Physiopathology, Diagnosis, and Treatment of GH Hypersecretion

  • Leandro Kasuki
  • Marília Duarte Dalmolin
  • Mônica Gadelha
Reference work entry
Part of the Endocrinology book series (ENDOCR)


Growth hormone excess leads to acromegaly or gigantism, multisystemic diseases associated with great morbidity, and increased mortality when not early recognized and adequately treated. It is caused, in the vast majority of the cases, by a pituitary adenoma (somatotropinoma) that can occur sporadically or associated with some familial diseases. In this chapter the physiopathology, the diagnosis, and the management of GH excess, according to the current knowledge, will be discussed.


Growth hormone Insulin-like growth factor type I Acromegaly Gigantism 


  1. Abu Dabrh AM, Mohammed K, Asi N, Farah WH, Wang Z, Farah MH, et al. Surgical interventions and medical treatments in treatment-naive patients with acromegaly: systematic review and meta-analysis. J Clin Endocrinol Metab. 2014;99(11):4003–14.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Abu Dabrh A, Asi N, Farah W, Mohammed K, Wang Z, Farah M, et al. Radiotherapy vs. radiosurgery in treating patients with acromegaly: systematic review and meta-analysis. Endocr Pract. 2015;18:1–33.CrossRefGoogle Scholar
  3. Annamalai AK, Webb A, Kandasamy N, Elkhawad M, Moir S, Khan F, et al. A comprehensive study of clinical, biochemical, radiological, vascular, cardiac, and sleep parameters in an unselected cohort of patients with acromegaly undergoing presurgical somatostatin receptor ligand therapy. J Clin Endocrinol Metab. 2013;98(3):1040–50.PubMedCrossRefGoogle Scholar
  4. Auriemma RS, Pivonello R, Ferreri L, Priscitelli P, Colao A. Cabergoline use for pituitary tumors and valvular disorders. Endocrinol Metab Clin N Am. 2015;44(1):89–97.CrossRefGoogle Scholar
  5. Baldelli R, Battista C, Leonetti F, Ghiggi MR, Ribaudo MC, Paoloni A, et al. Glucose homeostasis in acromegaly: effects of long-acting somatostatin analogues treatment. Clin Endocrinol. 2003;59(4):492–9.CrossRefGoogle Scholar
  6. Barkan A, Bronstein MD, Bruno OD, Cob A, Espinosa-de-los-Monteros AL, Gadelha MR, et al. Management of acromegaly in Latin America: expert panel recommendations. Pituitary. 2010;13(2):168–75.PubMedCrossRefGoogle Scholar
  7. Barker FG 2nd, Klibanski A, Swearingen B. Transsphenoidal surgery for pituitary tumors in the United States, 1996–2000: mortality, morbidity, and the effects of hospital and surgeon volume. J Clin Endocrinol Metab. 2003;88(10):4709–19.PubMedCrossRefGoogle Scholar
  8. Baumann G. Growth hormone heterogeneity: genes, isohormones, variants, and binding proteins. Endocr Rev. 1991;12(4):424–49.PubMedCrossRefGoogle Scholar
  9. Bengtsson BA, Eden S, Ernest I, Oden A, Sjogren B. Epidemiology and long-term survival in acromegaly. A study of 166 cases diagnosed between 1955 and 1984. Acta Med Scand. 1988;223(4):327–35.PubMedCrossRefGoogle Scholar
  10. Bengtsson D, Schroder HD, Andersen M, Maiter D, Berinder K, Feldt Rasmussen U, 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.PubMedCrossRefGoogle Scholar
  11. Ben-Shlomo A, Melmed S. Acromegaly. Endocrinol Metab Clin N Am. 2008;37(1):101–22.CrossRefGoogle Scholar
  12. Bernabeu I, Alvarez-Escola C, Paniagua AE, Lucas T, Pavon I, Cabezas-Agricola JM, et al. Pegvisomant and cabergoline combination therapy in acromegaly. Pituitary. 2013;16(1):101–8.PubMedCrossRefGoogle Scholar
  13. Bevan JS, Newell-Price J, Wass JA, Atkin SL, Bouloux PM, Chapman J, et al. Home administration of lanreotide autogel by patients with acromegaly, or their partners, is safe and effective. Clin Endocrinol. 2008;68(3):343–9.Google Scholar
  14. Buchfelder M, Schlaffer SM. Modern imaging of pituitary adenomas. Front Horm Res. 2010;38:109–20.PubMedCrossRefGoogle Scholar
  15. Buhk JH, Jung S, Psychogios MN, Goricke S, Hartz S, Schulz-Heise S, et al. Tumor volume of growth hormone-secreting pituitary adenomas during treatment with pegvisomant: a prospective multicenter study. J Clin Endocrinol Metab. 2010;95(2):552–8.PubMedCrossRefGoogle Scholar
  16. Carlsen SM, Lund-Johansen M, Schreiner T, Aanderud S, Johannesen O, Svartberg J, et al. Preoperative octreotide treatment in newly diagnosed acromegalic patients with macroadenomas increases cure short-term postoperative rates: a prospective, randomized trial. J Clin Endocrinol Metab. 2008;93(8):2984–90.PubMedCrossRefGoogle Scholar
  17. Carlsen SM, Svartberg J, Schreiner T, Aanderud S, Johannesen O, Skeie S, et al. Six-month preoperative octreotide treatment in unselected, de novo patients with acromegaly: effect on biochemistry, tumour volume, and postoperative cure. Clin Endocrinol. 2011;74(6):736–43.CrossRefGoogle Scholar
  18. Carmichael JD, Bonert VS, Mirocha JM, Melmed S. The utility of oral glucose tolerance testing for diagnosis and assessment of treatment outcomes in 166 patients with acromegaly. J Clin Endocrinol Metab. 2009;94(2):523–7.PubMedCrossRefGoogle Scholar
  19. Caron PJ, Bevan JS, Petersenn S, Flanagan D, Tabarin A, Prevost G, 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(4):1282–90.PubMedCrossRefGoogle Scholar
  20. Casagrande A, Bronstein MD, Jallad RS, Moraes AB, Elias PC, Castro M, et al. Long-term remission of acromegaly after octreotide withdrawal is an uncommon and frequently unsustainable event. Neuroendocrinology. 2017;104(3):273–9.Google Scholar
  21. Casini AF, Araujo PB, Fontes R, Xavier SS, Gadelha MR. Cardiac morphology and performance alterations and analysis of determinant factors of left ventricular hypertrophy in 40 patients with acromegaly. Arq Bras Endocrinol Metabol. 2006;50(1):82–90.PubMedCrossRefGoogle Scholar
  22. Casini AF, Neto LV, Fontes R, Franca RF, Xavier SS, Gadelha MR. Aortic root ectasia in patients with acromegaly: experience at a single center. Clin Endocrinol. 2011;75(4):495–500.CrossRefGoogle Scholar
  23. Cazabat L, Bouligand J, Salenave S, Bernier M, Gaillard S, Parker F, et al. Germline AIP mutations in apparently sporadic pituitary adenomas: prevalence in a prospective single-center cohort of 443 patients. J Clin Endocrinol Metab. 2012;97(4):E663–70.PubMedCrossRefGoogle Scholar
  24. Chanson P, Salenave S, Kamenicky P, Cazabat L, Young J. Pituitary tumours: acromegaly. Best Pract Res Clin Endocrinol Metab. 2009;23(5):555–74.PubMedCrossRefGoogle Scholar
  25. Colao A, Spinelli L, Marzullo P, Pivonello R, Petretta M, Di Somma C, et al. High prevalence of cardiac valve disease in acromegaly: an observational, analytical, case-control study. J Clin Endocrinol Metab. 2003;88(7):3196–201.PubMedCrossRefGoogle Scholar
  26. Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev. 2004;25(1):102–52.PubMedCrossRefGoogle Scholar
  27. Colao A, Pivonello R, Auriemma RS, Galdiero M, Savastano S, Lombardi G. Beneficial effect of dose escalation of octreotide-LAR as first-line therapy in patients with acromegaly. Eur J Endocrinol. 2007;157(5):579–87.PubMedCrossRefGoogle Scholar
  28. Colao A, Cappabianca P, Caron P, De Menis E, Farrall AJ, Gadelha MR, et al. Octreotide LAR vs. surgery in newly diagnosed patients with acromegaly: a randomized, open-label, multicentre study. Clin Endocrinol (Oxf). 2009a;70(5):757–68.CrossRefGoogle Scholar
  29. Colao A, Auriemma RS, Galdiero M, Lombardi G, Pivonello R. Effects of initial therapy for five years with somatostatin analogs for acromegaly on growth hormone and insulin-like growth factor-I levels, tumor shrinkage, and cardiovascular disease: a prospective study. J Clin Endocrinol Metab. 2009b;94(10):3746–56.PubMedCrossRefGoogle Scholar
  30. Colao A, Bronstein MD, Freda P, Gu F, Shen CC, Gadelha M, et al. Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. J Clin Endocrinol Metab. 2014;99(3):791–9.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Colao A, Auriemma RS, Pivonello R, Kasuki L, Gadelha MR. Interpreting biochemical control response rates with first-generation somatostatin analogues in acromegaly. Pituitary. 2016;19(3):235–47.Google Scholar
  32. Concolino P, Costella A, Capoluongo E. Multiple endocrine neoplasia type 1 (MEN1): an update of 208 new germline variants reported in the last nine years. Cancer Genet. 2016;209(1–2):36–41.PubMedCrossRefGoogle Scholar
  33. Cook DM. Long-term management of prolactinomas – use of long-acting dopamine agonists. Rev Endocr Metab Disord. 2005;6(1):15–21.PubMedCrossRefGoogle Scholar
  34. Correa LL, Taboada GF, Van Haute FR, Casini AF, Balarini GA, Vieira Neto L, et al. Evaluation of glucose metabolism in acromegalic patients before and after treatment with octreotide LAR. Arq Bras Endocrinol Metabol. 2008;52(1):55–64.PubMedCrossRefGoogle Scholar
  35. Correa R, Salpea P, Stratakis CA. Carney complex: an update. Eur J Endocrinol. 2015;173(4):M85–97.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA, Beckers A. High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege. Belgium J Clin Endocrinol Metab. 2006;91(12):4769–75.PubMedCrossRefGoogle Scholar
  37. Daly AF, Tichomirowa MA, Petrossians P, Heliovaara E, Jaffrain-Rea ML, Barlier A, et al. Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study. J Clin Endocrinol Metab. 2010;95(11):E373–83.PubMedCrossRefGoogle Scholar
  38. Davi MV, Dalle Carbonare L, Giustina A, Ferrari M, Frigo A, Lo Cascio V, et al. Sleep apnoea syndrome is highly prevalent in acromegaly and only partially reversible after biochemical control of the disease. Eur J Endocrinol. 2008;159(5):533–40.PubMedCrossRefGoogle Scholar
  39. Dekkers OM, Biermasz NR, Pereira AM, Romijn JA, Vandenbroucke JP. Mortality in acromegaly: a metaanalysis. J Clin Endocrinol Metab. 2008;93(1):61–7.PubMedCrossRefGoogle Scholar
  40. Denes J, Swords F, Rattenberry E, Stals K, Owens M, Cranston T, et al. Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort. J Clin Endocrinol Metab. 2015;100(3):E531–41.PubMedCrossRefGoogle Scholar
  41. dos Santos Silva CM, Gottlieb I, Volschan ICM, Kasuki L, Warszawski L, Lima GA, et al. Low frequency of cardiomyopathy using cardiac magnetic resonance imaging in an acromegaly contemporary cohort. J Clin Endocrinol Metab. 2015a;100(12):4447–55.PubMedCrossRefGoogle Scholar
  42. Dos Santos Silva CM, Lima GA, Volschan IC, Gottlieb I, Kasuki L, Neto LV, et al. Low risk of coronary artery disease in patients with acromegaly. Endocrine. 2015b;50(3):749–55.PubMedCrossRefGoogle Scholar
  43. Fathalla H, Cusimano MD, Di Ieva A, Lee J, Alsharif O, Goguen J, et al. Endoscopic versus microscopic approach for surgical treatment of acromegaly. Neurosurg Rev. 2015;38(3):541–8.PubMedCrossRefGoogle Scholar
  44. Fatti LM, Scacchi M, Lavezzi E, Pecori Giraldi F, De Martin M, Toja P, et al. Effects of treatment with somatostatin analogues on QT interval duration in acromegalic patients. Clin Endocrinol. 2006;65(5):626–30.CrossRefGoogle Scholar
  45. Fernandez A, Karavitaki N, Wass JA. Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin Endocrinol (Oxf). 2010;72(3):377–82.Google Scholar
  46. Ferone D, Gatto F, Arvigo M, Resmini E, Boschetti M, Teti C, et al. The clinical-molecular interface of somatostatin, dopamine and their receptors in pituitary pathophysiology. J Mol Endocrinol. 2009;42(5):361–70.PubMedCrossRefGoogle Scholar
  47. Flitsch J, Ludecke DK, Stahnke N, Wiebel J, Saeger W. Transsphenoidal surgery for pituitary gigantism and galactorrhea in a 3.5 year old child. Pituitary. 2000;2(4):261–7.PubMedCrossRefGoogle Scholar
  48. Fougner SL, Casar-Borota O, Heck A, Berg JP, Bollerslev J. Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly. Clin Endocrinol. 2012;76(1):96–102.CrossRefGoogle Scholar
  49. Fougner SL, Bollerslev J, Svartberg J, Oksnes M, Cooper J, Carlsen SM. Preoperative octreotide treatment of acromegaly: long-term results of a randomised controlled trial. Eur J Endocrinol. 2014;171(2):229–35.PubMedCrossRefGoogle Scholar
  50. Franck SE, Van der Lely AJ, Delhanty PJ, Jorgensen JO, Neggers SJ. Pegvisomant in combination with long-acting somatostatin analogues in acromegaly: the role of the growth hormone receptor deletion of exon 3. Eur J Endocrinol. 2015;173(5):553–61.PubMedCrossRefGoogle Scholar
  51. Freda PU, Katznelson L, van der Lely AJ, Reyes CM, Zhao S, Rabinowitz D. Long-acting somatostatin analog therapy of acromegaly: a meta-analysis. J Clin Endocrinol Metab. 2005;90(8):4465–73.PubMedCrossRefGoogle Scholar
  52. Gadelha MR. A paradigm shift in the medical treatment of acromegaly: from a ‘trial and error’ to a personalized therapeutic decision-making process. Clin Endocrinol. 2015;83(1):1–2.CrossRefGoogle Scholar
  53. Gadelha MR, Une KN, Rohde K, Vaisman M, Kineman RD, Frohman LA. Isolated familial somatotropinomas: establishment of linkage to chromosome 11q13.1-11q13.3 and evidence for a potential second locus at chromosome 2p16-12. J Clin Endocrinol Metab. 2000;85(2):707–14.PubMedGoogle Scholar
  54. Gadelha MR, Kasuki L, Korbonits M. Novel pathway for somatostatin analogs in patients with acromegaly. Trends Endocrinol Metab. 2013a;24(5):238–46.PubMedCrossRefGoogle Scholar
  55. Gadelha MR, Trivellin G, Hernandez Ramirez LC, Korbonits M. Genetics of pituitary adenomas. Front Horm Res. 2013b;41:111–40.PubMedCrossRefGoogle Scholar
  56. Gadelha MR, Bronstein MD, Brue T, Coculescu M, Fleseriu M, Guitelman M, et al. Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2014;2(11):875–84.PubMedCrossRefGoogle Scholar
  57. Gadelha MR, Kasuki L, Korbonits M. The genetic background of acromegaly. Pituitary. 2017a;20(1):10–21.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Gadelha MR, Wildemberg LE, Bronstein MD, Gatto F, Ferone D. Somatostatin receptor ligands in the treatment of acromegaly. Pituitary. 2017b;20(1):100–8.PubMedCrossRefGoogle Scholar
  59. Garby L, Caron P, Claustrat F, Chanson P, Tabarin A, Rohmer V, et al. Clinical characteristics and outcome of acromegaly induced by ectopic secretion of growth hormone-releasing hormone (GHRH): a French nationwide series of 21 cases. J Clin Endocrinol Metab. 2012;97(6):2093–104.PubMedCrossRefGoogle Scholar
  60. Giustina A, Bonadonna S, Bugari G, Colao A, Cozzi R, Cannavo S, 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(2):331–8.PubMedCrossRefGoogle Scholar
  61. Giustina A, Chanson P, Bronstein MD, Klibanski A, Lamberts S, Casanueva FF, et al. A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab. 2010;95(7):3141–8.PubMedCrossRefGoogle Scholar
  62. Giustina A, Mazziotti G, Torri V, Spinello M, Floriani I, Melmed S. Meta-analysis on the effects of octreotide on tumor mass in acromegaly. PLoS One. 2012;7(5):e36411.PubMedPubMedCentralCrossRefGoogle Scholar
  63. Giustina A, Chanson P, Kleinberg D, Bronstein MD, Clemmons DR, Klibanski A, et al. Expert consensus document: a consensus on the medical treatment of acromegaly. Nat Rev Endocrinol. 2014;10(4):243–8.PubMedCrossRefGoogle Scholar
  64. Giustina A, Arnaldi G, Bogazzi F, Cannavo S, Colao A, De Marinis L, et al. Pegvisomant in acromegaly: an update. J Endocrinol Invest. 2017;40(6):577–89.PubMedPubMedCentralCrossRefGoogle Scholar
  65. Gunawardane K, Krarup Hansen T, Sandahl Christiansen J, Lunde Jorgensen JO. Normal physiology of growth hormone in adults. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, et al., editors. Endotext. South Dartmouth (MA); 2000.Google Scholar
  66. Hatipoglu E, Bozcan S, Kadioglu P. Discontinuation of somatostatin analogs while acromegaly is in long-term remission. Pituitary. 2015;18(4):554–60.PubMedCrossRefGoogle Scholar
  67. Henry RR, Ciaraldi TP, Armstrong D, Burke P, Ligueros-Saylan M, Mudaliar S. Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers. J Clin Endocrinol Metab. 2013;98(8):3446–53.PubMedCrossRefGoogle Scholar
  68. Herman V, Fagin J, Gonsky R, Kovacs K, Melmed S. Clonal origin of pituitary adenomas. J Clin Endocrinol Metab. 1990;71(6):1427–33.PubMedCrossRefGoogle Scholar
  69. Hernandez-Ramirez LC, Gabrovska P, Denes J, Stals K, Trivellin G, Tilley D, et al. Landscape of familial isolated and young-onset pituitary adenomas: prospective diagnosis in AIP mutation carriers. J Clin Endocrinol Metab. 2015;100(9):E1242–54.PubMedPubMedCentralCrossRefGoogle Scholar
  70. Higham CE, Thomas JD, Bidlingmaier M, Drake WM, Trainer PJ. Successful use of weekly pegvisomant administration in patients with acromegaly. Eur J Endocrinol. 2009;161(1):21–5.PubMedCrossRefGoogle Scholar
  71. Higham CE, Atkinson AB, Aylwin S, Bidlingmaier M, Drake WM, Lewis A, et al. Effective combination treatment with cabergoline and low-dose pegvisomant in active acromegaly: a prospective clinical trial. J Clin Endocrinol Metab. 2012;97(4):1187–93.PubMedCrossRefGoogle Scholar
  72. Hofland LJ, van der Hoek J, van Koetsveld PM, de Herder WW, Waaijers M, Sprij-Mooij D, et al. The novel somatostatin analog SOM230 is a potent inhibitor of hormone release by growth hormone- and prolactin-secreting pituitary adenomas in vitro. J Clin Endocrinol Metab. 2004;89(4):1577–85.PubMedCrossRefGoogle Scholar
  73. 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(2):89–95.PubMedCrossRefGoogle Scholar
  74. Iacovazzo D, Caswell R, Bunce B, Jose S, Yuan B, Hernandez-Ramirez LC, et al. Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study. Acta Neuropathol Commun. 2016;4(1):56.PubMedPubMedCentralCrossRefGoogle Scholar
  75. Jahangiri A, Wagner J, Tran MT, Miller LM, Tom MW, Kunwar S, et al. Factors predicting postoperative hyponatremia and efficacy of hyponatremia management strategies after more than 1000 pituitary operations. J Neurosurg. 2013;119(6):1478–83.PubMedCrossRefGoogle Scholar
  76. Jallad RS, Musolino NR, Kodaira S, Cescato VA, Bronstein MD. Does partial surgical tumour removal influence the response to octreotide-LAR in acromegalic patients previously resistant to the somatostatin analogue? Clin Endocrinol. 2007;67(2):310–5.CrossRefGoogle Scholar
  77. Kasuki L, Vieira Neto L, Gadelha MR. Cabergoline treatment in acromegaly: cons. Endocrine. 2014;46(2):220–5.PubMedCrossRefGoogle Scholar
  78. Kato Y, Murakami Y, Sohmiya M, Nishiki M. Regulation of human growth hormone secretion and its disorders. Intern Med. 2002;41(1):7–13.PubMedCrossRefGoogle Scholar
  79. Katznelson L, Atkinson JL, Cook DM, Ezzat SZ, Hamrahian AH, Miller KK, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of acromegaly – 2011 update: executive summary. Endocr Pract. 2011;17(4):636–46.PubMedCrossRefGoogle Scholar
  80. Katznelson L, Laws ER Jr, Melmed S, Molitch ME, Murad MH, Utz A, et al. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(11):3933–51.PubMedCrossRefGoogle Scholar
  81. Kayano K, Takeo M, Morisue S, Yamamoto M, Mizuno Y, Meguro F. A case of human growth hormone (h-GH)-producing adenocarcinoma of the lung. Nippon Kyobu Geka Gakkai Zasshi. 1995;43(4):538–42.PubMedGoogle Scholar
  82. Killinger Z, Payer J, Lazurova I, Imrich R, Homerova Z, Kuzma M, et al. Arthropathy in acromegaly. Rheum Dis Clin N Am. 2010;36(4):713–20.CrossRefGoogle Scholar
  83. Korbonits M, Storr H, Kumar AV. Familial pituitary adenomas – who should be tested for AIP mutations? Clin Endocrinol. 2012;77(3):351–6.CrossRefGoogle Scholar
  84. Kristof RA, Rother M, Neuloh G, Klingmuller D. Incidence, clinical manifestations, and course of water and electrolyte metabolism disturbances following transsphenoidal pituitary adenoma surgery: a prospective observational study. J Neurosurg. 2009;111(3):555–62.PubMedCrossRefGoogle Scholar
  85. Kropf LL, Madeira M, Vieira Neto L, Gadelha MR, de Farias ML. Functional evaluation of the joints in acromegalic patients and associated factors. Clin Rheumatol. 2013;32(7):991–8.PubMedCrossRefGoogle Scholar
  86. Laron Z. Insulin-like growth factor 1 (IGF-1): a growth hormone. Mol Pathol. 2001;54(5):311–6.PubMedPubMedCentralCrossRefGoogle Scholar
  87. Lee CC, Vance ML, Xu Z, Yen CP, Schlesinger D, Dodson B, et al. Stereotactic radiosurgery for acromegaly. J Clin Endocrinol Metab. 2014;99(4):1273–81.PubMedCrossRefGoogle Scholar
  88. Lim S, Shahinian H, Maya MM, Yong W, Heaney AP. Temozolomide: a novel treatment for pituitary carcinoma. Lancet Oncol. 2006;7(6):518–20.PubMedCrossRefGoogle Scholar
  89. Lloyd RV, Kovacs K, Young WF Jr, Farrel WE, Asa SL, Trouillas J, et al. Pituitary tumours: introduction. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C, editors. WHO classification of tumours pathology and genetics tumours of endocrine organs. Lyon: IARC Press; 2004. p. 10–3.Google Scholar
  90. Lorcy Y, Dejager S, Chanson P, French Octreotide LARG. Time course of GH and IGF-1 levels following withdrawal of long-acting octreotide in acromegaly. Pituitary. 2000;3(3):193–7.PubMedCrossRefGoogle Scholar
  91. Losa M, Bogazzi F, Cannavo S, Ceccato F, Curto L, De Marinis L, et al. Temozolomide therapy in patients with aggressive pituitary adenomas or carcinomas. J Neuro-Oncol. 2016;126(3):519–25.CrossRefGoogle Scholar
  92. Machado EO, Taboada GF, Neto LV, van Haute FR, Correa LL, Balarini GA, et al. Prevalence of discordant GH and IGF-I levels in acromegalics at diagnosis, after surgical treatment and during treatment with octreotide LAR. Growth Hormon IGF Res. 2008;18(5):389–93.CrossRefGoogle Scholar
  93. Madeira M, Neto LV, de Lima GA, Moreira RO, de Mendonca LM, Gadelha MR, et al. Effects of GH-IGF-I excess and gonadal status on bone mineral density and body composition in patients with acromegaly. Osteoporos Int. 2010;21(12):2019–25.PubMedCrossRefGoogle Scholar
  94. Madeira M, Neto LV, de Paula Paranhos Neto F, Barbosa Lima IC, Carvalho de Mendonca LM, Gadelha MR, et al. Acromegaly has a negative influence on trabecular bone, but not on cortical bone, as assessed by high-resolution peripheral quantitative computed tomography. J Clin Endocrinol Metab. 2013a;98(4):1734–41.PubMedCrossRefGoogle Scholar
  95. Madeira M, Neto LV, Torres CH, de Mendonca LM, Gadelha MR, de Farias ML. Vertebral fracture assessment in acromegaly. J Clin Densitom. 2013b;16(2):238–43.PubMedCrossRefGoogle Scholar
  96. Manara R, Maffei P, Citton V, Rizzati S, Bommarito G, Ermani M, et al. Increased rate of intracranial saccular aneurysms in acromegaly: an MR angiography study and review of the literature. J Clin Endocrinol Metab. 2011;96(5):1292–300.PubMedCrossRefGoogle Scholar
  97. Marie P. Sur deux cas d'acromégalie: Hypertrophie singulière non congénitale des extremités supérieures, inférieures et céphaliques. Rev Med. 1886;6:297.Google Scholar
  98. Mattar P, Alves Martins MR, Abucham J. Short- and long-term efficacy of combined cabergoline and octreotide treatment in controlling igf-I levels in acromegaly. Neuroendocrinology. 2010;92(2):120–7.PubMedCrossRefGoogle Scholar
  99. McCormack AI, Wass JA, Grossman AB. Aggressive pituitary tumours: the role of temozolomide and the assessment of MGMT status. Eur J Clin Investig. 2011;41(10):1133–48.CrossRefGoogle Scholar
  100. Melmed S. Acromegaly pathogenesis and treatment. J Clin Invest. 2009;119(11):3189–202.PubMedPubMedCentralCrossRefGoogle Scholar
  101. Melmed S, Ezrin C, Kovacs K, Goodman RS, Frohman LA. Acromegaly due to secretion of growth hormone by an ectopic pancreatic islet-cell tumor. N Engl J Med. 1985;312(1):9–17.PubMedCrossRefGoogle Scholar
  102. Melmed S, Colao A, Barkan A, Molitch M, Grossman AB, Kleinberg D, et al. Guidelines for acromegaly management: an update. J Clin Endocrinol Metab. 2009;94(5):1509–17.PubMedCrossRefGoogle Scholar
  103. Melmed S, Casanueva FF, Klibanski A, Bronstein MD, Chanson P, Lamberts SW, et al. A consensus on the diagnosis and treatment of acromegaly complications. Pituitary. 2013;16(3):294–302.PubMedCrossRefGoogle Scholar
  104. Mercado M, Borges F, Bouterfa H, Chang TC, Chervin A, Farrall AJ, et al. A prospective, multicentre study to investigate the efficacy, safety and tolerability of octreotide LAR (long-acting repeatable octreotide) in the primary therapy of patients with acromegaly. Clin Endocrinol. 2007;66(6):859–68.CrossRefGoogle Scholar
  105. Mercado M, Gonzalez B, Vargas G, Ramirez C, de los Monteros AL, Sosa E, et al. Successful mortality reduction and control of comorbidities in patients with acromegaly followed at a highly specialized multidisciplinary clinic. J Clin Endocrinol Metab. 2014;99(12):4438–46.PubMedCrossRefGoogle Scholar
  106. Minniti G, Traish D, Ashley S, Gonsalves A, Brada M. Risk of second brain tumor after conservative surgery and radiotherapy for pituitary adenoma: update after an additional 10 years. J Clin Endocrinol Metab. 2005;90(2):800–4.PubMedCrossRefGoogle Scholar
  107. Minniti G, Scaringi C, Enrici RM. Radiation techniques for acromegaly. Radiat Oncol. 2011;6:167.PubMedPubMedCentralCrossRefGoogle Scholar
  108. Muller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, et al. Ghrelin. Mol Metab. 2015;4(6):437–60.PubMedPubMedCentralCrossRefGoogle Scholar
  109. Murray PG, Higham CE, Clayton PE. 60 YEARS OF NEUROENDOCRINOLOGY: the hypothalamo-GH axis: the past 60 years. J Endocrinol. 2015;226(2):T123–40.PubMedCrossRefGoogle Scholar
  110. Neggers SJ, van der Lely AJ. Combination treatment with somatostatin analogues and pegvisomant in acromegaly. Growth Hormon IGF Res. 2011;21(3):129–33.CrossRefGoogle Scholar
  111. Neggers SJ, de Herder WW, Feelders RA, van der Lely AJ. Conversion of daily pegvisomant to weekly pegvisomant combined with long-acting somatostatin analogs, in controlled acromegaly patients. Pituitary. 2011;14(3):253–8.PubMedPubMedCentralCrossRefGoogle Scholar
  112. Neggers SJ, Franck SE, de Rooij FW, Dallenga AH, Poublon RM, Feelders RA, et al. Long-term efficacy and safety of pegvisomant in combination with long-acting somatostatin analogs in acromegaly. J Clin Endocrinol Metab. 2014;99(10):3644–52.PubMedCrossRefGoogle Scholar
  113. Neggers SJ, Pronin V, Balcere I, Lee MK, Rozhinskaya L, Bronstein MD, et al. Lanreotide autogel 120 mg at extended dosing intervals in patients with acromegaly biochemically controlled with octreotide LAR: the LEAD study. Eur J Endocrinol. 2015;173(3):313–23.PubMedPubMedCentralCrossRefGoogle Scholar
  114. Nomikos P, Buchfelder M, Fahlbusch R. The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical ‘cure’. Eur J Endocrinol. 2005;152(3):379–87.PubMedCrossRefGoogle Scholar
  115. Obari A, Sano T, Ohyama K, Kudo E, Qian ZR, Yoneda A, et al. Clinicopathological features of growth hormone-producing pituitary adenomas: difference among various types defined by cytokeratin distribution pattern including a transitional form. Endocr Pathol. 2008;19(2):82–91.PubMedCrossRefGoogle Scholar
  116. Paisley AN, Hayden K, Ellis A, Anderson J, Wieringa G, Trainer PJ. Pegvisomant interference in GH assays results in underestimation of GH levels. Eur J Endocrinol. 2007;156(3):315–9.PubMedCrossRefGoogle Scholar
  117. Pendleton C, Adams H, Mathioudakis N, Quinones-Hinojosa A. Sellar door: Harvey Cushing’s entry into the pituitary gland, the unabridged Johns Hopkins experience 1896–1912. World Neurosurg. 2013;79(2):394–403.PubMedCrossRefGoogle Scholar
  118. Pita-Gutierrez F, Pertega-Diaz S, Pita-Fernandez S, Pena L, Lugo G, Sangiao-Alvarellos S, et al. Place of preoperative treatment of acromegaly with somatostatin analog on surgical outcome: a systematic review and meta-analysis. PLoS One. 2013;8(4):e61523.PubMedPubMedCentralCrossRefGoogle Scholar
  119. Ramirez C, Vargas G, Gonzalez B, Grossman A, Rabago J, Sosa E, et al. Discontinuation of octreotide LAR after long term, successful treatment of patients with acromegaly: is it worth trying? Eur J Endocrinol. 2012;166(1):21–6.PubMedCrossRefGoogle Scholar
  120. Reid TJ, Post KD, Bruce JN, Nabi Kanibir M, Reyes-Vidal CM, Freda PU. Features at diagnosis of 324 patients with acromegaly did not change from 1981 to 2006: acromegaly remains under-recognized and under-diagnosed. Clin Endocrinol. 2010;72(2):203–8.CrossRefGoogle Scholar
  121. Rokkas T, Pistiolas D, Sechopoulos P, Margantinis G, Koukoulis G. Risk of colorectal neoplasm in patients with acromegaly: a meta-analysis. World J Gastroenterol. 2008;14(22):3484–9.PubMedPubMedCentralCrossRefGoogle Scholar
  122. Ronchi CL, Rizzo E, Lania AG, Pivonello R, Grottoli S, Colao A, et al. Preliminary data on biochemical remission of acromegaly after somatostatin analogs withdrawal. Eur J Endocrinol. 2008;158(1):19–25.PubMedCrossRefGoogle Scholar
  123. Rostomyan L, Daly AF, Petrossians P, Nachev E, Lila AR, Lecoq AL, et al. Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients. Endocr Relat Cancer. 2015;22(5):745–57.PubMedCrossRefGoogle Scholar
  124. Salvatori R, Nachtigall LB, Cook DM, Bonert V, Molitch ME, Blethen S, et al. Effectiveness of self- or partner-administration of an extended-release aqueous-gel formulation of lanreotide in lanreotide-naive patients with acromegaly. Pituitary. 2010;13(2):115–22.PubMedCrossRefGoogle Scholar
  125. Sandret L, Maison P, Chanson P. Place of cabergoline in acromegaly: a meta-analysis. J Clin Endocrinol Metab. 2011;96(5):1327–35.PubMedCrossRefGoogle Scholar
  126. Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E. Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med. 2007 Jan 4;356(1):29–38.PubMedCrossRefGoogle Scholar
  127. Schilbach K, Bidlingmaier M. Growth hormone binding protein – physiological and analytical aspects. Best Pract Res Clin Endocrinol Metab. 2015;29(5):671–83.PubMedCrossRefGoogle Scholar
  128. Starke RM, Raper DM, Payne SC, Vance ML, Oldfield EH, Jane JA Jr. Endoscopic vs microsurgical transsphenoidal surgery for acromegaly: outcomes in a concurrent series of patients using modern criteria for remission. J Clin Endocrinol Metab. 2013;98(8):3190–8.PubMedCrossRefGoogle Scholar
  129. Taboada GF, Luque RM, Neto LV, Machado Ede O, Sbaffi BC, Domingues RC, et al. Quantitative analysis of somatostatin receptor subtypes (1-5) gene expression levels in somatotropinomas and correlation to in vivo hormonal and tumor volume responses to treatment with octreotide LAR. Eur J Endocrinol. 2008;158(3):295–303.PubMedCrossRefGoogle Scholar
  130. Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol. 2014;386(1–2):2–15.PubMedPubMedCentralCrossRefGoogle Scholar
  131. Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012;97(9):2990–3011.PubMedCrossRefGoogle Scholar
  132. Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, van der Lely AJ, et al. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med. 2000;342(16):1171–7.PubMedCrossRefGoogle Scholar
  133. Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO, et al. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N Engl J Med. 2014;371(25):2363–74.PubMedPubMedCentralCrossRefGoogle Scholar
  134. Tutuncu Y, Berker D, Isik S, Ozuguz U, Akbaba G, Kucukler FK, et al. Comparison of octreotide LAR and lanreotide autogel as post-operative medical treatment in acromegaly. Pituitary. 2012;15(3):398–404.PubMedCrossRefGoogle Scholar
  135. Uchoa HB, Lima GA, Correa LL, Vidal AP, Cavallieri SA, Vaisman M, et al. Prevalence of thyroid diseases in patients with acromegaly: experience of a Brazilian center. Arq Bras Endocrinol Metabol. 2013;57(9):685–90.PubMedCrossRefGoogle Scholar
  136. van der Lely AJ, Hutson RK, Trainer PJ, Besser GM, Barkan AL, Katznelson L, et al. Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet. 2001;358(9295):1754–9.PubMedCrossRefGoogle Scholar
  137. van der Lely AJ, Biller BM, Brue T, Buchfelder M, Ghigo E, Gomez R, et al. Long-term safety of pegvisomant in patients with acromegaly: comprehensive review of 1288 subjects in ACROSTUDY. J Clin Endocrinol Metab. 2012;97(5):1589–97.PubMedCrossRefGoogle Scholar
  138. van Haute FR, Taboada GF, Correa LL, Lima GA, Fontes R, Riello AP, et al. Prevalence of sleep apnea and metabolic abnormalities in patients with acromegaly and analysis of cephalometric parameters by magnetic resonance imaging. Eur J Endocrinol. 2008;158(4):459–65.PubMedCrossRefGoogle Scholar
  139. Vandeva S, Elenkova A, Natchev E, Kirilov G, Tcharaktchiev D, Yaneva M, et al. Treatment outcome results from the Bulgarian Acromegaly Database: adjuvant dopamine agonist therapy is efficient in less than one fifth of non-irradiated patients. Exp Clin Endocrinol Diabetes. 2015;123(1):66–71.PubMedCrossRefGoogle Scholar
  140. Vieira Neto L, Taboada GF, Correa LL, Polo J, Nascimento AF, Chimelli L, et al. Acromegaly secondary to growth hormone-releasing hormone secreted by an incidentally discovered pheochromocytoma. Endocr Pathol. 2007;18(1):46–52.PubMedCrossRefGoogle Scholar
  141. Vieira Neto L, Abucham J, Araujo LA, Boguszewski CL, Bronstein MD, Czepielewski M, et al. Recommendations of Neuroendocrinology Department from Brazilian Society of Endocrinology and Metabolism for diagnosis and treatment of acromegaly in Brazil. Arq Bras Endocrinol Metabol. 2011;55(2):91–105.PubMedCrossRefGoogle Scholar
  142. Vierimaa O, Georgitsi M, Lehtonen R, Vahteristo P, Kokko A, Raitila A, et al. Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science. 2006;312(5777):1228–30.PubMedCrossRefGoogle Scholar
  143. Vilar L, Azevedo MF, Naves LA, Casulari LA, Albuquerque JL, Montenegro RM, et al. Role of the addition of cabergoline to the management of acromegalic patients resistant to longterm treatment with octreotide LAR. Pituitary. 2011;14(2):148–56.PubMedCrossRefGoogle Scholar
  144. Vilar L, Fleseriu M, Naves LA, Albuquerque JL, Gadelha PS, dos Santos Faria M, et al. Can we predict long-term remission after somatostatin analog withdrawal in patients with acromegaly? Results from a multicenter prospective trial. Endocrine. 2014;46(3):577–84.PubMedGoogle Scholar
  145. Villano JL, Seery TE, Bressler LR. Temozolomide in malignant gliomas: current use and future targets. Cancer Chemother Pharmacol. 2009;64(4):647–55.PubMedCrossRefGoogle Scholar
  146. Volschan I, Kasuki L, Silva CM, Alcantara ML, Saraiva RM, Xavier SS, et al. Two-dimensional speckle tracking echocardiography demonstrates no effect of active acromegaly on left ventricular strain. Pituitary. 2017;20:349–57.PubMedCrossRefGoogle Scholar
  147. Warszawski L, Kasuki L, Sa R, Dos Santos Silva CM, Volschan I, Gottlieb I, et al. Low frequency of cardiac arrhythmias and lack of structural heart disease in medically-naive acromegaly patients: a prospective study at baseline and after 1 year of somatostatin analogs treatment. Pituitary. 2016;19(6):582–9.PubMedCrossRefGoogle Scholar
  148. Wassenaar MJ, Cazemier M, Biermasz NR, Pereira AM, Roelfsema F, Smit JW, et al. Acromegaly is associated with an increased prevalence of colonic diverticula: a case-control study. J Clin Endocrinol Metab. 2010;95(5):2073–9.PubMedCrossRefGoogle Scholar
  149. Wildemberg LE, Gadelha MR. Pasireotide for the treatment of acromegaly. Expert Opin Pharmacother. 2016;17(4):579–88.PubMedCrossRefGoogle Scholar
  150. Wildemberg LE, Neto LV, Costa DF, Nasciuti LE, Takiya CM, Alves LM, et al. Low somatostatin receptor subtype 2, but not dopamine receptor subtype 2 expression predicts the lack of biochemical response of somatotropinomas to treatment with somatostatin analogs. J Endocrinol Investig. 2013;36(1):38–43.Google Scholar
  151. Zanettini R, Antonini A, Gatto G, Gentile R, Tesei S, Pezzoli G. Valvular heart disease and the use of dopamine agonists for Parkinson’s disease. N Engl J Med. 2007;356(1):39–46.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Leandro Kasuki
    • 1
    • 2
  • Marília Duarte Dalmolin
    • 1
  • Mônica Gadelha
    • 1
    • 2
  1. 1.Neuroendocrinology Research CenterHospital Universitário Clementino Fraga Filho of Universidade Federal do Rio de Janeiro (HUCFF/UFRJ)Rio de JaneiroBrazil
  2. 2.Neuroendocrinology Unit and Molecular Genetics LaboratoryInstituto Estadual do Cérebro Paulo Niemeyer (IECPN)Rio de JaneiroBrazil

Personalised recommendations