Cushing’s disease medical therapy

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Cushing's disease (also known as Cushing disease, tertiary or secondary hypercortisolism, tertiary or secondary hypercorticism, Itsenko-Cushing disease)[1][2] is a cause of Cushing's syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary (secondary hypercortisolism). This is most often as a result of a pituitary adenoma (specifically pituitary basophilism) or due to excess production of hypothalamus CRH (Corticotropin releasing hormone) (tertiary hypercortisolism/hypercorticism) that stimulates the synthesis of cortisol by the adrenal glands. Pituitary adenomas are responsible for 80% of endogenous Cushing's syndrome,[3] when excluding Cushing's syndrome from exogenously administered corticosteroids. This should not be confused with ectopic Cushing syndrome or exogenous steroid use.[4]

Medical Therapy

The first-line treatment of Cushing's disease is surgical resection of ACTH-secreting pituitary adenoma; this surgery involves removal of the tumor via transsphenoidal surgery (TSS).[5] There are two possible options for access to sphenoidal sinus including of endonosal approach (through the nostril) or sublabial approach (through an incision under the top lip); many factors such as the size of nostril, the size of the lesion, and the preferences of the surgeon cause the selection of one access route over the other.[6] Some tumors do not contain a discrete border between tumor and pituitary gland; therefore, careful sectioning through pituitary gland may be required to identify the location of tumor.[7] The probability of successful resection is higher in patients where the tumor was identified at initial surgery in compare to patients where no tumor was found initially; the overall remission rates in patients with microadenomas undergoing TSS are in range of 65%-90%, and the remission rate in patients with macroadenomas are lower than 65%.[7] patients with persistent disease after initial surgery are treated with repeated pituitary surgery as soon as the active persistent disease is evident; however, reoperation has lower success rate and increases the risk of pituitary insufficiency.[7] Pituitary radiation therapy is another option for treatment of postoperative persisting hypercortisolemia following unsuccessful transsphenoidal surgery.[8] External-beam pituitary RT is more effective treatment for pediatric CD in children with cure rates of 80%-88%. Hypopituitarism specifically growth hormone deficiency has been reported as the only most common late morbidity of this treatment; GHD has been reported in 36% and 68% of the patients undergoing post pituitary RT for Cushing's disease.[8] Bilateral adrenalectomy is another treatment which provides immediate reduction of cortisol level and control of hypercortisolism. However, it requires education of patients, because lifelong glucocorticoid and mineralocorticoid replacement therapy is needed for these patients. One of the major complications of this treatment is progression of Nelson's syndrome which is caused by enhance level of tumor growth and ACTH secretion post adrenalectomy in 8%-29% of patients with CD.[9]

During post surgical recovery, patients collect 24-hour urine sample and blood sample for detecting the level of cortisol with the purpose of cure test; level of cortisol near the detection limit assay, corresponds to cure. Hormonal replacement such as steroid is given to patients because of steroid withdrawal. After the completion of collecting urine and blood samples, patients are asked to switch to glucocorticoid such as prednisone to decrease symptoms associated with adrenal withdrawal.[10] A study of 3,525 cases of TSS for Cushing's disease in the nationally representative sample of US hospitals between 1993 and 2002 was conducted and revealed the following results: the in-hospital mortality rate was 0.7%; the complication rate was 42.1%. Diabetes insipidus (15%), fluid and electrolyte abnormalities (12.5%), and neurological deficits (5.6%) were the most common complications reported. The analyses of the study show that complications were more likely in patients with pre-operative comorbidities. Patients older than 64 years were more likely to have an adverse outcome and prolonged hospital stay. Women were 0.3 times less likely to have adverse outcomes in comparison to men.[11]


  1. "Whonamedit - Nikolai Mikhailovich Itsenko". "Nikolai Mikhailovich Itsenko investigated neural infections, vegetative nervous system diseases and cerebral tumors. In 1926 he was the first one who described Itsenko-Cushing's disease, six years before Cushing."
  2. A.I. Gozhenko, I.P. Gurkalova, W. Zukow, Z. Kwasnik, B. Mroczkowska (2009). "Trematoda". Pathology: Medical Student's Library. Radomska Szkola Wyžsza uk. Zubrzyckiego. p. 280. ISBN 978-83-61047-18-6.
  3. Lanzino, Giuseppe; Maartens, Niki F.; Laws, Edward R. (2002). "Cushing's case XLV: Minnie G.". Journal of Neurosurgery. 97 (1): 231–234. doi:10.3171/jns.2002.97.1.0231. PMID 12134925. |access-date= requires |url= (help)
  5. Ding, Dale; Robert M. Starke; Jason P. Sheehan (2013). "Treatment paradigms for pituitary adenomas: defining the roles of radiosurgery and radiation therapy". J Neurooncol. 117: 445–457. doi:10.1007/s11060-013-1262-8.
  6. Laws, Edward R (2010). Transsphenoidal Surgery. Elsevier Inc.
  7. 7.0 7.1 7.2 Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR, Hofland LJ, Klibanski A, Lacroix A, Lindsay JR, Newell-Price J, Nieman LK, Petersenn S, Sonino N, Stalla GK, Swearingen B, Vance ML, Wass JA, Boscaro M (2008). "Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement". J Clin Endocrinol Metab. 93 (7): 2454–2462. doi:10.1210/jc.2007-2734. PMC 3214276. PMID 18413427.
  8. 8.0 8.1 Storr, HL; Plowman PN; Carroll PV; François I; Krassas GE; Afshar F; Besser GM; Grossman AB; Savage MO. (2003). "Clinical and Endocrine Responses to Pituitary Radiotherapy in Pediatric Cushing's Disease: An Effective Second-Line Treatment". J Clin Endocrinol Metab. 88 (1): 34–37. doi:10.1210/jc.2002-021032.
  9. Gadelha, Mônica R.; Leonardo Vieira Neto (2014). "Efficacy of medical treatment in Cushing's disease: a systematic review". Clinical Endocrinology. 80: 1–12. doi:10.1111/cen.12345.
  10. Fairfield, Wesley P. (2003). "Cushing's Disease after Successful Transsphenoidal Surgery - What to Expect and How to Manage". Retrieved Jan 31, 2014.
  11. Patil, CG; Lad, SP; Harsh, GR; Laws ER, Jr; Boakye, M (2007). "National trends, complications, and outcomes following transsphenoidal surgery for Cushing's disease from 1993 to 2002". Neurosurgical focus. 23 (3): E7. doi:10.3171/foc.2007.23.3.9. PMID 17961019.