THERAPY OF CUSHINGS-SYNDROME WITH STEROID-BIOSYNTHESIS INHIBITORS

Several substances with different inhibitory effects on adrenal steroi d biosynthesis were investigated in patients with Cushing's syndrome. It has been shown that trilostane, a 3 beta-hydroxysteroid-dehydrogena se inhibitor, is not potent enough to block cortisol biosynthesis in p atients with hypercortisolism. Aminoglutethimide inhibits side chain c leavage of cortisol synthesis, but it has been demonstrated that the b locking effect on cortisol secretion is not strong enough to normalize urinary cortisol excretion in patients with Cushing's disease. For me tyrapone, an inhibitor of adrenal 11 beta-hydroxylase, promising resul ts were reported for the treatment of Cushing's syndrome. However, the drug has several side effects and depending on the definition of the desired reduction of cortisol secretion a true remission was only foun d in a minority of patients. The antifungal drug ketoconazole in vitro predominantly blocks 17,20-desmolase (IC50 1 mu M) and to a lesser ex tent 17 alpha-hydroxylase (IC50 10 mu M) and 11 beta-hydroxylase (IC50 15-40 mu M). Therefore, ketoconazole in vivo most potently suppresses androgen secretion and only to a lesser extent cortisol biosynthesis. Several therapeutic trials with ketoconazole treatment in patients wi th pituitary Cushing's disease showed various remission rates between 30 and 90%. In contrast, in almost all patients with benign, primary a drenal Cushing's syndrome cortisol levels were normalized. In patients with ectopic ACTH syndrome ketoconazole was effective in about 50% of all reported cases, while cortisol hypersecretion due to adrenocortic al carcinoma was only rarely inhibited by ketoconazole. The main side effect of ketoconazole treatment was liver toxicity which occurred in 12% of all treated patients. In contrast to ketoconazole, the narcotic drug etomidate shows' a strong inhibitory effect on 11 beta-hydroxyla se (IC50 0.03-0.15 mu M) but only a weak inhibition of 17,20 desmolase (IC50 380 mu M). This correlates with in vivo studies where even low, non-hypnotic doses of etomidate induced a pronounced fall in serum co rtisol levels in normals and in patients with Cushing's syndrome. Howe ver, its clinical use is limited by its mandatory intravenous applicat ion and its sedative effects. In conclusion, ketoconazole remains the only available steroid-inhibitory drug for a therapeutic trial in pati ents with Cushing's syndrome who cannot be treated definitively by sur gery.