Skip to main content

Advertisement

SpringerLink
Log in

Acromegaly: correlation between expression of somatostatin receptor subtypes and response to octreotide-lar treatment

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

About one-third of acromegalics are resistant to the clinically available somatostatin analogs (SA). The resistance is related to density reduction or different expression of somatostatin receptor subtypes (SSTR). This study analyzes SSTR’s expression in somatotrophinomas, comparing to SA response, hormonal levels, and tumor volume. We analyzed 39 somatotrophinomas; 49% were treated with SA. The most expressed SSTR was SSTR5, SSTR3, SSTR2, SSTR1, and SSTR4, respectively. SSTR1 and SSTR2 had higher expression in patients that had normalized GH and IGF-I. SSTR3 was more expressed in patients with tumor reduction. There was a positive correlation between the percentage of tumor reduction and SSTR1, SSTR2 and SSTR3 expression. Also, a positive correlation between SSTR2 mRNA expression and the immunohistochemical reactivity of SSTR2 was found. Our study confirmed the association between the SA response to GH and IGF-I and the SSTR2. Additionally, this finding was also demonstrated in relation to SSTR1.

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

Similar content being viewed by others

References

  1. Brazeau P, Vale W, Burgus R et al (1973) Hypotalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 179(8):77–79. doi:10.1126/science.179.4068.77

    Article  CAS  PubMed  Google Scholar 

  2. Moller LN, Stidsen CE, Hartmann B et al (2003) Review: somatostatin receptors. Biochim Biophys Acta 1616:1–84. doi:10.1016/S0005-2736(03)00235-9

    Article  CAS  PubMed  Google Scholar 

  3. Schonbrunm A, Tashjian H Jr (1978) Characterization of functional receptors for somatostatin in rat pituitary cells in culture. J Biol Chem 253(18):6473–6483

    Google Scholar 

  4. Reisine T, Bell G (1995) Molecular biology of somatostatin receptors. Endocr Rev 16:427–442

    CAS  PubMed  Google Scholar 

  5. Hofland LJ, Lamberts S (2003) The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocr Rev 24:28–47. doi:10.1210/er.2000-0001

    Article  CAS  PubMed  Google Scholar 

  6. Taboada GF, Luque RM, Bastos W et al (2007) Quantitative analysis of somatostatin receptor subtype (SSTR1-5) gene expression levels in somatotropinomas and non-functioning pituitary adenomas. Eur J Endocrinol 156:65–74. doi:10.1530/eje.1.02313

    Article  CAS  PubMed  Google Scholar 

  7. Ballare E, Persani L, Lania AG 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. doi:10.1210/jc.86.8.3809

    Article  CAS  PubMed  Google Scholar 

  8. Barlier A, Boullier LP, Gunz G et al (1999) Impact of gsp oncogene on expression of genes coding for Gsa, Pit-1, Gi2a, and somatostatin receptor 2 in human somatotroph adenomas: involvement in octreotide sensitivity. J Clin Endocrinol Metab 84:2759–2765. doi:10.1210/jc.84.8.2759

    Article  CAS  PubMed  Google Scholar 

  9. Danila DC, Haidar JNS, Zhang X et al (2001) Somatostatin receptor-specific analogs: effects on cell proliferation and growth hormone secretion in human somatotroph tumors. Clin Endocrinol Metab 86:2976–2981. doi:10.1210/jc.86.7.2976

    Article  CAS  Google Scholar 

  10. Elberg G, Hipkin W, Schonbrunn A (2002) Homologus and heterologus regulation of somatostatin receptor 2. Mol Endocrinol 16:2502–2514. doi:10.1210/me.2002-0207

    Article  CAS  PubMed  Google Scholar 

  11. Greenman Y, Melmed S (1994) Expression of three somatostatin receptor subtypes in pituitary adenomas: evidence for preferential SSTR5 expression in the mammosomatotroph lineage. J Clin Endocrinol Metab 79:724–729. doi:10.1210/jc.79.3.724

    Article  CAS  PubMed  Google Scholar 

  12. Teijeiro R, Rios R, Costoya J et al (2002) Activation of human somatostatin receptor 2 promotes apoptosis through a mechanism that is independent from induction of p53. Cell Physiol Biochem 12:31–38. doi:10.1159/000047824

    Article  CAS  PubMed  Google Scholar 

  13. Csaba Z, Dournaud P (2001) Cellular biology of somatostatin receptors. Neuropeptides 35:1–23. doi:10.1054/npep.2001.0848

    Article  CAS  PubMed  Google Scholar 

  14. Freda PU, Katznelson L, Van der Lely AJ et al (2005) Long-acting somatostatin analog therapy of acromegaly: a meta-analysis. J Clin Endocrinol Metab 90:4465–4473. doi:10.1210/jc.2005-0260

    Article  CAS  PubMed  Google Scholar 

  15. Jallad RS, Musolino NR, Salgado LR et al (2005) Treatment of acromegaly with octreotide-LAR: extensive experience in a Brazilian institution. Clin Endocrinol (Oxf) 63:168–175. doi:10.1111/j.1365-2265.2005.02317.x

    Article  CAS  Google Scholar 

  16. Bronstein M, Musolino N, Jallad R et al (2005) Pharmacokinetic profile of lanreotide Autogel in patients with acromegaly after four deep subcutaneous injections of 60, 90 or 120 mg every 28 days. Clin Endocrinol (Oxf) 63:514–519. doi:10.1111/j.1365-2265.2005.02372.x

    Article  CAS  Google Scholar 

  17. Freda PU (2002) Clinical review 150: somatostatin analogs in acromegaly. J Clin Endocrinol Metab 87(7):3013–3018. doi:10.1210/jc.87.7.3013

    Article  CAS  PubMed  Google Scholar 

  18. Lamberts SWJ, Lely V, Hofland LJ (2002) New somatostatin analogs: will they fulfil old promises? Eur J Endocrinol 146:701–705. doi:10.1530/eje.0.1460701

    Article  CAS  PubMed  Google Scholar 

  19. Petersenn S, Heynes M, Ludecke DK et al (2000) Absence of somatostatin receptor type 2A mutation and Gip ongogene in pituitary somatotroph adenomas. Clin Endocrinol (Oxf) 52:35–42. doi:10.1046/j.1365-2265.2000.00880.x

    Article  CAS  Google Scholar 

  20. Petersenn S, Rasch AC, Bonhke et al (2002) Identification of an upstream pituitary-active promoter of human somatostatin receptor subtype 5. Endocrinology 143:2626–2634. doi:10.1210/en.143.7.2626

    Article  CAS  PubMed  Google Scholar 

  21. Saveanu A, Lavaque E, Gunz G et al (2002) Demonstration of enhanced potency of a chimeric somatostatin–dopamine molecule, BIM-23 A 387, in suppressing growth hormone and prolactin secretion from human pituitary somatotroph adenomas cells. J Clin Endocrinol Metab 87:5545–5552. doi:10.1210/jc.2002-020934

    Article  CAS  PubMed  Google Scholar 

  22. Saveanu A, Gunz G, Dufour H et al (2001) BIM-23244, a somatostatin receptor subtype 2 and 5-selective analog with enhanced efficacy in suppressing growth hormone (GH) from octreotide—resistant human GH secreting adenomas. J Clin Endocrinol Metab 86:140–145. doi:10.1210/jc.86.1.140

    Article  CAS  PubMed  Google Scholar 

  23. Jallad RS, Musolino NR, Kodaira S et al (2007) Does partial surgical tumor removal influence the response to octreotide-LAR in acromegalic patients previously resistant to the somatostatin analogue? Clin Endocrinol (Oxf) 67(2):310–315. doi:10.1111/j.1365-2265.2007.02885.x

    Article  CAS  Google Scholar 

  24. Antonov J, Goldstein DR, Oberli A et al (2005) Reliable gene expression measurements from degraded RNA by quantitative real-time PCR depend on short amplicons and a proper normalization. Lab Invest 85(8):1040–1050. doi:10.1038/labinvest.3700303

    Article  CAS  PubMed  Google Scholar 

  25. Ponchel F, Toomes C, Bransfield K et al (2003) Real-time PCR based on SYBR-Green I fluorescence: an alternative to the TaqMan assay for a relative quantification of gene rearrangements, gene amplifications and micro gene deletions. BMC Biotechnol 13:3–18

    Google Scholar 

  26. Jaquet P, Saveanu A, Gunz G et al (2000) Human somatostatin receptors subtypes in acromegaly: distinct patterns of menssenger ribonucleic acid expression and hormone suppression identify distinct tumoral phenotypes. J Clin Endocrinol Metab 85:781–792. doi:10.1210/jc.85.2.781

    Article  CAS  PubMed  Google Scholar 

  27. Panetta R, Patel YC (1995) Expression of mRNA for all five human somatostatin receptors (hSSTR1–5) in pituitary tumors. Life Sci 56:333–342. doi:10.1016/0024-3205(94)00956-2

    Article  CAS  PubMed  Google Scholar 

  28. Miller GM, Alexander JM, Bikkal HA et al (1995) Somatostatin receptor subtype gene expression in pituitary adenomas. J Clin Endocrinol Metab 80:1386–1392. doi:10.1210/jc.80.4.1386

    Article  CAS  PubMed  Google Scholar 

  29. Greenman Y, Melmed S (1194) Heterogenous expression of two somatostatin receptor subtypes in pituitary tumors. J Clin Endocrinol Metab 78:398–403. doi:10.1210/jc.78.2.398

    Article  Google Scholar 

  30. Lamberts SW, Krenning EP, Reubi JC (1991) The role of somatostatin and its analogs in the diagnosis and treatment of tumors. Endocr Rev 12:450–482. doi:10.1210/edrv-12-4-450

    Article  CAS  PubMed  Google Scholar 

  31. Lamberts SW, Lely AJVL, Herder WW et al (1196) Octreotide. N Engl J Med 334:246–254. doi:10.1056/NEJM199601253340408

    Article  Google Scholar 

  32. Florio T, Thellung S, Corsaro A et al (2003) 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) 59:115–128. doi:10.1046/j.1365-2265.2003.01811.x

    Article  CAS  Google Scholar 

  33. Hofland LJ, Hoek JVD, Koetsveld PMV et al (2004) 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 89(4):1577–1585. doi:10.1210/jc.2003-031344

    Article  CAS  PubMed  Google Scholar 

  34. Park C, Yang I, Woo J 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. doi:10.1507/endocrj.51.227

    Article  CAS  PubMed  Google Scholar 

  35. Lissett CA, Shalet SM (2000) Management of pituitary tumours: strategy for investigation and follow-up. Horm Res 53(3):65–70. doi:10.1159/000023537

    Article  CAS  PubMed  Google Scholar 

  36. Colao A, Ferone D, Marzullo P et al (2004) Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev 25:102–152. doi:10.1210/er.2002-0022

    Article  CAS  PubMed  Google Scholar 

  37. Etxabe J, Gaztambide S, Latorre P et al (1993) Acromegaly: an epidemiological study. J Endocrinol Invest 16:181–187

    CAS  PubMed  Google Scholar 

  38. Thodou E, Kontogeorgos G, Theodossiou D et al (2006) Mapping of somatostatin receptor types in GH or/and PRL producing pituitary adenomas. J Clin Pathol 59:274–279. doi:10.1136/jcp.2005.026914

    Article  CAS  PubMed  Google Scholar 

  39. Ezzat S, Kontogeorgos G, Redelmeier DA et al (1995) In vivo responsiveness of morphological variants of growth hormone-producing pituitary adenomas to octreotide. Eur J Endocrinol 133(6):686–690. doi:10.1530/eje.0.1330686

    Article  CAS  PubMed  Google Scholar 

  40. Van Der Lely AJ, Harris AG, Lamberts SW (1992) The sensitivity of growth hormone secretion to medical treatment in acromegalic patients: influence of age and sex. Clin Endocrinol (Oxf) 37:181–185. doi:10.1111/j.1365-2265.1992.tb02304.x

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  42. Jaquet P, Gunz G, Saveanu A et al (2005) Efficacy of chimeric molecules directed towards multiple somatostatin and dopamine receptors on inhibition of GH and prolactin secretion from GH-secreting pituitary adenomas classified as partially responsive to somatostatin analog therapy. Eur J Endocrinol 153:135–141. doi:10.1530/eje.1.01950

    Article  CAS  PubMed  Google Scholar 

  43. Hofland LJ, Lamberts SW (2004) Somatostatin receptors in pituitary function, diagnosis and therapy. Front Horm Res 32:235–252. doi:10.1159/000079048

    Article  CAS  PubMed  Google Scholar 

  44. Bronstein MD (2006) Acromegaly: molecular expression os somatostatin receptor subtypes and treatment outcome. Front Horm Res 35:129–134. doi:10.1159/000094315

    Article  CAS  PubMed  Google Scholar 

  45. Newman CB, Melmed S, George A et al (1998) Octreotide as primary therapy for acromegaly. J Clin Endocrinol Metab 83:3034–3040. doi:10.1210/jc.83.9.3034

    Article  CAS  PubMed  Google Scholar 

  46. Bevan JS (2005) The antitumoral effects of somatostatin analog therapy in acromegaly. J Clin Endocrinol Metab 90:1856–1863. doi:10.1210/jc.2004-1093

    Article  CAS  PubMed  Google Scholar 

  47. Cozzi R, Attanasio R, Montini M et al (2003) Four-year treatment with octreotide-long-acting repeatable in 110 acromegalic patients: predictive value of short-term results? J Clin Endocrinol Metab 88:3090–3098. doi:10.1210/jc.2003-030110

    Article  CAS  PubMed  Google Scholar 

  48. Matrone C, Pivonello R, Colao A et al (2004) Expression and function of somatostatin receptor subtype 1 in human growth hormone secreting pituitary tumors deriving from patients partially responsive or resistant to long-term treatment with somatostatin analogs. Neuroendocrinology 79:142–148. doi:10.1159/000077272

    Article  CAS  PubMed  Google Scholar 

  49. Zatelli MC, Piccin D, Tagliati F et al (2003) Somatostatin receptor subtype 1 selective activation in human growth hormone (GH)- and prolactin (PRL)-secreting pituitary adenomas: effects on cell viability, GH and PRL secretion. J Clin Endocrinol Metab 88:2797–2802. doi:10.1210/jc.2002-021825

    Article  CAS  PubMed  Google Scholar 

  50. Olias G, Viollet C, Kusserow H et al (2004) Regulation and fuction os somatostatin receptors. J Neurochem 89:1057–1091. doi:10.1111/j.1471-4159.2004.02402.x

    Article  CAS  PubMed  Google Scholar 

  51. Casarini AP, Pinto EM, Jallad RS et al (2006) Dissociation between tumor shrinkage and hormonal response during somatostatin analog treatment in an acromegalic patient: preferential expression of somatostatin receptor subtype 3. J Endocrinol Invest 29(9):826–830

    CAS  PubMed  Google Scholar 

  52. Resmini E, Dadati P, Ravetti JL et al (2007) Rapid pituitary tumor shrinkage with dissociation between antiproliferative and antisecretory effects of a long-acting Octreotide in an acromegalic patient. J Clin Endocrinol Metab 92(5):1592–1599. doi:10.1210/jc.2006-2084

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neuroendocrine Unit, Division of Endocrinology and Metabolism, University of Sao Paulo Medical School, Av. 9 de Julho 3858 01406-100, Sao Paulo, SP, Brazil

    Ana Paula M. Casarini, Raquel S. Jallad & Marcello D. Bronstein

  2. Endocrine and Development Unit Laboratory of Hormone and Molecular Genetics (LIM42), University of Sao Paulo Medical School, Sao Paulo, SP, Brazil

    Emília M. Pinto

  3. Division of Neurosurgery, University of Sao Paulo Medical School, Sao Paulo, SP, Brazil

    Nina R. Musolino

  4. Laboratory Cellular and Molecular Endocrinology (LIM25), University of Sao Paulo Medical School, Sao Paulo, SP, Brazil

    Daniel Giannella-Neto

  5. Department of Pathology, Hospital of Clinicas, University of Sao Paulo Medical School, Sao Paulo, SP, Brazil

    Iberê C. Soares, Suely Nonogaki & Venâncio A. F. Alves

Authors
  1. Ana Paula M. Casarini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raquel S. Jallad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emília M. Pinto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Iberê C. Soares
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Suely Nonogaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daniel Giannella-Neto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nina R. Musolino
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Venâncio A. F. Alves
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marcello D. Bronstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marcello D. Bronstein.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Casarini, A.P.M., Jallad, R.S., Pinto, E.M. et al. Acromegaly: correlation between expression of somatostatin receptor subtypes and response to octreotide-lar treatment. Pituitary 12, 297–303 (2009). https://doi.org/10.1007/s11102-009-0175-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-009-0175-1

Keywords

Search

Navigation