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Exp Clin Endocrinol Diabetes 2024; 132(12): 723-731
DOI: 10.1055/a-2317-0801
Review

Medical Therapy of Endogenous Cushing’s Syndrome with Steroidogenesis Inhibitors: Treatment Rationale, Available Drugs, and Therapeutic Effects

Mario Detomas
1   Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany
,
Timo Deutschbein
1   Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany
2   Medicover Oldenburg MVZ, Oldenburg, Germany
,
Barbara Altieri
1   Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany
› Author Affiliations Funding information MD was supported by the Clinician Scientist program RISE, funded by the Else-Kröner-Fresenius-Stiftung and the Eva-Luise und Horst-Köhler Stiftung.
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Abstract

Endogenous Cushing’s syndrome (CS) is a rare disease characterized by a glucocorticoid excess. If inadequately treated, hypercortisolism can lead to increased morbidity and mortality. Surgical removal of the underlying tumor is the first-line treatment but is sometimes not feasible or even contraindicated. Additionally, in cases with severe CS, rapid control of hypercortisolism may be required. In these scenarios, steroidogenesis inhibitors represent a therapeutic alternative to surgery. Over the last years, the knowledge of the broad therapeutic effects of steroidogenesis inhibitors per se and the number of available drugs have increased. However, large comparative studies are still lacking. Accordingly, the decision on which drug to be used in a certain patient or clinical setting may be difficult. This review aims to summarize the main characteristics of steroidogenesis inhibitors.

Keywords

etomidate - hypercortisolism - ketoconazole - levoketoconazole - medical therapy - metyrapone - mitotane - osilodrostat


Publication History

Received: 01 February 2024
Received: 18 April 2024

Accepted Manuscript online:
30 April 2024

Article published online:
14 June 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Reincke M, Fleseriu M. Cushing syndrome: A review. JAMA 2023; 330: 170-181
    CrossrefPubMedSearch in Google Scholar
  • 2 Pivonello R, Isidori AM, De Martino MC. et al. Complications of Cushing's syndrome: State of the art. Lancet Diabetes Endocrinol 2016; 4: 611-629
    CrossrefPubMedSearch in Google Scholar
  • 3 Pivonello R, Simeoli C, Di Paola N. et al. Cushing's disease: Adrenal steroidogenesis inhibitors. Pituitary 2022; 25: 726-732
    CrossrefPubMedSearch in Google Scholar
  • 4 Gilis-Januszewska A, Boguslawska A, Rzepka E. et al. Individualized medical treatment options in Cushing disease. Front Endocrinol (Lausanne) 2022; 13: 1060884
    CrossrefPubMedSearch in Google Scholar
  • 5 Castinetti F, Guignat L, Giraud P. et al. Ketoconazole in Cushing's disease: Is it worth a try?. J Clin Endocrinol Metab 2014; 99: 1623-1630
    CrossrefPubMedSearch in Google Scholar
  • 6 Viecceli C, Mattos ACV, Hirakata VN. et al. Ketoconazole as second-line treatment for Cushing's disease after transsphenoidal surgery: Systematic review and meta-analysis. Front Endocrinol (Lausanne) 2023; 14: 1145775
    CrossrefPubMedSearch in Google Scholar
  • 7 Young J, Bertherat J, Vantyghem MC. et al. Hepatic safety of ketoconazole in Cushing's syndrome: Results of a Compassionate Use Programme in France. Eur J Endocrinol 2018; 178: 447-458
    CrossrefPubMedSearch in Google Scholar
  • 8 Pivonello R, De Leo M, Cozzolino A. et al. The treatment of Cushing's disease. Endocr Rev 2015; 36: 385-486
    CrossrefPubMedSearch in Google Scholar
  • 9 Fleseriu M, Pivonello R, Elenkova A. et al. Efficacy and safety of levoketoconazole in the treatment of endogenous Cushing's syndrome (SONICS): A phase 3, multicentre, open-label, single-arm trial. Lancet Diabetes Endocrinol 2019; 7: 855-865
    CrossrefPubMedSearch in Google Scholar
  • 10 Pivonello R, Zacharieva S, Elenkova A. et al. Levoketoconazole in the treatment of patients with endogenous Cushing's syndrome: A double-blind, placebo-controlled, randomized withdrawal study (LOGICS). Pituitary 2022; 25: 911-926
    CrossrefPubMedSearch in Google Scholar
  • 11 Daniel E, Aylwin S, Mustafa O. et al. Effectiveness of metyrapone in treating Cushing's syndrome: A retrospective multicenter study in 195 patients. J Clin Endocrinol Metab 2015; 100: 4146-4154
    CrossrefPubMedSearch in Google Scholar
  • 12 Ceccato F, Zilio M, Barbot M. et al. Metyrapone treatment in Cushing's syndrome: A real-life study. Endocrine 2018; 62: 701-711
    CrossrefPubMedSearch in Google Scholar
  • 13 Nieman LK, BM Scaroni CM, Deutschbein T. et al. Metyrapone treatment in endogenous Cushing’s syndrome: Results at week 12 from PROMPT, a prospective international multicenter, open-label, phase III/IV study. J Endocr Soc 2021; 5: A515
    CrossrefPubMedSearch in Google Scholar
  • 14 Detomas M, Altieri B, Deutschbein T. et al. Metyrapone versus osilodrostat in the short-term therapy of endogenous Cushing's syndrome: Results from a single center cohort study. Front Endocrinol (Lausanne) 2022; 13: 903545
    CrossrefPubMedSearch in Google Scholar
  • 15 Pivonello R, Fleseriu M, Newell-Price J. et al. Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3): A multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol 2020; 8: 748-761
    CrossrefPubMedSearch in Google Scholar
  • 16 Gadelha M, Bex M, Feelders RA. et al. Randomized trial of osilodrostat for the treatment of Cushing disease. J Clin Endocrinol Metab 2022; 107: e2882-e2895
    CrossrefPubMedSearch in Google Scholar
  • 17 Dormoy A, Haissaguerre M, Vitellius G. et al. Efficacy and safety of osilodrostat in paraneoplastic Cushing syndrome: A real-world multicenter study in France. J Clin Endocrinol Metab 2023; 108: 1475-1487
    CrossrefPubMedSearch in Google Scholar
  • 18 Ferriere A, Salenave S, Puerto M. et al. Prolonged adrenal insufficiency following discontinuation of osilodrostat treatment for intense hypercortisolism. Eur J Endocrinol 2024; 190: L1-L3
    CrossrefPubMedSearch in Google Scholar
  • 19 Castinetti F, Amodru V, Brue T. Osilodrostat in Cushing's disease: The risk of delayed adrenal insufficiency should be carefully monitored. Clin Endocrinol (Oxf) 2023; 98: 629-630
    CrossrefPubMedSearch in Google Scholar
  • 20 Poirier J, Bonnet-Serrano F, Thomeret L. et al. Prolonged adrenocortical blockade following discontinuation of Osilodrostat. Eur J Endocrinol 2023; 188: K29-K32
    CrossrefPubMedSearch in Google Scholar
  • 21 Baudry C, Coste J, Bou Khalil R. et al. Efficiency and tolerance of mitotane in Cushing's disease in 76 patients from a single center. Eur J Endocrinol 2012; 167: 473-481
    CrossrefPubMedSearch in Google Scholar
  • 22 Altieri B, Kimpel O, Megerle F. et al. Recovery of adrenal function after stopping mitotane in patients with adrenocortical carcinoma. Eur J Endocrinol 2024; 190: 139
    CrossrefPubMedSearch in Google Scholar
  • 23 Altieri B, Lalli E, Faggiano A. Mitotane treatment in adrenocortical carcinoma: Mechanisms of action and predictive markers of response to therapy. Minerva Endocrinol (Torino) 2022; 47: 203-214
    CrossrefPubMedSearch in Google Scholar
  • 24 Detomas M, Pivonello C, Pellegrini B. et al. MicroRNAs and long non-coding RNAs in adrenocortical carcinoma. Cells 2022; 11: 2234
    CrossrefPubMedSearch in Google Scholar
  • 25 Fassnacht M, Dekkers OM, Else T. et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 2018; 179: G1-G46
    CrossrefPubMedSearch in Google Scholar
  • 26 Calabrese A, Basile V, Puglisi S. et al. Adjuvant mitotane therapy is beneficial in non-metastatic adrenocortical carcinoma at high risk of recurrence. Eur J Endocrinol 2019; 180: 387-396
    CrossrefPubMedSearch in Google Scholar
  • 27 Donadille B, Groussin L, Waintrop C. et al. Management of Cushing's syndrome due to ectopic adrenocorticotropin secretion with 1,ortho-1, para'-dichloro-diphenyl-dichloro-ethane: Findings in 23 patients from a single center. J Clin Endocrinol Metab 2010; 95: 537-544
    CrossrefPubMedSearch in Google Scholar
  • 28 Altieri B, Sbiera S, Herterich S. et al. Effects of germline CYP2W1*6 and CYP2B6*6 single nucleotide polymorphisms on mitotane treatment in adrenocortical carcinoma: A multicenter ENSAT study. Cancers (Basel) 2020; 12: 359
    CrossrefPubMedSearch in Google Scholar
  • 29 Altieri B, Kimpel O, Quinkler M. et al. Adverse events of mitotane treatment in patients with adrenocortical carcinoma. Endocrine Abstracts 2021; 73
    CrossrefPubMedSearch in Google Scholar
  • 30 Fleseriu M, Castinetti F. Updates on the role of adrenal steroidogenesis inhibitors in Cushing's syndrome: A focus on novel therapies. Pituitary 2016; 19: 643-653
    CrossrefPubMedSearch in Google Scholar
  • 31 Pence A, McGrath M, Lee SL. et al. Pharmacological management of severe Cushing's syndrome: The role of etomidate. Ther Adv Endocrinol Metab 2022; 13 20420188211058583
    CrossrefPubMedSearch in Google Scholar
  • 32 Greening JE, Brain CE, Perry LA. et al. Efficient short-term control of hypercortisolaemia by low-dose etomidate in severe paediatric Cushing's disease. Horm Res 2005; 64: 140-143
    CrossrefPubMedSearch in Google Scholar
  • 33 Vergara Molina N, Ruiz Andres N, Casas Martin N. et al. Etomidate in the treatment of Cushing syndrome. Rev Esp Anestesiol Reanim (Engl Ed) 2023; 70: 473-476
    CrossrefPubMedSearch in Google Scholar
  • 34 Schulte HM, Benker G, Reinwein D. et al. Infusion of low dose etomidate: correction of hypercortisolemia in patients with Cushing's syndrome and dose-response relationship in normal subjects. J Clin Endocrinol Metab 1990; 70: 1426-1430
    CrossrefPubMedSearch in Google Scholar
  • 35 Payen JF, Dupuis C, Trouve-Buisson T. et al. Corticosteroid after etomidate in critically ill patients: A randomized controlled trial. Crit Care Med 2012; 40: 29-35
    CrossrefPubMedSearch in Google Scholar
  • 36 Kamenicky P, Droumaguet C, Salenave S. et al. Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing's syndrome. J Clin Endocrinol Metab 2011; 96: 2796-2804
    CrossrefPubMedSearch in Google Scholar
  • 37 Corcuff JB, Young J, Masquefa-Giraud P. et al. Rapid control of severe neoplastic hypercortisolism with metyrapone and ketoconazole. Eur J Endocrinol 2015; 172: 473-481
    CrossrefPubMedSearch in Google Scholar
  • 38 Amodru V, Brue T, Castinetti F. Synergistic cortisol suppression by ketoconazole-osilodrostat combination therapy. Endocrinol Diabetes Metab Case Rep 2021; 2021: 21-0071
    CrossrefPubMedSearch in Google Scholar
  • 39 Castinetti F. Pharmacological treatment of Cushing's syndrome. Arch Med Res 2023; 54: 102908
    CrossrefPubMedSearch in Google Scholar
  • 40 Castinetti F, Nieman LK, Reincke M. et al. Approach to the patient treated with steroidogenesis inhibitors. J Clin Endocrinol Metab 2021; 106: 2114-2123
    CrossrefPubMedSearch in Google Scholar
  • 41 Monaghan PJ, Owen LJ, Trainer PJ. et al. Comparison of serum cortisol measurement by immunoassay and liquid chromatography-tandem mass spectrometry in patients receiving the 11beta-hydroxylase inhibitor metyrapone. Ann Clin Biochem 2011; 48: 441-446
    CrossrefPubMedSearch in Google Scholar
  • 42 Petersenn S, Newell-Price J, Findling JW. et al. High variability in baseline urinary free cortisol values in patients with Cushing's disease. Clin Endocrinol (Oxf) 2014; 80: 261-269
    CrossrefPubMedSearch in Google Scholar
  • 43 Newell-Price J, Pivonello R, Tabarin A. et al. Use of late-night salivary cortisol to monitor response to medical treatment in Cushing's disease. Eur J Endocrinol 2020; 182: 207-217
    CrossrefPubMedSearch in Google Scholar
  • 44 Vega-Beyhart A, Laguna-Moreno J, Diaz-Catalan D. et al. Ketoconazole- and metyrapone-induced reductions on urinary steroid metabolites alter the urinary free cortisol immunoassay reliability in Cushing syndrome. Front Endocrinol (Lausanne) 2022; 13: 833644
    CrossrefPubMedSearch in Google Scholar
  • 45 Detomas M, Deutschbein T, Tamburello M. et al. Erythropoiesis in Cushing syndrome: Sex-related and subtype-specific differences. Results from a monocentric study. J Endocrinol Invest 2024; 47: 101-113
    CrossrefPubMedSearch in Google Scholar
  • 46 Detomas M, Altieri B, Chifu I. et al. Subtype-specific pattern of white blood cell differential in endogenous hypercortisolism. Eur J Endocrinol 2022; 187: 439-449
    CrossrefPubMedSearch in Google Scholar
  • 47 Detomas M, Ceccato F, Aulinas A. et al. Comparison of Metyrapone, OSilodrostat and KEToconazolE in the short-term thERapy of endogenous Cushing’s syndrome: Preliminary results of the MOSKETEER study. Endocrine Abstracts 2023; 90: 811
    CrossrefPubMedSearch in Google Scholar
  • 48 Nowotny HF, Braun L, Vogel F. et al. 11-Oxygenated C19 steroids are the predominant androgens responsible for hyperandrogenemia in Cushing's disease. Eur J Endocrinol 2022; 187: 663-673
    CrossrefPubMedSearch in Google Scholar
  • 49 Bonnet-Serrano F, Poirier J, Vaczlavik A. et al. Differences in the spectrum of steroidogenic enzyme inhibition between osilodrostat and metyrapone in ACTH-dependent Cushing syndrome patients. Eur J Endocrinol 2022; 187: 315-322
    CrossrefPubMedSearch in Google Scholar
  • 50 Fleseriu M, Biller BMK. Treatment of Cushing's syndrome with osilodrostat: Practical applications of recent studies with case examples. Pituitary 2022; 25: 795-809
    CrossrefPubMedSearch in Google Scholar
  • 51 Pivonello R, Ferrigno R, De Martino MC. et al. Medical treatment of Cushing's disease: An overview of the current and recent clinical trials. Front Endocrinol (Lausanne) 2020; 11: 648
    CrossrefPubMedSearch in Google Scholar
  • 52 LaPensee CR, Mann JE, Rainey WE. et al. ATR-101, a selective and potent inhibitor of acyl-CoA acyltransferase 1, induces apoptosis in H295R adrenocortical cells and in the adrenal cortex of dogs. Endocrinology 2016; 157: 1775-1788
    CrossrefPubMedSearch in Google Scholar
  • 53 Wu N, Katz DA, An G. A Target-mediated drug disposition model to explain nonlinear pharmacokinetics of the 11beta-hydroxysteroid dehydrogenase type 1 inhibitor SPI-62 in healthy adults. J Clin Pharmacol 2021; 61: 1442-1453
    CrossrefPubMedSearch in Google Scholar