Drugs in the medical treatment of Cushing's syndrome

Abstract

Cushing's syndrome is a complex endocrine condition with potential serious complications if untreated or inadequately treated. Transsphenoidal surgery with resection of a pituitary adenoma is successful in 75 - 80% of patients, but approximately 20 - 25% show persistence of Cushing's, and a similar proportion may experience recurrence within 2 - 4 years post-op. When surgery fails, medical treatment can temporarily suppress excessive cortisol production and ameliorate its clinical manifestations while more definitive therapy becomes effective. We describe pharmacological approaches to the treatment of Cushing's syndrome. Drugs used to suppress cortisol secretion are mostly inhibitors of steroidogenesis. Ketoconazole, fluconazole aminoglutethimide, metyrapone, mitotane and etomidate are in that category. Ketoconazole is in current use while other drugs, although mostly available in the past, continue to have a potential role either alone or in combination. Drugs that suppress adrenocorticotropic hormone (ACTH) secretion are less popular as standard treatment and include cyproheptadine, valproic acid, cabergoline, somatostatin analogs, PPAR-gamma agonists, vasopressin antagonists. Some of these drugs have been tested in limited clinical trials but there is potential therapeutic benefit in analogs with better specificity for the class of receptors present in ACTH-secreting tumors. A third category of drugs is glucocorticoid receptor antagonists. Mifepristone is currently being tested in clinical trials in patients with persistent or recurrent Cushing's disease and in patients with metastatic adrenal cortical carcinoma or ectopic ACTH syndrome not amenable to surgery. We also review replacement therapy after surgery and non-specific drugs to treat complications in patients with severe hypercortisol. The review provides a complete survey of the drugs used in the medical treatment of Cushing's, and new advances in the development of pituitary-active drugs as well as receptor blockers of glucocorticoid action. It also provides avenues for exploration of new drugs active on somatostatin, dopamine and vasopressin receptors. There are effective pharmacological agents capable of chronically reversing biochemical and clinical manifestations of hypercortisolemia in Cushing's syndrome but new drugs are needed with action at the pituitary level.