Current and Emerging Pharmacological Therapies for Cushing's Disease
- Authors: Divaris E.1, Kostopoulos G.2, Efstathiadou Z.3
-
Affiliations:
- Department of Endocrinology, "Hippokration" General Hospital of Thessaloniki,
- Department of Endocrinology,, "Hippokration" General Hospital of Thessaloniki,
- Department of Endocrinology,, "Hippokration" General Hospital of Thessaloniki
- Issue: Vol 30, No 10 (2024)
- Pages: 757-777
- Section: Immunology, Inflammation & Allergy
- URL: https://vestnikugrasu.org/1381-6128/article/view/645422
- DOI: https://doi.org/10.2174/0113816128290025240216110928
- ID: 645422
Cite item
Full Text
Abstract
Cushings Disease (CD), hypercortisolism due to pituitary ACTH secreting neuroendocrine neoplasm, is associated with increased morbidity and, if untreated, mortality in about half of the affected individuals. Consequently, the timely initiation of effective treatment is mandatory. Neurosurgery is the first line and the only potentially curative treatment; however, 30% of patients will have persistent disease post-surgery. Furthermore, a small percentage of those initially controlled will develop hypercortisolism during long-term follow- up. Therefore, patients with persistent or recurrent disease, as well as those considered non-eligible for surgery, will need a second-line therapeutic approach, i.e., pharmacotherapy. Radiation therapy is reserved as a third-line therapeutic option due to its slower onset of action and its unfavorable profile regarding complications. During the past few years, the understanding of molecular mechanisms implicated in the physiology of the hypothalamus-pituitary-adrenal axis has evolved, and new therapeutic targets for CD have emerged. In the present review, currently available treatments, compounds currently tested in ongoing clinical trials, and interesting, potentially new targets emerging from unraveling molecular mechanisms involved in the pathophysiology of Cushings disease are discussed.
About the authors
Efstathios Divaris
Department of Endocrinology, "Hippokration" General Hospital of Thessaloniki,
Email: info@benthamscience.net
Georgios Kostopoulos
Department of Endocrinology,, "Hippokration" General Hospital of Thessaloniki,
Email: info@benthamscience.net
Zoe Efstathiadou
Department of Endocrinology,, "Hippokration" General Hospital of Thessaloniki
Author for correspondence.
Email: info@benthamscience.net
References
- Loriaux DL. Diagnosis and differential diagnosis of Cushings syndrome. N Engl J Med 2017; 376(15): 1451-9. doi: 10.1056/NEJMra1505550 PMID: 28402781
- Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushings disease: A guideline update. Lancet Diabetes Endocrinol 2021; 9(12): 847-75. doi: 10.1016/S2213-8587(21)00235-7 PMID: 34687601
- Clayton RN, Raskauskiene D, Reulen RC, Jones PW. Mortality and morbidity in Cushings disease over 50 years in Stoke-on-Trent, UK: Audit and meta-analysis of literature. J Clin Endocrinol Metab 2011; 96(3): 632-42. doi: 10.1210/jc.2010-1942 PMID: 21193542
- Gadelha MR, Vieira Neto L. Efficacy of medical treatment in Cushings disease: A systematic review. Clin Endocrinol (Oxf) 2014; 80(1): 1-12. doi: 10.1111/cen.12345 PMID: 24118077
- Bertagna X, Guignat L. Approach to the Cushings disease patient with persistent/recurrent hypercortisolism after pituitary surgery. J Clin Endocrinol Metab 2013; 98(4): 1307-18. doi: 10.1210/jc.2012-3200 PMID: 23564942
- Aghi MK. Management of recurrent and refractory Cushing disease. Nat Clin Pract Endocrinol Metab 2008; 4(10): 560-8. doi: 10.1038/ncpendmet0947 PMID: 18711406
- Patil CG, Veeravagu A, Prevedello DM, Katznelson L, Vance ML, Laws ER Jr. Outcomes after repeat transsphenoidal surgery for recurrent Cushings disease. Neurosurgery 2008; 63(2): 266-71. doi: 10.1227/01.NEU.0000313117.35824.9F PMID: 18797356
- Rutkowski MJ, Flanigan PM, Aghi MK. Update on the management of recurrent Cushings disease. Neurosurg Focus 2015; 38(2): E16. doi: 10.3171/2014.11.FOCUS14703 PMID: 25639318
- Feelders RA, Newell-Price J, Pivonello R, Nieman LK, Hofland LJ, Lacroix A. Advances in the medical treatment of Cushings syndrome. Lancet Diabetes Endocrinol 2019; 7(4): 300-12. doi: 10.1016/S2213-8587(18)30155-4 PMID: 30033041
- Tritos NA, Biller BMK, Swearingen B. Management of Cushing disease. Nat Rev Endocrinol 2011; 7(5): 279-89. doi: 10.1038/nrendo.2011.12 PMID: 21301487
- Pivonello R, De Martino MC, Cappabianca P, et al. The medical treatment of Cushings disease: Effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab 2009; 94(1): 223-30. doi: 10.1210/jc.2008-1533 PMID: 18957500
- Ferriere A, Cortet C, Chanson P, et al. Cabergoline for Cushings disease: A large retrospective multicenter study. Eur J Endocrinol 2017; 176(3): 305-14. doi: 10.1530/EJE-16-0662 PMID: 28007845
- Casulari LA, Naves LA, Mello PA, Pereira Neto A, Papadia C. Nelsons syndrome: Complete remission with cabergoline but not with bromocriptine or cyproheptadine treatment. Horm Res Paediatr 2004; 62(6): 300-5. doi: 10.1159/000082235 PMID: 15557761
- Woo I, Ehsanipoor RM. Cabergoline therapy for Cushing disease throughout pregnancy. Obstet Gynecol 2013; 122(2): 485-7. doi: 10.1097/AOG.0b013e31829e398a PMID: 23884269
- Godbout A, Manavela M, Danilowicz K, Beauregard H, Bruno OD, Lacroix A. Cabergoline monotherapy in the long-term treatment of Cushings disease. Eur J Endocrinol 2010; 163(5): 709-16. doi: 10.1530/EJE-10-0382 PMID: 20702648
- Dodd ML, Klos KJ, Bower JH, Geda YE, Josephs KA, Ahlskog JE. Pathological gambling caused by drugs used to treat Parkinson disease. Arch Neurol 2005; 62(9): 1377-81. doi: 10.1001/archneur.62.9.noc50009 PMID: 16009751
- Klos KJ, Bower JH, Josephs KA, Matsumoto JY, Ahlskog JE. Pathological hypersexuality predominantly linked to adjuvant dopamine agonist therapy in Parkinsons disease and multiple system atrophy. Parkinsonism Relat Disord 2005; 11(6): 381-6. doi: 10.1016/j.parkreldis.2005.06.005 PMID: 16109498
- Auriemma RS, Pivonello R, Ferreri L, Priscitelli P, Colao A. Cabergoline use for pituitary tumors and valvular disorders. Endocrinol Metab Clin North Am 2015; 44(1): 89-97. doi: 10.1016/j.ecl.2014.10.007 PMID: 25732645
- de Bruin C, Pereira AM, Feelders RA, et al. Coexpression of dopamine and somatostatin receptor subtypes in corticotroph adenomas. J Clin Endocrinol Metab 2009; 94(4): 1118-24. doi: 10.1210/jc.2008-2101 PMID: 19141584
- de Bruin C, Feelders RA, Waaijers AM, et al. Differential regulation of human dopamine D2 and somatostatin receptor subtype expression by glucocorticoids in vitro. J Mol Endocrinol 2009; 42(1): 47-56. doi: 10.1677/JME-08-0110 PMID: 18852217
- Hofland LJ, van der Hoek J, Feelders R, et al. The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5. Eur J Endocrinol 2005; 152(4): 645-54. doi: 10.1530/eje.1.01876 PMID: 15817922
- Colao A, Petersenn S, Newell-Price J, et al. A 12-month phase 3 study of pasireotide in Cushings disease. N Engl J Med 2012; 366(10): 914-24. doi: 10.1056/NEJMoa1105743 PMID: 22397653
- Schopohl J, Gu F, Rubens R, et al. Pasireotide can induce sustained decreases in urinary cortisol and provide clinical benefit in patients with Cushings disease: Results from an open-ended, open-label extension trial. Pituitary 2015; 18(5): 604-12. doi: 10.1007/s11102-014-0618-1 PMID: 25537481
- Lacroix A, Gu F, Gallardo W, et al. Efficacy and safety of once- monthly pasireotide in Cushings disease: A 12 month clinical trial. Lancet Diabetes Endocrinol 2018; 6(1): 17-26. doi: 10.1016/S2213-8587(17)30326-1 PMID: 29032078
- Albani A, Perez-Rivas LG, Tang S, et al. Improved pasireotide response in USP8 mutant corticotroph tumours in vitro. Endocr Relat Cancer 2022; 29(8): 503-11. doi: 10.1530/ERC-22-0088 PMID: 35686696
- Colao A, De Block C, Gaztambide MS, Kumar S, Seufert J, Casanueva FF. Managing hyperglycemia in patients with Cushings disease treated with pasireotide: Medical expert recommendations. Pituitary 2014; 17(2): 180-6. doi: 10.1007/s11102-013-0483-3 PMID: 23564338
- Petersenn S, Salgado LR, Schopohl J, et al. Long-term treatment of Cushings disease with pasireotide: 5-year results from an open-label extension study of a Phase III trial. Endocrine 2017; 57(1): 156-65. doi: 10.1007/s12020-017-1316-3 PMID: 28597198
- Gadelha M, Gatto F, Wildemberg LE, Fleseriu M. Cushings syndrome. Lancet 2023; 402(10418): 2237-52. doi: 10.1016/S0140-6736(23)01961-X PMID: 37984386
- McCormack AI, Wass JAH, Grossman AB. Aggressive pituitary tumours: The role of temozolomide and the assessment of MGMT status. Eur J Clin Invest 2011; 41(10): 1133-48. doi: 10.1111/j.1365-2362.2011.02520.x PMID: 21496012
- Stupp R, Gander M, Leyvraz S, Newlands E. Current and future developments in the use of temozolomide for the treatment of brain tumours. Lancet Oncol 2001; 2(9): 552-60. doi: 10.1016/S1470-2045(01)00489-2 PMID: 11905710
- Hirohata T, Asano K, Ogawa Y, et al. DNA mismatch repair protein (MSH6) correlated with the responses of atypical pituitary adenomas and pituitary carcinomas to temozolomide: the national cooperative study by the Japan Society for Hypothalamic and Pituitary Tumors. J Clin Endocrinol Metab 2013; 98(3): 1130-6. doi: 10.1210/jc.2012-2924 PMID: 23365123
- Hinojosa-Amaya JM, Cuevas-Ramos D, Fleseriu M. Medical management of Cushings syndrome: Current and emerging treatments. Drugs 2019; 79(9): 935-56. doi: 10.1007/s40265-019-01128-7 PMID: 31098899
- Raverot G, Castinetti F, Jouanneau E, et al. Pituitary carcinomas and aggressive pituitary tumours: Merits and pitfalls of temozolomide treatment. Clin Endocrinol (Oxf) 2012; 76(6): 769-75. doi: 10.1111/j.1365-2265.2012.04381.x PMID: 22404748
- McCormack A, Dekkers OM, Petersenn S, et al. Treatment of aggressive pituitary tumours and carcinomas: Results of a European Society of Endocrinology (ESE) survey 2016. Eur J Endocrinol 2018; 178(3): 265-76. doi: 10.1530/EJE-17-0933 PMID: 29330228
- Dillard TH, Gultekin SH, Delashaw JB Jr, Yedinak CG, Neuwelt EA, Fleseriu M. Temozolomide for corticotroph pituitary adenomas refractory to standard therapy. Pituitary 2011; 14(1): 80-91. doi: 10.1007/s11102-010-0264-1 PMID: 20972839
- Bengtsson D, Schrøder HD, Andersen M, et al. Long-term outcome and MGMT as a predictive marker in 24 patients with atypical pituitary adenomas and pituitary carcinomas given treatment with temozolomide. J Clin Endocrinol Metab 2015; 100(4): 1689-98. doi: 10.1210/jc.2014-4350 PMID: 25646794
- Zhang D, Heaney AP. Nuclear receptors as regulators of pituitary corticotroph pro-opiomelanocortin transcription. Cells 2020; 9(4): 900. doi: 10.3390/cells9040900 PMID: 32272677
- Páez-Pereda M, Kovalovsky D, Hopfner U, et al. Retinoic acid prevents experimental Cushing syndrome. J Clin Invest 2001; 108(8): 1123-31. doi: 10.1172/JCI11098 PMID: 11602619
- Pecori Giraldi F, Ambrogio AG, Andrioli M, et al. Potential role for retinoic acid in patients with Cushings disease. J Clin Endocrinol Metab 2012; 97(10): 3577-83. doi: 10.1210/jc.2012-2328 PMID: 22851491
- Vilar L, Albuquerque JL, Lyra R, et al. The role of isotretinoin therapy for Cushings disease: Results of a prospective study. Int J Endocrinol 2016; 2016: 1-9. doi: 10.1155/2016/8173182 PMID: 27034666
- Occhi G, Regazzo D, Albiger NM, et al. Activation of the dopamine receptor type-2 (DRD2) promoter by 9-cis retinoic acid in a cellular model of Cushings disease mediates the inhibition of cell proliferation and ACTH secretion without a complete corticotroph-to-melanotroph transdifferentiation. Endocrinology 2014; 155(9): 3538-49. doi: 10.1210/en.2013-1820 PMID: 24926820
- Jordan S, Lidhar K, Korbonits M, Lowe DG, Grossman AB. Cyclin D and cyclin E expression in normal and adenomatous pituitary. Eur J Endocrinol 2000; 143(1): R1-6. doi: 10.1530/eje.0.143r001 PMID: 10870044
- Roussel-Gervais A, Bilodeau S, Vallette S, et al. Cooperation between cyclin E and p27(Kip1) in pituitary tumorigenesis. Mol Endocrinol 2010; 24(9): 1835-45. doi: 10.1210/me.2010-0091 PMID: 20660298
- Liu NA, Jiang H, Ben-Shlomo A, et al. Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin-dependent kinase (CDK) inhibitor. Proc Natl Acad Sci 2011; 108(20): 8414-9. doi: 10.1073/pnas.1018091108 PMID: 21536883
- Liu NA, Araki T, Cuevas-Ramos D, et al. Cyclin E-mediated human proopiomelanocortin regulation as a therapeutic target for Cushing disease. J Clin Endocrinol Metab 2015; 100(7): 2557-64. doi: 10.1210/jc.2015-1606 PMID: 25942479
- Liu NA, Ben-Shlomo A, Carmichael JD, et al. Treatment of Cushing disease with pituitary-targeting seliciclib. J Clin Endocrinol Metab 2023; 108(3): 726-35. doi: 10.1210/clinem/dgac588 PMID: 36214832
- Perez-Rivas LG, Theodoropoulou M, Ferraù F, et al. The gene of the ubiquitin-specific protease 8 is frequently mutated in adenomas causing Cushings disease. J Clin Endocrinol Metab 2015; 100(7): E997-E1004. doi: 10.1210/jc.2015-1453 PMID: 25942478
- Theodoropoulou M, Reincke M, Fassnacht M, Komada M. Decoding the genetic basis of Cushings disease: USP8 in the spotlight. Eur J Endocrinol 2015; 173(4): M73-83. doi: 10.1530/EJE-15-0320 PMID: 26012588
- Reincke M, Sbiera S, Hayakawa A, et al. Mutations in the deubiquitinase gene USP8 cause Cushings disease. Nat Genet 2015; 47(1): 31-8. doi: 10.1038/ng.3166 PMID: 25485838
- Shen Y, Ji C, Jian X, et al. Regulation of the EGFR pathway by HSP90 is involved in the pathogenesis of Cushings disease. Front Endocrinol (Lausanne) 2021; 11: 601984. doi: 10.3389/fendo.2020.601984 PMID: 33537004
- Ma ZY, Song ZJ, Chen JH, et al. Recurrent gain-of-function USP8 mutations in Cushings disease. Cell Res 2015; 25(3): 306-17. doi: 10.1038/cr.2015.20 PMID: 25675982
- Kageyama K, Asari Y, Sugimoto Y, Niioka K, Daimon M. Ubiquitin-specific protease 8 inhibitor suppresses adrenocorticotropic hormone production and corticotroph tumor cell proliferation. Endocr J 2020; 67(2): 177-84. doi: 10.1507/endocrj.EJ19-0239 PMID: 31666445
- Treppiedi D, Di Muro G, Marra G, et al. USP8 inhibitor RA-9 reduces ACTH release and cell growth in tumor corticotrophs. Endocr Relat Cancer 2021; 28(8): 573-82. doi: 10.1530/ERC-21-0093 PMID: 34086599
- Duhamel C, Ilie MD, Salle H, et al. Immunotherapy in corticotroph and lactotroph aggressive tumors and carcinomas: Two case reports and a review of the literature. J Pers Med 2020; 10(3): 88. doi: 10.3390/jpm10030088 PMID: 32823651
- Clark AJ, Forfar R, Hussain M, et al. ACTH antagonists. Front Endocrinol 2016; 7: 101. doi: 10.3389/fendo.2016.00101 PMID: 27547198
- Crinetics Pharmaceuticals Oral ACTH Antagonist, CRN04894, Demonstrates Pharmacologic Proof-of-Concept with Strong Dose-Dependent Cortisol Suppression in Phase 1 Single Ascending Dose Study. 2021. Available from: https://crinetics.com/crn04894-demonstrates-pharmacologic-proof-of-concept/
- A Phase 1b/2a Open-label Multiple-ascending Dose Exploratory Study of CRN04894 in ACTH-dependent Cushing's Syndrome (Cushing's Disease or Ectopic ACTH Syndrome). 2023. Available from: https://www.medifind.com/articles/clinical-trial/439615084
- Feldhaus AL, Anderson K, Dutzar B, et al. ALD1613, a novel long-acting monoclonal antibody to control acth-driven pharmacology. Endocrinology 2016; 158(1): 1-8. doi: 10.1210/en.2016-1455
- Nensey NK, Bodager J, Gehrand AL, Raff H. Effect of novel melanocortin type 2 receptor antagonists on the corticosterone response to ACTH in the neonatal rat adrenal gland in vivo and in vitro. Front Endocrinol 2016; 7: 23. doi: 10.3389/fendo.2016.00023 PMID: 27047449
- Hu C, Yang J, Qi Z, et al. Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities. MedComm 2022; 3(3): e161. doi: 10.1002/mco2.161 PMID: 35928554
- Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushings syndrome. Lancet 2015; 386(9996): 913-27. doi: 10.1016/S0140-6736(14)61375-1 PMID: 26004339
- Riebold M, Kozany C, Freiburger L, et al. A C-terminal HSP90 inhibitor restores glucocorticoid sensitivity and relieves a mouse allograft model of Cushing disease. Nat Med 2015; 21(3): 276-80. doi: 10.1038/nm.3776 PMID: 25665180
- Sugiyama A, Kageyama K, Murasawa S, Ishigame N, Niioka K, Daimon M. Inhibition of heat shock protein 90 decreases ACTH production and cell proliferation in AtT-20 cells. Pituitary 2015; 18(4): 542-53. doi: 10.1007/s11102-014-0607-4 PMID: 25280813
- Giraldi PF, Cassarino MF, Sesta A, Lasio G, Losa M. Silibinin, an HSP90 inhibitor, on human ACTH-secreting adenomas. Neuroendocrinology 2023; 113(6): 606-14. doi: 10.1159/000529710 PMID: 36791678
- Du L, Bergsneider M, Mirsadraei L, et al. Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease. Proc Natl Acad Sci 2013; 110(21): 8555-60. doi: 10.1073/pnas.1306182110 PMID: 23653479
- Xia L, Shen D, Zhang Y, et al. Targeting the TR4 nuclear receptor with antagonist bexarotene can suppress the proopiomelanocortin signalling in AtT-20 cells. J Cell Mol Med 2021; 25(5): 2404-17. doi: 10.1111/jcmm.16074 PMID: 33491272
- Fukuoka H, Cooper O, Ben-Shlomo A, et al. EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. J Clin Invest 2011; 121(12): 4712-21. doi: 10.1172/JCI60417 PMID: 22105169
- Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti AK, Batra SK. Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets 2012; 16(1): 15-31. doi: 10.1517/14728222.2011.648617 PMID: 22239438
- Andl CD, Mizushima T, Oyama K, Bowser M, Nakagawa H, Rustgi AK. EGFR-induced cell migration is mediated predominantly by the JAK-STAT pathway in primary esophageal keratinocytes. Am J Physiol Gastrointest Liver Physiol 2004; 287(6): G1227-37. doi: 10.1152/ajpgi.00253.2004 PMID: 15284024
- Asari Y, Kageyama K, Nakada Y, et al. Inhibitory effects of a selective Jak2 inhibitor on adrenocorticotropic hormone production and proliferation of corticotroph tumor AtT20 cells. OncoTargets Ther 2017; 10: 4329-38. doi: 10.2147/OTT.S141345 PMID: 28919782
- Xu AW, Ste-Marie L, Kaelin CB, Barsh GS. Inactivation of signal transducer and activator of transcription 3 in proopiomelanocortin (Pomc) neurons causes decreased pomc expression, mild obesity, and defects in compensatory refeeding. Endocrinology 2007; 148(1): 72-80. doi: 10.1210/en.2006-1119 PMID: 17023536
- Sekizaki T, Kameda H, Nakamura A, et al. Neuromedin B receptor as a potential therapeutic target for corticotroph adenomas. Pituitary 2023; 26(5): 597-610. doi: 10.1007/s11102-023-01350-3 PMID: 37642928
- Hagiwara R, Kageyama K, Iwasaki Y, Niioka K, Daimon M. Effects of tubastatin A on adrenocorticotropic hormone synthesis and proliferation of AtT-20 corticotroph tumor cells. Endocr J 2022; 69(9): 1053-60. doi: 10.1507/endocrj.EJ21-0778 PMID: 35296577
- Nakada Y, Kageyama K, Sugiyama A, et al. Inhibitory effects of trichostatin A on adrenocorticotropic hormone production and proliferation of corticotroph tumor AtT-20 cells. Endocr J 2015; 62(12): 1083-90. doi: 10.1507/endocrj.EJ15-0369 PMID: 26497760
- Hagiwara R, Kageyama K, Niioka K, Takayasu S, Tasso M, Daimon M. Involvement of histone deacetylase 1/2 in adrenocorticotropic hormone synthesis and proliferation of corticotroph tumor AtT-20 cells. Peptides 2021; 136: 170441. doi: 10.1016/j.peptides.2020.170441 PMID: 33181265
- Lu J, Chatain GP, Bugarini A, et al. Histone deacetylase inhibitor SAHA is a promising treatment of Cushing disease. J Clin Endocrinol Metab 2017; 102(8): 2825-35. doi: 10.1210/jc.2017-00464 PMID: 28505327
- Zhang D, Damoiseaux R, Babayan L, et al. Targeting corticotroph HDAC and PI3-kinase in Cushing disease. J Clin Endocrinol Metab 2021; 106(1): e232-46. doi: 10.1210/clinem/dgaa699 PMID: 33000123
- Luque RM, Ibáñez-Costa A, López-Sánchez LM, et al. A cellular and molecular basis for the selective desmopressin-induced ACTH release in Cushing disease patients: Key role of AVPR1b receptor and potential therapeutic implications. J Clin Endocrinol Metab 2013; 98(10): 4160-9. doi: 10.1210/jc.2013-1992 PMID: 23884782
- Rocheville M, Lange DC, Kumar U, Patel SC, Patel RC, Patel YC. Receptors for dopamine and somatostatin: Formation of hetero-oligomers with enhanced functional activity. Science 2000; 288(5463): 154-7. doi: 10.1126/science.288.5463.154 PMID: 10753124
- Günther T, Tulipano G, Dournaud P, et al. International union of basic and clinical pharmacology. CV. Somatostatin receptors: Structure, function, ligands, and new nomenclature. Pharmacol Rev 2018; 70(4): 763-835. doi: 10.1124/pr.117.015388 PMID: 30232095
- Cantone MC, Dicitore A, Vitale G. Somatostatin-dopamine chimeric molecules in neuroendocrine neoplasms. J Clin Med 2021; 10(3): 501. doi: 10.3390/jcm10030501 PMID: 33535394
- Pivonello R, De Leo M, Cozzolino A, Colao A. The treatment of Cushings disease. Endocr Rev 2015; 36(4): 385-486. doi: 10.1210/er.2013-1048 PMID: 26067718
- Feelders RA, Hofland LJ, de Herder WW. Medical treatment of Cushings syndrome: Adrenal-blocking drugs and ketaconazole. Neuroendocrinology 2010; 92 (Suppl. 1): 111-5. doi: 10.1159/000314292 PMID: 20829630
- Tritos NA. Adrenally directed medical therapies for Cushing syndrome. J Clin Endocrinol Metab 2021; 106(1): 16-25. doi: 10.1210/clinem/dgaa778 PMID: 33118025
- Viecceli C, Mattos ACV, Hirakata VN, Garcia SP, Rodrigues TC, Czepielewski MA. Ketoconazole as second-line treatment for Cushings disease after transsphenoidal surgery: Systematic review and meta-analysis. Front Endocrinol 2023; 14: 1145775. doi: 10.3389/fendo.2023.1145775 PMID: 37223017
- Galendi SCJ, Correa Neto ANS, Demetres M, Boguszewski CL, Nogueira VSN. Effectiveness of medical treatment of Cushings disease: A systematic review and meta-analysis. Front Endocrinol 2021; 12: 732240. doi: 10.3389/fendo.2021.732240 PMID: 34603209
- Broersen LHA, Jha M, Biermasz NR, Pereira AM, Dekkers OM. Effectiveness of medical treatment for Cushings syndrome: A systematic review and meta-analysis. Pituitary 2018; 21(6): 631-41. doi: 10.1007/s11102-018-0897-z PMID: 29855779
- Castinetti F, Guignat L, Giraud P, et al. Ketoconazole in Cushings disease: Is it worth a try? J Clin Endocrinol Metab 2014; 99(5): 1623-30. doi: 10.1210/jc.2013-3628 PMID: 24471573
- Viecceli C, Mattos ACV, Costa MCB, Melo RB, Rodrigues TC, Czepielewski MA. Evaluation of ketoconazole as a treatment for Cushings disease in a retrospective cohort. Front Endocrinol 2022; 13: 1017331. doi: 10.3389/fendo.2022.1017331 PMID: 36277689
- Valassi E, Crespo I, Gich I, Rodríguez J, Webb SM. A reappraisal of the medical therapy with steroidogenesis inhibitors in Cushings syndrome. Clin Endocrinol 2012; 77(5): 735-42. doi: 10.1111/j.1365-2265.2012.04424.x PMID: 22533782
- Young J, Bertherat J, Vantyghem MC, et al. Hepatic safety of ketoconazole in Cushings syndrome: Results of a compassionate use programme in France. Eur J Endocrinol 2018; 178(5): 447-58. doi: 10.1530/EJE-17-0886 PMID: 29472378
- Daniel E, Aylwin S, Mustafa O, et al. Effectiveness of metyrapone in treating Cushings syndrome: A retrospective multicenter study in 195 patients. J Clin Endocrinol Metab 2015; 100(11): 4146-54. doi: 10.1210/jc.2015-2616 PMID: 26353009
- Nieman LK, Boscaro M, Scaroni CM, et al. Metyrapone treatment in endogenous Cushings syndrome: Results at week 12 from PROMPT, a prospective international multicenter, open-label, phase III/IV study. J Endocr Soc 2021; 5(S1): A515-5. doi: 10.1210/jendso/bvab048.1053
- Caimari F, Valassi E, Garbayo P, et al. Cushings syndrome and pregnancy outcomes: A systematic review of published cases. Endocrine 2017; 55(2): 555-63. doi: 10.1007/s12020-016-1117-0 PMID: 27704478
- Pivonello R, Simeoli C, Di Paola N, Colao A. Cushings disease: Adrenal steroidogenesis inhibitors. Pituitary 2022; 25(5): 726-32. doi: 10.1007/s11102-022-01262-8 PMID: 36036308
- Bertagna X, Pivonello R, Fleseriu M, et al. LCI699, a potent 11β-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushings disease: Results from a multicenter, proof-of-concept study. J Clin Endocrinol Metab 2014; 99(4): 1375-83. doi: 10.1210/jc.2013-2117 PMID: 24423285
- Fleseriu M, Pivonello R, Young J, et al. Osilodrostat, a potent oral 11β-hydroxylase inhibitor: 22-week, prospective, Phase II study in Cushings disease. Pituitary 2016; 19(2): 138-48. doi: 10.1007/s11102-015-0692-z PMID: 26542280
- Pivonello R, Fleseriu M, Newell-Price J, et al. Efficacy and safety of osilodrostat in patients with Cushings disease (LINC 3): A multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol 2020; 8(9): 748-61. doi: 10.1016/S2213-8587(20)30240-0 PMID: 32730798
- Gadelha M, Bex M, Feelders RA, et al. Randomized trial of osilodrostat for the treatment of cushing disease. J Clin Endocrinol Metab 2022; 107(7): e2882-95. doi: 10.1210/clinem/dgac178 PMID: 35325149
- Fleseriu M, Newell-Price J, Pivonello R, et al. Long-term outcomes of osilodrostat in Cushings disease: LINC 3 study extension. Eur J Endocrinol 2022; 187(4): 531-41. doi: 10.1530/EJE-22-0317 PMID: 35980235
- Gadelha M, Snyder PJ, Witek P, et al. Long-term efficacy and safety of osilodrostat in patients with Cushings disease: Results from the LINC 4 study extension. Front Endocrinol 2023; 14: 1236465. doi: 10.3389/fendo.2023.1236465 PMID: 37680892
- Newell-Price J, Pivonello R, Tabarin A, et al. Use of late-night salivary cortisol to monitor response to medical treatment in Cushings disease. Eur J Endocrinol 2020; 182(2): 207-17. doi: 10.1530/EJE-19-0695 PMID: 31804965
- Fleseriu M, Biller BMK, Bertherat J, et al. Long-term efficacy and safety of osilodrostat in Cushings disease: Final results from a Phase II study with an optional extension phase (LINC 2). Pituitary 2022; 25(6): 959-70. doi: 10.1007/s11102-022-01280-6 PMID: 36219274
- Detomas M, Altieri B, Deutschbein T, Fassnacht M, Dischinger U. Metyrapone versus osilodrostat in the short-term therapy of endogenous Cushings syndrome: Results from a single center cohort study. Front Endocrinol 2022; 13: 903545. doi: 10.3389/fendo.2022.903545 PMID: 35769081
- Bonnet-Serrano F, Poirier J, Vaczlavik A, et al. Differences in the spectrum of steroidogenic enzyme inhibition between Osilodrostat and Metyrapone in ACTH-dependent Cushing syndrome patients. Eur J Endocrinol 2022; 187(2): 315-22. doi: 10.1530/EJE-22-0208 PMID: 35699971
- Poirier J, Bonnet-Serrano F, Thomeret L, Bouys L, Bertherat J. Prolonged adrenocortical blockade following discontinuation of Osilodrostat. Eur J Endocrinol 2023; 188(6): K29-32. doi: 10.1093/ejendo/lvad060 PMID: 37300549
- Heleno CT, Hong SPD, Cho HG, Kim MJ, Park Y, Chae YK. Cushings syndrome in adenocarcinoma of lung responding to osilodrostat. Case Rep Oncol 2023; 16(1): 130-4. doi: 10.1159/000527824 PMID: 36876215
- Haissaguerre M, Puerto M, Nunes ML, Tabarin A. Efficacy and tolerance of osilodrostat in patients with severe Cushings syndrome due to non-pituitary cancers. Eur J Endocrinol 2020; 183(4): L7-9. doi: 10.1530/EJE-20-0557 PMID: 32688343
- Dormoy A, Haissaguerre M, Vitellius G, et al. Efficacy and safety of osilodrostat in paraneoplastic cushing syndrome: A real-world multicenter study in France. J Clin Endocrinol Metab 2023; 108(6): 1475-87. doi: 10.1210/clinem/dgac691 PMID: 36470583
- Creemers SG, Feelders RA, de Jong FH, et al. Levoketoconazole, the 2S,4R enantiomer of ketoconazole, a new steroidogenesis inhibitor for Cushings syndrome treatment. J Clin Endocrinol Metab 2021; 106(4): 1618-30. doi: 10.1210/clinem/dgaa989 PMID: 33399817
- Fleseriu M, Pivonello R, Elenkova A, et al. Efficacy and safety of levoketoconazole in the treatment of endogenous Cushings syndrome (SONICS): A phase 3, multicentre, open-label, single-arm trial. Lancet Diabetes Endocrinol 2019; 7(11): 855-65. doi: 10.1016/S2213-8587(19)30313-4 PMID: 31542384
- Pivonello R, Zacharieva S, Elenkova A, et al. Levoketoconazole in the treatment of patients with endogenous Cushings syndrome: A double-blind, placebo-controlled, randomized withdrawal study (LOGICS). Pituitary 2022; 25(6): 911-26. doi: 10.1007/s11102-022-01263-7 PMID: 36085339
- Fleseriu M, Auchus RJ, Greenman Y, et al. Levoketoconazole treatment in endogenous Cushings syndrome: Extended evaluation of clinical, biochemical, and radiologic outcomes. Eur J Endocrinol 2022; 187(6): 859-71. doi: 10.1530/EJE-22-0506 PMID: 36251618
- Pivonello R, Elenkova A, Fleseriu M, et al. Levoketoconazole in the treatment of patients with Cushings syndrome and diabetes mellitus: Results from the SONICS phase 3 study. Front Endocrinol 2021; 12: 595894. doi: 10.3389/fendo.2021.595894 PMID: 33897615
- Preda VA, Sen J, Karavitaki N, Grossman AB. THERAPY IN ENDOCRINE DISEASE: Etomidate in the management of hypercortisolaemia in Cushings syndrome: A review. Eur J Endocrinol 2012; 167(2): 137-43. doi: 10.1530/EJE-12-0274 PMID: 22577107
- Carroll TB, Peppard WJ, Herrmann DJ, et al. Continuous etomidate infusion for the management of severe Cushing syndrome: Validation of a standard protocol. J Endocr Soc 2019; 3(1): 1-12. doi: 10.1210/js.2018-00269 PMID: 30560224
- Schulte HM, Benker G, Reinwein D, Sippell WG, Allolio B. Infusion of low dose etomidate: Correction of hypercortisolemia in patients with Cushings syndrome and dose-response relationship in normal subjects. J Clin Endocrinol Metab 1990; 70(5): 1426-30. doi: 10.1210/jcem-70-5-1426 PMID: 2159485
- Łebek-Szatańska A, Nowak KM, Zgliczyński W, Baum E, Żyłka A, Papierska L. Low-dose etomidate for the management of severe hypercortisolaemia in different clinical scenarios: A case series and review of the literature. Ther Adv Endocrinol Metab 2019; 10: 2042018819825541. doi: 10.1177/2042018819825541 PMID: 30800267
- McGrath M, Ma C, Raines DE. Dimethoxy-etomidate: A nonhypnotic etomidate analog that potently inhibits steroidogenesis. J Pharmacol Exp Ther 2018; 364(2): 229-37. doi: 10.1124/jpet.117.245332 PMID: 29203576
- Orth DN, Liddle GW. Results of treatment in 108 patients with Cushings syndrome. N Engl J Med 1971; 285(5): 243-7. doi: 10.1056/NEJM197107292850501 PMID: 4326256
- Baudry C, Coste J, Bou Khalil R, et al. Efficiency and tolerance of mitotane in Cushings disease in 76 patients from a single center. Eur J Endocrinol 2012; 167(4): 473-81. doi: 10.1530/EJE-12-0358 PMID: 22815335
- LaPensee CR, Mann JE, Rainey WE, Crudo V, Hunt SW III, Hammer GD. ATR-101, a selective and potent inhibitor of Acyl-CoA acyltransferase 1, induces apoptosis in h295r adrenocortical cells and in the adrenal cortex of dogs. Endocrinology 2016; 157(5): 1775-88. doi: 10.1210/en.2015-2052 PMID: 26986192
- Smith DC, Kroiss M, Kebebew E, et al. A phase 1 study of nevanimibe HCl, a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, in adrenocortical carcinoma. Invest New Drugs 2020; 38(5): 1421-9. doi: 10.1007/s10637-020-00899-1 PMID: 31984451
- El-Maouche D, Merke DP, Vogiatzi MG, et al. A phase 2, multicenter study of nevanimibe for the treatment of congenital adrenal hyperplasia. J Clin Endocrinol Metab 2020; 105(8): 2771-8. doi: 10.1210/clinem/dgaa381 PMID: 32589738
- Burris-Hiday SD, Scott EE. Steroidogenic cytochrome P450 17A1 structure and function. Mol Cell Endocrinol 2021; 528: 111261. doi: 10.1016/j.mce.2021.111261 PMID: 33781841
- Fiorentini C, Fragni M, Perego P, et al. Antisecretive and antitumor activity of abiraterone acetate in human adrenocortical cancer: A preclinical study. J Clin Endocrinol Metab 2016; 101(12): 4594-602. doi: 10.1210/jc.2016-2414 PMID: 27626976
- Auchus RJ, Buschur EO, Chang AY, et al. Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency. J Clin Endocrinol Metab 2014; 99(8): 2763-70. doi: 10.1210/jc.2014-1258 PMID: 24780050
- Chacko R, Abdel-Razeq NH, Abu Rous F, Loutfi R. Abiraterone acetate for treatment of ectopic Cushing syndrome caused by ACTH-producing neuroendocrine tumor: A case report. J Gastrointest Oncol 2022; 13(5): 2626-32. doi: 10.21037/jgo-22-376 PMID: 36388644
- Wu N, Katz DA, An G. Population target-mediated pharmacokinetic/pharmacodynamic modeling to evaluate SPI-62 exposure and hepatic 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) inhibition in healthy adults. Clin Pharmacokinet 2023; 62(9): 1275-88. doi: 10.1007/s40262-023-01278-8 PMID: 37452998
- Brown DR, East HE, Eilerman BS, et al. Clinical management of patients with Cushing syndrome treated with mifepristone: Consensus recommendations. Clin Diabetes Endocrinol 2020; 6(1): 18. doi: 10.1186/s40842-020-00105-4 PMID: 33292727
- Fleseriu M, Biller BMK, Findling JW, et al. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushings syndrome. J Clin Endocrinol Metab 2012; 97(6): 2039-49. doi: 10.1210/jc.2011-3350 PMID: 22466348
- Pivonello R, Ferrigno R, De Martino MC, et al. Medical treatment of Cushings disease: An overview of the current and recent clinical trials. Front Endocrinol 2020; 11: 648. doi: 10.3389/fendo.2020.00648 PMID: 33363514
- Fein HG, Vaughan TB III, Kushner H, Cram D, Nguyen D. Sustained weight loss in patients treated with mifepristone for Cushings syndrome: A follow-up analysis of the SEISMIC study and long-term extension. BMC Endocr Disord 2015; 15(1): 63. doi: 10.1186/s12902-015-0059-5 PMID: 26507877
- Ault TA, Braxton DR, Watson RA, Marcus AO, Fong TL. Mifepristone induced liver injury in a patient with Cushing syndrome: A case report and review of the literature. J Med Case Reports 2023; 17(1): 33. doi: 10.1186/s13256-022-03696-x PMID: 36732814
- Castinetti F, Fassnacht M, Johanssen S, et al. Merits and pitfalls of mifepristone in Cushings syndrome. Eur J Endocrinol 2009; 160(6): 1003-10. doi: 10.1530/EJE-09-0098 PMID: 19289534
- Guarda FJ, Findling J, Yuen KCJ, Fleseriu M, Nachtigall LB. Mifepristone increases thyroid hormone requirements in patients with central hypothyroidism: A multicenter study. J Endocr Soc 2019; 3(9): 1707-14. doi: 10.1210/js.2019-00188 PMID: 31528830
- Pivonello R, Munster PN, Terzolo M, et al. Glucocorticoid receptor antagonism upregulates somatostatin receptor subtype 2 expression in acth-producing neuroendocrine tumors: New insight based on the selective glucocorticoid receptor modulator relacorilant. Front Endocrinol 2022; 12: 793262. doi: 10.3389/fendo.2021.793262 PMID: 35058882
- Molitch ME. Glucocorticoid receptor blockers. Pituitary 2022; 25(5): 733-6. doi: 10.1007/s11102-022-01227-x PMID: 35507245
- Pivonello R, Bancos I, Feelders RA, et al. Relacorilant, a selective glucocorticoid receptor modulator, induces clinical improvements in patients with Cushing syndrome: Results from a prospective, open-label phase 2 study. Front Endocrinol 2021; 12: 662865. doi: 10.3389/fendo.2021.662865 PMID: 34335465
- Donegan DM, Pivonello R, Stigliano A, et al. Relacorilant, a selective glucocorticoid receptor modulator in development for the treatment of patients with Cushing syndrome, does not cause prolongation of the cardiac QT interval. Endocr Pract 2024; 30(1): 11-8. doi: 10.1016/j.eprac.2023.09.011 PMID: 37805100
- Vilar L, Naves LA, Azevedo MF, et al. Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushings disease. Pituitary 2010; 13(2): 123-9. doi: 10.1007/s11102-009-0209-8 PMID: 19943118
- Barbot M, Albiger N, Ceccato F, et al. Combination therapy for Cushings disease: Effectiveness of two schedules of treatment. Should we start with cabergoline or ketoconazole? Pituitary 2014; 17(2): 109-17. doi: 10.1007/s11102-013-0475-3 PMID: 23468128
- Kamenický P, Droumaguet C, Salenave S, et al. Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushings syndrome. J Clin Endocrinol Metab 2011; 96(9): 2796-804. doi: 10.1210/jc.2011-0536 PMID: 21752886
- Pivonello R, Kadioglu P, Bex M, Devia DG, Boguszewski C, Yavuz DG. Pasireotide alone or in combination with cabergoline effectively controls urinary free cortisol levels: Results from a prospective study in patients with Cushings disease (CAPACITY). Endocr Abstr 2017. 49: Bioscientifica. doi: 10.1530/endoabs.49.GP187
- Feelders RA, de Bruin C, Pereira AM, et al. Pasireotide alone or with cabergoline and ketoconazole in Cushings disease. N Engl J Med 2010; 362(19): 1846-8. doi: 10.1056/NEJMc1000094 PMID: 20463350
- Amodru V, Brue T, Castinetti F. Synergistic cortisol suppression by ketoconazoleosilodrostat combination therapy. Endocrinol Diabetes Metab Case Rep 2021; 2021: 21-0071. doi: 10.1530/EDM-21-0071 PMID: 34877930
- Bogusławska A, Kluczyński Ł, Godlewska M, Rzepka E, Hubalewska-Dydejczyk A, Gilis-Januszewska A. Multimodal treatment including temozolomide (TMZ) and pasireotide for aggressive, giant silent corticotroph PiTNET in a young patient. Endocr Abstr 2022. 81: Bioscientifica. doi: 10.1530/endoabs.81.P693
- Castinetti F, Morange I, Jaquet P, Conte-Devolx B, Brue T. Ketoconazole revisited: A preoperative or postoperative treatment in Cushings disease. Eur J Endocrinol 2008; 158(1): 91-9. doi: 10.1530/EJE-07-0514 PMID: 18166822
- Ghervan C, Nemes C, Valea A, Silaghi A, Georgescu CE, Ghervan L. Ketoconazole treatment in Cushings syndrome: Results of a tertiary referral center in Romania. Acta Endocrinol 2015; 11(1): 46-54. doi: 10.4183/aeb.2015.46
- Invitti C, Giraldi PF, de Martin M, Cavagnini F. Diagnosis and management of Cushings syndrome: Results of an Italian multicentre study. J Clin Endocrinol Metab 1999; 84(2): 440-8. doi: 10.1210/jc.84.2.440 PMID: 10022398
- Luisetto G, Zangari M, Camozzi V, Boscaro M, Sonino N, Fallo F. Recovery of bone mineral density after surgical cure, but not by ketoconazole treatment, in Cushings syndrome. Osteoporos Int 2001; 12(11): 956-60. doi: 10.1007/s001980170025 PMID: 11804023
- Moncet D, Morando DJ, Pitoia F, et al. Ketoconazole therapy: An efficacious alternative to achieve eucortisolism in patients with Cushing's syndrome. Medicina 2007; 67(1): 26-31.
- Sonino N, Boscaro M, Paoletta A, Mantero F, Zillotto D. Ketoconazole treatment in Cushings syndrome: Experience in 34 patients. Clin Endocrinol 1991; 35(4): 347-52. doi: 10.1111/j.1365-2265.1991.tb03547.x PMID: 1752063
- van den Bosch OFC, Stades AME, Zelissen PMJ. Increased long-term remission after adequate medical cortisol suppression therapy as presurgical treatment in Cushings disease. Clin Endocrinol 2014; 80(2): 184-90. doi: 10.1111/cen.12286 PMID: 23841642
- Ceccato F, Zilio M, Barbot M, et al. Metyrapone treatment in Cushings syndrome: A real-life study. Endocrine 2018; 62(3): 701-11. doi: 10.1007/s12020-018-1675-4 PMID: 30014438
- Verhelst JA, Trainer PJ, Howlett TA, et al. Short and long-term responses to metyrapone in the medical management of 91 patients with Cushings syndrome. Clin Endocrinol 1991; 35(2): 169-78. doi: 10.1111/j.1365-2265.1991.tb03517.x PMID: 1657460
- Thorén M, Adamson U, Sjöberg HE. Aminoglutethimide and metyrapone in the management of Cushings syndrome. Eur J Endocrinol 1985; 109(4): 451-7. doi: 10.1530/acta.0.1090451 PMID: 3898689
- Jeffcoate WJ, Rees LH, Tomlin S, Jones AE, Edwards CR, Besser GM. Metyrapone in long-term management of Cushings disease. BMJ 1977; 2(6081): 215-7. doi: 10.1136/bmj.2.6081.215 PMID: 195666
- Schteingart D, Tsao HS, Taylor CI, McKenzie A, Victoria R, Therrien BA. Sustained remission of Cushings disease with mitotane and pituitary irradiation. Ann Intern Med 1980; 92(5): 613-9. doi: 10.7326/0003-4819-92-5-613 PMID: 6247946
- Luton JP, Mahoudeau JA, Bouchard P, et al. Treatment of Cushings disease by o,p′DDD. N Engl J Med 1979; 300(9): 459-64. doi: 10.1056/NEJM197903013000903 PMID: 215912
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