Horm Metab Res 2020; 52(01): 8-24
DOI: 10.1055/a-1066-4592
Review
© Georg Thieme Verlag KG Stuttgart · New York

Updates in the Medical Treatment of Pituitary Adenomas

Monica Livia Gheorghiu
1   CI Parhon National Institute of Endocrinology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
,
Francesca Negreanu
2   Northwest Pituitary Center, and Departments of Medicine (Endocrinology) and Neurological Surgery, Oregon Health & Science University, Portland, United States
,
Maria Fleseriu
2   Northwest Pituitary Center, and Departments of Medicine (Endocrinology) and Neurological Surgery, Oregon Health & Science University, Portland, United States
› Author Affiliations
Further Information

Publication History

received 03 October 2019

accepted 13 November 2019

Publication Date:
20 December 2019 (online)

Abstract

Pituitary adenomas represent approximately 15% of brain tumors; incidence is significantly on the increase due to widespread use of magnetic resonance imaging. Surgery remains the first-line treatment for most tumors overall. The role of dopaminergic agonists (DAs) and somatostatin receptor ligands (SRLs) in the treatment of pituitary adenomas is quite well established for prolactinomas and growth hormone (GH) excess. However, over the last decade new multi-receptor binding SRLs are increasingly used for treatment of acromegaly and Cushing’s disease. SRLs/DA chimeric compounds seem to have enhanced potency and efficacy when compared to that of individual SRLs or DA receptor agonists according to preclinical data. However, following negative results, more research is needed to determine if this interesting mechanism will translate into positive clinical effects for acromegaly patients. Furthermore, new agents that block adrenal steroidogenesis have been developed in phase III clinical trials for Cushing’s disease and several new compounds working at the pituitary level and/or blocking the glucocorticoid receptor are also in development. Combination therapy of drugs with similar or different mechanisms (possibly synergistic) are also on the increase. A growing awareness regarding all mechanisms involved in both control of pituitary secretion and cellular proliferation might allow for sole medical treatment of pituitary adenomas, especially macroadenomas, rather than surgery and/or radiation therapy, in the future. Moreover, the underlying decision on how to treat patients with pituitary adenomas should be individualized on a case-by-case basis with not only a goal of tumor shrinkage and biochemical control, but also of improving patients’ quality of life.

 
  • References

  • 1 Melmed S, Casanueva FF, Hoffman AR. et al. Diagnosis and Treatment of Hyperprolactinemia: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2011; 96: 273-288
  • 2 Wong A, Eloy JA, Couldwell WT. et al. Update on prolactinomas. Part 1: Clinical manifestations and diagnostic challenges. J Clin Neurosci 2015; 22: 1562-1567
  • 3 Burke WT, Penn DL, Castlen JP. et al. Prolactinomas and nonfunctioning adenomas: preoperative diagnosis of tumor type using serum prolactin and tumor size. J Neurosurg. 2019; 1-8 doi:10.3171/2019.3.jns19121
  • 4 Mancini T, Casanueva FF, Giustina A. Hyperprolactinemia and prolactinomas. Endocrinol Metab Clin North Am 2008; 37: 67-99
  • 5 Ciccarelli A, Daly AF, Beckers A. The epidemiology of prolactinomas. Pituitary 2005; 8: 3-6
  • 6 Gheorghiu M. Age-related endocrine tumors: Non-functioning adrenal tumors as compared to pituitary adenomas. Acta Endocrinologica (Bucharest) 2009; 5: 371-384
  • 7 Varlamov EV, McCartney S, Fleseriu M. Functioning pituitary adenomas – current treatment options and emerging medical therapies. Eur Endocrinol 2019; 15: 30
  • 8 Wong A, Eloy JA, Couldwell WT. et al. Update on prolactinomas. Part 2: Treatment and management strategies. J Clin Neurosci 2015; 22: 1568-1574
  • 9 Vroonen L, Daly Adrian F, Beckers A. Epidemiology and management challenges in prolactinomas. Neuroendocrinology 2019; 109: 20-27
  • 10 Anvari K, Seilanian Toussi M, Shahidsales S. et al. Treatment outcomes and prognostic factors in adult astrocytoma: In North East of Iran. Iran J Cancer Prevent 2016; 9: e4099
  • 11 Delgrange E, Sassolas G, Perrin G. et al. Clinical and histological correlations in prolactinomas, with special reference to bromocriptine resistance. Acta Neurochir (Wien) 2005; 147: 751-758
  • 12 Liu W, Zahr RS, McCartney S. et al. Clinical outcomes in male patients with lactotroph adenomas who required pituitary surgery: a retrospective single center study. Pituitary 2018; 21: 454-462
  • 13 Cooper O, Greenman Y. Dopamine Agonists for Pituitary Adenomas. Front Endocrinol (Lausanne) 2018; 9: 469
  • 14 Barake M, Klibanski A, Tritos NA. Management of endocrine disease: Impulse control disorders in patients with hyperpolactinemia treated with dopamine agonists: how much should we worry?. Eur J Endocrinol 2018; R287-R296
  • 15 Katznelson L, Klibanski A. Prolactinomas. In Cancer Treat Res. Springer; US: 1997: 41-55
  • 16 Molitch ME. Diagnosis and Treatment of Pituitary Adenomas. JAMA 2017; 317: 516
  • 17 Webster J, Piscitelli G, Polli A. et al. A Comparison of Cabergoline and Bromocriptine in the Treatment of Hyperprolactinemic Amenorrhea. Obstet Gynecol Surv 1995; 50: 205-207
  • 18 Kelley BJ, Duker AP, Chiu P. Dopamine Agonists and Pathologic Behaviors. Parkinsons Dis 2012; 2012; 1-5
  • 19 Webster J. A Comparative Review of the Tolerability Profiles of Dopamine Agonists in the Treatment of Hyperprolactinaemia and Inhibition of Lactation. Drug Saf 1996; 14: 228-238
  • 20 Colao A. The prolactinoma. Best Pract Res Clin Endocrinol Metab 2009; 23: 575-596
  • 21 Paepegaey A-C, Salenave S, Kamenicky P. et al. Cabergoline Tapering Is Almost Always Successful in Patients With Macroprolactinomas. J Endocr Soc 2017; 1: 221-230
  • 22 Gillam MP, Molitch ME, Lombardi G. et al. Advances in the Treatment of Prolactinomas. Endocr Rev 2006; 27: 485-534
  • 23 Akinduro OO, Lu VM, Izzo A. et al. Radiographic and Hormonal Regression in Prolactinomas: An Analysis of Treatment Failure. World Neurosurg 2019; 129: e686-e694
  • 24 Maiter D. Management of Dopamine Agonist-Resistant Prolactinoma. Neuroendocrinology 2019; 109: 42-50
  • 25 Smith T, Hulou M, Huang K. et al. Current Indications for the Surgical Treatment of Prolactinomas. J Neurol Surg 2015; 22: 1785-1791
  • 26 Langlois F, McCartney S, Fleseriu M. Recent Progress in the Medical Therapy of Pituitary Tumors. Endocrinol Metab 2017; 32: 162
  • 27 Casanueva FF, Molitch ME, Schlechte JA. et al. Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas. Clin Endocrinol (Oxf) 2006; 65: 265-273
  • 28 Caputo C, Prior D, Inder WJ. The Third Case of Cabergoline-Associated Valvulopathy: The Value of Routine Cardiovascular Examination for Screening. J Endocr Soc 2018; 2: 965-969
  • 29 Gamble D, Fairley R, Harvey R. et al. Screening for valve disease in patients with hyperprolactinaemia disorders prescribed cabergoline: a service evaluation and literature review. Therap Adv. Drug Safety 2017; 8: 215-229
  • 30 Ioachimescu AG, Fleseriu M, Hoffman AR. et al. Psychological effects of dopamine agonist treatment in patients with hyperprolactinemia and prolactin-secreting adenomas. Eur J Endocrinol 2019; 31-40
  • 31 Noronha S, Stokes V, Karavitaki N. et al. Treating prolactinomas with dopamine agonists: always worth the gamble?. Endocrine 2015; 51: 205-210
  • 32 Bancos I, Nannenga MR, Bostwick JM. et al. Impulse control disorders in patients with dopamine agonist-treated prolactinomas and nonfunctioning pituitary adenomas: a case-control study. Clin Endocrinol (Oxf) 2013; 80: 863-868
  • 33 Santos Andrade EH, Pan PM, da Silva PF. et al. New insights in the management of antipsychotics in the treatment of schizophrenia in a patient with prolactinoma: a case report and review of the literature. Case Rep Med 2010; 2010: 573252
  • 34 Sheldrick AJ, Grunder G. Aripiprazole reduces serum prolactin in a woman with prolactinoma and acute psychosis. Pharmacopsychiatry 2008; 41: 160
  • 35 Al-Semaan YM, Clay HA, Meltzer HY. Clozapine in treatment of bromocriptine-induced psychosis. J Clin Psychopharmacol 1997; 17: 126-128
  • 36 Wang F, Zhou T, Wei S. et al. Endoscopic endonasal transsphenoidal surgery of 1 166 pituitary adenomas. Surg Endosc 2014; 29: 1270-1280
  • 37 Turner HE, Adams CB, Wass JA. Trans-sphenoidal surgery for microprolactinoma: an acceptable alternative to dopamine agonists?. Eur J Endocrinol 1999; 43-47
  • 38 Buchfelder M, Zhao Y. Surgical Treatment of Nonfunctioning Pituitary Tumors. In Encyclopedia of Endocrine Diseases. Amsterdam: Elsevier; 2019: 281-288
  • 39 Rehman L, Rehman UL, Jabeen R. et al. Endoscopic Trans-Sphenoidal surgery: Efficacy and response in pituitary adenoma. Pakistan. J Med Sci 2018; 34: 412-417
  • 40 Amar AP, Couldwell WT, Chen JCT. et al. Predictive value of serum prolactin levels measured immediately after transsphenoidal surgery. J Neurosurg 2002; 97: 307-314
  • 41 Gheorghiu M. Stereotactic Radiation Therapy in Pituitary Adenomas, is it Better than Conventional Radiation Therapy. Acta Endocrinol (Bucharest) 2017; 13: 476-490
  • 42 Wilson PJ, Williams JR, Smee RI. Single-centre experience of stereotactic radiosurgery and fractionated stereotactic radiotherapy for prolactinomas with the linear accelerator. J Med Imaging Radiat Oncol 2014; 59: 371-378
  • 43 Wass JAH. When to discontinue treatment of prolactinoma?. Nat Clin Pract Endocrinol Metab 2006; 2: 298-299
  • 44 Ji MJ, Kim JH, Lee JH. et al. Best candidates for dopamine agonist withdrawal in patients with prolactinomas. Pituitary 2017; 20: 578-584
  • 45 Watanabe S, Akutsu H, Takano S. et al. Long-term results of cabergoline therapy for macroprolactinomas and analyses of factors associated with remission after withdrawal. Clin Endocrinol (Oxf) 2017; 86: 207-213
  • 46 McDonald RJ, McDonald JS, Kallmes DF. et al. Gadolinium Deposition in Human Brain Tissues after Contrast-enhanced MR Imaging in Adult Patients without Intracranial Abnormalities. Radiology 2017; 285: 546-554
  • 47 Nachtigall LB, Karavitaki N, Kiseljak-Vassiliades K. et al. Physicians’ awareness of gadolinium retention and MRI timing practices in the longitudinal management of pituitary tumors: a “Pituitary Society” survey. Pituitary 2018; 22: 37-45
  • 48 Syro LV, Rotondo F, Camargo M. et al. Temozolomide and Pituitary Tumors: Current Understanding, Unresolved Issues, and Future Directions. Front Endocrinol (Lausanne) 2018; 9: 318
  • 49 Ilie MD, Lasolle H, Raverot G. Emerging and Novel Treatments for Pituitary Tumors. J Clin Med 2019; 8 pii: E1107 doi:10.3390/jcm8081107
  • 50 Bollerslev J, Heck A, Olarescu NC. Management of Endocrine disease: Individualised management of acromegaly. Eur J Endocrinol 2019; 181: R57-R71
  • 51 Elbaum M, Mizera Ł, Bolanowski M. The real costs of acromegaly: analysis of different therapies. Endokrynol Pol 2019; 70: 74-85
  • 52 Melmed S. Acromegaly pathogenesis and treatment. J Clin Invest 2009; 119: 3189-3202
  • 53 Gadelha MR, Kasuki L, Lim DST. et al. Systemic Complications of Acromegaly and the Impact of the Current Treatment Landscape: An Update. Endocr Rev 2018; 40: 268-332
  • 54 Katznelson L, Laws ER, Melmed S. et al. Acromegaly: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2014; 99: 3933-3951
  • 55 Melmed S, Bronstein MD, Chanson P. et al. A Consensus Statement on acromegaly therapeutic outcomes. Nat Rev Endocrinol 2018; 14: 552-561
  • 56 Paragliola RM, Salvatori R. Novel Somatostatin Receptor Ligands Therapies for Acromegaly. Front Endocrinol (Lausanne). 2018; 9: 78 doi:10.3389/fendo.2018.00078. eCollection 2018
  • 57 Fleseriu M, Hoffman AR, Katznelson L. American Association of Clinical Endocrinologists and American College of Endocrinology disease state clinical review. Management of acromegaly patients: What is the role of pre-operative medical therapy?. Endocr Pract 2015; 21: 668-673
  • 58 Bex M, Abs R, T’Sjoen G. et al. AcroBel – the Belgian registry on acromegaly: a survey of the ‘real–life’ outcome in 418 acromegalic subjects. Eur J Endocrinol 2007; 157: 399-409
  • 59 Maione L, Brue T, Beckers A. et al. Changes in the management and comorbidities of acromegaly over three decades: the French Acromegaly Registry. Eur J Endocrinol 2017; 176: 645-655
  • 60 Solari D, Pivonello R, Caggiano C. et al. Pituitary Adenomas: What Are the Key Features? What Are the Current Treatments? Where Is the Future Taking Us?. World Neurosurg 2019; 127: 695-709
  • 61 Fahlbusch R, Kleinberg D, Biller B. et al. Surgical debulking of pituitary adenomas improves responsiveness to octreotide lar in the treatment of acromegaly. Pituitary 2017; 20: 668-675
  • 62 Gheorghiu ML, Găloiu S, Vintilă M. et al. Beneficial effect of dose escalation and surgical debulking in patients with acromegaly treated with somatostatin analogs in a Romanian tertiary care center. Hormones 2016; 15: 224-234
  • 63 Zahr R, Fleseriu M. Updates in Diagnosis and Treatment of Acromegaly. Eur Endocrinol 2018; 14: 57
  • 64 Ben-Shlomo A, Melmed S. Somatostatin agonists for treatment of acromegaly. Mol Cell Endocrinol 2008; 286: 192-198
  • 65 Carmichael JD, Bonert VS, Nuño M. et al. Acromegaly Clinical Trial Methodology Impact on Reported Biochemical Efficacy Rates of Somatostatin Receptor Ligand Treatments: A Meta-Analysis. J Clin Endocrinol Metab 2014; 99: 1825-1833
  • 66 Colao A, Auriemma RS, Pivonello R. et al. Interpreting biochemical control response rates with first-generation somatostatin analogues in acromegaly. Pituitary 2016; 19: 235-247
  • 67 Giustina A, Bonadonna S, Bugari G. et al. High-dose intramuscular octreotide in patients with acromegaly inadequately controlled on conventional somatostatin analogue therapy: a randomised controlled trial. Eur J Endocrinol 2009; 161: 331-338
  • 68 Fleseriu M. Clinical efficacy and safety results for dose escalation of somatostatin receptor ligands in patients with acromegaly: a literature review. Pituitary 2011; 14: 184-193
  • 69 Brzana J, Yedinak CG, Gultekin SH. et al. Growth hormone granulation pattern and somatostatin receptor subtype 2A correlate with postoperative somatostatin receptor ligand response in acromegaly: a large single center experience. Pituitary 2013; 16: 490-498
  • 70 Potorac I, Beckers A, Bonneville J-F. T2-weighted MRI signal intensity as a predictor of hormonal and tumoral responses to somatostatin receptor ligands in acromegaly: a perspective. Pituitary 2017; 20: 116-120
  • 71 Cuevas-Ramos D, Fleseriu M. Somatostatin receptor ligands and resistance to treatment in pituitary adenomas. J Mol Endocrinol 2014; 52: R223-R240
  • 72 Caron PJ, Bevan JS, Petersenn S. et al. Tumor Shrinkage With Lanreotide Autogel 120 mg as Primary Therapy in Acromegaly: Results of a Prospective Multicenter Clinical Trial. J Clin Endocrinol Metab 2014; 99: 1282-1290
  • 73 Colao A, Bronstein MD, Freda P. et al. Pasireotide Versus Octreotide in Acromegaly: A Head-to-Head Superiority Study. J Clin Endocrinol Metab 2014; 99: 791-799
  • 74 Sheppard M, Bronstein MD, Freda P. et al. Pasireotide LAR maintains inhibition of GH and IGF-1 in patients with acromegaly for up to 25 months: results from the blinded extension phase of a randomized, double-blind, multicenter, Phase III study. Pituitary 2014; 18: 385-394
  • 75 Schreiber I, Buchfelder M, Droste M. et al. Treatment of acromegaly with the GH receptor antagonist pegvisomant in clinical practice: Safety and efficacy evaluation from the German Pegvisomant Observational Study. Eur J Endocrinol 2007; 156: 75-82
  • 76 Boguszewski CL, Huayllas MKP, Vilar L. et al. Brazilian multicenter study on pegvisomant treatment in acromegaly. Arch Endocrinol Metab. 2019; DOI: 10.20945/2359-3997000000159.
  • 77 Lim DST, Fleseriu M. The role of combination medical therapy in the treatment of acromegaly. Pituitary 2016; 20: 136-148
  • 78 Leonart LP, Ferreira VL, Tonin FS. et al. Medical Treatments for Acromegaly: A Systematic Review and Network Meta-Analysis. Value Health 2018; 21: 874-880
  • 79 Lesén E, Granfeldt D, Houchard A. et al. Comorbidities, treatment patterns and cost-of-illness of acromegaly in Sweden: a register-linkage population-based study. Eur J Endocrinol 2017; 176: 203-212
  • 80 Biermasz NR, Roelfsema F, Pereira AM. et al. Cost-effectiveness of lanreotide Autogel® in treatment algorithms of acromegaly. Expert Rev Pharmacoecon Outcomes Res 2009; 9: 223-234
  • 81 Strasburger CJ, Mattsson A, Wilton P. et al. Increasing frequency of combination medical therapy in the treatment of acromegaly with the GH receptor antagonist pegvisomant. Eur J Endocrinol 2018; 178: 321-329
  • 82 Barbot M, Albiger N, Ceccato F. et al. Combination therapy for Cushing’s disease: effectiveness of two schedules of treatment. Should we start with cabergoline or ketoconazole?. Pituitary 2013; 17: 109-117
  • 83 Feelders RA, de Bruin C, Pereira AM. et al. Pasireotide Alone or with Cabergoline and Ketoconazole in Cushing's Disease. N Engl J Med 2010; 362: 1846-1848
  • 84 Higham CE, Atkinson AB, Aylwin S. et al. Effective Combination Treatment with Cabergoline and Low-Dose Pegvisomant in Active Acromegaly. Obstet Gynecol Surv 2012; 67: 475-476
  • 85 Hinojosa-Amaya JM, Cuevas-Ramos D, Fleseriu M. Medical Management of Cushing’s Syndrome: Current and Emerging Treatments. Drugs 2019; 79: 935-956
  • 86 Kamenický P, Droumaguet C, Salenave S. et al. Mitotane, Metyrapone, and Ketoconazole Combination Therapy as an Alternative to Rescue Adrenalectomy for Severe ACTH-Dependent Cushing's Syndrome. J Clin Endocrinol Metab 2011; 96: 2796-2804
  • 87 Muhammad A, van der Lely AJ, Janssen J, Neggers S. Efficacy and safety of switching to pasireotide LAR alone or in combination with pegvisomant in acromegaly patients controlled with combination treatment of first-generation somatostatin analogues and weekly pegvisomant (PAPE study): a prospective open-label 48 week study, preliminary results 24 weeks. Endocr Abst. 2017; DOI: 10.1530/endoabs.49.gp174:.
  • 88 Pivonello R, Kadioglu P, Bex M. et al. Pasireotide alone or in combination with cabergoline effectively controls urinary free cortisol levels: results from a prospective study in patients with Cushing's disease (CAPACITY). Endocr Abst. 2017; DOI: 10.1530/endoabs.49.gp187.
  • 89 Valassi E, Crespo I, Gich I. et al. A reappraisal of the medical therapy with steroidogenesis inhibitors in Cushing’s syndrome. Clin Endocrinol (Oxf) 2012; 77: 735-742
  • 90 Vilar L, Naves LA, Azevedo MF. Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing’s disease. Pituitary 2009; 13: 123-129
  • 91 Lasolle H, Ferriere A, Vasiljevic A. et al. Pasireotide-LAR in acromegaly patients treated with a combination therapy: a real-life study. Endocr Connect 2019; pii: EC-19-0332.R1 DOI: 10.1530/EC-19-0332.. [Epub ahead of print]
  • 92 Feola T, Cozzolino A, Simonelli I. et al. Pegvisomant Improves Glucose Metabolism in Acromegaly: A Meta-Analysis of Prospective Interventional Studies. J Clin Endocrinol Metab 2019; 104: 2892-2902
  • 93 Lee SY, Kim JH, Lee JH. et al. The efficacy of medical treatment in patients with acromegaly in clinical practice. Endocr J 2017; 65: 33-41
  • 94 Freda PU, Reyes CM, Nuruzzaman AT. et al. Cabergoline Therapy of Growth Hormone & Growth Hormone/Prolactin Secreting Pituitary Tumors. Pituitary 2004; 7: 21-30
  • 95 Sandret L, Maison P, Chanson P. Place of Cabergoline in Acromegaly: A Meta-Analysis. J Clin Endocrinol Metab 2011; 96: 1327-1335
  • 96 Sherlock M, Fernandez-Rodriguez E, Alonso AA. et al. Medical Therapy in Patients with Acromegaly: Predictors of Response and Comparison of Efficacy of Dopamine Agonists and Somatostatin Analogues. J Clin Endocrinol Metab 2009; 94: 1255-1263
  • 97 Muhammad A, Coopmans EC, Delhanty PJD. et al. Efficacy and safety of switching to pasireotide in acromegaly patients controlled with pegvisomant and somatostatin analogues: PAPE extension study. Eur J Endocrinol 2018; 269-277
  • 98 Barkan A. Preoperative treatment of growth hormone (GH) producing macroadenomas with somatostatin receptor ligands (SRLs) to improve surgical outcome: a critical analysis. SERG 2018; 12: 7-18
  • 99 Melmed S, Popovic V, Bidlingmaier M. et al. Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial. J Clin Endocrinol Metab 2015; 100: 1699-1708
  • 100 Madan A, Zhu YF, Markison S. et al. SAT-429 Final Results from the First in Man Phase 1 Clinical Trial of CRN00808, an Orally Bioavailable sst2-Selective, Nonpeptide Somatostatin Biased Agonist, for the Treatment of Acromegaly: Safety, Pharmacokinetics, Pharmacodynamics, and Midazolam Drug Interaction in Healthy Volunteers. J Endocr Soc 2019; 3: SAT-429
  • 101 Trainer PJ, Newell-Price JDC, Ayuk J. et al. A randomised, open-label, parallel group phase 2 study of antisense oligonucleotide therapy in acromegaly. Eur J Endocrinol 2018; 179: 97-108
  • 102 Geraedts VJ, Andela CD, Stalla GK. et al. Predictors of Quality of Life in Acromegaly: No Consensus on Biochemical Parameters. Front Endocrinol (Lausanne) 2017; 8: 40
  • 103 Johnson MD, Woodburn CJ, Vance ML. Quality of Life in Patients with a Pituitary Adenoma. Pituitary 2003; 6: 81-87
  • 104 Colao A, Zgliczyński W, Komorowski J. et al. Efficacy and safety of high-dose long-acting repeatable octreotide as monotherapy or in combination with pegvisomant or cabergoline in patients with acromegaly not adequately controlled by conventional regimens: results of an open-label, multicentre study. Endokrynol Pol 2019; 70: 305-312
  • 105 Holdaway IM, Bolland MJ, Gamble GD. A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly. Eur J Endocrinol 2008; 159: 89-95
  • 106 SJCMM Neggers, van Aken MO, de Herder WW. et al. Quality of Life in Acromegalic Patients during Long-Term Somatostatin Analog Treatment with and without Pegvisomant. J Clin Endocrinol Metab 2008; 93: 3853-3859
  • 107 Lima TRL, Kasuki L, Gadelha M. et al. Physical exercise improves functional capacity and quality of life in patients with acromegaly: a 12-week follow-up study. Endocrine 2019; 66: 301-309
  • 108 Yedinak CG, Fleseriu M. Self-perception of cognitive function among patients with active acromegaly, controlled acromegaly, and non-functional pituitary adenoma: a pilot study. Endocrine 2013; 46: 585-593
  • 109 Nieman LK, Biller BMK, Findling JW. et al. Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2015; 100: 2807-2831
  • 110 Sharma ST, Nieman LK, Feelders RA. Comorbidities in Cushing's disease. Pituitary 2015; 18: 188-194
  • 111 Wengander S, Trimpou P, Papakokkinou E. et al. The incidence of endogenous Cushing's syndrome in the modern era. Clin Endocrinol (Oxf) 2019; 91: 263-270
  • 112 Lodish MB, Keil MF, Stratakis CA. Cushing’s Syndrome in Pediatrics. Endocrinol Metab Clin North Am 2018; 47: 451-462
  • 113 Dekkers OM, Horváth-Puhó E, Jørgensen JOL. et al. Multisystem Morbidity and Mortality in Cushing's Syndrome: A Cohort Study. J Clin Endocrinol Metab 2013; 98: 2277-2284
  • 114 Daly AF, Rixhon M, Adam C. et al. High Prevalence of Pituitary Adenomas: A Cross-Sectional Study in the Province of Liège, Belgium. J Clin Endocrinol Metab 2006; 91: 4769-4775
  • 115 Sharma ST, Nieman LK, Feelders RA. Cushing's syndrome: epidemiology and developments in disease management. Clin Epidemiol 2015; 7: 281-293
  • 116 KumarBora S, Suri A, Khadgawat R. et al. “Management of Cushing’s disease: Changing trend from microscopic to endoscopic surgery”. World Neurosurg. 2019; DOI: 10.1016/j.wneu.2019.08.165.
  • 117 Agam MS, Wedemeyer MA, Wrobel B. et al. Complications associated with microscopic and endoscopic transsphenoidal pituitary surgery: experience of 1153 consecutive cases treated at a single tertiary care pituitary center. J Neurosurg 2019; 130: 1576-1583
  • 118 Ammirati M, Wei L, Ciric I. Short-term outcome of endoscopic versus microscopic pituitary adenoma surgery: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2012; 84: 843-849
  • 119 Fleseriu M, Hamrahian AH, Hoffman AR. et al. American Association of Clinical Endocrinolöogists and American College of Endocrinology disease state clinical review: Diagnosis of recurrence in Cushing disease. Endocr Pract 2016; 22: 1436-1448
  • 120 Pivonello R, De Leo M, Cozzolino A. et al. The Treatment of Cushing's Disease. Endocr Rev 2015; 36: 385-486
  • 121 Shepard MJ, Mehta GU, Xu Z. et al. Technique of Whole-Sellar Stereotactic Radiosurgery for Cushing Disease: Results from a Multicenter, International Cohort Study. World Neurosurg 2018; 116: e670-e679
  • 122 Assie G, Bahurel Hln, Coste Jl. et al. Corticotroph Tumor Progression after Adrenalectomy in Cushing’s Disease: A Reappraisal of Nelson’s Syndrome. J Clin Endocrinol Metab 2007; 92: 172-179
  • 123 Chabre O. Treatment of Cushing’s Syndrome: What Place for Medical Treatment?. Acta Endocrinol (Bucharest) 2019; 15: 237-243
  • 124 Langlois F, Chu J, Fleseriu M. Pituitary-Directed Therapies for Cushing’s Disease. Front Endocrinol (Lausanne). 2018; 9: 164 doi:10.3389/fendo.2018.00164. eCollection 2018
  • 125 Lacroix A, Gu F, Gallardo W. et al. Efficacy and safety of once-monthly pasireotide in Cushing's disease: a 12 month clinical trial. Lancet Diabetes Endocrinol 2018; 6: 17-26
  • 126 Colao A, Petersenn S, Newell-Price J. et al. A 12-Month Phase 3 Study of Pasireotide in Cushing’s Disease. N Engl J Med 2012; 366: 914-924
  • 127 Fleseriu M, Petersenn S, Biller BMK. et al. Long-term efficacy and safety of once-monthly pasireotide in Cushing’s disease: A Phase III extension study. Clin Endocrinol (Oxf). 2019; DOI: 10.1111/cen.14081.
  • 128 Mandanas S, Mathiopoulou L, Boudina M. et al. Loss of Efficacy of Pasireotide after its Re-Administration: is There a Reason Why?. Rare Tumors 2016; 8: 173-175
  • 129 Petersenn S, Salgado LR, Schopohl J. Long-term treatment of Cushing’s disease with pasireotide: 5-year results from an open-label extension study of a Phase III trial. Endocrine 2017; 57: 156-165
  • 130 Burman P, Edén-Engström B, Ekman B. et al. Limited value of cabergoline in Cushing’s disease: a prospective study of a 6-week treatment in 20 patients. Eur J Endocrinol 2016; 174: 17-24
  • 131 Ferriere A, Cortet C, Chanson P. et al. Cabergoline for Cushing’s disease: a large retrospective multicenter study. Eur J Endocrinol 2017; 176: 305-314
  • 132 Godbout A, Manavela M, Danilowicz K. et al. Cabergoline monotherapy in the long-term treatment of Cushing's disease. Eur J Endocrinol 2010; 163: 709-716
  • 133 Lila A, Gopal R, Acharya S. et al. Efficacy of Cabergoline in Uncured (Persistent or Recurrent) Cushing Disease After Pituitary Surgical Treatment with or without Radiotherapy. Endocr Pract 2010; 16: 968-976
  • 134 Pivonello R, De Martino MC, Cappabianca P. et al. 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
  • 135 Nakhleh A, Saiegh L, Reut M. et al. Cabergoline treatment for recurrent Cushing’s disease during pregnancy. Hormones 2016; 15: 453-458
  • 136 Sek KS-Y, Deepak DS, Lee KO. Use of cabergoline for the management of persistent Cushing’s disease in pregnancy. BMJ Case Rep. 2017; pii: bcr-2016-217855 DOI: 10.1136/bcr-2016-217855.
  • 137 Liu N-A, 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: 2557-2564
  • 138 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: 4712-4721
  • 139 Faucz FR, Tirosh A, Tatsi C. et al. Somatic USP8 Gene Mutations Are a Common Cause of Pediatric Cushing Disease. J Clin Endocrinol Metab 2017; 102: 2836-2843
  • 140 Perez-Rivas L, Theodoropoulou M, Ferraù F. et al. The ubiquitin-specific peptidase 8 (USP8) gene is frequently mutated in adenomas causing Cushing's disease. Exp Clin Endocrinol Diabetes 2015; 100: E997-E1004
  • 141 Castinetti F, Guignat L, Giraud P. et al. Ketoconazole in Cushing's Disease: Is It Worth a Try?. J Clin Endocrinol Metab 2014; 99: 1623-1630
  • 142 Sonino N, Boscaro M, Paoletta A. et al. Ketoconazole treatment in Cushing's syndrome: experience in 34 patients. Clin Endocrinol (Oxf) 1991; 35: 347-352
  • 143 Young J, Bertherat J, Vantyghem MC. et al. Hepatic safety of ketoconazole in Cushing's syndrome: results of a Compassionate Use Programme in France. Eur J Endocrinol 2018; 178: 447-458
  • 144 Ceccato F, Zilio M, Barbot M. et al. Metyrapone treatment in Cushing’s syndrome: a real-life study. Endocrine 2018; 62: 701-711
  • 145 Daniel E, Aylwin S, Mustafa O. et al. Effectiveness of Metyrapone in Treating Cushing's Syndrome: A Retrospective Multicenter Study in 195 Patients. J Clin Endocrinol Metab 2015; 100: 4146-4154
  • 146 Lim WH, Torpy DJ, Jeffries WS. The medical management of Cushing's syndrome during pregnancy. Eur J Obstetr Gynecol Reproduct. Biol 2013; 168: 1-6
  • 147 Baudry C, Coste J, Bou Khalil R. et al. Efficiency and tolerance of mitotane in Cushing's disease in 76 patients from a single center. Eur J Endocrinol 2012; 167: 473-481
  • 148 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 2018; 3: 1-12
  • 149 Fleseriu M, Pivonello R, Elenkova A. et al. Efficacy and safety of levoketoconazole in the treatment of endogenous Cushing's syndrome (SONICS): a phase 3, multicentre, open-label, single-arm trial. Lancet Diabetes Endocrinol 2019; 7: 855-865
  • 150 Biller BMK, Newell-Price J, Fleseriu M et al. OR16-2 Osilodrostat Treatment in Cushing's Disease (CD): Results from a Phase III, Multicenter, Double-Blind, Randomized Withdrawal Study (LINC 3). J Endocr Soc. 2019; 3: (Suppl 1): OR 16-2
  • 151 Fleseriu M, Biller BMK, Findling JW. et al. Mifepristone, a Glucocorticoid Receptor Antagonist, Produces Clinical and Metabolic Benefits in Patients with Cushing's Syndrome. J Clin Endocrinol Metab 2012; 97: 2039-2049
  • 152 Fleseriu M, Findling JW, Koch CA. et al. Changes in Plasma ACTH Levels and Corticotroph Tumor Size in Patients With Cushing’s Disease During Long-term Treatment With the Glucocorticoid Receptor Antagonist Mifepristone. J Clin Endocrinol Metab 2014; 99: 3718-3727
  • 153 Newell-Price J, Pivonello R, Tabarin A. et al. Late-night salivary cortisol (LNSC) levels in a Phase III study of long-acting pasireotide in patients with Cushing's disease (CD). Endocr Abst. 2018; DOI: 10.1530/endoabs.56.oc12.4.
  • 154 Petersenn S, Newell-Price J, Findling JW. et al. High variability in baseline urinary free cortisol values in patients with Cushing's disease. Clin Endocrinol (Oxf) 2013; 80: 261-269
  • 155 Colao A, Di Somma C, Pivonello R. et al. Medical therapy for clinically non-functioning pituitary adenomas. Endocr Relat Cancer 2008; 15: 905-915
  • 156 Gagliano T, Filieri C, Minoia M. et al. Cabergoline reduces cell viability in non functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion. Pituitary 2012; 16: 91-100
  • 157 Garcia EC, Naves LA, Silva AO. et al. Short-term treatment with cabergoline can lead to tumor shrinkage in patients with nonfunctioning pituitary adenomas. Pituitary 2012; 16: 189-194
  • 158 Greenman Y, Cooper O, Yaish I. et al. Treatment of clinically nonfunctioning pituitary adenomas with dopamine agonists. Eur J Endocrinol 2016; 175: 63-72