Ketoconazole and Plasma and Urine Steroid Levels in Cushing's Disease

Mortimer, Robin H.; Cannell, G. R.; Thew, Caroline M.; Galligan, John

doi:10.1111/j.1440-1681.1991.tb01492.x

Cited by 19 publications

(13 citation statements)

References 19 publications

(32 reference statements)

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“…Although an increase in basal ACTH levels during chronic ketoconazole administration is seen in normal subjects (41), conflicting results were reported in patients with CD. It has been shown that in patients with CD basal ACTH levels remain unchanged (30)(31)(32)(33)42), increase (34), and even decrease (29,35) after ketoconazole treatment. In vitro studies were performed in order to verify a possible direct effect of ketoconazole on pituitary cells.…”

Section: Discussionmentioning

confidence: 99%

Effect of one month ketoconazole treatment on GH, cortisol and ACTH release after ghrelin, GHRP-6 and GHRH administration in patients with cushing’s disease

Correa‐Silva

Nascif

Silva

et al. 2007

Arq Bras Endocrinol Metab

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GH responses to ghrelin, GHRP-6, and GHRH in Cushing's disease (CD) are markedly blunted. There is no data about the effect of reduction of cortisol levels with steroidogenesis inhibitors, like ketoconazole, on GH secretion in CD. ACTH levels during ketoconazole treatment are controversial. The aims of this study were to compare the GH response to ghrelin, GHRP-6, and GHRH, and the ACTH and cortisol responses to ghrelin and GHRP-6 before and after one month of ketoconazole treatment in 6 untreated patients with CD. Before treatment peak GH (µg/L; mean ± SEM) after ghrelin, GHRP-6, and GHRH administration was 10.0 ± 4.5; 3.8 ± 1.6, and 0.6 ± 0.2, respectively. After one month of ketoconazole there was a significant decrease in urinary cortisol values (mean reduction: 75%), but GH responses did not change (7.0 ± 2.0; 3.1 ± 0.8; 0.9 ± 0.2, respectively). After treatment, there was a significant reduction in cortisol (µg/dL) responses to ghrelin (before: 30.6 ± 5.2; after: 24.2 ± 5.1). No significant changes in ACTH (pg/mL) responses before (ghrelin: 210.9 ± 69.9; GHRP-6: 199.8 ± 88.8) and after treatment (ghrelin: 159.7 ± 40.3; GHRP-6: 227 ± 127.2) were observed. In conclusion, after short-term ketoconazole treatment there are no changes in GH or ACTH responses, despite a major decrease of cortisol levels. A longer period of treatment might be necessary for the recovery of pituitary function. RESUMO Efeito do Tratamento com Ketoconazole por um Mês na Liberação de GH, Cortisol e ACHT Após Administração de GHrelin, GHRP-6 e GHRH em Pacientes com Síndrome de Cushing.Na doença de Cushing (DC), as respostas do GH à ghrelina, ao GHRP-6 e ao GHRH estão diminuídas. Não existem dados sobre o efeito da redução dos níveis de cortisol, após cetoconazol, na secreção de GH na DC. Nessa situação, os níveis de ACTH são variáveis. Os objetivos do estudo são comparar as respostas do GH à administração de ghrelina, GHRP-6 e GHRH, e de ACTH e cortisol à ghrelina e ao GHRP-6 antes e após um mês de tratamento com cetoconazol em 6 pacientes com DC não tratados. Antes do tratamento, o pico de GH (µg/L; média ± EPM) após a administração de ghrelina, GHRP-6 e GHRH foi de 10,0 ± 4,5; 3,8 ± 1,6 e 0,6 ± 0,2, respectivamente. Após um mês de cetoconazol, ocorreu diminuição significante do cortisol urinário (redução média: 75%), mas as respostas de GH permaneceram inalteradas (7,0 ± 2,0; 3,1 ± 0,8; 0,9 ± 0,2, respectivamente). Após o tratamento, houve redução da resposta de cortisol (µg/dL) à ghrelina (antes: 30,6 ± 5,2; após: 24,2 ± 5,1), mas não ocorreram mudanças nas respostas de ACTH (pg/mL) (ghrelina antes: 210,9 ± 69,9; após: 159,7 ± 40,3;8 ± 88,8; após: 227 ± 127,2). Assim, o tratamento a curto prazo com cetoconazol não modificou as respostas de GH ou ACTH, apesar da redução do cortisol. Para a recuperação da função hipofisária deve ser necessário um período de tratamento maior.

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Section: Discussionmentioning

confidence: 99%

Effect of one month ketoconazole treatment on GH, cortisol and ACTH release after ghrelin, GHRP-6 and GHRH administration in patients with cushing’s disease

Correa‐Silva

Nascif

Silva

et al. 2007

Arq Bras Endocrinol Metab

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“…Taking all case series together, ketoconazole monotherapy (at daily doses of 400 -1200 mg) normalized UFC in 57 of 82 patients with presumed CD (25-93% rate in individual studies); normalization was not dependent on the dose or duration of treatment (113)(114)(115)(116)(117)(118)(119)(120). Recent data confirm these findings with a greater than 50% drop in UFC in 75% of 200 patients, and with clinical improvements in diabetes, hypertension, and hypokalemia (121).…”

Section: Evidence Ketoconazolementioning

confidence: 97%

Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline

Nieman

Biller

Findling

et al. 2015

The Journal of Clinical Endocrinology & Metabolism

948

959

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Treatment of Cushing's syndrome is essential to reduce mortality and associated comorbidities. Effective treatment includes the normalization of cortisol levels or action. It also includes the normalization of comorbidities via directly treating the cause of Cushing's syndrome and by adjunctive treatments (eg, antihypertensives). Surgical resection of the causal lesion(s) is generally the first-line approach. The choice of second-line treatments, including medication, bilateral adrenalectomy, and radiation therapy (for corticotrope tumors), must be individualized to each patient.

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“…At high concentrations, it has been shown to be an antagonist of the glucocorticoid receptor in cultured hepatoma cells (21) and it binds to glucocorticoid receptors in cytosolic preparations of human mononuclear cells (22). Earlier studies and case reports have described its effects in a total of about 100 patients, including 85 patients with CD (23)(24)(25)(26)(27)(28)(29). However, published studies were always based on few patients (!10) except one on 28 patients with CD previously treated with conventional radiotherapy (30).…”

Section: Introductionmentioning

confidence: 99%

Ketoconazole revisited: a preoperative or postoperative treatment in Cushing's disease

Castinetti¹,

Morange²,

Jaquet³

et al. 2008

European Journal of Endocrinology

162

122

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Context: Although transsphenoidal surgery remains the first-line treatment in Cushing's disease (CD), recurrence is observed in about 20% of cases. Adjunctive treatments each have specific drawbacks. Despite its inhibitory effects on steroidogenesis, the antifungal drug ketoconazole was only evaluated in series with few patients and/or short-term follow-up. Objective: Analysis of long-term hormonal effects and tolerance of ketoconazole in CD. Design: A total of 38 patients were retrospectively studied with a mean follow-up of 23 months (6-72). Setting: All patients were treated at the same Department of Endocrinology in Marseille, France. Patients: The 38 patients with CD, of whom 17 had previous transsphenoidal surgery. Intervention: Ketoconazole was begun at 200-400 mg/day and titrated up to 1200 mg/day until biochemical remission. Main outcome measures: Patients were considered controlled if 24-h urinary free cortisol was normalized. Results: Five patients stopped ketoconazole during the first week because of clinical or biological intolerance. On an intention to treat basis, 45% of the patients were controlled as were 51% of those treated long term. Initial hormonal levels were not statistically different between patients controlled or uncontrolled. Ketoconazole was similarly efficacious as a primary or postoperative treatment. Among 15 patients without visible adenoma at initial evaluation, subsequent follow-up allowed identification of the lesion in five cases. No adrenal insufficiency was observed. Adverse effects were rare in patients treated long term. Conclusions: Ketoconazole is a safe and efficacious treatment in CD, particularly in patients for whom surgery is contraindicated, or delayed because of the absence of image of adenoma on magnetic resonance imaging.European Journal of Endocrinology 158 91-99

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Ketoconazole and Plasma and Urine Steroid Levels in Cushing's Disease

Cited by 19 publications

References 19 publications

Effect of one month ketoconazole treatment on GH, cortisol and ACTH release after ghrelin, GHRP-6 and GHRH administration in patients with cushing’s disease

Effect of one month ketoconazole treatment on GH, cortisol and ACTH release after ghrelin, GHRP-6 and GHRH administration in patients with cushing’s disease

Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline

Ketoconazole revisited: a preoperative or postoperative treatment in Cushing's disease

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