title: Systemic therapy of Cushing's syndrome.
abstract: Cushing's disease (CD) in a stricter sense derives from pathologic adrenocorticotropic hormone (ACTH) secretion usually triggered by micro- or macroadenoma of the pituitary gland. It is, thus, a form of secondary hypercortisolism. In contrast, Cushing's syndrome (CS) describes the complexity of clinical consequences triggered by excessive cortisol blood levels over extended periods of time irrespective of their origin. CS is a rare disease according to the European orphan regulation affecting not more than 5/10,000 persons in Europe. CD most commonly affects adults aged 20-50 years with a marked female preponderance (1:5 ratio of male vs. female). Patient presentation and clinical symptoms substantially vary depending on duration and plasma levels of cortisol. In 80% of cases CS is ACTH-dependent and in 20% of cases it is ACTH-independent, respectively. Endogenous CS usually is a result of a pituitary tumor. Clinical manifestation of CS, apart from corticotropin-releasing hormone (CRH-), ACTH-, and cortisol-producing (malign and benign) tumors may also be by exogenous glucocorticoid intake. Diagnosis of hypercortisolism (irrespective of its origin) comprises the following: Complete blood count including serum electrolytes, blood sugar etc., urinary free cortisol (UFC) from 24 h-urine sampling and circadian profile of plasma cortisol, plasma ACTH, dehydroepiandrosterone, testosterone itself, and urine steroid profile, Low-Dose-Dexamethasone-Test, High-Dose-Dexamethasone-Test, after endocrine diagnostic tests: magnetic resonance imaging (MRI), ultra-sound, computer tomography (CT) and other localization diagnostics. First-line therapy is trans-sphenoidal surgery (TSS) of the pituitary adenoma (in case of ACTH-producing tumors). In patients not amenable for surgery radiotherapy remains an option. Pharmacological therapy applies when these two options are not amenable or refused. In cases when pharmacological therapy becomes necessary, Pasireotide should be used in first-line in CD. CS patients are at an overall 4-fold higher mortality rate than age- and gender-matched subjects in the general population. The following article describes the most prominent substances used for clinical management of CS and gives a systematic overview of safety profiles, pharmacokinetic (PK)-parameters, and regulatory framework.
authors.affiliation: Federal Institute of Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3, Bonn, 53175, Germany. niels.eckstein@bfarm.de.
authors.forename: Niels
authors.initials: N
authors.lastname: Eckstein
authors.forename: Bodo
authors.initials: B
authors.lastname: Haas
authors.forename: Moritz David Sebastian
authors.initials: MD
authors.lastname: Hass
authors.forename: Vladlena
authors.initials: V
authors.lastname: Pfeifer
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D003480:Cushing Syndrome / Q000188:drug therapy* / Q000453:epidemiology; D006801:Humans
chemical_list: D000305:Adrenal Cortex Hormones
references.citation: J Clin Endocrinol Metab. 2008 May;93(5):1526-40
references.pmid: 18334580
references.citation: Horm Metab Res. 2011 Nov;43(12):854-7
references.pmid: 21989554
references.citation: J Steroid Biochem. 1989 Jan;32(1A):21-5
references.pmid: 2913396
references.citation: Cancer. 2008 Jul 1;113(1):5-21
references.pmid: 18473355
references.citation: Clinics (Sao Paulo). 2012;67 Suppl 1:119-23
references.pmid: 22584716
references.citation: J Cancer Res Clin Oncol. 2007 Dec;133(12):917-28
references.pmid: 17659359
references.citation: Pediatr Endocrinol Rev. 2013 Jul;10(4):450-9
references.pmid: 23957196
references.citation: Nat Rev Endocrinol. 2013 May;9(5):265-76
references.pmid: 23381030
references.citation: Clin Pharmacokinet. 2003;42(7):633-45
references.pmid: 12844325
references.citation: J Clin Invest. 2002 Jan;109(2):277-83
references.pmid: 11805140
references.citation: Eur J Intern Med. 2012 Apr;23(3):278-82
references.pmid: 22385888
references.citation: Eur J Endocrinol. 2013 Oct 08;169(5):715-23
references.pmid: 23996696
references.citation: J Vet Intern Med. 2014 Mar-Apr;28(2):473-80
references.pmid: 24495125
references.citation: J Clin Endocrinol Metab. 2008 Jul;93(7):2454-62
references.pmid: 18413427
references.citation: Endocrine. 2012 Oct;42(2):366-74
references.pmid: 22527887
references.citation: Neurosurg Clin N Am. 2012 Oct;23(4):653-68
references.pmid: 23040750
references.citation: Am J Med. 1952 Nov;13(5):597-614
references.pmid: 12996538
references.citation: Eur J Endocrinol. 2012 Sep;167(3):311-26
references.pmid: 22728347
references.citation: J Cancer Sci Ther. 2012 Jul 21;4(7):ix-xi
references.pmid: 22984635
references.citation: Br J Cancer. 1999 Nov;81(6):1022-30
references.pmid: 10576660
references.citation: Eur J Endocrinol. 2011 Sep;165(3):383-92
references.pmid: 21715416
references.citation: Eur J Endocrinol. 2004 Jun;150(6):863-75
references.pmid: 15191358
references.citation: Eur J Endocrinol. 2004 Aug;151(2):173-8
references.pmid: 15296471
references.citation: J Clin Endocrinol Metab. 2001 Jan;86(1):117-23
references.pmid: 11231987
references.citation: J Clin Endocrinol Metab. 2004 Jan;89(1):281-7
references.pmid: 14715862
references.citation: Am Fam Physician. 2013 Sep 1;88(5):319-27
references.pmid: 24010395
references.citation: N Engl J Med. 2007 Jun 7;356(23):2372-80
references.pmid: 17554118
references.citation: Curr Opin Obstet Gynecol. 2009 Aug;21(4):318-24
references.pmid: 19602929
references.citation: AJR Am J Roentgenol. 2010 Jun;194(6):W541
references.pmid: 20489078
references.citation: Int J Oncol. 2003 Aug;23(2):369-80
references.pmid: 12851686
references.citation: Neuro Endocrinol Lett. 2005 Feb;26(1):51-4
references.pmid: 15726020
references.citation: Eur J Endocrinol. 2008 Jan;158(1):91-9
references.pmid: 18166822
references.citation: Endocr Pract. 2013 May-Jun;19(3):515-21
references.pmid: 23425643
references.citation: Clin Endocrinol (Oxf). 2006 Feb;64(2):219-24
references.pmid: 16430724
references.citation: Curr Opin Endocrinol Diabetes Obes. 2007 Jun;14(3):219-25
references.pmid: 17940443
references.citation: Klin Wochenschr. 1988 Apr 15;66(8):361-4
references.pmid: 3392892
references.citation: Cancer Detect Prev. 2008;32(3):259-66
references.pmid: 18789607
references.citation: Biochem Biophys Res Commun. 2000 Mar 16;269(2):415-21
references.pmid: 10708568
references.citation: J Clin Endocrinol Metab. 2014 May;99(5):1623-30
references.pmid: 24471573
references.citation: Br J Dermatol. 2007 Jul;157(1):142-8
references.pmid: 17501951
references.citation: Eur J Endocrinol. 2013 Oct 04;169(5):R139-52
references.pmid: 23985132
references.citation: Endocrinol Metab Clin North Am. 2012 Dec;41(4):793-803
references.pmid: 23099271
references.citation: J Clin Invest. 1983 May;71(5):1495-9
references.pmid: 6304148
references.citation: J Clin Endocrinol Metab. 1967 Dec;27(12):1657-66
references.pmid: 6060954
references.citation: Nat Med. 2002 Nov;8(11):1281-7
references.pmid: 12379847
references.citation: N Engl J Med. 1984 May 31;310(22):1415-21
references.pmid: 6325910
references.citation: Nature. 1990 Oct 18;347(6294):645-50
references.pmid: 2129546
references.citation: Clin Endocrinol (Oxf). 2013 Apr;78(4):481-8
references.pmid: 23134530
references.citation: Clin Endocrinol (Oxf). 2005 Jul;63(1):118-9
references.pmid: 15963072
references.citation: Orphanet J Rare Dis. 2012 Jun 18;7:41
references.pmid: 22710101
references.citation: Rev Endocr Metab Disord. 2009 Jun;10(2):91-102
references.pmid: 18642088
references.citation: BMJ. 2013 Mar 27;346:f945
references.pmid: 23535464
references.citation: Acta Endocrinol (Copenh). 1985 Aug;109(4):451-7
references.pmid: 3898689
references.citation: Clin Endocrinol (Oxf). 2005 Feb;62(2):259-61
references.pmid: 15670207
references.citation: Eur J Endocrinol. 2012 Aug;167(2):137-43
references.pmid: 22577107
references.citation: Lancet. 1982 Sep 18;2(8299):646-9
references.pmid: 6125785
references.citation: Fertil Steril. 1988 Aug;50(2):245-9
references.pmid: 2840310
references.citation: Clin Endocrinol (Oxf). 1994 Apr;40(4):479-84
references.pmid: 8187313
references.citation: BMC Cancer. 2011 May 27;11:207
references.pmid: 21619605
references.citation: Lancet. 2006 May 13;367(9522):1605-17
references.pmid: 16698415
references.citation: Clin Cancer Res. 2003 Aug 1;9(8):3198-203
references.pmid: 12912973
references.citation: Drug Metab Dispos. 1977 Sep-Oct;5(5):482-6
references.pmid: 20298
references.citation: Diagn Pathol. 2010 Aug 31;5:56
references.pmid: 20807418
references.citation: J Neurol Surg A Cent Eur Neurosurg. 2014 Mar;75(2):91-7
references.pmid: 23965751
references.citation: Exp Clin Endocrinol Diabetes. 2011 Jan;119(1):21-5
references.pmid: 20827660
references.citation: J Clin Endocrinol Metab. 2013 Jul;98(7):2667-78
references.pmid: 23640970
references.citation: Anesthesiology. 2011 Mar;114(3):695-707
references.pmid: 21263301
references.citation: Expert Opin Investig Drugs. 2010 Jul;19(7):889-98
references.pmid: 20533892
references.citation: Anaesthesia. 1984 Oct;39(10):973-81
references.pmid: 6496912
references.citation: N Engl J Med. 2012 Mar 8;366(10):914-24
references.pmid: 22397653
references.citation: N Engl J Med. 2005 Mar 10;352(10):987-96
references.pmid: 15758009
references.citation: J Clin Endocrinol Metab. 2005 Mar;90(3):1340-6
references.pmid: 15585550
references.citation: Anesth Analg. 1976 Mar-Apr;55(2):286-9
references.pmid: 943993
references.citation: JAMA. 1966 Nov 28;198(9):1007-10
references.pmid: 5953457