Abstract
Ketoconazole is an inhibitor of adrenal steroidogenesis used in the treatment of Cushing’s disease. Previous data obtained with single blood sampling were controversial as to increased ACTH levels compensatory to the Cortisol fall. We have evaluated by chronobiological procedures the circadian profiles of plasma ACTH and Cortisol in three patients with Cushing’s disease before and after a six-month course of therapy with ketoconazole (600 mg daily). None of the patients complained of any adverse subjective reaction; in particular no sign or symptom of hypoadrenalism and/or hepatotoxicity was recorded. Ketoconazole treatment markedly improved the clinical setting and caused a highly significant (p< 0.0001) reduction of mean 24-h Cortisol values (ciradian MESOR). The expected rise of ACTH did not take place; rather, we detected a slight decrease of the mean circadian MESOR (p < 0.05). Our data, althought obtained in a very small number of patients, suggest that ketoconazole may have an additional action at central level, at least in some cases of Cushing’s disease.
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Pont A., Williams P.L., Loose D.S., Feldman D., Rutz R.E., Bochra C., Stevens D.A. Ketoconazole blocks adrenal steroid synthesis. Ann. Intern. Med. 97: 370, 1982.
Loose D.S., Kan P.B., Hirst M.A., Marcus R.A., Feldam D. Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes. J. Clin. Invest. 77: 1495, 1983.
Kan P.B., Hirst M.A., Feldman D. Inhibition of steroidogenic cytochrome P450 enzymes in rat testis by ketoconazole and related imidazole antifungal drugs. J. Steroid Biochem. 23: 1023, 1985.
Nagai K., Miyamory I., Ideda M., Koshida H., Takeda R., Suhara K., Katagiri M. Effect of ketoconazole (an imidazole antimycotic agent) and other inhibitors of steroidogenesis on cytochrome P450-catalyzed reactions. J. Steroid Biochem. 24: 321, 1986.
De Felice R., Johsons D.J., Galgiani J.N. Gynecomastia with ketoconazole. Antimicrob. Agents Chemother. 19: 1073, 1981.
Tucker W.S., Snell B.B., Island D.P., Clarke R., Gregg M.D. Reversible adrenal insufficiency induced by ketoconazole. JAMA 253: 2413, 1985.
McCance D.R., Hadden D.R., Kennedy L., Sheridan B., Atkinson A.B. Clinical experience with ketoconazole as a therapy for patients with Cushing’s syndrome. Cliin. Endocrinol. (Oxf.) 27: 593, 1987.
Pont A., Garybill J.R., Craven P.C., Galgiani J.N., Dismukes W.E., Reitz R.E., Stevens D.A. High-dose ketoconazole therapy and adrenal and testicular function in humans. Arch. Intern. Med. 144: 2150, 1984.
Engelhardt D., Mann K., Hormann R., Braun S., Karl H.J. Ketoconazole inhibits Cortisol secretion of an adrenal adenoma in vivo and in vitro. Klin. Wochenschr. 61: 373, 1983.
Angeli A., Frairia R. Ketoconazole therapy in Cushing’s disease. Lancet 1: 821, 1985.
Contreras R., Rojas A., Blagini L., Gonzales P., Massardo T. Regression of metastatic adrenal carcinoma during palliative ketoconazole treatment. Lancet 2: 151, 1985.
Shepherd F.A., Hoffert B., Evans W.K., Emery G., Trachtenberg J. Ketoconazole use in the treatment of ectopic adrenocorticotropic hormone production and Cushing’s syndrome in small-cell lung cancer. Arch Intern. Med. 145: 863, 1985.
Sonino N., Boscaro M., Merola G., Mantero F. Prolonged treatment of Cushing’s disease by ketoconazole. J. Clin. Endocrinol. Metab. 61: 718, 1985.
Loli P., Berselli M.E., Tagliaferri M. Use of ketoconazole in the treatment of Cushing’s syndrome. J. Clin. Endocrinol. Metab. 63: 1365, 1986.
Halberg F., Tong Y.L., Johnson E.A. Circadian system phase. An aspect of temporal morphology; procedures and illustrative examples. In: Von Mayersbach H. (Ed.), The Cellular Aspects of Biorhythms. Springer Verlag, Berlin, 1967, p. 20
Angeli A., Agrimonti F., Bertello P.D., Frairia R., Violino P.L., Barbadoro E., Ceresa F. Circadian patterns of plasma Cortisol and testosterone in chronic male alcoholics. Chronobiologia 9: 115, 1982.
Lewis J.H., Zimmerman H.J., Renson G.D., Ishak K.G. Hepatic injury associated with ketoconazole therapy. Gastroenterology 86: 503, 1984.
Boscaro M., Sonino N., Rampazzo A., Mantero F. Response of pituitary-adrenal axis to corticotrophin releasing hormone in patients with Cushing’s disease before and after ketoconazole treatment. Clin. Endocrinol. (Oxf.) 27: 461, 1987.
Loose D.S., Stover P., Feldman D. Ketoconazole binds to glucocorticoid receptors and exhibits glucocorticoid antagonist activity in cultured cells. J. Clin. Invest. 72: 404, 1983.
Stalla G.K., Stalla J., Huber M., Muller O.A. Ketoconazole inhibits cAMP generation and ACTH secretion in rat anterior pituitary cell culture. Acta Endocrinol. (Kbh.) 114: 32, 1987.
Burrin J.M., Yeo T.H., Ashby M.J., Bloom S.R. Effect of ketoconazole on adrenocorticotrophic hormone secretion in vitro and in vivo. J. Endocrinol. 108: 37, 1986.
Nakamura M., Hirano M., Ibayashi H., Fujita T., Ohsawa N., Uchikawa T., Okinawa S., Kumamoto Y., Hirose K., Ichikawa T. A case of Cushing’s syndrome studied by urinary corticotrophin assay. Acta Endocrinol. (Kbh.) 42: 163, 1963.
Refetoff S., Van Cauter E., Fang V.S., Laderman C., Graybeal M.L., Landau R.L. The effect of dexamethasone on the 24-hour profiles of adrenocorticotrophin and Cortisol in Cushing’s syndrome. J. Clin. Endocrinol. Metab. 60: 527, 1985.
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Terzolo, M., Panarelli, M., Piovesan, A. et al. Ketoconazole treatment in Cushing’s disease. Effect on the circadian profile of plasma ACTH and Cortisol. J Endocrinol Invest 11, 717–721 (1988). https://doi.org/10.1007/BF03350926
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DOI: https://doi.org/10.1007/BF03350926