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

Abstract

Abstract. To investigate the potential pathophysiologic role of human SRIF receptor gene expression in GH-secreting adenomas in acromegalic patients, we studied the relationship between the SRIF receptor gene expression, endogenous SRIF activity and exogenous response to octreotide in 16 acromagalic patients. Hypothalamic somatostatinergic activity (HSA) was assessed by glucose-induced suppression of TRH-stimulated TSH secretion. As an indicator of somatotrope sensitivity to HSA, glucose-induced suppression of TRH-stimulated GH secretion was determined. For the acute octreotide response, a 100 mg bolus of octreotide was injected intravenously and GH was measured hourly for 6 hr. Pituitary tumor SRIF receptor subtype 2 and 5 (sst2 and sst5) mRNA levels were measured by real-time RT-PCR. Gsp oncogene was also detected by direct PCR sequencing. Sst2 and sst5 mRNA levels were detected in all tumors. Sst2 mRNA levels positively correlated with that of sst5. Sst2 and sst5 mRNA levels did not show any correlation with basal GH values (nadir or peak). Expression of sst2, but not sst5, showed a positive correlation with the GH response to HSA, while the octreotide response positively correlated with the sum of sst2 and sst5 mRNA levels. Individuals with gsp-positive tumors were more responsive to octreotide than those with gsp-negative tumors but sst2 and sst5 mRNA levels did not differ between these two groups. These results suggest common transcriptional and/or post-transcriptonal regulatory mechanisms for these SRIF receptor subtypes within GH-secreting pituitary adenomas. The functional observations suggest that the degree (or level) of sst2 and sst5 expression is critical for the ultimate GH response of somatotropinomas to endogenous SRIF tone and exogenous SRIF analogue therapy. However, sst2 and sst5 mRNA levels are not the only factors mediating the response to SRIF.

Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study

“…Numerous factors are associated with resistance to first-generation SSAs (10), including reduced expression of SSTR2a (11,12,13,14,15,16,17,18), sparsely granulated adenoma subtype (19,20,21,22) and a higher Ki-67 proliferation index (23,24). Adenomas that occur in patients with AIP mutations and AIP mutation-negative sporadic somatotroph adenomas with reduced AIP expression show increased invasiveness (25,26,27,28) and are frequently resistant to first generation SSAs (29).…”

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

“…When molecular analysis of the resected tumor is possible, the presence of the gsp oncogene is indicative of a good response to SA treatment (18). In addition, expression profiles of the somatostatin receptor subtypes (SSTR) in tumor fragments may serve as a predictive tool of response to SA therapy, although further study is required (19)(20)(21)(22)(23)(24).…”

Somatostatin receptors subtypes 2 and 5, dopamine receptor type 2 expression and gsp status as predictors of octreotide LAR® responsiveness in acromegaly

“…Although this analysis was not done in patient #2, the fact that patient #1 is gsp positive increases her chance to be successfully controlled with octreotide LAR ® . In fact, several studies explored SA responsiveness in the light of gsp status and it seems that gsp positive patients are better responders (20)(21)(22)(23)(24)(25)(26), although there is some controversy in the literature (18).…”

“…Immunohistochemical detection of somatostatin receptor subtype 2 (SSTR2) correlates positively with percent GH reduction on acute test and IGF-I after 6 months of treatment (18,19). When molecular analysis of the ressected tumor is possible, the presence of the gsp oncogene seems to be indicative of a good response to SA treatment (20)(21)(22)(23)(24)(25)(26). Despite the fact that most studies suggest that gsp-positive adenomas respond better to octreotide LAR ® compared to gsp-negative tumors, a recent study failed to fi nd differences in octreotide LAR ® sensitivity according to gsp status (18).…”

“…Despite the fact that most studies suggest that gsp-positive adenomas respond better to octreotide LAR ® compared to gsp-negative tumors, a recent study failed to fi nd differences in octreotide LAR ® sensitivity according to gsp status (18). In addition, expression profi les of the mRNA somatostatin receptor subtypes (SSTR) in tumor fragments may serve as a predictive tool of biochemical and tumor volume response to SA therapy (24,(27)(28)(29)(30)(31)(32).…”