Top

Published in:

Open Access 01-12-2012 | Review

Cushing’s disease

Authors: Frederic Castinetti, Isabelle Morange, Bernard Conte-Devolx, Thierry Brue

Published in: Orphanet Journal of Rare Diseases | Issue 1/2012

Abstract

Cushing’s disease, or pituitary ACTH dependent Cushing’s syndrome, is a rare disease responsible for increased morbidity and mortality. Signs and symptoms of hypercortisolism are usually non specific: obesity, signs of protein wasting, increased blood pressure, variable levels of hirsutism. Diagnosis is frequently difficult, and requires a strict algorithm. First-line treatment is based on transsphenoidal surgery, which cures 80% of ACTH-secreting microadenomas. The rate of remission is lower in macroadenomas. Other therapeutic modalities including anticortisolic drugs, radiation techniques or bilateral adrenalectomy will thus be necessary to avoid long-term risks (metabolic syndrome, osteoporosis, cardiovascular disease) of hypercortisolism. This review summarizes potential pathophysiological mechanisms, diagnostic approaches, and therapies.

Available only for authorised users

Bertagna X, Guignat L, Groussin L, Bertherat J: Cushing's disease. Best Pract Res Clin Endocrinol Metab. 2009, 23: 607-623.CrossRefPubMed

Melmed S, Polonsky K, Reed Larsen P, Kronenberg H: William's Textbook of Endocrinology 12th edition. Philadelphia: Elsevier/Saunders; 2011.

Steffensen C, Bak AM, Rubeck KZ, Jorgensen JO: Epidemiology of Cushing's syndrome. Neuroendocrinology. 2010, 92 (Suppl 1): 1-5.CrossRefPubMed

Jeffcoate WJ, Silverstone JT, Edwards CR, Besser GM: Psychiatric manifestations of Cushing's syndrome: response to lowering of plasma cortisol. Q J Med. 1979, 48: 465-472.PubMed

Newell-Price J, Bertagna X, Grossman AB, Nieman LK: Cushing's syndrome. Lancet. 2006, 367: 1605-1617.CrossRefPubMed

Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93: 1526-1540.PubMedCentralCrossRefPubMed

Ross EJ, Linch DC: Cushing's syndrome–killing disease: discriminatory value of signs and symptoms aiding early diagnosis. Lancet. 1982, 2: 646-649.CrossRefPubMed

Alexandraki KI, Kaltsas GA, Isidori AM, Akker SA, Drake WM, Chew SL, Monson JP, Besser GM, Grossman AB: The prevalence and characteristic features of cyclicity and variability in Cushing's disease. Eur J Endocrinol. 2009, 160: 1011-1018.CrossRefPubMed

Gicquel C, Le Bouc Y, Luton JP, Girard F, Bertagna X: Monoclonality of corticotroph macroadenomas in Cushing's disease. J Clin Endocrinol Metab. 1992, 75: 472-475.PubMed

10.

Woo YS, Isidori AM, Wat WZ, Kaltsas GA, Afshar F, Sabin I, Jenkins PJ, Monson JP, Besser GM, Grossman AB: Clinical and biochemical characteristics of adrenocorticotropin-secreting macroadenomas. J Clin Endocrinol Metab. 2005, 90: 4963-4969.CrossRefPubMed

11.

Brew Atkinson A, Mullan KR: What is the best approach to suspected cyclical Cushing syndrome? Strategies for managing Cushing's Syndrome with variable laboratory data. Clin Endocrinol (Oxf). 2011, Still epub ahead of print 2011 Feb 26

12.

Raverot G, Wierinckx A, Jouanneau E, Auger C, Borson-Chazot F, Lachuer J, Pugeat M, Trouillas J: Clinical, hormonal and molecular characterization of pituitary ACTH adenomas without (silent corticotroph adenomas) and with Cushing's disease. Eur J Endocrinol. 2010, 163: 35-43.CrossRefPubMed

13.

Holthouse DJ, Robbins PD, Kahler R, Knuckey N, Pullan P: Corticotroph pituitary carcinoma: case report and literature review. Endocr Pathol. 2001, 12: 329-341.CrossRefPubMed

14.

Biller BM: Pathogenesis of pituitary Cushing's syndrome. Pituitary versus hypothalamic. Endocrinol Metab Clin North Am. 1994, 23: 547-554.PubMed

15.

Yaneva M, Vandeva S, Zacharieva S, Daly AF, Beckers A: Genetics of Cushing's syndrome. Neuroendocrinology. 2010, 92 (Suppl 1): 6-10.CrossRefPubMed

16.

Bilodeau S, Vallette-Kasic S, Gauthier Y, Figarella-Branger D, Brue T, Berthelet F, Lacroix A, Batista D, Stratakis C, Hanson J, et al: Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease. Genes Dev. 2006, 20: 2871-2886.PubMedCentralCrossRefPubMed

17.

Drouin J, Bilodeau S, Vallette S: Of old and new diseases: genetics of pituitary ACTH excess (Cushing) and deficiency. Clin Genet. 2007, 72: 175-182.CrossRefPubMed

18.

Davis SW, Castinetti F, Carvalho LR, Ellsworth BS, Potok MA, Lyons RH, Brinkmeier ML, Raetzman LT, Carninci P, Mortensen AH, et al: Molecular mechanisms of pituitary organogenesis: In search of novel regulatory genes. Mol Cell Endocrinol. 2010, 323 (1): 4-19.PubMedCentralCrossRefPubMed

19.

Kelberman D, Rizzoti K, Lovell-Badge R, Robinson IC, Dattani MT: Genetic regulation of pituitary gland development in human and mouse. Endocr Rev. 2009, 30: 790-829.PubMedCentralCrossRefPubMed

20.

Nieman LK: Difficulty in the diagnosis of Cushing disease. Nat Clin Pract Endocrinol Metab. 2006, 2: 53-57. quiz following 57CrossRefPubMed

21.

Tabarin A, Perez P: Pros and cons of screening for occult Cushing syndrome. Nat Rev Endocrinol. 2011, 7 (8): 445-455.CrossRefPubMed

22.

Hopkins RL, Leinung MC: Exogenous Cushing's syndrome and glucocorticoid withdrawal. Endocrinol Metab Clin North Am. 2005, 34: 371-384. ixCrossRefPubMed

23.

Newell-Price J, Trainer P, Perry L, Wass J, Grossman A, Besser M: A single sleeping midnight cortisol has 100 % sensitivity for the diagnosis of Cushing's syndrome. Clin Endocrinol (Oxf). 1995, 43: 545-550.CrossRef

24.

Guignat L, Bertherat J: The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline: commentary from a European perspective. Eur J Endocrinol. 2010, 163: 9-13.CrossRefPubMed

25.

Findling JW, Raff H: Screening and diagnosis of Cushing's syndrome. Endocrinol Metab Clin North Am. 2005, 34: 385-402. ix-xCrossRefPubMed

26.

Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, Fava GA, Findling JW, Gaillard RC, Grossman AB, et al: Diagnosis and complications of Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2003, 88: 5593-5602.CrossRefPubMed

27.

Newell-Price J, Trainer P, Besser M, Grossman A: The diagnosis and differential diagnosis of Cushing's syndrome and pseudo-Cushing's states. Endocr Rev. 1998, 19: 647-672.PubMed

28.

Carroll T, Raff H, Findling JW: Late-night salivary cortisol for the diagnosis of Cushing syndrome: a meta-analysis. Endocr Pract. 2009, 15: 335-342.CrossRefPubMed

29.

Nunes ML, Vattaut S, Corcuff JB, Rault A, Loiseau H, Gatta B, Valli N, Letenneur L, Tabarin A: Late-night salivary cortisol for diagnosis of overt and subclinical Cushing's syndrome in hospitalized and ambulatory patients. J Clin Endocrinol Metab. 2009, 94: 456-462.CrossRefPubMed

30.

Yaneva M, Mosnier-Pudar H, Dugue MA, Grabar S, Fulla Y, Bertagna X: Midnight salivary cortisol for the initial diagnosis of Cushing's syndrome of various causes. J Clin Endocrinol Metab. 2004, 89: 3345-3351.CrossRefPubMed

31.

Tirabassi G, Papa R, Faloia E, Boscaro M, Arnaldi G: Corticotrophin-releasing hormone and desmopressin tests in the differential diagnosis between Cushing's disease and pseudo-Cushing state: a comparative study. Clin Endocrinol (Oxf). 2011, 75: 666-672.CrossRef

32.

Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK: Cushing's syndrome due to ectopic corticotropin secretion: twenty years' experience at the National Institutes of Health. J Clin Endocrinol Metab. 2005, 90: 4955-4962.CrossRefPubMed

33.

Boscaro M, Arnaldi G: Approach to the patient with possible Cushing's syndrome. J Clin Endocrinol Metab. 2009, 94: 3121-3131.CrossRefPubMed

34.

Chrousos GP, Schulte HM, Oldfield EH, Gold PW, Cutler GB Jr, Loriaux DL: The corticotropin-releasing factor stimulation test. An aid in the evaluation of patients with Cushing's syndrome. N Engl J Med. 1984, 310: 622-626.CrossRefPubMed

35.

Tsagarakis S, Tsigos C, Vasiliou V, Tsiotra P, Kaskarelis J, Sotiropoulou C, Raptis SA, Thalassinos N: The desmopressin and combined CRH-desmopressin tests in the differential diagnosis of ACTH-dependent Cushing's syndrome: constraints imposed by the expression of V2 vasopressin receptors in tumors with ectopic ACTH secretion. J Clin Endocrinol Metab. 2002, 87: 1646-1653.PubMed

36.

Hall WA, Luciano MG, Doppman JL, Patronas NJ, Oldfield EH: Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population. Ann Intern Med. 1994, 120: 817-820.CrossRefPubMed

37.

Batista D, Gennari M, Riar J, Chang R, Keil MF, Oldfield EH, Stratakis CA: An assessment of petrosal sinus sampling for localization of pituitary microadenomas in children with Cushing disease. J Clin Endocrinol Metab. 2006, 91: 221-224.CrossRefPubMed

38.

Castinetti F, Morange I, Dufour H, Jaquet P, Conte-Devolx B, Girard N, Brue T: Desmopressin test during petrosal sinus sampling: a valuable tool to discriminate pituitary or ectopic ACTH-dependent Cushing's syndrome. Eur J Endocrinol. 2007, 157: 271-277.CrossRefPubMed

39.

Kaskarelis IS, Tsatalou EG, Benakis SV, Malagari K, Komninos I, Vassiliadi D, Tsagarakis S, Thalassinos N: Bilateral inferior petrosal sinuses sampling in the routine investigation of Cushing's syndrome: a comparison with MRI. AJR Am J Roentgenol. 2006, 187: 562-570.CrossRefPubMed

40.

Oldfield EH, Doppman JL, Nieman LK, Chrousos GP, Miller DL, Katz DA, Cutler GB Jr, Loriaux DL: Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing's syndrome. N Engl J Med. 1991, 325: 897-905.CrossRefPubMed

41.

Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR, Hofland LJ, et al: Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2008, 93: 2454-2462.PubMedCentralCrossRefPubMed

42.

Tritos NA, Biller BM, Swearingen B, Medscape: Management of Cushing disease. Nat Rev Endocrinol. 2011, 7: 279-289.CrossRefPubMed

43.

Hofmann BM, Hlavac M, Martinez R, Buchfelder M, Muller OA, Fahlbusch R: Long-term results after microsurgery for Cushing disease: experience with 426 primary operations over 35 years. J Neurosurg. 2008, 108: 9-18.CrossRefPubMed

44.

Hoybye C, Grenback E, Thoren M, Hulting AL, Lundblad L, von Holst H, Anggard A: Transsphenoidal surgery in Cushing disease: 10 years of experience in 34 consecutive cases. J Neurosurg. 2004, 100: 634-638.CrossRefPubMed

45.

Shimon I, Ram Z, Cohen ZR, Hadani M: Transsphenoidal surgery for Cushing's disease: endocrinological follow-up monitoring of 82 patients. Neurosurgery. 2002, 51: 57-61. discussion 61–52CrossRefPubMed

46.

Jagannathan J, Sheehan JP, Jane JA: Evaluation and management of Cushing syndrome in cases of negative sellar magnetic resonance imaging. Neurosurg Focus. 2007, 23: E3.CrossRefPubMed

47.

Atkinson AB, Kennedy A, Wiggam MI, McCance DR, Sheridan B: Long-term remission rates after pituitary surgery for Cushing's disease: the need for long-term surveillance. Clin Endocrinol (Oxf). 2005, 63: 549-559.CrossRef

48.

Esposito F, Dusick JR, Cohan P, Moftakhar P, McArthur D, Wang C, Swerdloff RS, Kelly DF: Clinical review: Early morning cortisol levels as a predictor of remission after transsphenoidal surgery for Cushing's disease. J Clin Endocrinol Metab. 2006, 91: 7-13.CrossRefPubMed

49.

Valero R, Vallette-Kasic S, Conte-Devolx B, Jaquet P, Brue T: The desmopressin test as a predictive factor of outcome after pituitary surgery for Cushing's disease. Eur J Endocrinol. 2004, 151: 727-733.CrossRefPubMed

50.

Pereira AM, van Aken MO, van Dulken H, Schutte PJ, Biermasz NR, Smit JW, Roelfsema F, Romijn JA: Long-term predictive value of postsurgical cortisol concentrations for cure and risk of recurrence in Cushing's disease. J Clin Endocrinol Metab. 2003, 88: 5858-5864.CrossRefPubMed

51.

Chen JC, Amar AP, Choi S, Singer P, Couldwell WT, Weiss MH: Transsphenoidal microsurgical treatment of Cushing disease: postoperative assessment of surgical efficacy by application of an overnight low-dose dexamethasone suppression test. J Neurosurg. 2003, 98: 967-973.CrossRefPubMed

52.

Valassi E, Biller BM, Swearingen B, Pecori Giraldi F, Losa M, Mortini P, Hayden D, Cavagnini F, Klibanski A: Delayed remission after transsphenoidal surgery in patients with Cushing's disease. J Clin Endocrinol Metab. 2010, 95: 601-610.PubMedCentralCrossRefPubMed

53.

Aghi MK: Management of recurrent and refractory Cushing disease. Nat Clin Pract Endocrinol Metab. 2008, 4: 560-568.CrossRefPubMed

54.

Wagenmakers MA, Netea-Maier RT, van Lindert EJ, Timmers HJ, Grotenhuis JA, Hermus AR: Repeated transsphenoidal pituitary surgery (TS) via the endoscopic technique: a good therapeutic option for recurrent or persistent Cushing's disease (CD). Clin Endocrinol (Oxf). 2009, 70: 274-280.CrossRef

55.

Locatelli M, Vance ML, Laws ER: Clinical review: the strategy of immediate reoperation for transsphenoidal surgery for Cushing's disease. J Clin Endocrinol Metab. 2005, 90: 5478-5482.CrossRefPubMed

56.

Nader N, Raverot G, Emptoz-Bonneton A, Dechaud H, Bonnay M, Baudin E, Pugeat M: Mitotane has an estrogenic effect on sex hormone-binding globulin and corticosteroid-binding globulin in humans. J Clin Endocrinol Metab. 2006, 91: 2165-2170.CrossRefPubMed

57.

Robinson BG, Hales IB, Henniker AJ, Ho K, Luttrell BM, Smee IR, Stiel JN: The effect of o, p'-DDD on adrenal steroid replacement therapy requirements. Clin Endocrinol (Oxf). 1987, 27: 437-444.CrossRef

58.

Cooper PR, Shucart WA: Treatment of Cushing's disease with o, p'-DDD. N Engl J Med. 1979, 301: 48-49.PubMed

59.

Luton JP, Mahoudeau JA, Bouchard P, Thieblot P, Hautecouverture M, Simon D, Laudat MH, Touitou Y, Bricaire H: Treatment of Cushing's disease by O,p'DDD. Survey of 62 cases. N Engl J Med. 1979, 300: 459-464.CrossRefPubMed

60.

Castinetti F, Morange I, Jaquet P, Conte-Devolx B, Brue T: Ketoconazole revisited: a preoperative or postoperative treatment in Cushing's disease. Eur J Endocrinol. 2008, 158: 91-99.CrossRefPubMed

61.

Obinata D, Yamaguchi K, Hirano D, Yoshida T, Soma M, Takahashi S: Preoperative management of Cushing's syndrome with metyrapone for severe psychiatric disturbances. Int J Urol. 2008, 15: 361-362.CrossRefPubMed

62.

Mettauer N, Brierley J: A novel use of etomidate for intentional adrenal suppression to control severe hypercortisolemia in childhood. Pediatr Crit Care Med. 2009, 10: e37-40.CrossRefPubMed

63.

Castinetti F, Fassnacht M, Johanssen S, Terzolo M, Bouchard P, Chanson P, Do Cao C, Morange I, Pico A, Ouzounian S, et al: Merits and pitfalls of mifepristone in Cushing's syndrome. Eur J Endocrinol. 2009, 160: 1003-1010.CrossRefPubMed

64.

Vilar L, Naves LA, Azevedo MF, Arruda MJ, Arahata CM, Moura ESL, Agra R, Pontes L, Montenegro L, Albuquerque JL, Canadas V: Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing's disease. Pituitary. 2010, 13: 123-129.CrossRefPubMed

65.

Petrossians P, Thonnard AS, Beckers A: Medical treatment in Cushing's syndrome: dopamine agonists and cabergoline. Neuroendocrinology. 2010, 92 (Suppl 1): 116-119.CrossRefPubMed

66.

Pivonello R, De Martino MC, Cappabianca P, De Leo M, Faggiano A, Lombardi G, Hofland LJ, Lamberts SW, Colao A: The medical treatment of Cushing's disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab. 2009, 94: 223-230.CrossRefPubMed

67.

Arnaldi G, Boscaro M: Pasireotide for the treatment of Cushing's disease. Expert Opin Investig Drugs. 2010, 19: 889-898.CrossRefPubMed

68.

Feelders RA, de Bruin C, Pereira AM, Romijn JA, Netea-Maier RT, Hermus AR, Zelissen PM, van Heerebeek R, de Jong FH, van der Lely AJ, et al: Pasireotide alone or with cabergoline and ketoconazole in Cushing's disease. N Engl J Med. 2010, 362: 1846-1848.CrossRefPubMed

69.

Boscaro M, Ludlam WH, Atkinson B, Glusman JE, Petersenn S, Reincke M, Snyder P, Tabarin A, Biller BM, Findling J, et al: Treatment of pituitary-dependent Cushing's disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial. J Clin Endocrinol Metab. 2009, 94: 115-122.CrossRefPubMed

70.

Estrada J, Boronat M, Mielgo M, Magallon R, Millan I, Diez S, Lucas T, Barcelo B: The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing's disease. N Engl J Med. 1997, 336: 172-177.CrossRefPubMed

71.

Castinetti F, Regis J, Dufour H, Brue T: Role of stereotactic radiosurgery in the management of pituitary adenomas. Nat Rev Endocrinol. 2010, 6: 214-223.CrossRefPubMed

72.

Smith PW, Turza KC, Carter CO, Vance ML, Laws ER, Hanks JB: Bilateral adrenalectomy for refractory Cushing disease: a safe and definitive therapy. J Am Coll Surg. 2009, 208: 1059-1064.CrossRefPubMed

73.

Assie G, Bahurel H, Coste J, Silvera S, Kujas M, Dugue MA, Karray F, Dousset B, Bertherat J, Legmann P, Bertagna X: Corticotroph tumor progression after adrenalectomy in Cushing's Disease: A reappraisal of Nelson's Syndrome. J Clin Endocrinol Metab. 2007, 92: 172-179.CrossRefPubMed

74.

Bush ZM, Longtine JA, Cunningham T, Schiff D, Jane JA Jr, Vance ML, Thorner MO, Laws ER Jr, Lopes MB: Temozolomide treatment for aggressive pituitary tumors: correlation of clinical outcome with O(6)-methylguanine methyltransferase (MGMT) promoter methylation and expression. J Clin Endocrinol Metab. 2010, 95: E280-290.CrossRefPubMed

75.

Raverot G, Sturm N, de Fraipont F, Muller M, Salenave S, Caron P, Chabre O, Chanson P, Cortet-Rudelli C, Assaker R, et al: Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas: a French multicenter experience. J Clin Endocrinol Metab. 2010, 95: 4592-4599.CrossRefPubMed

76.

Bode H, Seiz M, Lammert A, Brockmann MA, Back W, Hammes HP, Thome C: SOM230 (pasireotide) and temozolomide achieve sustained control of tumour progression and ACTH secretion in pituitary carcinoma with widespread metastases. Exp Clin Endocrinol Diabetes. 2010, 118: 760-763.CrossRefPubMed

77.

Trementino L, Arnaldi G, Appolloni G, Daidone V, Scaroni C, Casonato A, Boscaro M: Coagulopathy in Cushing's syndrome. Neuroendocrinology. 2010, 92 (Suppl 1): 55-59.CrossRefPubMed

78.

Giordano R, Picu A, Marinazzo E, D'Angelo V, Berardelli R, Karamouzis I, Forno D, Zinna D, Maccario M, Ghigo E, Arvat E: Metabolic and Cardiovascular Outcomes in Patients with Cushing's Syndrome of Different Aetiologies during Active Disease and 1 Year after Remission. Clin Endocrinol (Oxf). 2011, 75 (3): 354-360.CrossRef

79.

Clayton RN, Raskauskiene D, Reulen RC, Jones PW: Mortality and morbidity in Cushing's disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature. J Clin Endocrinol Metab. 2011, 96: 632-642.CrossRefPubMed

80.

Cavagnini F, Pecori GF: Epidemiology and follow-up of Cushing's disease. Ann Endocrinol (Paris). 2001, 62: 168-172.

81.

Sonino N, Fallo F, Fava GA: Psychosomatic aspects of Cushing's syndrome. Rev Endocr Metab Disord. 2010, 11: 95-104.CrossRefPubMed

Title: Cushing’s disease
Authors: Frederic Castinetti
Isabelle Morange
Bernard Conte-Devolx
Thierry Brue
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Orphanet Journal of Rare Diseases / Issue 1/2012
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/1750-1172-7-41

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Cushing’s disease

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2012

Clinical expression of Menkes disease in females with normal karyotype

Improvement of genetic stability in lymphocytes from Fanconi anemia patients through the combined effect of α-lipoic acid and N-acetylcysteine

Clinical characteristics predicting internal neurofibromas in 357 children with neurofibromatosis-1: results from a cross-selectional study

The trisomy 18 syndrome

Specific combination of compound heterozygous mutations in 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4) defines a new subtype of D-bifunctional protein deficiency

Serological diagnosis of autoimmune bullous skin diseases: Prospective comparison of the BIOCHIP mosaic-based indirect immunofluorescence technique with the conventional multi-step single test strategy