Somatostatin (SRIH), a cyclic tetradecapeptide hormone originally isolated from mammalian hypothalamus, is a potent suppressor of pituitary growth hormone (GH) secretion. SRIH acts through a family of G-protein-coupled membrane receptors containing seven transmembrane domains. Five genes encoding distinct SRIH receptor (SSTR) subtypes have so far been cloned in human and other species and termed SSTR1–5. In human somatotrophe pituitary adenomas GH secretion is controlled by both SSTR2 and SSTR5. However, in clinical practice only somatostatin analogs selective for SSTR2 (octreotide and lanreotide) are available. This may explain why clinical and in vitro responses to these analogs in acromegaly are only partial. In this study, we investigated the inhibitory effect of two new SRIH analogs with high selectivity for SSTR2 (NC-4-28B) and SSTR5 (BIM-23268) and compared it to that of native somatostatin (SRIH-14) on a large number of GH-secreting adenomas obtained by transphenoidal neurosurgery. Tissues from 16 adenomas were enzymatically dispersed and plated in 24-well dishes at 50,000 cells/well. After 3 days, groups of three wells were incubated for 4 h with medium alone, SRIH-14 or analogs NC-4-28B or BIM-23268, at the concentrations of 0.01, 0.1 and 1 µM. Our results show that 9 out of 16 adenomas were responsive (GH suppression: 20–40% vs. control, p < 0.05) to SRIH. In this group only 4 adenomas showed similar responses to both selective analogs, with 2 nonresponders (expression of other SRIH receptor subtypes) and 2 responders (concomitant expression of SSTR2 and SSTR5) to both analogs. GH release was selectively inhibited by NC-4-28B in 3 adenomas and by BIM-23268 in the remaining 2 adenomas, suggesting predominant expression of SSTR2 and SSTR5, respectively. SRIH failed to inhibit GH release in 7 adenomas (43%). Interestingly, in that group a better inhibitory effect was obtained with BIM-23268 (5 out of 7 adenomas) than with NC-4-28B, suggesting expression of a few SSTR5 receptors only, or of both SSTR2 and SSTR5, respectively. We conclude that the availability of somatostatin analogs selective for SSTR5 will enhance the treatment potency and spectrum in acromegaly.

1.
Patel YC: Somatostatin and its receptor family. Front Neuroendocrinol 1999;20:157–198.
2.
Muller EE, Locatelli V, Cocchi D: Neuroendocrine control of growth hormone secretion. Physiol Rev 1999;79:511–607.
3.
Schindler M, Humphrey PP, Emson PC: Somatostatin receptors in the central nervous system. Prog Neurobiol 1996;50:9–47.
4.
Panetta R, Patel YC: Expression of mRNA for all five human somatostatin receptors (hSSTR1–5) in pituitary tumors. Life Sci 1995;56:333–342.
5.
Miller GM, Alexander JM, Bikkal HA, Katznelson L, Zervas NT, Klibanski A: Somatostatin receptor subtype gene expression in pituitary adenomas. J Clin Endocrinol Metab 1995;80:1386–1392.
6.
Greenman Y, Melmed S: Expression of three somatostatin receptor subtypes in pituitary adenomas: Evidence for preferential SSTR5 expression in the mammosomatotroph lineage. J Clin Endocrinol Metab 1994;79:724–729.
7.
Greenman Y, Melmed S: Heterogeneous expression of two somatostatin receptor subtypes in pituitary tumors. J Clin Endocrinol Metab 1994;78:398–403.
8.
Jaquet P, Ouafik L, Saveanu A, Gunz G, Fina F, Dufour H, Culler MD, Moreau JP, Enjalbert A: Quantitative and functional expression of somatostatin receptor subtypes in human prolactinoma. J Clin Endocrinol Metab 1999;84:3268–3276.
9.
Lamberts SW, Zweens M, Klijin JG, van Vroonhoven CC, Stefanko SZ, Del Pozo E: The sensitivity of growth hormone and prolactin secretion to the somatostatin analogue SMS 201-995 in patients with prolactinomas and acromegaly. Clin Endocrinol (Oxf) 1986;25:201–212.
10.
Giustina A, Zaltieri G, Negrini F, Wehrenberg WB: The pharmacological aspects of the treatment of acromegaly. Pharmacol Res 1996;34:247–268.
11.
Coy DH, Taylor JE: Receptor-specific somatostatin analogs: Correlations with biological activity. Metabolism 1996;45(suppl 1):21–23.
12.
Fahlbusch R, Honneger J, Buchfelder M: Surgical management of acromegaly. Endocrinol Metab Clin North Am 1992;21:669–692.
13.
Ezzat S, Snyder PJ, Young WF, et al: Octreotide treatment of acromegaly: A randomized, multicenter study. Ann Intern Med 1992;117:711–718.
14.
Newman CB, Melmed S, Snyder PJ, Young WF, Boyajy LD, Levy R, Stewart WN, Klibanski A, Molitch ME, Gagel RF: Safety and efficacy of long term octreotide therapy of acromegaly: Results of a multicenter trial in 103 patients – A clinical research center study. J Clin Endocrinol Metab 1995;80:2768–2775.
15.
Melmed S, Ho K, Klibanski A, Reichlin S, Thorner M: Clinical review. Recent advances in pathogenesis, diagnosis and management of acromegaly. J Clin Endocrinol Metab 1995;80:3395–3402.
16.
Newman CB: Medical therapy for acromegaly. Endocrinol Metab Clin North Am 1999;28:171–190.
17.
Shimon I, Taylor JE, Dong JZ, Bitonte RA, Kim S, Morgan B, Coy DH, Culler MD, Melmed S: 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 1997;99:789–798.
18.
Shimon I, Xinmin Y, Taylor JE, Weiss MH, Culler MD, Melmed S: 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 1997;100:2386–2392.
19.
Jaquet P, Saveanu A, Gunz G, Fina F, Zamora J, Grino M, Culler MD, Moreau JP, Enjalbert A, Ouafik LH: Human somatostatin receptor subtypes in acromegaly: Distinct patterns of messenger ribonucleic acid expression and hormone suppression identify different tumoral phenotypes. J Clin Endocrinol Metab 2000;85:781–792.
20.
Raynor K, Murphy WA, Coy DH, Taylor JE, Moreau JP, Yasuda K, Bell GI, Reisine T: Cloned somatostatin receptors: Identification of subtypes selective peptides and demonstration of high affinity binding of linear peptides. Mol Pharmacol 1993;43:838–844.
21.
Zambre Y, Ling ZD, Chen MC, et al: Inhibition of human pancreatic islet insulin release by receptor-selective somatostatin analogs directed to somatostatin receptor subtype 5. Biochem Pharmacol 1999;57:1159–1164.
22.
Giustina A, Ragni G, Bollati A, Cozzi R, Licini M, Poiesi C, Turazzi S, Bonfanti C: Inhibitory effects of galanin on growth hormone (GH) release in cultured GH-secreting adenoma cells: Comparative study with octreotide, GH-releasing hormone and thyrotropin-releasing hormone. Metabolism 1997;46:425–430.
23.
Giustina A, Bresciani E, Bussi AR, Bollati A, Bonfanti C, Bugari G, Chiesa L, Giustina G: Characterization of the paradoxical growth hormone inhibitory effect of galanin in acromegaly. J Clin Endocrinol Metab 1995;80:1333–1340.
24.
Giustina A, Veldhuis JD: Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the humans. Endocr Rev 1998;19:717–797.
25.
Giustina A, Barkan A, Casanueva FF, Cavagnini F, Frohman L, Ho K, Veldhuis J, Wass J, Von Werder K, Melmed S: Criteria for cure of acromegaly: A consensus statement. J Clin Endocrinol Metab 2000;85:526–529.
26.
Vance ML, Harris AG: Long term treatment of 189 acromegalic patients with the somatostatin analogue octreotide. Arch Intern Med 1991;151:1573–1578.
27.
Kristof RA, Stoffel-Wagner B, Klingmuller D, Schramm J: Does octreotide treatment improve the surgical results of macro-adenomas in acromegaly? A randomized study. Acta Neurochir (Wien) 1999;141:399–405.
28.
Reubi JC, Landolt AM: The growth hormone responses to octreotide in acromegaly correlate with adenoma somatostatin receptor status. J Clin Endocrinol Metab 1989;68:844–850.
29.
Reisine T, Bell GI: Molecular biology of somatostatin receptors. Endocr Rev 1995;16:427–442.
30.
Flogstad AK, Halse J, Bakke S, Lancranjan I, Marbach P, Bruns C, Jervell J: Sandostatin LAR in acromegalic patients: Long-term treatment. J Clin Endocrinol Metab 1997;82:23–28.
31.
Manelli F, Bossoni S, Burattin A, Doga M, Solerte SB, Romanelli G, Giustina A: Exercise-induced microalbuminuria in patients with active acromegaly: Acute effects of slow-release lanreotide, a long-acting somatostatin analog. Metabolism 2000;49:634–639.
32.
Caron P, Morange-Ramos I, Cogne M, Jaquet P: Three year follow-up of acromegalic patients treated with intramuscular slow-release lanreotide. J Clin Endocrinol Metab 1997;82:18–22.
33.
Lin JD, Lee ST, Weng HF: An open, phase III study of lanreotide (Somatuline PR) in the treatment of acromegaly. Endocr J 1999;46:193–198.
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