A. (2026) · BMC Endocrine Disorders · doi:10.1186/s12902-026-02171-8
“A retrospective multicenter study indicates that using steroid production inhibitors for 4 months before surgery can normalize cortisol levels in 50–72% of cases, but only approximately 33% of the cases showed improvement in subjective symptoms [18].”
Medical therapies for Cushing’s syndrome
Pivonello, R., Paola, N. D., Simeoli, C., & Colao, A. (2026) · Elsevier eBooks · doi:10.1016/b978-0-323-96100-4.00001-6
Cushing’s disease: Pituitary tumors causing CS—Diagnosis and treatment
Alcubierre, D. D., Kassi, E., Isidori, A. M., & Hasenmajer, V. (2026) · Elsevier eBooks · doi:10.1016/b978-0-323-96100-4.00010-7
Medical therapy of hypercortisolism
Feelders, R. A. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-13825-6.00390-3
Chasseloup, F. (2022) · theses.fr (ABES) · doi:10.70675/ddec5b6dzf376z4aadz9970zf0bf052c6f02
Persistent Adrenocortical Insufficiency After Long-Term Metyrapone Treatment for Cushing’s Disease
Yamagata, S., Kawaguchi, T., Nakamura, H. M., Mori, T., Sawada, S., & Kageyama, K. (2026) · AACE Endocrinology and Diabetes · doi:10.1016/j.aed.2026.03.013
“3,4,6,8 It selectively inhibits 11 β -hydroxylase, suppressing cortisol synthesis and typically increasing 11-deoxycortisol levels.”
Ectopic ACTH syndrome in an adult with metastatic Ewing sarcoma
Osafehinti, D. A., Kaplan, J. M., Haddad, E. F. N., & Waguespack, S. G. (2026) · JCEM Case Reports · doi:10.1210/jcemcr/luag096
“Metyrapone, an 11-β hydroxylase inhibitor known to be effective in treating Cushing syndrome [30], was selected for this patient due to its rapid onset of action and availability for inpatient use, and this provided rapid normalization of cortisol.”
Approach to the patient: investigation of postmenopausal androgen excess
Madden-Doyle, L., Bowers, K., Sherlock, M., & O’Reilly, M. (2026) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgag221 · Cited by 1
Rare pituitary diseases in dogs and cats and their human companions
van Stee, L. L., van der Steen, F. E. M. M., Galac, S., Kooistra, H. S., & Meij, B. P. (2026) · Rare Disease and Orphan Drugs Journal · doi:10.20517/rdodj.2025.78 · Cited by 2
Metyrapone in the Management of Severe Hypercortisolism Secondary to Ectopic Cushing’s Syndrome
Sydney, G. I., Ntelis, S., & Majumdar, S. K. (2026) · Case Reports in Endocrinology · doi:10.1155/crie/1796526
“Metyrapone, a steroidogenesis inhibitor targeting 11-β hydroxylase, has shown effectiveness in controlling hypercortisolism, yet little is known about the practical aspects of its initiation, use, and effectiveness in ECS [3 – 6].”
Liu, Y., Yi, L., & Tan, H. (2026) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgag361
Castro, M. A., Bancos, I., Detomas, M., Reincke, M., Kaštelan, D., Naglic, M., Nekić, A. B., Biagetti, B., Casteràs, A., Cardona-Arias, A., et al. (2026) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgag373
Chacko, S. R., Yu, K., Fell, V., Powell, C., Ndovu, B., Rosenberg, R., Ferreira, E. Y., Saini, J., Nevin, S., Larson, J. J., et al. (2026) · EClinicalMedicine · doi:10.1016/j.eclinm.2026.104210
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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