Ketoconazole blocks cortisol secretion in man by inhibition of adrenal 11β-hydroxylase

Engelhardt, D.; Dörr, Gaëlle; Jaspers, Ch.; Knorr, D

doi:10.1007/bf01733014

Cited by 69 publications

(36 citation statements)

References 8 publications

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“…Our observation in culture no. 2 is in accordance with what Engelhardt et al (1985) reported, as they also found a ketoconazole-induced inhibition of 11b-hydroxylase activity. The inhibitory effect of ketoconazole on both 11b-hydroxylase and 17-hydroxylase enzyme activities illustrates that this drug can also decrease androgen and aldosterone production.…”

Section: Discussionsupporting

confidence: 93%

“…When administered at relatively high dosages, ketoconazole inhibits adrenocortical steroidogenesis by blocking steroidogenic enzymes, e.g. 17-hydroxylase and 11b-hydroxylase (Santen et al 1983, Engelhardt et al 1985, Loli et al 1986, Lamberts et al 1987, Sonino 1987, Johansson et al 2002, Veytsman et al 2009, Ohlsson et al 2010. However, ketoconazole has serious, mainly gastrointestinal, side effects and is hepatotoxic (McCance et al 1987, Sonino et al 1991, Como & Dismukes 1994, Nieman 2002, Castinetti et al 2008.…”

Section: Introductionmentioning

confidence: 99%

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Fluconazole inhibits human adrenocortical steroidogenesis in vitro

Pas¹,

Hofland²,

Hofland³

et al. 2012

Journal of Endocrinology

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The antifungal agent ketoconazole is often used to suppress cortisol production in patients with Cushing's syndrome (CS). However, ketoconazole has serious side effects and is hepatotoxic. Here, the in vitro effects of ketoconazole and fluconazole, which might be less toxic, on human adrenocortical steroidogenesis were compared. The effects on steroidogenesis were examined in primary cultures of nine human adrenocortical tissues and two human adrenocortical carcinoma cell lines. Moreover, the effects on mRNA expression levels of steroidogenic enzymes and cell growth were assessed. Ketoconazole significantly inhibited 11-deoxycortisol (H295R cells; maximum inhibition 99%; EC 50 0 . 73 mM) and cortisol production (HAC15 cells; 81%; EC 50 0 . 26 mM and primary cultures (mean EC 50 0 . 75 mM)). In cultures of normal adrenal cells, ketoconazole increased pregnenolone, progesterone, and deoxycorticosterone levels, while concentrations of 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol, DHEA, and androstenedione decreased. Fluconazole also inhibited 11-deoxycortisol production in H295R cells (47%; only at 1 mM) and cortisol production in HAC15 cells (maximum inhibition 55%; EC 50 35 mM) and primary cultures (mean EC 50 67 . 7 mM). In the cultures of normal adrenals, fluconazole suppressed corticosterone, 17-hydroxypregnenolone, and androstenedione levels, whereas concentrations of progesterone, deoxycorticosterone, and 11-deoxycortisol increased. Fluconazole (1 mM) slightly increased STAR mRNA expression in both cell lines. Neither compound affected mRNA levels of other steroidogenic enzymes or cell number. In conclusion, by inhibiting 11b-hydroxylase and 17-hydroxylase activity, pharmacological concentrations of fluconazole dose dependently inhibit cortisol production in human adrenocortical cells in vitro. Although fluconazole seems less potent than ketoconazole, it might become an alternative for ketoconazole to control hypercortisolism in CS. Furthermore, patients receiving fluconazole because of mycosis might be at risk for developing adrenocortical insufficiency.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Fluconazole inhibits human adrenocortical steroidogenesis in vitro

Pas¹,

Hofland²,

Hofland³

et al. 2012

Journal of Endocrinology

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“…[68][69][70] In vitro, ketoconazole binds the glucocorticoid receptor directly to prevent ligand binding and stimulation. 71 Ketoconazole inhibition of CYP3A4 occurs at antifungal doses and at the higher cancer treatment doses.…”

Section: 67mentioning

confidence: 99%

Management of Endocrine Manifestations and the Use of Mitotane As a Chemotherapeutic Agent for Adrenocortical Carcinoma

Veytsman

Nieman

Fojo

2009

JCO

133

128

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Adrenal cortical carcinoma (ACC) is a rare malignancy in which patients have poor overall 5-year survival. Patients with ACC can present with symptoms of hormone excess, including Cushing's syndrome, virilization, feminization, or—less frequently—hypertension with hypokalemia. In many patients with ACC, advanced disease at presentation precludes surgery or is followed by local relapse or distant metastatic disease that cannot be managed surgically. In these instances, chemotherapy is often tried, but its limited efficacy all too often leaves the problem of persistent hormonal excess. Physicians who treat patients with ACC and severe hypercortisolism should recognize that uncontrolled hormone production is a malignant disease, which has severe consequences that require aggressive management. Because chemotherapy benefits only a small percentage of patients, steroidogenesis inhibitors, including mitotane, ketoconazole, metyrapone, and etomidate, should be used singly or in combination even as chemotherapy is administered. Diligent management with frequent adjustments is required, especially in patients with chemotherapy-refractory tumors that continue to grow. In the absence of randomized, controlled trials, adjuvant use of mitotane remains controversial, although the authors of a recent case-control study argue for its use. Despite difficulty administering effective doses, most clinicians agree that mitotane should be used if the tumor cannot be removed surgically or should be used as adjuvant therapy if there is a high likelihood of recurrence. The option of long-term monotherapy is restricted to patients who tolerate mitotane and either experience a clinical response or are at high risk for recurrence. Recommendations are provided to help manage patients with this difficult disease and to improve the quality of their lives.

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“…between 400 and 1600 mg/day (Castinetti et al 2008). Its main mechanism of action is inhibition of the steroidogenic enzymes 17-hydroxylase and 17,20-lyase and it is one of the most frequently used cortisol-lowering drugs (Engelhardt et al 1985, Loli et al 1986, Lamberts et al 1987, McCance et al 1987, Sonino 1987, Farwell et al 1988, Sonino et al 1991, Castinetti et al 2008. Ketoconazole is hepatotoxic, can cause gynecomastia, and has serious, mainly gastrointestinal, side effects, which together can limit its long-term use (McCance et al 1987, Sonino et al 1991, Como & Dismukes 1994, Nieman 2002, Castinetti et al 2008.…”

Section: Inhibitors Of Adrenocortical Steroidogenesismentioning

confidence: 99%

New developments in the medical treatment of Cushing's syndrome

Pas¹,

Herder²,

Hofland³

et al. 2012

Endocrine-Related Cancer

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Cushing's syndrome (CS) is a severe endocrine disorder characterized by chronic cortisol excess due to an ACTH-secreting pituitary adenoma, ectopic ACTH production, or a cortisol-producing adrenal neoplasia. Regardless of the underlying cause, untreated CS is associated with considerable morbidity and mortality. Surgery is the primary therapy for all causes of CS, but surgical failure and ineligibility of the patient to undergo surgery necessitate alternative treatment modalities. The role of medical therapy in CS has been limited because of lack of efficacy or intolerability. In recent years, however, new targets for medical therapy have been identified, both at the level of the pituitary gland (e.g. somatostatin, dopamine, and epidermal growth factor receptors) and the adrenal gland (ectopically expressed receptors in ACTH-independent macronodular adrenal hyperplasia). In this review, results of preclinical and clinical studies with drugs that exert their action through these molecular targets, as well as already established medical treatment options, will be discussed.

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Ketoconazole blocks cortisol secretion in man by inhibition of adrenal 11β-hydroxylase

Cited by 69 publications

References 8 publications

Fluconazole inhibits human adrenocortical steroidogenesis in vitro

Fluconazole inhibits human adrenocortical steroidogenesis in vitro

Management of Endocrine Manifestations and the Use of Mitotane As a Chemotherapeutic Agent for Adrenocortical Carcinoma

New developments in the medical treatment of Cushing's syndrome

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