Skip to main content
SpringerLink
Log in

Molecular Pathogenesis of Pituitary Adenomas

  • Chapter
Diagnosis and Management of Pituitary Disorders

Part of the book series: Contemporary Endocrinology ((COE))

  • 1743 Accesses

Summary

The genesis of pituitary tumors is still under debate. Although these neoplasia are monoclonal in origin, mutations of GNAS1, the gene encoding the α subunit of Gs is the only mutational change unequivocally associated with GH-secreting adenomas. In addition, multiple events, including the overexpression of cell cycle regulators, growth factors, and stimulatory hormones together with epigenetic disruption of genes with antioncogenic properties, frequently occur in pituitary tumors; their relative importance is still uncertain.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Farrel WE, Clayton RN. Molecular pathogenesis of pituitary tumors. Front Neuroendocrinol 2000;21:174–98.

    Article  CAS  Google Scholar 

  2. Lania A, Mantovani G, Spada A. G protein mutations in endocrine diseases. Eur J Endocrinol 2001145, 543–59.

    Google Scholar 

  3. Asa SL, Ezzat S. The pathogenesis of pituitary tumours. Nat Rev Cancer 2002;2:836–49.

    Article  PubMed  CAS  Google Scholar 

  4. Ezzat S, Asa SL. Mechanisms of disease: The pathogenesis of pituitary tumors. Nat Clin Pract 2006;2:220–30.

    Article  CAS  Google Scholar 

  5. Alexander JM, Biller BMK, Bikkal H, Zervas NT, Arnold A, Klibanski A. Clinically non functioning pituitary adenomas are monoclonal in origin. J Clin Invest 1990; 86:336–40.

    Article  PubMed  CAS  Google Scholar 

  6. Herman V, Fagin J, Gonsky R, Kovacs K, Melmed S. Clonal origin of pituitary adenomas. J Clin Endocrinol Metab 1990;71:1427–33.

    PubMed  CAS  Google Scholar 

  7. Burrow GN, Wortzman G, Rewcastle NB, Hodgate RC, Kovacs K. Microadenomas of the pituitary and abnormal sella tomograms in an unselected autopsy series. N Engl J Med 1981;304:156–8.

    Article  PubMed  CAS  Google Scholar 

  8. Elster AD. Modern imaging of the pituitary. Radiology 1993;187:1–14.

    PubMed  CAS  Google Scholar 

  9. Karga HJ, Alexander JM, Hedley-Whyte ET, Klibanski A, Jameson JL. Ras mutations in human pituitary tumors. J Clin Endocrinol Metab 1992;74:914–9.

    Article  PubMed  CAS  Google Scholar 

  10. Cai WY, Alexander JM, Hedley-Whyte ET, et al. Ras mutations in human prolactinomas and pituitary carcinomas. J Clin Endocrinol Metab 1994;78:89–93.

    Article  PubMed  CAS  Google Scholar 

  11. Pei L, Melmed S, Scheithauer B, Kovacs K, Prager D. H-ras mutations in human pituitary carcinoma metastasis. J Clin Endocrinol Metab 1994;78:842–6.

    Article  PubMed  CAS  Google Scholar 

  12. Vallar L, Spada A, Giannattasio G. Altered Gs and adenylate cyclase activity in human GH-secreting pituitary adenomas. Nature 1987;330:566–7.

    Article  PubMed  CAS  Google Scholar 

  13. Landis C, Masters SB, Spada A, Pace AM, Bourne HR, Vallar L. GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 1989;340:692–6.

    Article  PubMed  CAS  Google Scholar 

  14. Spada A, Arosio M, Bochicchio D, et al. Clinical, biochemical, and morphological correlates in patients bearing growth hormone-secreting pituitary tumors with or without constitutively active adenylyl cyclase. J Clin Endocrinol Metab 1990;71:1421–6.

    PubMed  CAS  Google Scholar 

  15. Adams EF, Brockmeier S, Friedmann E, Roth M, Buchfelder M, Fahlbusch R. Clinical and biochemical characteristics of acromegalic patients harboring gsp-positive and gsp-negative pituitary tumors. Neurosurgery 1993;33:198–201.

    Article  PubMed  CAS  Google Scholar 

  16. Yang I, Park S, Ryu M, et al. Characteristics of gsp-positive growth hormone-secreting pituitary tumors in Korean acromegalic patients Eur J Endocrinol 1996;134:720–6.

    Article  PubMed  CAS  Google Scholar 

  17. Barlier A, Gunz G, Zamora AJ, et al. Prognostic and therapeutic consequences of Gs alpha mutations in somatotroph adenomas. J Clin Endocrinol Metab 1998;83:1604–10.

    Article  PubMed  CAS  Google Scholar 

  18. Lania A, Persani L, Ballaré E, Mantovani S, Losa M, Spada A. Constitutively active Gsα is associated with an increased phosphodiesterase activity in human growth hormone secreting adenomas. J Clin Endocrinol Metab 1998;83:1624–8.

    Article  PubMed  CAS  Google Scholar 

  19. Persani L, Borgato S, Lania A, et al. Relevant cAMP-specific phosphodiesterase isoforms in human pituitary: effect of Gs(alpha) mutations. J Clin Endocrinol Metab 2001;86:3795–800.

    Article  PubMed  CAS  Google Scholar 

  20. Bertherat J, Chanson P, Montiminy M. The cyclic adenosine 3’-5’-monophosphate-responsive factor CREB is constitutively activated in human somatotrophs. Mol Endocrinol 1995;9:777–83.

    Article  PubMed  CAS  Google Scholar 

  21. Peri A, Conforti B, Baglioni-Peri S, et al. Expression of cyclic adenosine 3’,5’-monophosphate (cAMP)-responsive element binding protein and inducible-cAMP early repressor genes in growth hormone-secreting pituitary adenomas with or without mutations of the Gs alpha gene. J Clin Endocrinol Metab 2001;86:2111–7.

    Article  PubMed  CAS  Google Scholar 

  22. Ballare E, Mantovani S, Lania A, Di Blasio AM, Vallar L, Spada A. Activating mutations of the Gs alpha gene are associated with low levels of Gs alpha protein in growth hormone-secreting tumors. J Clin Endocrinol Metab 1998;83:4386–90.

    Article  PubMed  CAS  Google Scholar 

  23. Hayward BE, Kamiya M, Strain L, et al. The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins. Proc Natl Acad Sci USA 1998;95:10038–43.

    Article  PubMed  CAS  Google Scholar 

  24. Hayward B, Bonthron DT. An imprinted antisense transcript at the human GNAS1 locus. Hum Mol Genet 2000;9:835–41.

    Article  PubMed  CAS  Google Scholar 

  25. Hayward BE, Barlier A, Korbonits M, et al. Imprinting of the G(s)alpha gene GNAS1 in the pathogenesis of acromegaly. J Clin Invest 2001;107:R31–6.

    Google Scholar 

  26. Mantovani G, Ballare E, Giammona E, Beck-Peccoz P, Spada A. The Gsα gene: predominant maternal origin of transcription in human thyroid gland and gonads. J Clin Endocrinol Metab 2002;87:4736–40.

    Article  PubMed  CAS  Google Scholar 

  27. Mantovani G, Bondioni S, Lania AG, et al. Parental origin of Gsalpha mutations in the McCune-Albright syndrome and in isolated endocrine tumors. J Clin Endocrinol Metab 2004;89:3007–9.

    Article  PubMed  CAS  Google Scholar 

  28. Tordjman K, Stern N, Ouaknine G, et al. Activating mutations of the Gs alpha gene in non functioning pituitary adenomas. J Clin Endocrinol Metab 1993;77:765–9.

    Article  PubMed  CAS  Google Scholar 

  29. Williamson EA, Ince PG, Harrison D, Kendall-Taylor P, Harris PE. G-protein mutations in human adrenocorticotrophic (ACTH) hormone-secreting adenomas. Eur J Clin Invest 1995;25:128–31.

    PubMed  CAS  Google Scholar 

  30. Williamson EA, Daniels M, Foster S, Kelly WF, Kendall-Taylor P, Harris PE. Gs alpha and Gi alpha mutations in clinically non-functioning pituitary tumours. Clin Endocrinol 1994;41:815–20.

    CAS  Google Scholar 

  31. Petersenn S, Heyens M, Ludecke DK, Beil FU, Schulte HM. Absence of somatostatin receptor type 2 A mutations and gip oncogene in pituitary somatotroph adenomas Clin Endocrinol (Oxf) 2000;52, 35–42.

    Article  CAS  Google Scholar 

  32. Alvaro V, Levy L, Dubray C, et al. Invasive human pituitary tumors express a point-mutated alpha-protein kinase C. J Clin Endocrinol Metab 1993;77:1125–9.

    Article  PubMed  CAS  Google Scholar 

  33. Dong Q, Brucker-Davis F, Weintraub BD, et al. Screening of candidate oncogenes in human thyrotroph tumors: absence of activating mutations of the G alpha q, G alpha 11, G alpha s, or thyrotropin-releasing hormone receptor genes. J Clin Endocrinol Metab 1996;81:1134–40.

    Article  PubMed  CAS  Google Scholar 

  34. Ezzat S, Zheng L, Zhu XF, Wu GE, Asa SL. Targeted expression of a human pituitary tumor-derived isoform of FGF receptor-4 recapitulates pituitary tumorigenesis. J Clin Invest 2002;109:69–78.

    PubMed  CAS  Google Scholar 

  35. Cavallaro U, Niedermeyer J, Fuxa M, Christofori G. N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling. Nat Cell Biol 2001;3:650–7.

    Article  PubMed  CAS  Google Scholar 

  36. Jordan S, Lidhar K, Karbonits M, Lowe DG, Grossman AB. Cyclin D and cyclin E expression in normal and adenomatous pituitary. Eur J Endocrinol 2000;143:R1–6.

    Google Scholar 

  37. Hibberts NA, Simpson DJ, Bicknell JE, et al. Analysis of cyclin DI (CCND1) allelic imbalance and overexpression in sporadic pituitary tumors. Clin Cancer Res 1999;5:2133–9.

    PubMed  CAS  Google Scholar 

  38. Pei L, Melmed S. Isolation and characterization of a pituitary tumor-transforming gene (PTTG). Mol Endocrinol 1997;11:433–41.

    Article  PubMed  CAS  Google Scholar 

  39. Chen LL, Puri R, Lefkowitz EJ, Kakar SS. Identification of the human pituitary tumor transforming gene (HPTTG) family: molecular structure, expression, and chromosomal localization. Gene 2000;246:41–50.

    Article  Google Scholar 

  40. Zhou Y, Mehta KR, Choi AP, Scolavino S, Zhang X. DNA damage-induced inhibition of securin expression is mediated by p53. J Biol Chem 2003;278:462–70.

    Article  PubMed  CAS  Google Scholar 

  41. Fedele M, Battista S, Kenyon L, et al. Overexpression of the HMGA2 gene in transgenic mice leads to the onset of pituitary adenomas. Oncogene 2002;21:3190–8.

    Article  PubMed  CAS  Google Scholar 

  42. Finelli P, Pierantoni GM, Giardino D, et al. The High Mobility Group A2 gene is amplified and overexpressed in human prolactinomas. Cancer Res 2002;62, 2398–405.

    PubMed  CAS  Google Scholar 

  43. Danila DC, Inder WJ, Zhang X, et al. Activin effects on neoplastic proliferation of human pituitary tumors. J Clin Endocrinol Metab 2000;85:1009–15.

    Article  PubMed  CAS  Google Scholar 

  44. Wessels HT, Hofland LJ, van der Wal R, et al. In vitro secretion of FSH by cultured clinically nonfunctioning and gonadotroph pituitary adenomas is directly correlated with locally produced levels of activin A. Clin Endocrinol (Oxf) 2001;54:485–92.

    Article  CAS  Google Scholar 

  45. Thapar K, Kovacs K, Stefaneau L, et al. Overexpression of the growth-hormone-releasing hormone gene in acromegaly associated pituitary tumors. An event associated with neoplastic progression and aggressive behavior. Am J Pathol 1997;151:769–84.

    PubMed  CAS  Google Scholar 

  46. Lee EJ, Kotlar TJ, Ciric I, et al. Absence of constitutively activating mutations in the GHRH receptor in GH-producing pituitary tumors. J Clin Endocrinol Metab 2001;86:3989–95.

    Article  PubMed  CAS  Google Scholar 

  47. de Keyzer Y, Rene P, Beldjord C, Lenne F, Bertagna X. Overexpression of vasopressin (V3) and corticotrophin-releasing hormone receptor genes in corticotroph tumours. Clin Endocrinol (Oxf) 1998;49:475–82.

    Article  Google Scholar 

  48. Spada A, Reza Elahi F, Lania A, Gil del Alamo P, Bassetti M, Faglia G. Hypothalamic peptides modulate cytosolic free Ca$2+$ levels and adenylyl cyclase activity in human nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 1991;71:913–8.

    Article  Google Scholar 

  49. Tucker T, Friedman JM. Pathogenesis of hereditary tumors: beyond the “two-hit” hypothesis. Clin Genet 2002;62:345–57.

    Article  PubMed  CAS  Google Scholar 

  50. Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA Effects of an Rb mutation in the mouse. Nature 1992;359:295–300.

    Article  PubMed  CAS  Google Scholar 

  51. Nakayama K, Ishida N, Shirane M, et al. Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 1996;85:707–72.

    Article  PubMed  CAS  Google Scholar 

  52. Simpson DJ, Magnay J, Bicknell JE, et al. Chromosome 13q deletion mapping in pituitary tumors: infrequent loss of the retinoblastoma susceptibility gene (RB1) despite loss of RB1 product in somatotropinomas. Cancer Res 1999;59:1562–6.

    PubMed  CAS  Google Scholar 

  53. Levy A, Hall L, Yeudall WA, Lightman SL. p53 gene mutations in pituitary adenomas: rare events. Clin. Endocrinol 1994;41:809–14.

    CAS  Google Scholar 

  54. Tanaka C, Kimura T, Yang P, et al. Analysis of loss of heterozygosity on chromosome 11 and infrequent inactivation of the MEN-1 gene in sporadic pituitary adenomas. J Clin Endocrinol Metab 1998;83:2631–4.

    Article  PubMed  CAS  Google Scholar 

  55. Kaltsas GA, Kola B, Borboli N, et al. Sequence analysis of the PRKAR1A gene in sporadic somatotroph and other pituitary tumours. Clin Endocrinol (Oxf) 2002;57:443–8.

    Article  CAS  Google Scholar 

  56. Vierimaa O, Georgitsi M, Lehtonen R, et al. Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science 2006;312:1228–30.

    Article  PubMed  CAS  Google Scholar 

  57. Yu R, Bonert V, Saporta I, Raffel LJ, Melmed S. Aryl hydrocarbon receptor protein variants in sporadic pituitary sporadic adenomas. J Clin Endocrinol Metab 2006;91:5126–9.

    Article  PubMed  CAS  Google Scholar 

  58. Karl M, Lamberts SW, Koper JW, et al. Cushing’s disease preceded by generalized glucocorticoid resistance: clinical consequences of a novel, dominant-negative glucocorticoid receptor mutation. Proc Assoc Am Physicians 1996;108:296–307.

    PubMed  CAS  Google Scholar 

  59. Huizenga NA, de Lange P, Koper JW, et al. Human adrenocorticotropin-secreting pituitary adenomas show frequent loss of heterozygosity at the glucocorticoid receptor gene locus. J Clin Endocrinol Metab 1998;83:917–21.

    Article  PubMed  CAS  Google Scholar 

  60. Ando S, Sarlis NJ, Oldfield EH, Yen PM. Somatic mutation of TRbeta can cause a defect in negative regulation of TSH in a TSH-secreting pituitary tumor. J Clin Endocrinol Metab 2001;86:5572–6.

    Article  Google Scholar 

  61. Simpson DJ, Hibberts NA, McNicol AM, Clayton RN, Farrell WE. Loss of pRb expression in pituitary adenomas is associated with methylation of the RB1 CpG island. Cancer Res 2000;60:1211–6.

    PubMed  CAS  Google Scholar 

  62. Bamberger CM, Fehn M, Bamberger AM, et al. Reduced expression levels of the cell-cycle inhibitor p27Kip1 in human pituitary adenomas. Eur J Endocrinol 1999;140:250–5.

    Article  PubMed  CAS  Google Scholar 

  63. Simpson DJ, Bicknell JE, McNicol AM, Clayton RN, Farrell WE. Hypermethylation of the p16/CDKN2A/MTSI gene and loss of protein expression is associated with nonfunctional pituitary adenomas but not somatotrophinomas. Genes Chromosomes Cancer 1999;24:328–36.

    Article  PubMed  CAS  Google Scholar 

  64. Pagotto U, Arzberger T, Theodoropoulou M, et al. The expression of the antiproliferative gene ZAC is lost or highly reduced in nonfunctioning pituitary adenomas. Cancer Res 2000;60:6794–9.

    PubMed  CAS  Google Scholar 

  65. Asa SL, Kelly MA, Grandy DK, Low MJ. Pituitary lactotroph adenomas develop after prolonged lactotroph hyperplasia in dopamine D2 receptor-deficient mice. Endocrinology 1999;140:5348–55.

    Article  PubMed  CAS  Google Scholar 

  66. Friedman E, Adams EF, Hoog A, et al. Normal structural dopamine type 2 receptor gene in prolactin-secreting and other pituitary tumors. J Clin Endocrinol Metab 1994;78:568–74.

    Article  PubMed  CAS  Google Scholar 

  67. Caccavelli L, Feron F, Morange I, et al. Decreased expression of the two D2 dopamine receptor isoforms in bromocriptine-resistant prolactinomas. Neuroendocrinology 1994;60:314–22.

    PubMed  CAS  Google Scholar 

  68. Winkelmann J, Pagotto U, Theodoropoulou M, et al. Retention of dopamine 2 receptor mRNA and absence of the protein in craniospinal and extracranial metastasis of a malignant prolactinoma: a case report. Eur J Endocrinol 2002;146:81–8.

    Article  PubMed  CAS  Google Scholar 

  69. Ballare E, Persani L, Lania AG, et al. Mutation of somatostatin receptor type 5 in an acromegalic patient resistant to somatostatin analog treatment. J Clin Endocrinol Metab. 2001;86:3809–14.

    Article  PubMed  CAS  Google Scholar 

  70. Jaquet P, Saveanu A, Gunz G, et al. Human somatostatin receptor subtypes in acromegaly: distinct patterns of messenger ribonucleic acid expression and hormone suppression identify different tumoral phenotypes. J Clin Endocrinol Metab 2000;85:781–92.

    Article  PubMed  CAS  Google Scholar 

  71. Lania AG, Mantovani G, Ferrero S, et al. Proliferation of transformed somatotroph cells related to low or absent expression of protein kinase a regulatory subunit 1A protein. Cancer Res 2004;64:9193–8.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. Andrea Lania MD, PHD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giovanna Mantovani MD, PHD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Spada MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Neurosurgery Massachusetts, General Hospital Harvard Medical School, Boston, MA, USA

    Brooke Swearingen MD

  2. Neuroendocrine Unit Department of Medicine, Massachusetts General Hospital Harvard Medical School, Boston, MA, USA

    Beverly M. K. Biller MD

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Humana Press, Totowa, NJ

About this chapter

Cite this chapter

Lania, A., Mantovani, G., Spada, A. (2008). Molecular Pathogenesis of Pituitary Adenomas. In: Swearingen, B., Biller, B.M. (eds) Diagnosis and Management of Pituitary Disorders. Contemporary Endocrinology. Humana Press. https://doi.org/10.1007/978-1-59745-264-9_1

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-264-9_1

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-922-2

  • Online ISBN: 978-1-59745-264-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation