SOMATOSTATIN RECEPTOR (SSTR) SUBTYPE-SELECTIVE ANALOGS DIFFERENTIALLYSUPPRESS IN-VITRO GROWTH-HORMONE AND PROLACTIN IN HUMAN PITUITARY-ADENOMAS - NOVEL POTENTIAL THERAPY FOR FUNCTIONAL PITUITARY-TUMORS

Previously, we have shown somatostatin receptor (SSTR) subtype-specifi c regulation of growth hormone (GH), thyroid-stimulating hormone, and prolactin (PRL) secretion in human fetal pituitary cultures, where GH and thyroid-stimulating hormone are mediated by both SSTR2 and SSTR5, whereas SSTR2 preferentially mediates PRL secretion. We now tested SST R subtype-selective analogues in primary human GH-and PRL-secreting pi tuitary adenoma cultures. Analogue affinities determined by membrane r adioligand binding in cells stably expressing human SSTR forms were ei ther SSTR2 or SSTR5-selective. Analogues preferential either for SSTR2 , including octreotide, lanreotide, and novel compounds with improved affinity for SSTR2, or new SSTR5-selective compounds suppressed GH in tumor cell cultures (up to 44% of control; P < 0.0005). However, novel analogues from both groups were 30-40% more potent than octreotide an d lanreotide in suppressing GH (P < 0.05). Heterologous analogue combi nations containing both SSTR2- and SSTR5-selective compounds were more potent in decreasing GH than analogues used alone (P < 0.05), or than combinations of compounds specific for the same receptor subtype (P < 0.005). In contrast, SSTR2-selective analogues did not suppress PRL r elease from six cultured prolactinomas studied. However, new SSTR5-sel ective analogues suppressed in vitro PRL secretion (30-40%; P < 0.05) in four of six prolactinomas. These results suggest that both SSTR2 an d SSTR5 are involved in GH regulation in somatotroph adenoma cells, wh ereas SSTR5 exclusively regulates PRL secretion from prolactinoma cell s. Thus, somatostatin analogues with improved selective binding affini ty for these receptor subtypes may be effective in the treatment of ei ther GH-or PRL-secreting adenomas.