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 microM. 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.