The endocrine effects of ketoconazole.

Abstract

INTRODUCTION Ketoconazole l has been employed extensively in clinical practice during the last 5 years as an innovative treatment for fungal disease (1 ). This is due largely to its properties: broad-spectrum activity, easy mode of administration, widespread tissue distribution, low degree of inactivation, good patient tolerance, low toxicity profile (2). This orally-active imidazole derivative (3-5) interferes with the synthesis of ergosterol in fungi and cholesterol in mammalian cells by blocking the 14-demethylation of lanosterol (2, 6, 7). Its effects on sterol synthesis and the development of gynecomastia in some patients treated for mycosis (8-1 0), led to investigations of its ability to induce alterations in steroid hormone synthesis or action. By in vivo and in vitro studies, the drug was shown to act as a potent inhibitor of both gonadal (10) and adrenal (11) steroidogenesis. In addition to inhibition of cholesterol synthesis, several sites of action have been demonstrated. At the same time, clinical trials have established that the properties of ketoconazole as a steroid inhibitor make it a valuable tool in the management of endocrine disorders that benefit from suppression of either gonadal or adrenal hormone production. Examples include prostatic cancer and Cushing's syndrome, respectively (12). Although serum cholesterol levels are decreased in patients during chronic high dose regimens (13), there is no evidence as yet for a potential therapeutic use of ketoconazole in the management of hypercholesterolemia, since the effects of cholesterol precursor accumulation are not known (14, 15).