Human somatostatin receptor subtypes in acromegaly: Distinct patterns of messenger ribonucleic acid expression and hormone suppression identify different tumoral phenotypes

Recently, studies using somatostatin (SRIF) analogs preferential for either the SRIF receptor 2 (SSTR2) or the SSTR5 subtype demonstrated a variable s uppression of GH and PRL release fi om GH-secreting human adenomas. These d ata suggested the concept of SSTR subtype specificity in such tumors. In th e present study the quantitative expression of messenger ribonucleic acid ( mRNA) far the 5 SSTR subtypes and the inhibitory effects of SRIF14; SRIF28; octreotide; the SSTR2-preferential analog, BIM-23197; and the SSTR5-prefer ential analog, BIM-23268, on GH and PRL secretion were analyzed in cells cu ltured from 15 acromegalic tumors. RT-PCR analysis revealed a consistent pa ttern of SSTR2 and SSTR5 mRNA expression. SSTR5 mRNA was expressed at a hig her level(1052 +/- 405 pg/pg glyceraldehyde-3-phosphate dehydrogenase) than SSTR2 mRNA (100 +/- 30 pg/pg glyceraldehyde-3-phosphate dehydrogenase). Ho wever, only SSTR2 mRNA expression correlated with the degree of GH inhibiti on induced by SRIF14, SRIF28, and BIM-23197. The SSTR5-preferential compoun d inhibited GH release in only 7 of 15 cases. In cells cultured from the 10 mixed adenomas that secreted both GH and PRL, RT-PCR analysis revealed a consistent coexpression of SSTR5, SSTR2, and SS TR1 mRNA. In all cases SRIF14, SRIF28, and the SSTR5-preferential analog, B IM-23268, significantly suppressed PRL, secretion, with a mean maximal inhi bition of 48 +/- 4%. In contrast, the SSTR2-preferential analogs, BIM-23197 and octreotide, were effective in suppressing PRL in only 6 of 10 cases. I n cells cultured from adenomas taken from patients partially responsive to the SRIF analog, octreotide, partial additivity in suppressing both GH and PRL secretion was observed when the SSTR2- and SSTR5-preferring analogs, BI M-23197 and BIM-23268, were tested in combination. Our data show a highly v ariable ratio of the SSTR2 and SSTR5 transcripts, according to tumors. The SSTR2-preferring compound consistently inhibits GH release, whereas the SST R5-preferring compound is the main inhibitor of PRL secretion. When both dr ugs are combined, the partial additivity observed in mixed GH- plus PRL-sec reting adenomas may be of interest in the therapeutic approach of such tumo rs.