Introduction: It has been reported in some series that gsp+ somatotropinomas are more sensitive to somatostatin analogues (SA) and dopamine’s actions which may be related to their somatostatin receptor (SSTR) and dopamine receptor (DR) profile. No previous studies have been undertaken to evaluate the SSTR and DR profile related with the gsp status in somatotropinomas. Objectives: To determine if (1) gsp status is correlated with response to octreotide LAR (LAR) and tumor expression patterns of SSTR1-5 and DR1-5 and (2) cAMP level can directly modulate SSTR and DR mRNA levels. Methods: Response to SA was evaluated by GH and IGF-I percent reduction after 3 and 6 months of treatment with LAR. Conventional PCR and sequencing were used to identify gsp+ tumors. Quantitative real-time PCR was used to determine SSTR and DR tumor expression. Primary pituitary cell cultures of primates were used to study whether SSTR and DR expression is regulated by forskolin. Results: The response to LAR did not significantly differ between patients with gsp+ and gsp– tumors; however, gsp+ tumors expressed higher levels of SSTR1, SSTR2, DR2 and a lower level of SSTR3. Forskolin increased SSTR1, SSTR2, DR1 and DR2 expression in cell cultures. Conclusion: Elevated SSTR1, SSTR2, and DR2 tumor expression may help improve responsiveness to SA and DA therapy; however, this study may not have been appropriately powered to observe significant effects in the clinical response. Elevated cAMP levels could be directly responsible for the upregulation in SSTR1, SSTR2 and DR2 mRNA levels observed in gsp+ patients.

Herman V, Fagin J, Gonsky R, Kovacs K, Melmed S: Clonal origin of pituitary adenomas. J Clin Endocrinol Metab 1990;71:1427–433.
Landis CA, Harsh G, Lyons J, Davis RL, McCormick F, Bourne HR: Clinical characteristics of acromegalic patients whose pituitary tumors contain mutant Gs protein. J Clin Endocrinol Metab 1990;71:1416–1420.
Drews RT, Gravel RA, Collu R: Identification of G protein α-subunit mutations in human growth hormone (GH)- and GH/prolactin-secreting pituitary tumors by single-strand conformation polymorphism (SSCP) analysis. Mol Cell Endocrinol 1992;87:125–129.
Yoshimoto K, Iwahana H, Fukuda A, Sano T, Itakura M: Rare mutations of the Gs α-subunit gene in human endocrine tumors. Mutation detection by polymerase chain reaction-primer-introduced restriction analysis. Cancer 1993;72:1386–1393.
Hosoi E, Yokogoshi Y, Hosoi E, Horie H, Sano T, Yamada S, Saito S: Analysis of the Gs α gene in growth hormone-secreting pituitary adenomas by the polymerase chain reaction-direct sequencing method using paraffin-embedded tissues. Acta Endocrinol 1993;129:301–306.
Adams EF, Brockmeier S, Friedmann E, Roth M, Buchfelder M, Fahlbusch R: Clinical and biochemical characteristics of acromegalic patients harboring gsp-p ositive and gsp-negative pituitary tumors. Neurosurgery 1993;33:198–203.
Yang I, Park S, Ryu M, Woo J, Kim S, Kim J, Kim Y, Choi Y: Characteristics of gsp-positive growth hormone-secreting pituitary tumors in Korean acromegalic patients. Eur J Endocrinol 1996;134:720–726.
Ballaré E, Mantovani S, Lania A, Di Blasio AM, Vallar L, Spada A: Activating mutations of the Gs α gene are associated with low levels of Gs α protein in growth hormone-secreting tumors. J Clin Endocrinol Metab 1998;83:4386–4390.
Barlier A, Gunz G, Zamora AJ, Morange-Ramos I, Figarella-Branger D, Dufour H, Enjalbert A, Jaquet P: Prognostic and therapeutic consequences of Gs α mutations in somatotroph adenomas. J Clin Endocrinol Metab 1998;83:1604–1610.
Buchfelder M, Fahlbusch R, Merz T, Symowski H, Adams EF: Clinical correlates in acromegalic patients with pituitary tumors expressing gsp oncogenes. Pituitary 1999;1:181–185.
Kim HJ, Kim MS, Park YJ, Kim SW, Park DJ, Park KS, Kim SY, Cho BY, Lee HK, Jung HW, Han DH, Lee HS, Chi JG: Prevalence of Gs α mutations in Korean patients with pituitary adenomas. J Endocrinol 2001;168:221–226.
Corbetta S, Ballaré E, Mantovani G, Lania A, Losa M, Di Blasio AM, Spada A: Somatostatin receptor subtype 2 and 5 in human GH-secreting pituitary adenomas: analysis of gene sequence and mRNA expression. Eur J Clin Invest 2001;31:208–214.
Kan B, Esapa C, Sipahi T, Nacar C, Ozer F, Sayhan NB, Kaynar MY, Sarioğlu AC, Harris PE: G protein mutations in pituitary tumors: a study on Turkish patients. Pituitary 2003;6:75–80.
Park C, Yang I, Woo J, Kim S, Kim J, Kim Y, Sohn S, Kim E, Lee M, Park H, Jung J, Park S: 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 2004;51:227–236.
Mendoza V, Sosa E, Espinosa-de-Los-Monteros AL, Salcedo M, Guinto G, Cheng S, Sandoval C, Mercado M: GSPα mutations in Mexican patients with acromegaly: potential impact on long term prognosis. Growth Horm IGF Res 2005;15:28–32.
Yasufuku-Takano J, Takano K, Morita K, Takakura K, Teramoto A, Fujita T: 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 2006;64:91–96.
Metzler M, Luedecke DK, Saeger W, Grueters A, Haberl H, Kiess W, Repp R, Rascher W, Doetsch J: Low prevalence of Gs α mutations in somatotroph adenomas of children and adolescents. Cancer Genet Cytogenet 2006;166:146–151.
Freda PU, Chung WK, Matsuoka N, Walsh JE, Kanibir MN, Kleinman G, Wang Y, Bruce JN, Post KD: 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 2007;10:275–282.
Fougner SL, Borota OC, Berg JP, Hald JK, Ramm-Pettersen J, Bollerslev J: The clinical response to somatostatin analogues in acromegaly correlates to the somatostatin receptor subtype 2a protein expression of the adenoma. Clin Endocrinol 2008;68:458–465.
Taboada GF, Tabet AL, Naves LA, de Carvalho DP, Gadelha MR: Prevalence of gsp oncogene in somatotropinomas and clinically non-functioning pituitary adenomas: our experience. Pituitary 2009;12:165–169.
Landis CA, Masters SB, Spada A, Pace AM, Bourne HR, Vallar L: GTPase inhibiting mutations activate the α chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 1989;340:692–696.
Spada A, Arosio M, Bochicchio D, Bazzoni N, Vallar L, Bassetti M, Faglia G: Clinical, biochemical, and morphological correlates in patients bearing growth hormone-secreting pituitary tumors with or without constitutively active adenylyl cyclase. J Clin Endocrinol Metab 1990;71:1421–1426.
Faglia G, Arosio M, Spada A: Gs protein mutations and pituitary tumors: functional correlates and possible therapeutic implications. Metabolism 1996;45:S117–S119.
Kim E, Sohn S, Lee M, Park C, Jung J, Park S: Effect of gsp oncogene on somatostatin receptor subtype 1 and 2 mRNA levels in GHRH-responsive GH3 cells. Pituitary 2005;8:155–162.
Barlier A, Pellegrini-Bouiller I, Gunz G, Zamora AJ, Jaquet P, Enjalbert A: Impact of gsp oncogene on the expression of genes coding for Gsα, Pit-1, Gi2α, and somatostatin receptor 2 in human somatotroph adenomas: involvement in octreotide sensitivity. J Clin Endocrinol Metab 1999;84:2759–2765.
Ferone D, de Herder WW, Pivonello R, Kros JM, van Koetsveld PM, Jong T, Minuto F, Colao A, Lamberts SWJ, Hofland LJ: Correlation of in vitroand in vivosomatotropic adenoma responsiveness to somatostatin analogs and dopamine agonists with immunohistochemical evaluation of somatostatin and dopamine receptors and electron microscopy. J Clin Endocrinol Metab 2008;93:1412–1417.
Neto LV, de Oliveira Machado E, Luque RM, Taboada GF, Marcondes JB, Chimelli LM, Quintella LP, Niemeyer P Junior, de Carvalho DP, Kineman RD, Gadelha MR: Expression analysis of dopamine receptor subtypes in normal human pituitaries, non-functioning pituitary adenomas and somatotropinomas, and the association between dopamine and somatostatin receptors with clinical response to octreotide-LAR in acromegaly. J Clin Endocrinol Metab 2009;94:1931–1937.
Taboada GF, Luque RM, Bastos W, Guimaraes RF, Marcondes JB, Chimelli LM, Fontes R, Mata PJ, Filho PN, Carvalho DP, Kineman RD, Gadelha MR: Quantitative analysis of somatostatin receptor subtype (SSTR1-5) gene expression levels in somatotropinomas and non-functioning pituitary adenomas. Eur J Endocrinol 2007;156:65–74.
Taboada GF, Luque RM, Neto LV, de Oliveira Machado E, Sbaffi BC, Domingues RC, Marcondes JB, Chimelli LM, Fontes R, Niemeyer P, de Carvalho DP, Kineman RD, Gadelha MR: 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 2008;158:295–303.
Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F: Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 2002;3:1–12.
Luque RM, Gahete MD, Hochgeschwender U, Kineman RD: Evidence that endogenous SST inhibits ACTH and ghrelin expression by independent pathways. Am J Physiol Endocrinol Metab 2006;291:E395–E403.
Luque RM, Gahete MD, Valentine RJ, Kineman RD: Examination of the direct effects of metabolic factors on somatotrope function in a non-human primate model, Papio anubis. J Mol Endocrinol 2006;37:25–38.
Kineman RD, Luque RM: Evidence that ghrelin is as potent as growth hormone (GH)-releasing hormone (GHRH) in releasing GH from primary pituitary cell cultures of a nonhuman primate (Papio anubis), acting through intracellular signaling pathways distinct from GHRH. Endocrinology 2007;148:4440–4449.
Giustina A, Chanson P, Bronstein MD, Klibanski A, Lamberts S, Casanueva FF, Trainer P, Ghigo E, Ho K, Melmed S: A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab 2010;95:3141–3148.
Davis JR, Wilson EM, Vidal ME, Johnson AP, Lynch SS, Sheppard MC: Regulation of growth hormone secretion and messenger ribonucleic acid accumulation in human somatotropinoma cells in vitro. J Clin Endocrinol Metab 1989;69:704–708.
Nakashima M, Takano K, Matsuno A: Analyses of factors influencing the acute effect of octreotide in growth hormone-secreting adenomas. Endocr J 2009;56:295–304.
Luque RM, Park S, Kineman RD: Role of endogenous somatostatin in regulating GH output under basal conditions and in response to metabolic extremes. Mol Cell Endocrinol 2008;286:155–168.
Rocheville M, Lange DC, Kumar U, Patel SC, Patel RC, Patel YC: Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 2000;288:154–157.
Baragli A, Alturaihi H, Watt HL, Abdallah A, Kumar U: Hetero-oligomerization of human dopamine receptor 2 and somatostatin receptor 2 Co-immunoprecipitation and fluorescence resonance energy transfer analysis. Cell Signal 2007;19:2304–2316.
Durán-Prado M, Malagón MM, Gracia-Navarro F, Castaño JP: Dimerization of G-protein-coupled receptors: new avenues for somatostatin receptor signalling, control and functioning. Mol Cell Endocrinol 2008;286:63–68.
Lania AG, Ferrero S, Pivonello R, Mantovani G, Pecerelli E, Di Sarno A, Beck-Peccoz P, Spada A, Colao A: Evolution of an aggressive prolactinoma into a growth hormone-secreting pituitary tumor coincident with GNAS gene mutation. J Clin Endocrinol Metab 2010;95:13–17.
Patel YC, Greenwood M, Kent G, Panetta R, Srikant CB: Multiple gene transcript of the somatostatin receptor SSTR2: tissue-selective distribution and cAMP regulation. Biochem Biophys Res Commun 1993;192:288–294.
Park S, Kamegai J, Johnson TA, Frohman LA, Kineman RD: Modulation of pituitary somatostatin receptor subtype (sst1-5) messenger ribonucleic acid levels by changes in the growth hormone axis. Endocrinology 2000;141:3556–3563.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.