Use of ketoconazole in the treatment of Cushing's disease and ectopic ACTH syndrome

Abstract

Ketoconazole, an imidazole derivative which inhibits adrenal steroidogenesis, has been used with success for the metabolic control of Cushing's disease. Few data are available about the use of ketoconazole in the management of the ectopic ACTH syndrome. We have used ketoconazole in eight patients: four patients with Cushing's disease, two patients with overt and two with occult ectopic ACTH syndrome. Among patients with Cushing's disease, reversible hypoadrenalism occurred once. All had full clinical and biochemical regression of the disease for more than 6 months with 400-1200 mg ketoconazole per day. Patients with ectopic ACTH syndrome received 1200 mg ketoconazole per day for at least 2 months. Partial biochemical regression was observed in two and a secondary escape to adrenal blockade in two others. These findings further indicate that ketoconazole is a valuable tool for the metabolic control of Cushing's disease. On the contrary, in ectopic ACTH syndrome, this aim can be impossible to reach with ketoconazole although the reasons for its ineffectiveness remain to be determined.

Treatment of Cushing's disease: a mechanistic update

“…Ketoconazole treatment is usually started at 200 mg twice a day, and biochemical effect is achieved at 600-1200 mg/day (Table 3; Nieman 2002. It has been suggested that ketoconazole may also have inhibitory effects on ACTH secretion by corticotrope tumor cells as ACTH shows no significant increase despite confirmed reduction in cortisol levels (Loose et al 1983, Loli et al 1986, Jimenez-Rema et al 1989, Tabarin et al 1991. Escape from pharmacological control has been reported (Sonino et al 1991).…”

“…There are inhibitory effects on several cytochrome P450 enzymes, mainly CYP3A4, CYP2C9, and CYP1A2 (Feldman 1986, Feelders et al 2010a, Fleseriu & Petersenn 2012, but minimal effect on aromatase enzyme (Miller & Crapo 1993). The first clinical reports on patients with CD described normalization of urinary or plasma cortisol values with ketoconazole doses of 600-1200 mg/day (Loli et al 1986, Tabarin et al 1991, Miller & Crapo 1993. Ketoconazole treatment is usually started at 200 mg twice a day, and biochemical effect is achieved at 600-1200 mg/day (Table 3; Nieman 2002.…”

A case of recurrent non-small-cell lung carcinoma and paraneoplastic Cushing's syndrome

“…11-␤-hydroxylase is the enzyme responsible for the hydroxylation of 11-deoxycortisol to cortisol while desmolase converts cholesterol to ı-5-pregnenolone [13][14][15]. Only a few reports about the usefulness of glucosteroid biosynthesis inhibitors in ectopic ACTH syndrome are published, and they report controversial results [16][17][18][19][20]. In the study of Winquist et al, the conclusions were that ketoconazole did not prolong survival, but it did provide a palliative hormonal response in two third of patients.…”

Papel da terapia medicamentosa na síndrome de Cushing

“…A redução da produção de cortisol com cetoconazol oral tem sido relatada por vários autores (44,45). Uma vantagem sobre outras alternativas terapêuticas é a pequena incidência de efeitos colaterais que ocasiona.…”