Cushing's disease: current medical therapies and molecular insights guiding future therapies

Neurosurg Focus. 2015 Feb;38(2):E11. doi: 10.3171/2014.10.FOCUS14700.


OBJECT Cushing's disease (CD) can lead to significant morbidity secondary to hormonal sequelae or mass effect from the pituitary tumor. A transsphenoidal approach to resection of the adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma is the first-line treatment. However, in the setting in which patients are unable to undergo surgery, have acute hypercortisolism, or have recurrent disease, medical therapy can play an important role. The authors performed a systematic review to highlight the efficacy of medical treatment of CD and discuss novel molecular insights that could guide the development of future medical treatments of CD. METHODS A search on current medical therapies for CD was performed. After individual medical therapeutic agents for CD were identified, each agent underwent a formal systematic search. The phrase "(name of agent) and Cushing's" was used as a search term in PubMed for all years up to 2014. The abstract of each article was reviewed for studies that evaluated the efficacy of medical treatment of CD. Only studies that enrolled at least 20 patients were included in the review. RESULTS A total of 11 articles on 6 individual agents were included in this review. Specific medical therapies were categorized based on the level of action: pituitary directed (cabergoline and pasireotide), adrenal/steroidogenesis directed (ketoconazole, metyrapone, and mitotane), and end-tissue directed/cortisol receptors (mifepristone). The studies identified consisted of a mix of retrospective reviews and small clinical trials. Only pasireotide and mifepristone have undergone Phase III clinical trials, from which they garnered FDA approval for the treatment of patients with CD. Overall, agents targeting ACTH secretion and steroidogenesis were found to be quite effective in reducing urine free cortisol (UFC) to levels near normal. A significant reduction in UFC was observed in 45%-100% of patients and a majority of patients gained clinical improvement. Similarly, inhibition at the end-tissue level led to clinical improvement in 87% of patients. However, side-effect rates associated with these drugs are high (up to 88%). Ketoconazole has been shown to enhance tumor appearance on MRI to facilitate pituitary resection. Promising molecular targets have been identified, including epidermal growth factor receptor, retinoic acid receptors, and cyclin dependent kinases. These pathways have been linked to the regulation of pro-opiomelanocortin expression, ACTH secretion, and tumor growth. CONCLUSIONS Despite encouraging Phase III clinical trials leading to FDA approval of 2 agents for treatment of patients with CD, no agent has yet produced results comparable to resection. As a result, the molecular insights gained into CD pathogenesis will need to continue to be expanded until they can lead to the development of medical therapies for CD with a favorable side-effect profile and efficacy comparable to resection. Ideally these agents should also reduce tumor size, which could potentially permit their eventual discontinuation.

Keywords: ACTH = adrenocorticotropic hormone; CD = Cushing's disease; CDK = cyclin-dependent kinase; CNC = Carney Complex; CS = Cushing's syndrome; Cushing's disease; EGFR = epidermal growth factor receptor; HbA1c = glycated hemoglobin; MAS = McCune Albright syndrome; MEN = multiple endocrine neoplasia; PAP = pituitary adenoma predisposition; POMC = pro-opiomelanocortin; UFC = urinary free cortisol; cortisol; medical therapy; molecular therapeutics; pituitary tumors.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Clinical Trials as Topic / trends
  • Drug Delivery Systems / trends*
  • Female
  • Forecasting
  • Humans
  • Male
  • Mitotane / metabolism
  • Mitotane / therapeutic use
  • Pituitary ACTH Hypersecretion / diagnosis*
  • Pituitary ACTH Hypersecretion / metabolism
  • Pituitary ACTH Hypersecretion / therapy*
  • Receptors, Retinoic Acid / metabolism
  • Retrospective Studies
  • Somatostatin / analogs & derivatives
  • Somatostatin / metabolism
  • Somatostatin / therapeutic use


  • Receptors, Retinoic Acid
  • Somatostatin
  • Mitotane
  • pasireotide