title: Treatment of Cushing's disease: a mechanistic update.
abstract: Cushing's disease (CD) is characterized by an ACTH-producing anterior corticotrope pituitary adenoma. If hypothalamus-pituitary-adrenal (HPA) axis physiology is disrupted, ACTH secretion increases, which in turn stimulates adrenocortical steroidogenesis and cortisol production. Medical treatment plays an important role for patients with persistent disease after surgery, for those in whom surgery is not feasible, or while awaiting effects of radiation. Multiple drugs, with different mechanisms of action and variable efficacy and tolerability for controlling the deleterious effects of chronic glucocorticoid excess, are available. The molecular basis and clinical data for centrally acting drugs, adrenal steroidogenesis inhibitors, and glucocorticoid receptor antagonists are reviewed, as are potential novel molecules and future possible targets for CD treatment. Although progress has been made in the understanding of specific corticotrope adenoma receptor physiology and recent clinical studies have detected improved effects with a combined medical therapy approach, there is a clear need for a more efficacious and better-tolerated medical therapy for patients with CD. A better understanding of the molecular mechanisms in CD and of HPA axis physiology should advance the development of new drugs in the future.
authors.affiliation: Department of MedicinePituitary Center, Cedars-Sinai Medical Center, Los Angeles, California, USANeuroendocrinology ClinicDepartment of Endocrinology and Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, MexicoDepartments of Medicine and Neurological Surgeryand Northwest Pituitary Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Road (BTE 472), Portland, Oregon 97239, USA Department of MedicinePituitary Center, Cedars-Sinai Medical Center, Los Angeles, California, USANeuroendocrinology ClinicDepartment of Endocrinology and Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, MexicoDepartments of Medicine and Neurological Surgeryand Northwest Pituitary Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Road (BTE 472), Portland, Oregon 97239, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cuevas-Ramos
authors.affiliation: Department of MedicinePituitary Center, Cedars-Sinai Medical Center, Los Angeles, California, USANeuroendocrinology ClinicDepartment of Endocrinology and Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, MexicoDepartments of Medicine and Neurological Surgeryand Northwest Pituitary Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Road (BTE 472), Portland, Oregon 97239, USA fleseriu@ohsu.edu.
authors.forename: Maria
authors.initials: M
authors.lastname: Fleseriu
mesh_terms: D000818:Animals; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D008024:Ligands; D058990:Molecular Targeted Therapy / Q000379:methods; D047748:Pituitary ACTH Hypersecretion / Q000188:drug therapy*; D010913:Pituitary-Adrenal System / Q000187:drug effects; D017481:Receptors, Somatostatin / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013004:Somatostatin / Q000031:analogs & derivatives / Q000627:therapeutic use; D065088:Steroid Synthesis Inhibitors / Q000627:therapeutic use*
chemical_list: D008024:Ligands; D017481:Receptors, Somatostatin; D065088:Steroid Synthesis Inhibitors; D013004:Somatostatin
keywords: ACTH; Cushing's disease; LCI699; cabergoline; cortisol; ketoconazole; mifepristone; pasireotide