Skip to main content
SpringerLink
Log in

Growth hormone granulation pattern and somatostatin receptor subtype 2A correlate with postoperative somatostatin receptor ligand response in acromegaly: a large single center experience

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

Acromegaly is associated with serious morbidity and mortality, if not well controlled. Approved somatostatin receptor ligands (SRLs) are a mainstay of medical therapy and exhibit preferential affinity for somatostatin receptor (SSTR) subtype 2. Our objective was to assess whether characteristic features of individual growth hormone (GH)-secreting adenomas at diagnosis, correlated with SRL sensitivity, using defined tumor markers. A retrospective review of 86 consecutive acromegaly surgeries (70 patients) performed between January 2006 and December 2011 was undertaken. Patients with any preoperative medical treatment were excluded. Response to SRL therapy was defined as normalization of insulin-like growth factor 1 (IGF1) and random GH < 1.0 ng/dl. Immunohistochemical staining pattern: sparsely granulated, densely granulated, mixed growth hormone-prolactin (GH/PRL) and SSRT2 positivity (+) were correlated with clinicopathologic features, adenoma recurrence, and SRL treatment response. Two-tailed t test, univariate ANOVA, Kruskal–Wallis and bivariate correlation were performed using PAWS 18. The cohort eligible for analysis comprised 59 patients (41 female and 18 male). Based on pre-surgery adenoma imaging dimensions, 81.3 % (48) were macroadenomas and average maximum tumor diameter was 18.1 ± 9.9 mm. Patients on SRLs were followed for 13.4 ± 15.8 (mean ± SD) months. Sparsely granulated adenomas were significantly larger at diagnosis, exhibited lower SSTR2 positivity and had a lower rate of biochemical normalization to SRLs. Densely granulated adenomas were highly responsive to SRLs. Overall, patients with SSTR2A+ adenomas responded more favorably to SRL treatment than those with SSTR2A− adenomas. Eighty-one percent of patients with SSTR2A+ adenomas were biochemically controlled (both GH and IGF1) on SRL treatment, e.g. a much higher normalization rate than that reported in the unselected acromegaly population (20–30 %). Detailed knowledge of adenoma GH granularity and the immunohistochemical SSTR2A+ status is a predictor of SRL response. These immunoreactive markers should be assessed routinely on surgical specimens to assess subsequent SRL responsiveness and potential need for adjunctive therapy after surgery.

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
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Melmed S (2009) Acromegaly pathogenesis and treatment. J Clin Invest 119(11):3189–3202. doi:10.1172/JCI39375

    Article  PubMed  CAS  Google Scholar 

  2. Melmed S (2006) Acromegaly. N Engl J Med 355(24):2558–2573. doi:10.1056/NEJMra062453

    Article  PubMed  CAS  Google Scholar 

  3. Melmed S, Yamashita S, Yamasaki H, Fagin J, Namba H, Yamamoto H, Weber M, Morita S, Webster J, Prager D (1996) IGF-I receptor signalling: lessons from the somatotroph. Recent Prog Horm Res 51:189–215 (discussion 186–215)

    PubMed  CAS  Google Scholar 

  4. Holdaway IM, Rajasoorya RC, Gamble GD (2004) Factors influencing mortality in acromegaly. J Clin Endocrinol Metab 89(2):667–674

    Article  PubMed  CAS  Google Scholar 

  5. Ben-Shlomo A, Sheppard MC, Stephens JM, Pulgar S, Melmed S (2011) Clinical, quality of life, and economic value of acromegaly disease control. Pituitary 14(3):284–294. doi:10.1007/s11102-011-0310-7

    Article  PubMed  CAS  Google Scholar 

  6. Arafat AM, Mohlig M, Weickert MO, Perschel FH, Purschwitz J, Spranger J, Strasburger CJ, Schofl C, Pfeiffer AF (2008) Growth hormone response during oral glucose tolerance test: the impact of assay method on the estimation of reference values in patients with acromegaly and in healthy controls, and the role of gender, age, and body mass index. J Clin Endocrinol Metab 93(4):1254–1262. doi:10.1210/jc.2007-2084

    Article  PubMed  CAS  Google Scholar 

  7. Giustina A, Chanson P, Bronstein MD, Klibanski A, Lamberts S, Casanueva FF, Trainer P, Ghigo E, Ho K, Melmed S (2010) A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab 95(7):3141–3148. doi:10.1210/jc.2009-2670

    Article  PubMed  CAS  Google Scholar 

  8. Klibanski A, Melmed S, Clemmons DR, Colao A, Cunningham RS, Molitch ME, Vinik AI, Adelman DT, Liebert KJ (2010) The endocrine tumor summit 2008: appraising therapeutic approaches for acromegaly and carcinoid syndrome. Pituitary 13(3):266–286. doi:10.1007/s11102-009-0210-2

    Article  PubMed  Google Scholar 

  9. Melmed S, Casanueva FF, Klibanski A, Bronstein MD, Chanson P, Lamberts SW, Strasburger CJ, Wass JA, Giustina A (2012) A consensus on the diagnosis and treatment of acromegaly complications. Pituitary. doi:10.1007/s11102-012-0420-x

    Google Scholar 

  10. Fleseriu M (2011) Clinical efficacy and safety results for dose escalation of somatostatin receptor ligands in patients with acromegaly: a literature review. Pituitary 14(2):184–193. doi:10.1007/s11102-010-0282-z

    Article  PubMed  CAS  Google Scholar 

  11. Astruc B, Marbach P, Bouterfa H, Denot C, Safari M, Vitaliti A, Sheppard M (2005) Long-acting octreotide and prolonged-release Lanreotide formulations have different pharmacokinetic profiles. J Clin Pharmacol 45(7):836–844. doi:10.1177/0091270005277936

    Article  PubMed  CAS  Google Scholar 

  12. Shimon I, Taylor JE, Dong JZ, Bitonte RA, Kim S, Morgan B, Coy DH, Culler MD, Melmed S (1997) Somatostatin receptor subtype specificity in human fetal pituitary cultures. Differential role of SSTR2 and SSTR5 for growth hormone, thyroid-stimulating hormone, and prolactin regulation. J Clin Invest 99(4):789–798

    Article  PubMed  CAS  Google Scholar 

  13. Shimon I, Yan X, Taylor JE, Weiss MH, Culler MD, Melmed S (1997) Somatostatin receptor (SSTR) subtype-selective analogues differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas. Novel potential therapy for functional pituitary tumors. J Clin Invest 100(9):2386–2392

    Article  PubMed  CAS  Google Scholar 

  14. Jaquet P, Saveanu A, Gunz G, Fina F, Zamora AJ, Grino M, Culler MD, Moreau JP, Enjalbert A, Ouafik LH (2000) Human somatostatin receptor subtypes in acromegaly: distinct patterns of messenger ribonucleic acid expression and hormone suppression identify different tumoral phenotypes. J Clin Endocrinol Metab 85(2):781–792

    Article  PubMed  CAS  Google Scholar 

  15. Colao A, Auriemma RS, Galdiero M, Lombardi G, Pivonello R (2009) Effects of initial therapy for five years with somatostatin analogs for acromegaly on growth hormone and insulin-like growth factor-I levels, tumor shrinkage, and cardiovascular disease: a prospective study. J Clin Endocrinol Metab 94(10):3746–3756

    Article  PubMed  CAS  Google Scholar 

  16. Giusti M, Ciccarelli E, Dallabonzana D, Delitala G, Faglia G, Liuzzi A, Gussoni G, Giordano Disem G (1997) Clinical results of long-term slow-release lanreotide treatment of acromegaly. Eur J Clin Invest 27(4):277–284

    Article  PubMed  CAS  Google Scholar 

  17. Mercado M, Borges F, Bouterfa H, Chang T-C, Chervin A, Farrall AJ, Patocs A, Petersenn S, Podoba J, Safari M, Wardlaw J, Group SBS (2007) A prospective, multicentre study to investigate the efficacy, safety and tolerability of octreotide LAR (long-acting repeatable octreotide) in the primary therapy of patients with acromegaly. Clin Endocrinol (Oxf) 66(6):859–868

    Article  CAS  Google Scholar 

  18. Colao A, Auriemma RS, Lombardi G, Pivonello R (2011) Resistance to somatostatin analogs in acromegaly. Endocr Rev 32(2):247–271. doi:10.1210/er.2010-0002

    Article  PubMed  CAS  Google Scholar 

  19. 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. doi:10.1111/j.1365-2265.2007.03065.x

    Article  CAS  Google Scholar 

  20. Taboada GF, Luque RM, Neto LV, Machado Ede O, Sbaffi BC, Domingues RC, Marcondes JB, Chimelli LM, Fontes R, Niemeyer P, de Carvalho DP, Kineman RD, Gadelha MR (2008) Quantitative analysis of somatostatin receptor subtypes (1–5) gene expression levels in somatotropinomas and correlation to in vivo hormonal and tumor volume responses to treatment with octreotide LAR. Eur J Endocrinol 158(3):295–303. doi:10.1530/EJE-07-0562

    Article  PubMed  CAS  Google Scholar 

  21. Reubi JC, Landolt AM (1989) The growth hormone responses to octreotide in acromegaly correlate with adenoma somatostatin receptor status. J Clin Endocrinol Metab 68(4):844–850

    Article  PubMed  CAS  Google Scholar 

  22. Park C, Yang I, Woo J, Kim S, Kim J, Kim Y, Sohn S, Kim E, Lee M, Park H, Jung J, Park S (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  PubMed  CAS  Google Scholar 

  23. Reubi JC, Waser B, Liu Q, Laissue JA, Schonbrunn A (2000) Subcellular distribution of somatostatin sst2A receptors in human tumors of the nervous and neuroendocrine systems: membranous versus intracellular location. J Clin Endocrinol Metab 85(10):3882–3891

    Article  PubMed  CAS  Google Scholar 

  24. Pisarek H, Pawlikowski M, Kunert-Radek J, Winczyk K (2010) Does the response of GH-secreting pituitary adenomas to octreotide depend on the cellular localization of the somatostatin receptor subtypes SSTR2 and SSTR5? Endokrynol Pol 61(2):178–181

    PubMed  CAS  Google Scholar 

  25. Reubi JC, Waser B, Cescato R, Gloor B, Stettler C, Christ E (2010) Internalized somatostatin receptor subtype 2 in neuroendocrine tumors of octreotide-treated patients. J Clin Endocrinol Metab 95(5):2343–2350. doi:10.1210/jc.2009-2487

    Article  PubMed  CAS  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 (Oxf) 76(1):96–102. doi:10.1111/j.1365-2265.2011.04163.x

    Article  CAS  Google Scholar 

  27. Kato M, Inoshita N, Sugiyama T, Tani Y, Shichiri M, Sano T, Yamada S, Hirata Y (2012) Differential expression of genes related to drug responsiveness between sparsely and densely granulated somatotroph adenomas. Endocr J 59(3):221–228

    Article  PubMed  CAS  Google Scholar 

  28. Lopes MB (2010) Growth hormone-secreting adenomas: pathology and cell biology. Neurosurg Focus 29(4):E2. doi:10.3171/2010.7.FOCUS10169

    Article  PubMed  Google Scholar 

  29. Osamura RY, Kajiya H, Takei M, Egashira N, Tobita M, Takekoshi S, Teramoto A (2008) Pathology of the human pituitary adenomas. Histochem Cell Biol 130(3):495–507. doi:10.1007/s00418-008-0472-1

    Article  PubMed  CAS  Google Scholar 

  30. Bakhtiar Y, Hirano H, Arita K, Yunoue S, Fujio S, Tominaga A, Sakoguchi T, Sugiyama K, Kurisu K, Yasufuku-Takano J, Takano K (2010) Relationship between cytokeratin staining patterns and clinico-pathological features in somatotropinomae. Eur J Endocrinol 163(4):531–539. doi:10.1530/eje-10-0586

    Article  PubMed  CAS  Google Scholar 

  31. Obari A, Sano T, Ohyama K, Kudo E, Qian ZR, Yoneda A, Rayhan N, Mustafizur Rahman M, Yamada S (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

    Article  PubMed  Google Scholar 

  32. Casarini AP, Jallad RS, Pinto EM, Soares IC, Nonogaki S, Giannella-Neto D, Musolino NR, Alves VA, Bronstein MD (2009) Acromegaly: correlation between expression of somatostatin receptor subtypes and response to octreotide-lar treatment. Pituitary 12(4):297–303

    Article  PubMed  CAS  Google Scholar 

  33. Remmele W, Stegner HE (1987) Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 8(3):138–140

    PubMed  CAS  Google Scholar 

  34. Hofland LJ, Lamberts SW (2003) The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocr Rev 24(1):28–47

    Article  PubMed  CAS  Google Scholar 

  35. Biermasz NR, van Dulken H, Roelfsema F (2000) Ten-year follow-up results of transsphenoidal microsurgery in acromegaly. J Clin Endocrinol Metab 85(12):4596–4602

    Article  PubMed  CAS  Google Scholar 

  36. Sherlock M, Fernandez-Rodriguez E, Alonso AA, Reulen RC, Ayuk J, Clayton RN, Holder G, Sheppard MC, Bates A, Stewart PM (2009) Medical therapy in patients with acromegaly: predictors of response and comparison of efficacy of dopamine agonists and somatostatin analogues. J Clin Endocrinol Metab 94(4):1255–1263

    Article  PubMed  CAS  Google Scholar 

  37. Melmed S, Cook D, Schopohl J, Goth MI, Lam KS, Marek J (2010) Rapid and sustained reduction of serum growth hormone and insulin-like growth factor-1 in patients with acromegaly receiving lanreotide autogel therapy: a randomized, placebo-controlled, multicenter study with a 52 week open extension. Pituitary 13(1):18–28

    Article  PubMed  CAS  Google Scholar 

  38. Yamada S, Aiba T, Sano T, Kovacs K, Shishiba Y, Sawano S, Takada K (1993) Growth hormone-producing pituitary adenomas: correlations between clinical characteristics and morphology. Neurosurgery 33(1):20–27

    Article  PubMed  CAS  Google Scholar 

  39. Bhayana S, Booth GL, Asa SL, Kovacs K, Ezzat S (2005) The implication of somatotroph adenoma phenotype to somatostatin analog responsiveness in acromegaly. J Clin Endocrinol Metab 90(11):6290–6295

    Article  PubMed  CAS  Google Scholar 

  40. Plöckinger U, Albrecht S, Mawrin C, Saeger W, Buchfelder M, Petersenn S, Schulz S (2008) Selective loss of somatostatin receptor 2 in octreotide-resistant growth hormone-secreting adenomas. J Clin Endocrinol Metab 93(4):1203–1210. doi:10.1210/jc.2007-1986

    Article  PubMed  Google Scholar 

  41. Stefaneanu L, Kovacs K, Thapar K, Horvath E, Melmed S, Greenman Y (2000) Octreotide effect on growth hormone and somatostatin subtype 2 receptor mRNAs of the human pituitary somatotroph adenomas. Endocr Pathol 11(1):41–48

    Article  PubMed  CAS  Google Scholar 

  42. Takei M, Suzuki M, Kajiya H, Ishii Y, Tahara S, Miyakoshi T, Egashira N, Takekoshi S, Sanno N, Teramoto A, Osamura RY (2007) Immunohistochemical detection of somatostatin receptor (SSTR) subtypes 2A and 5 in pituitary adenoma from acromegalic patients: good correlation with preoperative response to octreotide. Endocr Pathol 18(4):208–216. doi:10.1007/s12022-007-9004-0

    Article  PubMed  Google Scholar 

  43. Ferone D, de Herder WW, Pivonello R, Kros JM, van Koetsveld PM, de Jong T, Minuto F, Colao A, Lamberts SWJ, Hofland LJ (2008) Correlation of in vitro and in vivo somatotropic adenoma responsiveness to somatostatin analogs and dopamine agonists with immunohistochemical evaluation of somatostatin and dopamine receptors and electron microscopy. J Clin Endocrinol Metab 93(4):1412–1417

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank, Shirley McCartney, PhD for editorial assistance and Andy Rekito, MS for assistance with graphics.

Author information

Authors and Affiliations

  1. OHSU Northwest Pituitary Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Road (BTE 472), Portland, OR, 97239, USA

    Jessica Brzana, Chris G. Yedinak, Sakir H. Gultekin & Maria Fleseriu

  2. Department of Medicine, Oregon Health & Science University, Portland, OR, USA

    Jessica Brzana & Maria Fleseriu

  3. Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, USA

    Chris G. Yedinak & Maria Fleseriu

  4. Department of Pathology, Oregon Health & Science University, Portland, OR, USA

    Sakir H. Gultekin

  5. Department of Neurological Surgery, University of California, Irvine UC Irvine School of Medicine, 101 The City Drive South Building 56, Suite 400, Orange, CA, 92868, USA

    Johnny B. Delashaw

Authors
  1. Jessica Brzana
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chris G. Yedinak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sakir H. Gultekin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Johnny B. Delashaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria Fleseriu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria Fleseriu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brzana, J., Yedinak, C.G., Gultekin, S.H. et al. Growth hormone granulation pattern and somatostatin receptor subtype 2A correlate with postoperative somatostatin receptor ligand response in acromegaly: a large single center experience. Pituitary 16, 490–498 (2013). https://doi.org/10.1007/s11102-012-0445-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-012-0445-1

Keywords

Search

Navigation