The therapeutic value of
ketoconazole for long term treatment of patients with
Cushing's syndrome was studied. Seven patients with
Cushing's disease and one with an adrenal
adenoma received 600-800 mg/day
ketoconazole for 3-13 months. Plasma
ACTH,
cortisol, and
dehydroepiandrosterone sulfate levels and urinary
cortisol, 17-ketosteroid, and
tetrahydro-11-deoxycortisol excretion were determined periodically during the treatment period. Plasma
ACTH and
cortisol responses to CRH stimulation were determined before and during treatment. Rapid and subsequently persistent clinical improvement occurred in each patient; plasma
dehydroepiandrosterone sulfate and urinary 17-ketosteroid and
cortisol excretion decreased soon after the initiation of treatment, subsequently remaining normal or nearly so throughout the treatment period. Urinary
tetrahydro-11-deoxycortisol excretion increased significantly. Plasma
cortisol levels decreased. Plasma
ACTH levels did not change, and individual plasma
ACTH and
cortisol increments in response to CRH were comparable before and during treatment. The
cortisol response to
insulin-induced
hypoglycemia improved in one patient and was restored to normal in another. The seven patients tested recovered normal adrenal suppressibility in response to a low dose of
dexamethasone during
ketoconazole treatment.
Ketoconazole is effective for long term control of
hypercortisolism of either pituitary or adrenal origin. Its effect appears to be mediated by inhibition of adrenal
11 beta-hydroxylase and
17,20-lyase, and it, in some unknown way, prevents the expected rise in
ACTH secretion in patients with
Cushing's disease.