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Impact of gsp mutations in somatotroph pituitary adenomas on growth hormone response to somatostatin analogs: a meta-analysis

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Abstract

Objective

Somatic mutations in the GNAS1 gene, which encodes the alpha-subunit of G stimulatory proteins (gsp), are frequently detected in somatotroph pituitary tumors and have been associated to specific clinical and histopathological characteristics. However, the question whether the presence of a somatic gsp mutation affects the response to somatostatin analog treatment remains unresolved.

Design

Following a literature search, we performed a meta-analysis, including 8 eligible studies, in order to estimate the effect of gsp mutation on the percent reduction of growth hormone (GH) levels during an acute octreotide suppression test (OST). A total of 310 patients with acromegaly [126 gsp (+) and 184 gsp (−)] were included in the analysis.

Results

The presence of the gsp mutation was related with a greater reduction in GH levels on OST [Weighted Mean Difference (WMD): 9.08 % (95 % CI, 2.73, 15.42); p = 0.005; random effects model]. There was significant heterogeneity for this effect estimate (I2 = 58 %, p value for heterogeneity = 0.02). A sensitivity analysis after exclusion of a study with different methodology of OST provided similar estimates [WMD: 6.93 % (95 % CI, 1.40, 12.46); p = 0.01], albeit with no significant heterogeneity (I2 = 35 %, p value for heterogeneity = 0.16).

Conclusions

The present meta-analysis suggests a role for gsp mutation as a prognostic factor of treatment response to somatostatin analogs.

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References

  1. Fougner SL, Borota OC, Berg JP, Hald JK, Ramm-Pettersen J, Bollerslev J (2008) The clinical response to somatostatin analogs in acromegaly correlates to the somatostatin receptor subtype 2a protein expression of the adenoma. Clin Endocrinol 68(3):458–465

    Article  CAS  Google Scholar 

  2. Landis CA, Harsh G, Lyons J, Davis RL, McCormick F, Bourne HR (1990) Clinical characteristics of acromegalic patients whose pituitary tumors contain mutant Gs protein. J Clin Endocrinol Metab 71(6):1416–1420

    Article  CAS  PubMed  Google Scholar 

  3. Yasufuku-Takano J, Takano K, Morita K, Takakura K, Teramoto A, Fujita T (2006) Does the prevalence of gsp mutations in GH-secreting pituitary adenomas differ geographically or racially? Prevalence of gsp mutations in Japanese patients revisited. Clin Endocrinol 64(1):91–96

    Article  CAS  Google Scholar 

  4. Buchfelder M, Fahlbusch R, Merz T, Symowski H, Adams EF (1999) Clinical correlates in acromegalic patients with pituitary tumors expressing GSP oncogenes. Pituitary 1(3–4):181–185

    Article  CAS  PubMed  Google Scholar 

  5. 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

    CAS  PubMed  Google Scholar 

  6. Faglia G, Arosio M, Spada A (1996) GS protein mutations and pituitary tumors: functional correlates and possible therapeutic implications. Metab, Clin Exp 45(8 Suppl 1):117–119

    Article  CAS  Google Scholar 

  7. 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

    Article  CAS  PubMed  Google Scholar 

  8. Kim HJ, Kim MS, Park YJ, Kim SW, Park DJ, Park KS et al (2001) Prevalence of Gs alpha mutations in Korean patients with pituitary adenomas. J Endocrinol 168(2):221–226

    Article  CAS  PubMed  Google Scholar 

  9. 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

    Article  CAS  PubMed  Google Scholar 

  10. Yang I, Park S, Ryu M, Woo J, Kim S, Kim J et al (1996) Characteristics of gsp-positive growth hormone-secreting pituitary tumors in Korean acromegalic patients. Eur J Endocrinol Eur Fed Endocr Soc 134(6):720–726

    Article  CAS  Google Scholar 

  11. 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

    CAS  PubMed  Google Scholar 

  12. Larkin S, Reddy R, Karavitaki N, Cudlip S, Wass J, Ansorge O (2013) Granulation pattern, but not GSP or GHR mutation, is associated with clinical characteristics in somatostatin-naive patients with somatotroph adenomas. Eur J Endocrinol Eur Fed Endocr Soc 168(4):491–499

    Article  CAS  Google Scholar 

  13. Katznelson L, Atkinson JL, Cook DM, Ezzat SZ, Hamrahian AH, Miller KK et al (2011) American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of acromegaly-2011 update: executive summary. Endocr Prac Off J Am Coll Endocrinol Am Assoc Clin Endocrinol 17(4):636–646

    Google Scholar 

  14. Colao A, Auriemma RS, Lombardi G, Pivonello R (2011) Resistance to somatostatin analogs in acromegaly. Endocr Rev 32(2):247–271

    Article  CAS  PubMed  Google Scholar 

  15. Gadelha MR, Kasuki L, Korbonits M (2013) Novel pathway for somatostatin analogs in patients with acromegaly. Trends Endocrinol metab TEM 24(5):238–246

    Article  CAS  PubMed  Google Scholar 

  16. Hedges LV, Olkin I (1985) Statistical methods for meta-analysis. Academic Press, New York

    Google Scholar 

  17. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    Article  CAS  PubMed  Google Scholar 

  18. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560

    Article  PubMed Central  PubMed  Google Scholar 

  19. Adams EF, Brockmeier S, Friedmann E, Roth M, Buchfelder M, Fahlbusch R (1993) Clinical and biochemical characteristics of acromegalic patients harboring gsp-positive and gsp-negative pituitary tumors. Neurosurgery 33(2):198–203

    Article  CAS  PubMed  Google Scholar 

  20. Akintoye SO, Chebli C, Booher S, Feuillan P, Kushner H, Leroith D et al (2002) Characterization of gsp-mediated growth hormone excess in the context of McCune-Albright syndrome. J Clin Endocrinol Metab 87(11):5104–5112

    Article  CAS  PubMed  Google Scholar 

  21. Bakhtiar Y, Hirano H, Arita K, Yunoue S, Fujio S, Tominaga A et al (2010) Relationship between cytokeratin staining patterns and clinico-pathological features in somatotropinomae. Eur J Endocrinol Eur Feder Endocr Soc 163(4):531–539

    Article  CAS  Google Scholar 

  22. Ballare E, Persani L, Lania AG, Filopanti M, Giammona E, Corbetta S et al (2001) Mutation of somatostatin receptor type 5 in an acromegalic patient resistant to somatostatin analog treatment. J Clin Endocrinol Metab 86(8):3809–3814

    Article  CAS  PubMed  Google Scholar 

  23. Chanson P (1997) Predicting the effects of long-term medical treatment in acromegaly. At what cost? For what benefits? Eur J Endocrinol Eur Feder Endocr Soc 136(4):359–361

    Article  CAS  Google Scholar 

  24. Mendoza V, Sosa E, Espinosa-de-Los-Monteros AL, Salcedo M, Guinto G, Cheng S et al (2005) GSP alpha mutations in Mexican patients with acromegaly: potential impact on long term prognosis. Growth Horm IGF Res Off J Growth Horm Res Soc Int IGF Res Soc 15(1):28–32

    Article  CAS  Google Scholar 

  25. Park C, Yang I, Woo J, Kim S, Kim J, Kim Y et al (2004) Somatostatin (SRIF) receptor subtype 2 and 5 gene expression in growth hormone-secreting pituitary adenomas: the relationship with endogenous srif activity and response to octreotide. Endocr J 51(2):227–236

    Article  CAS  PubMed  Google Scholar 

  26. 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 76(1):96–102

    Article  CAS  Google Scholar 

  27. Vortmeyer AO, Glasker S, Mehta GU, Abu-Asab MS, Smith JH, Zhuang Z et al (2012) Somatic GNAS mutation causes widespread and diffuse pituitary disease in acromegalic patients with McCune-Albright syndrome. J Clin Endocrinol Metab 97(7):2404–2413

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Madsen H, Borges MT, Kerr JM, Lillehei KO, Kleinschmidt-Demasters BK (2011) McCune–Albright syndrome: surgical and therapeutic challenges in GH-secreting pituitary adenomas. J Neurooncol 104(1):215–224

    Article  CAS  PubMed  Google Scholar 

  29. Chanson P, Dib A, Visot A, Derome PJ (1994) McCune–Albright syndrome and acromegaly: clinical studies and responses to treatment in five cases. Eur J Endocrinol Eur Feder Endocr Soc 131(3):229–234

    Article  CAS  Google Scholar 

  30. Anagnostis P, Efstathiadou ZA, Polyzos SA, Adamidou F, Slavakis A, Sapranidis M et al (2011) Acromegaly: presentation, morbidity and treatment outcomes at a single centre. Int J Clin Pract 65(8):896–902

    Article  CAS  PubMed  Google Scholar 

  31. Dekkers OM, Biermasz NR, Pereira AM, Romijn JA, Vandenbroucke JP (2008) Mortality in acromegaly: a metaanalysis. J Clin Endocrinol Metab 93(1):61–67

    Article  CAS  PubMed  Google Scholar 

  32. 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

    Article  CAS  PubMed  Google Scholar 

  33. Jaffrain-Rea ML, Rotondi S, Turchi A, Occhi G, Barlier A, Peverelli E et al (2013) Somatostatin analogues increase AIP expression in somatotropinomas, irrespective of Gsp mutations. Endocr Relat Cancer 20(5):753–766

    Article  CAS  PubMed  Google Scholar 

  34. Adams EF, Lei T, Buchfelder M, Petersen B, Fahlbusch R (1995) Biochemical characteristics of human pituitary somatotropinomas with and without gsp mutations: in vitro cell culture studies. J Clin Endocrinol Metab 80(7):2077–2081

    CAS  PubMed  Google Scholar 

  35. Melmed S (2003) Mechanisms for pituitary tumorigenesis: the plastic pituitary. J Clin Investig 112(11):1603–1618

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Freda PU (2002) Somatostatin analogs in acromegaly. J Clin Endocrinol Metab 87(7):3013–3018

    Article  CAS  PubMed  Google Scholar 

  37. Gilbert JA, Miell JP, Chambers SM, McGregor AM, Aylwin SJ (2005) The nadir growth hormone after an octreotide test dose predicts the long-term efficacy of somatostatin analogue therapy in acromegaly. Clin Endocrinol 62(6):742–747

    Article  CAS  Google Scholar 

  38. Karavitaki N, Botusan I, Radian S, Coculescu M, Turner HE, Wass JA (2005) The value of an acute octreotide suppression test in predicting long-term responses to depot somatostatin analogs in patients with active acromegaly. Clin Endocrinol 62(3):282–288

    Article  CAS  Google Scholar 

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Acknowledgments

The Greek School of Endocrinology Initiative was organized and funded by Ipsen. Statistical support and publication costs associated with this paper were also funded by Ipsen. The development at all stages of the concept and content of this paper was the sole responsibility of the authors. The authors would like to thank Dr. Stine Lyngvi Fougner for contributing additional data and clarifications.

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Authors and Affiliations

  1. Department of Endocrinology, “Hippokration” General Hospital of Thessaloniki, Konstantinoupoleos 49, 54642, Thessaloníki, Greece

    Z. A. Efstathiadou

  2. Department of Endocrinology, University of Thessaly, Larissa, Greece

    A. Bargiota

  3. Department of Endocrinology-Endocrine Oncology, Theagenion Cancer Hospital, Thessaloniki, Greece

    A. Chrisoulidou

  4. Endocrine Unit, Athens Naval and VA General Hospital, Athens, Greece

    G. Kanakis

  5. Department of Endocrinology and Diabetes Center, Athens General Hospital “G. Gennimatas”, Athens, Greece

    L. Papanastasiou

  6. Division of Endocrinology, Department of Internal Medicine, University Hospital of Patras, Rio, Greece

    A. Theodoropoulou

  7. Department of Endocrinology, University of Ioannina, Ioannina, Greece

    S. K. Tigas

  8. Endocrine Unit, Second Department of Internal Medicine, University of Athens, Medical School, “Attikon” Hospital, Athens, Greece

    D. A. Vassiliadi

  9. Endocrine Unit, Department of Medical Therapeutics, Athens University School of Medicine, Athens, Greece

    M. Alevizaki

  10. Department of Endocrinology, Evangelismos Hospital, Athens, Greece

    S. Tsagarakis

Authors
  1. Z. A. Efstathiadou
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  2. A. Bargiota
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  3. A. Chrisoulidou
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  4. G. Kanakis
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  6. A. Theodoropoulou
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  7. S. K. Tigas
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  9. M. Alevizaki
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Corresponding author

Correspondence to Z. A. Efstathiadou.

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Conflict of interest

ST has received honoraria from Ipsen and Novartis and has participated in an advisory board for Novartis. All other authors have no interests to declare.

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

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  • DOI: https://doi.org/10.1007/s11102-015-0662-5

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