, Volume 21, Issue 2, pp 168–175 | Cite as

Management of NFAs: medical treatment

  • Naomi Even-Zohar
  • Yona Greenman



Non-functioning pituitary adenomas (NFPAs) are in general large tumors that present with symptoms secondary to local pressure on adjacent structures. Transsphenoidal surgery is the first line of treatment but residual tumor mass is often detected post-operatively. Medical therapy, in any stage of tumor management, is not well established.


A literature search was performed to review the available data on medical treatment of NFPAs.


Medications investigated for the treatment of NFPAs include dopamine receptor agonists (DA) and somatostatin receptor ligands. Randomized controlled trials are lacking, but available data suggest that DA have a positive effect on tumor remnant stabilization after surgery and could be considered in this setting. Temozolomide is reserved for aggressive tumors, although future studies are required.


NFPA are often not amenable to complete surgical resection. Conservative follow-up after surgery is associated with a high prevalence of tumor remnant progression. DA therapy may prevent residual tumor enlargement in over 85% of these patients, with a substantial consequent reduction in the need for repeat surgery or radiation therapy. It is our view that DA treatment should be routinely considered for the management of NFPA patients with incompletely resected tumors.


Non-functioning pituitary adenoma Medical treatment Dopamine agonists Somatostatin receptor agonists Temozolamide Peptide receptor radionuclide therapy (PRRT) 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Ezzat S, Asa SL, Couldwell WT, Barr CE, Dodge WE, Vance ML, McCutcheon IE (2004) The prevalence of pituitary adenomas: a systematic review. Cancer 101(3):613–619. CrossRefPubMedGoogle Scholar
  2. 2.
    Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA, Beckers A (2006) High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium. J Clin Endocrinol Metab 91(12):4769–4775. CrossRefPubMedGoogle Scholar
  3. 3.
    Fernandez A, Karavitaki N, Wass JA (2010) Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin Endocrinol 72(3):377–382. CrossRefGoogle Scholar
  4. 4.
    Fontana E, Gaillard R (2009) Epidemiology of pituitary adenoma: results of the first Swiss study. Rev Med Suisse 5(223):2172–2174PubMedGoogle Scholar
  5. 5.
    Raappana A, Koivukangas J, Ebeling T, Pirila T (2010) Incidence of pituitary adenomas in Northern Finland in 1992–2007. J Clin Endocrinol Metab 95(9):4268–4275. CrossRefPubMedGoogle Scholar
  6. 6.
    Molitch ME (2014) Nonfunctioning pituitary tumors. Handb Clin Neurol 124:167–184. CrossRefPubMedGoogle Scholar
  7. 7.
    Chen Y, Wang CD, Su ZP, Chen YX, Cai L, Zhuge QC, Wu ZB (2012) Natural history of postoperative nonfunctioning pituitary adenomas: a systematic review and meta-analysis. Neuroendocrinology 96(4):333–342. CrossRefPubMedGoogle Scholar
  8. 8.
    Greenman Y, Stern N (2009) Non-functioning pituitary adenomas. Best practice & research. Clin Endocrinol Metab 23(5):625–638. Google Scholar
  9. 9.
    Iglesias P, Arcano K, Trivino V, Garcia-Sancho P, Diez JJ, Villabona C, Cordido F (2017) Prevalence, clinical features, and natural history of incidental clinically non-functioning pituitary adenomas. Horm Metab Res. PubMedGoogle Scholar
  10. 10.
    Saeger W, Ludecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ, Petersenn S (2007) Pathohistological classification of pituitary tumors: 10 years of experience with the German pituitary tumor registry. Eur J Endocrinol 156(2):203–216. CrossRefPubMedGoogle Scholar
  11. 11.
    Lopes MBS (2017) The 2017 World Health Organization classification of tumors of the pituitary gland: a summary. Acta Neuropathol. Google Scholar
  12. 12.
    Sanchez-Tejada L, Sanchez-Ortiga R, Lamas C, Camara R, Riesgo P, Fajardo C, Aranda FI, Pico A (2017) Contribution of molecular analysis to the typification of the non-functioning pituitary adenomas. PLoS ONE 12(7):e0180039. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Mete O, Lopes MB (2017) Overview of the 2017 WHO classification of pituitary tumors. Endocr Pathol. Google Scholar
  14. 14.
    Asa SL (2008) Practical pituitary pathology: what does the pathologist need to know? Arch Pathol Lab Med 132(8):1231–1240.[1231:PPPWDT]2.0.CO;2PubMedGoogle Scholar
  15. 15.
    Larysz D, Blamek S, Rudnik A (2012) Clinical aspects of molecular biology of pituitary adenomas. Folia Neuropathol 50(2):110–117PubMedGoogle Scholar
  16. 16.
    Greenman Y, Stern N (2015) Optimal management of non-functioning pituitary adenomas. Endocrine 50(1):51–55. CrossRefPubMedGoogle Scholar
  17. 17.
    Dekkers OM, Pereira AM, Roelfsema F, Voormolen JH, Neelis KJ, Schroijen MA, Smit JW, Romijn JA (2006) Observation alone after transsphenoidal surgery for nonfunctioning pituitary macroadenoma. J Clin Endocrinol Metab 91(5):1796–1801. CrossRefPubMedGoogle Scholar
  18. 18.
    Losa M, Mortini P, Barzaghi R, Ribotto P, Terreni MR, Marzoli SB, Pieralli S, Giovanelli M (2008) Early results of surgery in patients with nonfunctioning pituitary adenoma and analysis of the risk of tumor recurrence. J Neurosurg 108(3):525–532. CrossRefPubMedGoogle Scholar
  19. 19.
    Woollons AC, Hunn MK, Rajapakse YR, Toomath R, Hamilton DA, Conaglen JV, Balakrishnan V (2000) Non-functioning pituitary adenomas: indications for postoperative radiotherapy. Clin Endocrinol 53(6):713–717CrossRefGoogle Scholar
  20. 20.
    Chanson P, Raverot G, Castinetti F, Cortet-Rudelli C, Galland F, Salenave S, French Endocrinology Society Non-functioning Pituitary Adenoma Work Group (2015) Management of clinically non-functioning pituitary adenoma. Ann Endocrinol 76(3): 239–247. CrossRefGoogle Scholar
  21. 21.
    Kuo JS, Barkhoudarian G, Farrell CJ, Bodach ME, Tumialan LM, Oyesiku NM, Litvack Z, Zada G, Patil CG, Aghi MK (2016) Congress of neurological surgeons systematic review and evidence-based guideline on surgical techniques and technologies for the management of patients with nonfunctioning pituitary adenomas. Neurosurgery 79(4):E536–E538. CrossRefPubMedGoogle Scholar
  22. 22.
    Lucas JW, Bodach ME, Tumialan LM, Oyesiku NM, Patil CG, Litvack Z, Aghi MK, Zada G (2016) Congress of neurological surgeons systematic review and evidence-based guideline on primary management of patients with nonfunctioning pituitary adenomas. Neurosurgery 79(4):E533–E535. CrossRefPubMedGoogle Scholar
  23. 23.
    Freda PU, Beckers AM, Katznelson L, Molitch ME, Montori VM, Post KD, Vance ML, Endocrine S (2011) Pituitary incidentaloma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 96(4):894–904. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Asemota AO, Ishii M, Brem H, Gallia GL (2017) Comparison of complications, trends, and costs in endoscopic vs microscopic pituitary surgery: analysis from a US health claims database. Neurosurgery 81(3):458–472. CrossRefPubMedGoogle Scholar
  25. 25.
    Iglesias P, Arcano K, Trivino V, Garcia-Sancho P, Diez JJ, Cordido F, Villabona C (2017) Non-functioning pituitary adenoma underwent surgery: a multicenter retrospective study over the last four decades (1977–2015). Eur J Intern Med 41:62–67. CrossRefPubMedGoogle Scholar
  26. 26.
    Chittiboina P (2017) iMRI during transsphenoidal surgery. Neurosurg Clin N Am 28(4):499–512. CrossRefPubMedGoogle Scholar
  27. 27.
    Dekkers OM, Hammer S, de Keizer RJ, Roelfsema F, Schutte PJ, Smit JW, Romijn JA, Pereira AM (2007) The natural course of non-functioning pituitary macroadenomas. Eur J Endocrinol 156(2):217–224. CrossRefPubMedGoogle Scholar
  28. 28.
    Chang EF, Zada G, Kim S, Lamborn KR, Quinones-Hinojosa A, Tyrrell JB, Wilson CB, Kunwar S (2008) Long-term recurrence and mortality after surgery and adjuvant radiotherapy for nonfunctional pituitary adenomas. J Neurosurg 108(4):736–745. CrossRefPubMedGoogle Scholar
  29. 29.
    Minniti G, Clarke E, Scaringi C, Enrici RM (2016) Stereotactic radiotherapy and radiosurgery for non-functioning and secreting pituitary adenomas. Rep Pract Oncol Radiother 21(4):370–378. CrossRefPubMedGoogle Scholar
  30. 30.
    Yamanaka R, Abe E, Sato T, Hayano A, Takashima Y (2017) Secondary intracranial tumors following radiotherapy for pituitary adenomas: a systematic review. Cancers. PubMedPubMedCentralGoogle Scholar
  31. 31.
    Brochier S, Galland F, Kujas M, Parker F, Gaillard S, Raftopoulos C, Young J, Alexopoulou O, Maiter D, Chanson P (2010) Factors predicting relapse of nonfunctioning pituitary macroadenomas after neurosurgery: a study of 142 patients. Eur J Endocrinol 163(2):193–200. CrossRefPubMedGoogle Scholar
  32. 32.
    O’Sullivan EP, Woods C, Glynn N, Behan LA, Crowley R, O’Kelly P, Smith D, Thompson CJ, Agha A (2009) The natural history of surgically treated but radiotherapy-naive nonfunctioning pituitary adenomas. Clin Endocrinol 71(5):709–714. CrossRefGoogle Scholar
  33. 33.
    Gatto F, Hofland LJ (2011) The role of somatostatin and dopamine D2 receptors in endocrine tumors. Endocr Relat Cancer 18(6):R233–R251. CrossRefPubMedGoogle Scholar
  34. 34.
    Neto LV, Machado Ede O, Luque RM, Taboada GF, Marcondes JB, Chimelli LM, Quintella LP, Niemeyer P Jr, de Carvalho DP, Kineman RD, Gadelha MR (2009) Expression analysis of dopamine receptor subtypes in normal human pituitaries, nonfunctioning pituitary adenomas and somatotropinomas, and the association between dopamine and somatostatin receptors with clinical response to octreotide-LAR in acromegaly. J Clin Endocrinol Metab 94(6):1931–1937. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Stefaneanu L, Kovacs K, Horvath E, Buchfelder M, Fahlbusch R, Lancranjan L (2001) Dopamine D2 receptor gene expression in human adenohypophysial adenomas. Endocrine 14(3):329–336CrossRefPubMedGoogle Scholar
  36. 36.
    Renner U, Arzberger T, Pagotto U, Leimgruber S, Uhl E, Muller A, Lange M, Weindl A, Stalla GK (1998) Heterogeneous dopamine D2 receptor subtype messenger ribonucleic acid expression in clinically nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 83(4):1368–1375. PubMedGoogle Scholar
  37. 37.
    Verde G, Oppizzi G, Chiodini PG, Dallabonzana D, Luccarelli G, Liuzzi A (1985) Effect of chronic bromocriptine administration on tumor size in patients with “nonsecreting” pituitary adenomas. J Endocrinol Investig 8(2):113–115. CrossRefGoogle Scholar
  38. 38.
    van Schaardenburg D, Roelfsema F, van Seters AP, Vielvoye GJ (1989) Bromocriptine therapy for non-functioning pituitary adenoma. Clin Endocrinol 30(5):475–484CrossRefGoogle Scholar
  39. 39.
    Pivonello R, Matrone C, Filippella M, Cavallo LM, Di Somma C, Cappabianca P, Colao A, Annunziato L, Lombardi G (2004) Dopamine receptor expression and function in clinically nonfunctioning pituitary tumors: comparison with the effectiveness of cabergoline treatment. J Clin Endocrinol Metab 89(4):1674–1683. CrossRefPubMedGoogle Scholar
  40. 40.
    Lohmann T, Trantakis C, Biesold M, Prothmann S, Guenzel S, Schober R, Paschke R (2001) Minor tumour shrinkage in nonfunctioning pituitary adenomas by long-term treatment with the dopamine agonist cabergoline. Pituitary 4(3):173–178CrossRefPubMedGoogle Scholar
  41. 41.
    Greenman Y, Cooper O, Yaish I, Robenshtok E, Sagiv N, Jonas-Kimchi T, Yuan X, Gertych A, Shimon I, Ram Z, Melmed S, Stern N (2016) Treatment of clinically nonfunctioning pituitary adenomas with dopamine agonists. Eur J Endocrinol 175(1):63–72. CrossRefPubMedGoogle Scholar
  42. 42.
    de Herder WW, Reijs AE, Feelders RA, van Aken MO, Krenning EP, Tanghe HL, van der Lely AJ, Kwekkeboom DJ (2006) Dopamine agonist therapy of clinically non-functioning pituitary macroadenomas. Is there a role for 123I-epidepride dopamine D2 receptor imaging? Eur J Endocrinol 155(5):717–723. CrossRefPubMedGoogle Scholar
  43. 43.
    Garcia EC, Naves LA, Silva AO, de Castro LF, Casulari LA, Azevedo MF (2013) Short-term treatment with cabergoline can lead to tumor shrinkage in patients with nonfunctioning pituitary adenomas. Pituitary 16(2):189–194. CrossRefPubMedGoogle Scholar
  44. 44.
    Vieira Neto L, Wildemberg LE, Moraes AB, Colli LM, Kasuki L, Marques NV, Gasparetto EL, de Castro M, Takiya CM, Gadelha MR (2015) Dopamine receptor subtype 2 expression profile in nonfunctioning pituitary adenomas and in vivo response to cabergoline therapy. Clin Endocrinol 82(5):739–746. CrossRefGoogle Scholar
  45. 45.
    Zanettini R, Antonini A, Gatto G, Gentile R, Tesei S, Pezzoli G (2007) Valvular heart disease and the use of dopamine agonists for Parkinson’s disease. N Engl J Med 356(1):39–46. CrossRefPubMedGoogle Scholar
  46. 46.
    Auriemma RS, Grasso LF, Pivonello R, Colao A (2016) The safety of treatments for prolactinomas. Exp Opin Drug Saf 15(4):503–512. CrossRefGoogle Scholar
  47. 47.
    Caputo C, Prior D, Inder WJ (2015) The need for annual echocardiography to detect cabergoline-associated valvulopathy in patients with prolactinoma: a systematic review and additional clinical data. The Lancet 3(11):906–913. PubMedGoogle Scholar
  48. 48.
    Eigler T, Ben-Shlomo A (2014) Somatostatin system: molecular mechanisms regulating anterior pituitary hormones. J Mol Endocrinol 53(1):R1–R19. CrossRefPubMedGoogle Scholar
  49. 49.
    Colao A, Pivonello R, Di Somma C, Savastano S, Grasso LF, Lombardi G (2009) Medical therapy of pituitary adenomas: effects on tumor shrinkage. Rev Endocr Metab Disord 10(2):111–123. CrossRefPubMedGoogle Scholar
  50. 50.
    Katznelson L, Laws ER Jr, Melmed S, Molitch ME, Murad MH, Utz A, Wass JA (2014) Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 99(11):3933–3951. CrossRefPubMedGoogle Scholar
  51. 51.
    Nazato DM, Abucham J (2017) Diagnosis and treatment of TSH-secreting adenomas: review of a longtime experience in a reference center. J Endocrinol Investig. Google Scholar
  52. 52.
    Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A (2015) Treatment of cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 100(8):2807–2831. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Lee M, Lupp A, Mendoza N, Martin N, Beschorner R, Honegger J, Schlegel J, Shively T, Pulz E, Schulz S, Roncaroli F, Pellegata NS (2015) SSTR3 is a putative target for the medical treatment of gonadotroph adenomas of the pituitary. Endocr Relat Cancer 22(1):111–119. CrossRefPubMedGoogle Scholar
  54. 54.
    Colao A, Di Somma C, Pivonello R, Faggiano A, Lombardi G, Savastano S (2008) Medical therapy for clinically non-functioning pituitary adenomas. Endocr Relat Cancer 15(4):905–915. CrossRefPubMedGoogle Scholar
  55. 55.
    Fusco A, Giampietro A, Bianchi A, Cimino V, Lugli F, Piacentini S, Lorusso M, Tofani A, Perotti G, Lauriola L, Anile C, Maira G, Pontecorvi A, De Marinis L (2012) Treatment with octreotide LAR in clinically non-functioning pituitary adenoma: results from a case-control study. Pituitary 15(4):571–578. CrossRefPubMedGoogle Scholar
  56. 56.
    Zawada NB, Kunert-Radek J, Pawlikowski M, Pisarek H, Radek M (2016) An evaluation of the effects of somatostatin analogue therapy in non-functioning pituitary adenomas in comparison to acromegaly. Endokrynol Polska 67(3):292–298. Google Scholar
  57. 57.
    Zatelli MC, Piccin D, Bottoni A, Ambrosio MR, Margutti A, Padovani R, Scanarini M, Taylor JE, Culler MD, Cavazzini L, degli Uberti EC (2004) Evidence for differential effects of selective somatostatin receptor subtype agonists on alpha-subunit and chromogranin a secretion and on cell viability in human nonfunctioning pituitary adenomas in vitro. J Clin Endocrinol Metab 89(10):5181–5188. CrossRefPubMedGoogle Scholar
  58. 58.
    Ibanez-Costa A, Rivero-Cortes E, Vazquez-Borrego MC, Gahete MD, Jimenez-Reina L, Venegas-Moreno E, de la Riva A, Arraez MA, Gonzalez-Molero I, Schmid HA, Maraver-Selfa S, Gavilan-Villarejo I, Garcia-Arnes JA, Japon MA, Soto-Moreno A, Galvez MA, Luque RM, Castano JP (2016) Octreotide and pasireotide (dis)similarly inhibit pituitary tumor cells in vitro. J Endocrinol 231(2):135–145. CrossRefPubMedGoogle Scholar
  59. 59.
    Ciato D, Mumbach AG, Paez-Pereda M, Stalla GK (2017) Currently used and investigational drugs for cushings disease. Exp Opin Investig Drugs 26(1):75–84. CrossRefGoogle Scholar
  60. 60.
    Priola SM, Esposito F, Cannavo S, Conti A, Abbritti RV, Barresi V, Baldari S, Ferrau F, Germano A, Tomasello F, Angileri FF (2017) Aggressive pituitary adenomas: the dark side of the moon. World Neurosurg 97:140–155. CrossRefPubMedGoogle Scholar
  61. 61.
    De Caro MDB, Solari D, Pagliuca F, Villa A, Guadagno E, Cavallo LM, Colao A, Pettinato G, Cappabianca P (2017) A typical pituitary adenomas: clinical characteristics and role of ki-67 and p53 in prognostic and therapeutic evaluation. A series of 50 patients. Neurosurg Rev 40(1):105–114. CrossRefGoogle Scholar
  62. 62.
    Halevy C, Whitelaw BC (2017) How effective is temozolomide for treating pituitary tumours and when should it be used? Pituitary 20(2):261–266. CrossRefPubMedGoogle Scholar
  63. 63.
    Hirohata T, Asano K, Ogawa Y, Takano S, Amano K, Isozaki O, Iwai Y, Sakata K, Fukuhara N, Nishioka H, Yamada S, Fujio S, Arita K, Takano K, Tominaga A, Hizuka N, Ikeda H, Osamura RY, Tahara S, Ishii Y, Kawamata T, Shimatsu A, Teramoto A, Matsuno A (2013) 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 98(3):1130–1136. CrossRefPubMedGoogle Scholar
  64. 64.
    Campdera M, Palacios N, Aller J, Magallon R, Martin P, Saucedo G, Lilienfeld H, Estrada J (2016) Temozolomide for aggressive ACTH pituitary tumors: failure of a second course of treatment. Pituitary 19(2):158–166. CrossRefPubMedGoogle Scholar
  65. 65.
    Raverot G, Castinetti F, Jouanneau E, Morange I, Figarella-Branger D, Dufour H, Trouillas J, Brue T (2012) Pituitary carcinomas and aggressive pituitary tumours: merits and pitfalls of temozolomide treatment. Clin Endocrinol 76(6):769–775. CrossRefGoogle Scholar
  66. 66.
    Raverot G, Sturm N, de Fraipont F, Muller M, Salenave S, Caron P, Chabre O, Chanson P, Cortet-Rudelli C, Assaker R, Dufour H, Gaillard S, Francois P, Jouanneau E, Passagia JG, Bernier M, Cornelius A, Figarella-Branger D, Trouillas J, Borson-Chazot F, Brue T (2010) Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas: a French multicenter experience. J Clin Endocrinol Metab 95(10):4592–4599. CrossRefPubMedGoogle Scholar
  67. 67.
    McCormack AI, Wass JA, Grossman AB (2011) Aggressive pituitary tumours: the role of temozolomide and the assessment of MGMT status. Eur J Clin Investig 41(10):1133–1148. CrossRefGoogle Scholar
  68. 68.
    Raverot G, Burman P, McCormack A, Heaney A, Petersenn S, Popovic V, Trouillas J, Dekkers OM (2018) European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. Eur J Endocrinol 178(1):G1–G24. CrossRefGoogle Scholar
  69. 69.
    Fani M, Nicolas GP, Wild D (2017) Somatostatin receptor antagonists for imaging and therapy. J Nucl Med 58(Suppl 2):61S–66S. Google Scholar
  70. 70.
    Komor J, Reubi JC, Christ ER (2014) Peptide receptor radionuclide therapy in a patient with disabling non-functioning pituitary adenoma. Pituitary 17(3):227–231. CrossRefPubMedGoogle Scholar
  71. 71.
    Baldari S, Ferrau F, Alafaci C, Herberg A, Granata F, Militano V, Salpietro FM, Trimarchi F, Cannavo S (2012) First demonstration of the effectiveness of peptide receptor radionuclide therapy (PRRT) with 111In-DTPA-octreotide in a giant PRL-secreting pituitary adenoma resistant to conventional treatment. Pituitary 15(Suppl 1):S57–S60. CrossRefPubMedGoogle Scholar
  72. 72.
    Maclean J, Aldridge M, Bomanji J, Short S, Fersht N (2014) Peptide receptor radionuclide therapy for aggressive atypical pituitary adenoma/carcinoma: variable clinical response in preliminary evaluation. Pituitary 17(6):530–538. CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Institute of Endocrinology, Metabolism and HypertensionTel Aviv-Sourasky Medical CenterTel AvivIsrael
  2. 2.Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael

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