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Cited by 285Pituitary Gland Disorders and TreatmentsAdrenal and Paraganglionic TumorsAdrenal Hormones and Disorders

Ketoconazole in Cushing's disease: is it worth a try?

Castinetti, Frederic, Guignat, Laurence, Giraud, Pauline, Muller, Marie, Kamenicky, Peter, Drui, Delphine, Caron, Philippe, Luca, Fiorina +22 more·2014·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2013-3628
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Abstract

BACKGROUND: The use of ketoconazole has been recently questioned after warnings from the European Medicine Agencies and the Food and Drug Administration due to potential hepatotoxicity. However, ketoconazole is frequently used as a drug to lower circulating cortisol levels. Several pharmacological agents have recently been approved for the treatment of Cushing's disease (CD) despite limited efficacy or significant side effects. Ketoconazole has been used worldwide for more than 30 years in CD, but in the absence of a large-scale study, its efficacy and tolerance are still under debate. PATIENTS AND METHODS: We conducted a French retrospective multicenter study reviewing data from patients treated by ketoconazole as a single agent for CD, with the aim of clarifying efficacy and tolerance to better determine the benefit/risk balance. RESULTS: Data from 200 patients were included in this study. At the last follow-up, 49.3% of patients had normal urinary free cortisol (UFC) levels, 25.6% had at least a 50% decrease, and 25.4% had unchanged UFC levels. The median final dose of ketoconazole was 600 mg/d. Forty patients (20%) received ketoconazole as a presurgical treatment; 40% to 50% of these patients showed improvement of hypertension, hypokalemia, and diabetes, and 48.7% had normal UFC before surgery. Overall, 41 patients (20.5%) stopped the treatment due to poor tolerance. Mild (<5N, inferior to 5-fold normal values) and major (>5N, superior to 5-fold normal values) increases in liver enzymes were observed in 13.5% and 2.5% of patients, respectively. No fatal hepatitis was observed. CONCLUSIONS: Ketoconazole is an effective drug with acceptable side effects. It should be used under close liver enzyme monitoring. Hepatotoxicity is usually mild and resolves after drug withdrawal.

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Crossref · 10.1210/jc.2013-3628

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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.

    “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 [129]

    The Patients and Methods section says UFC was averaged from 2–3 samples, monitored during ketoconazole treatment, and used to define disease control. The Discussion says the study used averaged UFC measurements to assess control. This supports the claim for patients with Cushing’s disease receiving ketoconazole, but the paper does not establish routine use across all forms of Cushing’s syndrome or medical therapies. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • In clinical trials, the efficacy of steroidogenesis inhibitors and pituitary-directed therapies in patients with CS was primarily evaluated by normalization of cortisol secretion per UFC.

    “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 [129]

    Patients and Methods (page not provided) defines control during ketoconazole treatment as normal 24-hour UFC at two consecutive evaluations, supporting UFC normalization as an efficacy measure for this steroidogenesis inhibitor. The study is retrospective and limited to ketoconazole in Cushing’s disease; it does not establish that clinical trials of steroidogenesis inhibitors and pituitary-directed therapies in Cushing’s syndrome primarily used that measure. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • 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.

    “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 [129]

    In Patients and Methods, treatment response in this ketoconazole cohort was assessed with urinary free cortisol (UFC), not restoration of a cortisol circadian rhythm. The Discussion says midnight salivary cortisol was unavailable for all patients and UFC was used to define disease control. The paper does not establish that circadian-rhythm restoration has not been investigated for most medications used to treat Cushing's syndrome, or that it is not routinely measured across those treatments. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • At doses of 200 to 1200 mg daily, ketoconazole has been shown to improve glucose metabolism in patients with Cushing syndrome and in those with type 2 diabetes.

    “At doses of  to  mg daily, this steroidogenesis inhibitor has been shown to improve glucose metabolism in patients with CS and in those with type  DM (-).”

    From Glucose Metabolism Abnormalities in Cushing Syndrome: From Molecular Basis to Clinical Management (2017) · cites this paper as [284]

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Cites

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Research works printed but not linked: 3

  1. [4]4. Dandona P, Mohiuddin J, Prentice HG. Ketoconazole and adreno- cortical secretion. Lancet 1985;1:227.
  2. [18]18. Sonino N, Boscaro M, Paoletta A, Mantero F, Ziliotto D. Keto- conazole treatment in Cushing's syndrome: experience in 34 pa- tients. Clin Endocrinol (Oxf). 1991;35:347-352.
  3. [32]32. Bercoff E, Bernuau J, Degott C, et al. Ketoconazole-induced fulmi- nant hepatitis. Gut. 1985;26:636 -638.

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Authors
Castinetti, F., Guignat, L., Giraud, P., Muller, M., Kamenicky, P., Drui, D., Caron, P., Luca, F., Donadille, B., Vantyghem, M. C., Bihan, H., Delemer, B., Raverot, G., Motte, E., Philippon, M., Morange, I., Conte-Devolx, B., Quinquis, L., Martinie, M., Vezzosi, D., Le Bras, M., Baudry, C., Christin-Maitre, S., Goichot, B., Chanson, P., Young, J., Chabre, O., Tabarin, A., Bertherat, J., & Brue, T.
Affiliations
  • Aix Marseille Université, Hopital de la Timone (F.C., M.P., I.M., B.C.-D., T.B.), Service d'Endocrinologie, 13005, Marseille, France
  • Hôpital Cochin (FR)
  • Centre Hospitalier Universitaire de Bordeaux (FR)
  • Hôpital Albert Michallon (FR)
  • Université Paris-Sud Service d'Endocrinologie et Maladies de la Reproduction (P.K., P.Ch., J.Y.), 94270, Le Kremlin Bicetre, France
  • Centre Hospitalier Universitaire de Nantes (FR)
  • Hôpital Larrey (FR)
  • Hôpital d'Hautepierre (FR)
  • Assistance Publique – Hôpitaux de Paris (FR)
  • Centre Hospitalier Universitaire de Lille (FR)
  • Hôpital Avicenne (FR)
  • Centre Hospitalier Universitaire de Reims (FR)
  • Hôpital Neuro-cardiologique Fédération d'Endocrinologie du Pôle Est (G.R.), 39500 Bron, France
  • Hôpital de Bicêtre Endocrinologie Pédiatrique (E.M.), 94270, Le Kremlin Bicetre, France
  • Aix-Marseille Université (FR)
  • CHU de Nantes Hôpital G & R Laënnec St-Herblain Endocrinologie, Maladies Métaboliques et Nutrition (D.D., M.L.B.), 44093, Nantes, France
  • Assistance Publique-Hôpitaux de Paris, Hôpital St-Antoine Service d'Endocrinologie-Diabétologie et Médecine de la Reproduction (B.Do., S.C.-M.), 75012, Paris, France
  • Université Paris-Sud (FR)
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2014-05-01
Volume
99
Issue
5
Pages
1623-1630
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2013-3628
OpenAlex
W2125518985
Semantic Scholar
06bf42858cb6de53f9f93e22f528a6e524a20a4a
Cited by
285
References
42
Citations by year
2026: 10 · 2025: 18 · 2024: 23 · 2023: 20 · 2022: 32 · 2021: 23 · 2020: 21 · 2019: 28 · 2018: 31 · 2017: 21 · 2016: 23 · 2015: 23 · 2014: 11
FWCI
20.90
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
  • Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
ketoconazole, Cushing's disease, hepatotoxicity, liver enzyme monitoring, urinary free cortisol, drug efficacy, drug tolerance, presurgical treatment, hypertension, hypokalemia, diabetes mellitus
MeSH terms
Adolescent, Adult, Aged, Aged, 80 and over, Child, Female, Humans, Hydrocortisone, Ketoconazole, Male, Middle Aged, Retrospective Studies, Treatment Outcome, Pituitary ACTH Hypersecretion, 14-alpha Demethylase Inhibitors

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