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Horm Metab Res 2003; 35(11/12): 664-666
DOI: 10.1055/s-2004-814165
Review
© Georg Thieme Verlag Stuttgart · New York

The Role of the GH/IGF System in Pituitary Tumorigenesis

W.  Zumkeller1
  • 1Department of Paediatrics, Johann Wolfgang Goethe-University, Frankfurt, Germany
Further Information

Publication History

Received 31 August 2003

Accepted without Revision 17 September 2003

Publication Date:
07 January 2004 (online)

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Abstract

Pituitary adenomas are mostly benign tumours that originate from differentiated anterior pituitary cells. Altered expression of growth factors or their receptors could enhance clonal expansion of pituitary adenoma cells. GHRH overstimulation or an activating point mutation in the Gsa-subunit leads to increased GH secretion and tumour formation. In contrast, IGF-I suppresses basal and GHRH-stimulated GH secretion in pituitary adenoma cells, whereas prolactin secretion is unaffected. Somatostatin analogues and pegvisomant, a novel growth hormone-receptor antagonist, results in a reduction of serum IGF-I levels and clinical improvement in patients suffering from pituitary adenoma. Thus, this review focuses on the role of the growth hormone/insulin-like growth factor system in pituitary tumorigenesis with particular focus on the genetic alterations described in pituitary adenomas up to now.

Key words

Pituitary - Adenoma - GHRH - Growth hormone - Insulin-like growth factor

References

  • 1 Webster J, Scanlon M F. Growth factors and the anterior pituitary.  Baillieres Clin Endocrinol Metab. 1991;  5 699-726
    PubMedSearch in Google Scholar
  • 2 Kineman R D, Teixeira L T, Amargo G V, Coschigano K T, Kopchick J J, Frohman L A. The effect of GHRH on somatotrope hyperplasia and tumor formation in the presence and absence of GH signaling.  Endocrinology. 2001;  142 3764-3773
    CrossrefPubMedSearch in Google Scholar
  • 3 Vallar L, Spada A, Giannattasio G. Altered Gs and adenylate cyclase activity in human GH-secreting pituitary adenomas.  Nature. 1987;  330 566-568
    Search in Google Scholar
  • 4 Lyons J, Landis C A, Harsh G, Vallar L, Grunewald K, Feichtinger H, Duh Q Y, Clark O H, Kawasaki E, Bourne H R, McCormick F. Two G protein oncogenes in human endocrine tumors.  Science. 1990;  249 655-659
    Search in Google Scholar
  • 5 Weinstein L S, Shenker A, Gejman P V, Merino M J, Friedman E, Spiegel A M. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome.  N Eng J Med. 1991;  325 1688-1695
    Search in Google Scholar
  • 6 Johnson M C, Codner E, Eggers M, Mosso L, Rodriguez J A, Cassorla F. Gsp mutations in Chilean patients harboring growth hormone-secreting pituitary tumors.  J Pediatr Endocrinol Metab. 1999;  12 381-387
    PubMedSearch in Google Scholar
  • 7 Akintoye S O, Chebli C, Booher S, Feuillan P, Kushner H, LeRoith D, Cherman N, Bianco P, Wientroub S, Robey P G, Collins M T. Characterization of gsp-mediated growth hormone excess in the context of McCune-Albright syndrome.  J Clin Endocrinol Metab. 2002;  87 5104-5112
    CrossrefPubMedSearch in Google Scholar
  • 8 Zhuang Z, Ezzart S Z, Vortmeyer A D, Huang S, Agarwal S K, Guru S C, Manickamp P, Debelenko L V, Kester M B, Olufemi S E, Heppner C, Crabtree J S, Burns A L, Spiegel A M, Marx S J, Chandrasekharappa S C, Liotta L A, Asa S L, Lubensky I A. Mutations of the MEN-1 tumor suppressor gene in pituitary tumors.  Cancer Res. 1997;  57 5446-5451
    PubMedSearch in Google Scholar
  • 9 Hermans M M, Lips C J, Bravenboer B. Growth hormone overproduction in a patient with multiple endocrine neoplasia type I.  J Intern Med. 2000;  248 525-530
    CrossrefPubMedSearch in Google Scholar
  • 10 Burgess J R, Shepherd J J, Parameswaran V, Hoffman L, Greenaway T M. Somatotrophinomas in multiple endocrine neoplasia type 1: a review of clinical phenotype and insulin-like growth factor-1 levels in a large multiple endocrine neoplasia type 1 kindred.  Am J Med. 1996;  100 544-547
    CrossrefPubMedSearch in Google Scholar
  • 11 Tanaka C, Yoshimoto K, Yamada S. Absence of germ-line mutations of the multiple endocrine neoplasia type 1 (MEN1) gene in familial pituitary adenoma in contrast to MEN1 in Japanese.  J Clin Endocrinol Metab. 1998;  83 960-965
    CrossrefPubMedSearch in Google Scholar
  • 12 Pei L, Melmed S. Isolation and characterization of a pituitary tumor-specific transforming gene.  Mol Endocrinol. 1997;  11 433-441
    CrossrefPubMedSearch in Google Scholar
  • 13 Molitch M E. Pituitary incidentalomas.  Endocrinol Metab Clinics North Am. 1997;  26 725-740
    PubMedSearch in Google Scholar
  • 14 Pagesy P, Li J Y, Kujas M, Peillon F, Delalande O, Visot A, Derome P. Apparently silent somatotroph adenomas.  Pathol Res Pract. 1991;  187 950-956
    PubMedSearch in Google Scholar
  • 15 Hirsch W, Zumkeller W, Teichler H, Jassoy A, Schluter A, Langer T. Microadenomas of the pituitary gland in children with and without hypophyseal dysfunction in magnetic resonance imaging.  J Pediatr Endocrinol Metab. 2002;  15 157-162
    PubMedSearch in Google Scholar
  • 16 Colao A, Amato G, Pedroncelli A M, Baldelli R, Grottoli S, Gasco V, Petretta M, Carella C, Pagani G, Tambura G, Lombardi G. Gender- and age-related differences in the endocrine parameters of acromegaly.  J Endocrinol Invest. 2002;  25 532-538
    CrossrefPubMedSearch in Google Scholar
  • 17 Ferretti E, Jaffrain Rea M L, Asteria C, Di Stefano D, Esposito V, Ferrante L, Daniele P, Tiberti C, Gallucci M, Bosman C, Alesse E, Gulino A, Beck-Peccoz P, Tamburrano G. Two familial giant pituitary adenomas associated with overweight: clinical, morphological and genetic features.  Eur J Endocrinol. 2001;  144 227-235
    CrossrefPubMedSearch in Google Scholar
  • 18 Kurtkaya-Yapicier O, Scheithauer B W, Carney J A, Kovacs K, Horvath E, Stratakis C A, Vidal S, Vella A, Young W F Jr, Atkinson J L, Lloyd R V, Kontogeorgos G. Pituitary adenoma in Carney complex: an immunohistochemical, ultrastructural, and immunoelectron microscopic study.  Ultrastruct Pathol. 2002;  26 345-353
    PubMedSearch in Google Scholar
  • 19 De Marinis L, Zuppi P, Valle D, Mancini A, Bianchi A, Lauriola L, Pasquini P, Anile C, Maira G, Giustina A. A retrospective hormonal and immunohistochemical evaluation of 47 acromegalic patients: prognostic value of preoperative plasma prolactin.  Horm Metab Res. 2002;  34 137-143
    Thieme ConnectPubMedSearch in Google Scholar
  • 20 Shimon I, Nass D, Gross D J. Pituitary macroadenoma secreting thyrotropin and growth hormone: remission of bihormonal hypersecretion in response to lanreotide therapy.  Pituitary. 2001;  4 265-269
    CrossrefPubMedSearch in Google Scholar
  • 21 Florio T, Thellung S, Corsaro A, Bocca L, Arena S, Pattarozzi A, Villa V, Massa A, Diana F, Schettini D, Barbieri F, Ravetti J L, Spaziante R, Giusti M, Schettini G. Characterization of the intracellular mechanisms mediating somatostatin and lanreotide inhibition of DNA synthesis and growth hormone release from dispersed human GH-secreting pituitary adenoma cells in vitro.  Clin Endocrinol (Oxf). 2003;  59 115-128
    CrossrefPubMedSearch in Google Scholar
  • 22 Hofland L J, Velkeniers B, vd Lely A J, van Koetsveld P M, Kazemzadeh M, Waaijers M, Hooghe-Peters E L, Lamberts S W. Long-term in-vitro treatment of human growth hormone (GH)-secreting pituitary adenoma cells with octreotide causes accumulation of intracellular GH and GH mRNA levels.  Clin Endocrinol (Oxf). 1992;  37 240-248
    PubMedSearch in Google Scholar
  • 23 Ezzat S, Kontogeorgos G, Redelmeier D A, Horvath E, Harris A G, Kovacs K. In vivo responsiveness of morphological variants of growth hormone-producing pituitary adenomas to octreotide.  Eur J Endocrinol. 1995;  133 686-690
    CrossrefPubMedSearch in Google Scholar
  • 24 Trainer P J, Drake W M, Katznelson L, Freda P U, Herman-Bonert V, van der Lely A J, Dimaraki E V, Stewart P M, Friend K E, Vance M L, Besser G M, Scarlett J A, Thorner M O, Parkinson C, Klibanski A, Powell J S, Barkan A L, Sheppard M C, Malsonado M, Rose D R, Clemmons D R, Johannsson G, Bengtsson B A, Stavrou S, Kleinberg D L, Cook D M, Phillips L S, Bidlingmaier M, Strasburger C J, Hackett S, Zib K, Bennett W F, Davis R J. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant.  N Engl J Med. 2000;  342 1171-1177
    CrossrefPubMedSearch in Google Scholar
  • 25 Wang L, Yang H, Adamo M L. Glucose starvation reduces IGF-I mRNA in tumor cells: evidence for an effect on mRNA stability.  Biochem Biophys Res Commun. 2000;  269 336-346
    CrossrefPubMedSearch in Google Scholar
  • 26 Yokoyama S, Thapar K, Kovacs K, Stefaneanu L. Localization of insulin-like growth factor-II mRNA in human pituitary adenomas.  Virchows Arch. 1998;  432 241-246
    CrossrefPubMedSearch in Google Scholar
  • 27 Atkin S L, Landolt A M, Foy P, Jeffreys R V, Hipkin L, White M C. Effects of insulin-like growth factor-I on growth hormone and prolactin secretion and cell proliferation of human somatotrophinomas and prolactinomas in vitro.  Clin Endocrinol (Oxf). 1994;  41 503-509
    PubMedSearch in Google Scholar
  • 28 Yamashita S, Weiss M, Melmed S. Insulin-like growth factor I regulates growth hormone secretion and messenger ribonucleic acid levels in human pituitary tumor cells.  J Clin Endocrinol Metab. 1986;  63 730-735
    PubMedSearch in Google Scholar
  • 29 Otsuka F, Tamiya T, Yamauchi T, Ogura T, Ohmoto T, Makino H. Quantitative analysis of growth-related factors in human pituitary adenomas. Lowered insulin-like growth factor-I and its receptor mRNA in growth hormone-producing adenomas.  Regul Pept. 1999;  83 31-38
    CrossrefPubMedSearch in Google Scholar
  • 30 Renner U, Mojto J, Arzt E, Lange M, Stalla J, Muller O A, Stalla G K. Secretion of polypeptide growth factors by human nonfunctioning pituitary adenoma cells in culture.  Neuroendocrinology. 1993;  57 825-834
    PubMedSearch in Google Scholar
  • 31 Shimokawa I, Higami Y, Tsuchiya T, Otani H, Komatsu T, Chiba T, Yamaza H. Life span extension by reduction of the growth hormone-insulin-like growth factor-1 axis: relation to caloric restriction.  FASEB J. 2003;  17 1108-1109
    PubMedSearch in Google Scholar

Dr. W. Zumkeller

Johann Wolfgang Goethe-University · Dept. of Paediatrics

Theodor-Stern-Kai 7 · 60590 Frankfurt/Main · Germany

Phone: + 49 (69) 63 01 50 25

Fax: + 49 (69) 63 01 78 32 ·

Email: walter.zumkeller@kgu.de