Central and peripheral actions of somatostatin on the growth hormone–IGF-I axis

Abstract

Somatostatin (SRIF) analogs provide safe and effective therapy for acromegaly. In a proportion of patients, however, SRIF analogs may lead to discordant growth hormone (GH) and IGF-I suppression, which suggests a more complex mechanism than attributable to inhibition of GH release alone. To elucidate whether SRIF acts peripherally on the GH-IGF-I axis, we showed that rat hepatocytes express somatostatin receptor subtypes-2 and -3 and that IGF-I mRNA and protein levels were suppressed in a dose-dependent manner by administration of octreotide. The inhibitory effect of SRIF was not apparent without added GH and in the presence of GH was specific for IGF-I induction and did not inhibit GH-induced c-myc or extracellular signal regulated kinase (ERK) phosphorylation. Pertussis toxin treatment of hepatocytes incubated with GH and SRIF, or with GH and octreotide, abrogated the inhibitory effect on GH-induced IGF-I, which confirms the requirement for the inhibitory G-protein. Treatment with SRIF and GH increased protein tyrosine phosphatase (PTP) activity and inhibited signal transducer and activator of transcription-5b (STAT5b) phosphorylation and nuclear localization. Octreotide also inhibited GH-stimulated IGF-I protein content of ex vivo-perfused rat livers. The results demonstrate that SRIF acts both centrally and peripherally to control the GH-IGF-I axis, providing a mechanistic explanation for SRIF analog action in treating patients with GH-secreting pituitary adenomas.

Rainbow trout somatostatin receptor subtypes SSTR1A, SSTR1B, and SSTR2 differentially activate the extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling pathways in transfected cells

“…In light of the activation of transcription factors such as C/EBPs and Stat3 in all the trout SSTR-expressing cells and the observed linakge between ERK and PI3K/Akt and these transcription factors in mammalian systems (Chung 1997, Schrem et al 2004, Cui et al 2008, it is possible that alterations in the activity state of C/EBPb and Stat3 and the modulation of GHR and IGF1 transcription may underlie SS inhibition of GHR and IGF1 expression in trout liver cells. SS-induced activation of Stat5 also was linked to reduced hepatic GH binding in rat hepatocytes (Murray et al 2004). It was shown recently that increased ERK and Akt activation was attended by increased p53 activation (Tanel & Averill-Bates 2007), suggesting that SSTR1A/ SSTR2-triggered ERK and/or PI3K/Akt activation of p53 may underlie, at least in part, SS-induced inhibition of IGFR expression in native gill filaments of trout.…”

Conventional and novel biomarkers of treatment outcome in patients with acromegaly: discordant results after somatostatin analog treatment compared with surgery

“…Moreover, the suppressive effect of somatostatin on insulin secretion (13) may result in reduced hepatic IGF1 production, and hence lower serum IGF1 levels, in as much as insulin stimulates hepatic GHR synthesis and activity (30). Moreover, data from rodent studies show that somatostatin directly suppresses hepatic IGF1 production and possibly also the receptor-mediated clearance of GH (12), and a study in healthy human subjects indicates that somatostatin exerts GH-antagonistic effects directly in skeletal muscle in vivo (31). It has also been suggested that somatostatin may antagonize the suppressive effect of oral glucose on GH secretion (8), and it is worth noting that the difference in GH levels in our study was mainly present during the OGTT.…”

“…In addition, slightly elevated GH levels in the presence of normalized IGF1 levels may be an early predictor of disease recurrence (10), but cases of persistent disease despite very low GH levels (and elevated IGF1 levels) also exist (7,11). Furthermore, somatostatin acts not only at the pituitary level to suppress GH release, but also exhibits inhibitory effects on GH signaling and thus GH receptor (GHR)-mediated clearance of GH (12). In addition, somatostatin suppresses insulin secretion (13), which may lower hepatic IGF1 production and hence also the circulating levels of IGF1 (14).…”

Antitumor effects of somatostatin

“…They inhibit pituitary GH release and sst2 and sst5 are the subtypes primary involved in this effect. They also inhibit hepatic GH-induced IGF-I production via sst2-and/or sst3-mediated activation of a tyrosine phosphatase leading to dephosphorylation of STAT5b and to a decrease in IGF-I gene transcription (Murray et al, 2004).…”

“…Tumor angiogenesis is essential for tumor growth, invasion and metastasis. Several experimental results indicate that somatostatin analogs inhibit angiogenesis in vitro and in vivo (Murray et al, 2004). Overexpression of peritumoral vascular somatostatin receptors with high-affinity for sst2-preferring analog octreotide has been reported in human primary colorectal carcinomas, small cell lung carcinoma, breast cancer, renal carcinoma and malignant lymphoma.…”