Steroid biosynthesis inhibitors in Cushing's syndrome

Conclusions About one-third of all patients with Cushing's syndrome cannot be cured by surgery (at the pituitary or adrenal level) or radiation therapy and are therefore candidates for medical treatment. As a conservative therapeutic approach to lower hypercortisolism, the use of steroid biosynthesis blocking substances has the greatest importance. Trilostane, an inhibitor of the adrenal 3-hydroxysteroid dehydrogenase 5,4-isomerase system, has been studied in only a few patients with Cushing's syndrome and was not potent enough to normalize hypercortisolism, especially in patients with pituitary-dependent Cushing's disease.Aminoglutethimide, predominantly blocking side-chain cleavage, normalized elevated serum or urinary cortisol levels in only a minority of patients with Cushing's disease and showed adverse reactions in the majority.Metyrapone, a strong inhibitor of adrenal 11-hydroxylase activity, has only an insufficient blocking effect on elevated cortisol levels in some patients with various forms of Cushing's syndrome and shows side effects in a significant number of patients.Ketoconazole in vitro blocks predominantly adrenal 17,20-desmolase activity and to a lesser extent 17- and 11-hydroxylase activity. Therefore the substance in vivo more markedly suppresses serum androgen levels (dehydroepiandrosterone sulfate, androstenedione, testosterone) than cortisol. However, clinical data from several groups show that the administration of ketoconazole normalizes the urinary excretion of cortisol in the mean in about 70% of patients with Cushing's disease. Furthermore, the antimycotic drug was effective in many patients with a benign primary adrenal form of Cushing's syndrome, in about 50% of patients with ectopic ACTH syndrome, but rarely in patients with adrenocortical carcinoma. The main side effect of ketoconazole is liver toxicity, in about 10% of all cases.Etomidate has strong inhibiting properties on adrenal 11-hydroxylase activity and in vivo is the most potent substance to normalize hypercortisolism. However, its widespread use is prevented by the necessity of intravenous administration.Mitotane inhibits various pathways of adrenal steroid biosynthesis, but its main effect is a cytolytic effect especially on adrenocortical cells. It is therefore a special cytostatic drug for patients with adrenocortical carcinoma. High doses of the substance lower or normalize elevated cortisol parameters in the majority of these patients, but objective tumor regression has been documented in only in few cases.Abbreviation ACTH adrenocortropic hormone