Medical treatment of Cushing's disease: Overview and recent findings

Abstract

Cushing's disease, due to pituitary adrenocorticotropic hormone (ACTH) hypersecretion, is the most common etiology of spontaneous excess cortisol production. The majority of pituitary tumors causing Cushing's disease measure 1 cm and the excess morbidity associated with these tumors is mostly due to the effects of elevated, nonsuppressible, ACTH levels leading to adrenal steroid hypersecretion. Elevated circulating cortisol levels lead to abnormal fat deposition, hypertension, diabetes, coronary artery disease, osteoporosis, muscle weakness and psychological disturbances. At experienced centers, initial surgical remission rate via transnasal, transphenoidal resection approaches 80% for tumors less than 1 cm, but may be as low as 30% for larger lesions and long-term recurrence in all groups approaches 25%. Residual disease may be managed with more radical surgery, pituitary-directed radiation, bilateral adrenalectomy, or medical therapy. This paper addresses current and novel therapies in various stages of development for Cushing's disease.

Management Strategies for Aggressive Cushing's Syndrome: From Macroadenomas to Ectopics

“…In the last years several novel therapies have been studied with a view to the potential biochemical control and inhibition of pituitary tumor growth [ 29 ].…”

Targeting the ERK pathway for the treatment of Cushing's disease

“…Pituitary adenomas are commonly encountered intracranial tumors and cause significant morbidity and mortality due to local compressive effects and hormonal hypersecretion [ 1 ]. In particular Cushing's disease, due to an adrenocorticotrophic hormone (ACTH)-secreting pituitary adenoma, results in excessive adrenal cortisol secretion, leading to increased morbidity and mortality [ 2 – 5 ].…”

“…In particular Cushing's disease, due to an adrenocorticotrophic hormone (ACTH)-secreting pituitary adenoma, results in excessive adrenal cortisol secretion, leading to increased morbidity and mortality [ 2 – 5 ]. Surgical removal via transnasal, transphenoidal resection is currently first-line therapy offering initial remission rates of 70-80% in expert centers for microadenomas [ 1 ]. However, recurrence rates approach 25% by 20 years and in larger tumors (macroadenomas > 1 cm), initial remission rates are 50% at best.…”

“…Thereafter, pituitary directed radiation or bilateral adrenalectomy can be offered but both these treatments are associated with significant morbidity. Currently available drugs for Cushing's disease treatment include the dopamine D2 receptor agonist, cabergoline and the somatostatin receptor ligand pasireotide that inhibit tumor-derived ACTH secretion; steroidogenesis inhibitors such as ketoconazole and metyrapone; and the glucocorticoid receptor antagonist mifepristone [ 1 , 6 ]. However, medical therapies are most commonly used as pre-operative treatment of severe hypercortisolism as side effects or escape from biochemical control otherwise limit long-term use.…”