Skip to main content
SpringerLink
Log in

Characterization of sporadic somatotropinomas with high GIP receptor expression

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

Purpose

To analyze the expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) in somatotropinomas specimens and compare clinical, biochemical, radiological, therapeutic, molecular, and pathological data among those who overexpressed (GIPR +) and those who did not overexpress (GIPR − ) GIPR.

Methods

Clinical, biochemical, radiological, molecular, and pathological data were collected. GNAS1 sequencing was performed with the Sanger method. Protein expression of somatostatin receptor subtypes 2 and 5 and CAM 5.2 were analyzed by immunohistochemistry. Quantitative real-time PCR was performed to analyze the mRNA expression of GIPR with the TaqMan® method. Positive expression was considered when the fold change (FC) was above 17.2 (GIPR +).

Results

A total of 74 patients (54% female) were included. Eighteen tumors (24%) were GIPR + . Gsp mutation was detected in 30 tumors (40%). GIPR + tumors were more frequently densely granulated adenomas (83% vs 47%, p = 0.028). There was no difference in clinical, biochemical, radiological, therapeutic (surgical cure or response to medical therapy), or other pathological features between GIPR + and GIPR −  tumors. Twenty-eight out of 56 (50%) GIPR −  tumors harbored a gsp mutation, whereas two out of 18 (11%) GIPR + tumors harbored a gsp mutation (p = 0.005).

Conclusion

We described, for the first time, that GIPR + and gsp mutations are not mutually exclusive, but gsp mutations are less common in GIPR + tumors. GIPR + and GIPR −  tumors have similar clinical, biochemical, radiological, therapeutic, and pathological features, with the exception of a high frequency of densely granulated adenomas among GIPR + tumors.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

Data is not available in dataset, but it is available per request.

References

  1. Gadelha MR, Kasuki L, Korbonits M (2017) The genetic background of acromegaly. Pituitary 20(1):10–21. https://doi.org/10.1007/s11102-017-0789-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Katznelson L, Laws ER Jr, Melmed S, Molitch ME, Murad MH, Utz A et al (2014) Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 99(11):3933–3951. https://doi.org/10.1210/jc.2014-2700

    Article  CAS  PubMed  Google Scholar 

  3. Melmed S, Casanueva FF, Klibanski A, Bronstein MD, Chanson P, Lamberts SW et al (2013) A consensus on the diagnosis and treatment of acromegaly complications. Pituitary 16(3):294–302. https://doi.org/10.1007/s11102-012-0420-x

    Article  CAS  PubMed  Google Scholar 

  4. Gadelha MR, Kasuki L, Lim DST, Fleseriu M (2019) Systemic complications of acromegaly and the impact of the current treatment landscape: an update. Endocr Rev 40(1):268–332. https://doi.org/10.1210/er.2018-00115

    Article  PubMed  Google Scholar 

  5. Bi WL, Horowitz P, Greenwald NF, Abedalthagafi M, Agarwalla PK, Gibson WJ et al (2017) Landscape of genomic alterations in pituitary adenomas. Clin Cancer Res 23(7):1841–1851. https://doi.org/10.1158/1078-0432.Ccr-16-0790

    Article  CAS  PubMed  Google Scholar 

  6. Ronchi CL, Peverelli E, Herterich S, Weigand I, Mantovani G, Schwarzmayr T et al (2016) Landscape of somatic mutations in sporadic GH-secreting pituitary adenomas. Eur J Endocrinol 174(3):363–372. https://doi.org/10.1530/eje-15-1064

    Article  CAS  PubMed  Google Scholar 

  7. Song ZJ, Reitman ZJ, Ma ZY, Chen JH, Zhang QL, Shou XF et al (2016) The genome-wide mutational landscape of pituitary adenomas. Cell Res 26(11):1255–1259. https://doi.org/10.1038/cr.2016.114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Välimäki N, Demir H, Pitkänen E, Kaasinen E, Karppinen A, Kivipelto L et al (2015) Whole-genome sequencing of growth hormone (GH)-secreting pituitary adenomas. J Clin Endocrinol Metab 100(10):3918–3927. https://doi.org/10.1210/jc.2015-3129

    Article  CAS  PubMed  Google Scholar 

  9. Fougner SL, Borota OC, Berg JP, Hald JK, Ramm-Pettersen J, Bollerslev J (2008) The clinical response to somatostatin analogues in acromegaly correlates to the somatostatin receptor subtype 2a protein expression of the adenoma. Clin Endocrinol (Oxf) 68(3):458–465. https://doi.org/10.1111/j.1365-2265.2007.03065.x

    Article  CAS  Google Scholar 

  10. Taboada GF, Neto LV, Luque RM, Córdoba-Chacón J, de Oliveira ME, de Carvalho DP et al (2011) Impact of gsp oncogene on the mRNA content for somatostatin and dopamine receptors in human somatotropinomas. Neuroendocrinology 93(1):40–47. https://doi.org/10.1159/000322040

    Article  CAS  PubMed  Google Scholar 

  11. Efstathiadou ZA, Bargiota A, Chrisoulidou A, Kanakis G, Papanastasiou L, Theodoropoulou A et al (2015) Impact of gsp mutations in somatotroph pituitary adenomas on growth hormone response to somatostatin analogs: a meta-analysis. Pituitary 18(6):861–867. https://doi.org/10.1007/s11102-015-0662-5

    Article  CAS  PubMed  Google Scholar 

  12. Occhi G, Losa M, Albiger N, Trivellin G, Regazzo D, Scanarini M et al (2011) The glucose-dependent insulinotropic polypeptide receptor is overexpressed amongst GNAS1 mutation-negative somatotropinomas and drives growth hormone (GH)-promoter activity in GH3 cells. J Neuroendocrinol 23(7):641–649. https://doi.org/10.1111/j.1365-2826.2011.02155.x

    Article  CAS  PubMed  Google Scholar 

  13. Harris PE, Alexander JM, Bikkal HA, Hsu DW, Hedley-Whyte ET, Klibanski A et al (1992) Glycoprotein hormone alpha-subunit production in somatotroph adenomas with and without Gs alpha mutations. J Clin Endocrinol Metab 75(3):918–923. https://doi.org/10.1210/jcem.75.3.1517386

    Article  CAS  PubMed  Google Scholar 

  14. Spada A, Arosio M, Bochicchio D, Bazzoni N, Vallar L, Bassetti M et al (1990) Clinical, biochemical, and morphological correlates in patients bearing growth hormone-secreting pituitary tumors with or without constitutively active adenylyl cyclase. J Clin Endocrinol Metab 71(6):1421–1426. https://doi.org/10.1210/jcem-71-6-1421

    Article  CAS  PubMed  Google Scholar 

  15. Yang IM, Woo JT, Kim SW, Kim JW, Kim YS, Choi YK (1995) Characteristics of acromegalic patients with a good response to octreotide, a somatostatin analogue. Clin Endocrinol (Oxf) 42(3):295–301. https://doi.org/10.1111/j.1365-2265.1995.tb01878.x

    Article  CAS  Google Scholar 

  16. Fougner SL, Casar-Borota O, Heck A, Berg JP, Bollerslev J (2012) Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly. Clin Endocrinol (Oxf) 76(1):96–102. https://doi.org/10.1111/j.1365-2265.2011.04163.x

    Article  CAS  Google Scholar 

  17. Freda PU, Chung WK, Matsuoka N, Walsh JE, Kanibir MN, Kleinman G et al (2007) Analysis of GNAS mutations in 60 growth hormone secreting pituitary tumors: correlation with clinical and pathological characteristics and surgical outcome based on highly sensitive GH and IGF-I criteria for remission. Pituitary 10(3):275–282. https://doi.org/10.1007/s11102-007-0058-2

    Article  CAS  PubMed  Google Scholar 

  18. Baggio LL, Drucker DJ (2007) Biology of incretins: GLP-1 and GIP. Gastroenterology 132(6):2131–2157. https://doi.org/10.1053/j.gastro.2007.03.054

    Article  CAS  PubMed  Google Scholar 

  19. Fehmann HC, Göke R, Göke B (1995) Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide. Endocr Rev 16(3):390–410. https://doi.org/10.1210/edrv-16-3-390

    Article  CAS  PubMed  Google Scholar 

  20. Calanna S, Christensen M, Holst JJ, Laferrère B, Gluud LL, Vilsbøll T et al (2013) Secretion of glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes: systematic review and meta-analysis of clinical studies. Diabetes Care 36(10):3346–3352. https://doi.org/10.2337/dc13-0465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Regazzo D, Barbot M, Scaroni C, Albiger N, Occhi G (2020) The pathogenic role of the GIP/GIPR axis in human endocrine tumors: emerging clinical mechanisms beyond diabetes. Rev Endocr Metab Disord 21(1):165–183. https://doi.org/10.1007/s11154-019-09536-6

    Article  CAS  PubMed  Google Scholar 

  22. Regazzo D, Losa M, Albiger NM, Terreni MR, Vazza G, Ceccato F et al (2017) The GIP/GIPR axis is functionally linked to GH-secretion increase in a significant proportion of gsp(-) somatotropinomas. Eur J Endocrinol 176(5):543–553. https://doi.org/10.1530/eje-16-0831

    Article  CAS  PubMed  Google Scholar 

  23. Peracchi M, Porretti S, Gebbia C, Pagliari C, Bucciarelli P, Epaminonda P et al (2001) Increased glucose-dependent insulinotropic polypeptide (GIP) secretion in acromegaly. Eur J Endocrinol 145(1):R1-4. https://doi.org/10.1530/eje.0.145r001

    Article  CAS  PubMed  Google Scholar 

  24. Scaroni C, Albiger N, Daniele A, Dassie F, Romualdi C, Vazza G et al (2019) Paradoxical GH increase during OGTT is associated with first-generation somatostatin analog responsiveness in acromegaly. J Clin Endocrinol Metab 104(3):856–862. https://doi.org/10.1210/jc.2018-01360

    Article  PubMed  Google Scholar 

  25. Beck P, Parker ML, Daughaday WH (1966) Paradoxical hypersecretion of growth hormone in response to glucose. J Clin Endocrinol Metab 26(4):463–469. https://doi.org/10.1210/jcem-26-4-463

    Article  CAS  PubMed  Google Scholar 

  26. Hage M, Janot C, Salenave S, Chanson P, Kamenický P (2021) Management of endocrine disease: etiology and outcome of acromegaly in patients with a paradoxical GH response to glucose. Eur J Endocrinol 184(6):R261–R268. https://doi.org/10.1530/eje-20-1448

    Article  CAS  PubMed  Google Scholar 

  27. Atquet V, Alexopoulou O, Maiter D (2021) Characteristics and treatment responsiveness of patients with acromegaly and a paradoxical GH increase to oral glucose load. Eur J Endocrinol. https://doi.org/10.1530/eje-21-0324

    Article  PubMed  Google Scholar 

  28. Umahara M, Okada S, Ohshima K, Mori M (2003) Glucose-dependent insulinotropic polypeptide induced growth hormone secretion in acromegaly. Endocr J 50(5):643–650. https://doi.org/10.1507/endocrj.50.643

    Article  CAS  PubMed  Google Scholar 

  29. Hage M, Chaligné R, Viengchareun S, Villa C, Salenave S, Bouligand J et al (2019) Hypermethylator phenotype and ectopic GIP receptor in GNAS mutation-negative somatotropinomas. J Clin Endocrinol Metab 104(5):1777–1787. https://doi.org/10.1210/jc.2018-01504

    Article  PubMed  Google Scholar 

  30. Micko AS, Wöhrer A, Wolfsberger S, Knosp E (2015) Invasion of the cavernous sinus space in pituitary adenomas: endoscopic verification and its correlation with an MRI-based classification. J Neurosurg 122(4):803–811. https://doi.org/10.3171/2014.12.Jns141083

    Article  PubMed  Google Scholar 

  31. Giustina A, Barkhoudarian G, Beckers A, Ben-Shlomo A, Biermasz N, Biller B et al (2020) Multidisciplinary management of acromegaly: a consensus. Rev Endocr Metab Disord 21(4):667–678. https://doi.org/10.1007/s11154-020-09588-z

    Article  PubMed  PubMed Central  Google Scholar 

  32. Normann KR, Øystese KAB, Berg JP, Lekva T, Berg-Johnsen J, Bollerslev J et al (2016) Selection and validation of reliable reference genes for RT-qPCR analysis in a large cohort of pituitary adenomas. Mol Cell Endocrinol 437:183–189. https://doi.org/10.1016/j.mce.2016.08.030

    Article  CAS  PubMed  Google Scholar 

  33. Gatto F, Feelders RA, van der Pas R, Kros JM, Waaijers M, Sprij-Mooij D et al (2013) Immunoreactivity score using an anti-sst2A receptor monoclonal antibody strongly predicts the biochemical response to adjuvant treatment with somatostatin analogs in acromegaly. J Clin Endocrinol Metab 98(1):E66-71. https://doi.org/10.1210/jc.2012-2609

    Article  CAS  PubMed  Google Scholar 

  34. Obari A, Sano T, Ohyama K, Kudo E, Qian ZR, Yoneda A et al (2008) Clinicopathological features of growth hormone-producing pituitary adenomas: difference among various types defined by cytokeratin distribution pattern including a transitional form. Endocr Pathol 19(2):82–91. https://doi.org/10.1007/s12022-008-9029-z

    Article  PubMed  Google Scholar 

  35. Lopes MBS (2017) The 2017 World Health Organization classification of tumors of the pituitary gland: a summary. Acta Neuropathol 134(4):521–535. https://doi.org/10.1007/s00401-017-1769-8

    Article  CAS  PubMed  Google Scholar 

  36. Peñalva A, Burguera B, Casabiell X, Tresguerres JA, Dieguez C, Casanueva FF (1989) Activation of cholinergic neurotransmission by pyridostigmine reverses the inhibitory effect of hyperglycemia on growth hormone (GH) releasing hormone-induced GH secretion in man: does acute hyperglycemia act through hypothalamic release of somatostatin? Clin Trial 49:551

    Google Scholar 

  37. Mancini A, Bianchi A, Gentilella R, Valle D, Giampietro A et al (2002) Preoperative growth hormone response to thyrotropin-releasing hormone and oral glucose tolerance test in acromegaly: a retrospective evaluation of 50 patients. Metabolism. 51(5):616–621. https://doi.org/10.1053/meta.2002.32017

    Article  CAS  PubMed  Google Scholar 

  38. Valcavi R (1996) Oral glucose tolerance test: an inhibitory or a stimulatory input to growth hormone secretion? J Endocrinol Invest 19(4):253–255. https://doi.org/10.1007/BF03349877

    Article  CAS  PubMed  Google Scholar 

  39. Barlier A, Gunz G, Zamora AJ, Morange-Ramos I, Figarella-Branger D, Dufour H et al (1998) Pronostic and therapeutic consequences of Gs alpha mutations in somatotroph adenomas. J Clin Endocrinol Metab 83(5):1604–1610. https://doi.org/10.1210/jcem.83.5.4797

    Article  CAS  PubMed  Google Scholar 

  40. Faglia G, Arosio M, Spada A (1996) GS protein mutations and pituitary tumors: functional correlates and possible therapeutic implications. Metabolism 45(8 Suppl 1):117–119. https://doi.org/10.1016/s0026-0495(96)90103-1

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Neuroendocrinology Research Center/Endocrinology Division, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rua Professor Rodolpho Paulo Rocco, 255, 9° andar, Setor 9F, Rio de Janeiro, 21941-913, Brazil

    Olivia Faria, Elisa Baranski Lamback, Leandro Kasuki & Mônica R. Gadelha

  2. Neuropathology and Molecular Genetics Laboratory, Instituto Estadual Do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil

    Renan Lyra Miranda, Carlos Henrique de Azeredo Lima, Alexandro Guterres, Aline Helen da Silva Camacho, Elisa Baranski Lamback, Felipe Andreiuolo, Leila Chimelli & Mônica R. Gadelha

  3. Radiology Division, Instituto Estadual Do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil

    Nina Ventura & Monique Alvares Barbosa

  4. Radiology Division, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil

    Nina Ventura

  5. Neuroradiology Department, Samaritano Hospital, São Paulo, Brazil

    Olivia Faria, Renan Lyra Miranda, Carlos Henrique de Azeredo Lima, Alexandro Guterres, Nina Ventura, Monique Alvares Barbosa, Aline Helen da Silva Camacho, Elisa Baranski Lamback, Felipe Andreiuolo, Leila Chimelli, Leandro Kasuki & Mônica R. Gadelha

  6. Neuroradiology Department, Grupo fleury, São Paulo, Brazil

    Olivia Faria, Renan Lyra Miranda, Carlos Henrique de Azeredo Lima, Alexandro Guterres, Nina Ventura, Monique Alvares Barbosa, Aline Helen da Silva Camacho, Elisa Baranski Lamback, Felipe Andreiuolo, Leila Chimelli, Leandro Kasuki & Mônica R. Gadelha

  7. Neuroendocrinology Division, Instituto Estadual Do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil

    Elisa Baranski Lamback, Leandro Kasuki & Mônica R. Gadelha

  8. Endocrinology Division, Hospital Federal de Bonsucesso, Rio de Janeiro, Brazil

    Leandro Kasuki

Authors
  1. Olivia Faria
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Renan Lyra Miranda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carlos Henrique de Azeredo Lima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexandro Guterres
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nina Ventura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Monique Alvares Barbosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aline Helen da Silva Camacho
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Elisa Baranski Lamback
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Felipe Andreiuolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Leila Chimelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Leandro Kasuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mônica R. Gadelha
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

OF Methodology, Investigation, Writing—Original Draft preparation. RLM Methodology, Investigation, Writing—Original Draft preparation. CHdAL Investigation, Validation. AG Investigation, Validation. NVW Investigation. MAB Investigation. AHdSC Investigation. EBL Investigation. FA Investigation. LC Investigation, Validation. LK Conceptualization, Supervision, Writing—Review & Editing. MRG Conceptualization, Supervision, Writing—Review & Editing.

Corresponding author

Correspondence to Mônica R. Gadelha.

Ethics declarations

Conflict of interest

MRG has received speaker fee from Novartis and Ipsen and is principal investigator in clinical trials from Novartis and Crinetics. LK has received speaker fee from Novartis and Ipsen. The other authors have nothing to declare.

Ethical approval

This study was approved by the IECPN Research and Ethics Committee (CAAE 36118820.1.0000.8110).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Faria, O., Miranda, R.L., de Azeredo Lima, C.H. et al. Characterization of sporadic somatotropinomas with high GIP receptor expression. Pituitary 25, 903–910 (2022). https://doi.org/10.1007/s11102-022-01272-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-022-01272-6

Keywords

Search

Navigation