SECRETORY MECHANISMS OF GROWTH-HORMONE (GH)-RELEASING PEPTIDE-INDUCED, GH-RELEASING HORMONE-INDUCED, AND THYROTROPIN-RELEASING HORMONE-INDUCED GH RELEASE IN PATIENTS WITH ACROMEGALY

The: GH secretory mechanism of GH-releasing hexapeptide (GHRP-6), GHRH , and TRH were studied in vivo and in vitro in seven patients with acr omegaly. In an in vivo study, these patients showed clear GH responses to single administration of GHRP (four of four patients), GHRH (seven of seven patients), and TRH (seven of seven patients) and enhanced re sponses to GHRP plus GHRH (two of four patients) or TRH plus GHRH (six of six patients). In an in vitro dispersed cell study, the majority o f patients examined also showed clear GH responses to GHRP (four of fo ur patients), GHRH (six of six patients), and TRH (four of four patien ts) and an enhanced response to GHRF plus GHRH (three of three patient s) or TRH plus GHRH (three of four patients). In one patient (no. 3). GHRP plus forskolin (adenylate cyclase activator), but not GHRP plus p horbol 12-myristate 13-acetate (protein kinase C activator), additivel y enhanced the GH response. Nordihydroguaiaretic acid (NDGA; inhibitor of arachidonic cascade) inhibited GH release induced by GHRP, TRH, GH RH, TRH plus GHRH. or GHRP plus GHRH, but did not inhibit basal GH sec retion. In contrast, NDGA distinctly elevated intracellular cAMP level s in another patient (no. 7) when coadministered with GHRP, GHRH, or G HRP plus GHRH, whereas cAMP lei els mere not modified by single admini stration of GHRP and NDGA. The GH response to the combined administrat ion of GHRP and GHRH was synergistic in this patient, but was additive in the other two patients. It is concluded that GHRF, TRH, and GHRH d irectly stimulate in vivo and in vitro GR release from human somatotrp inomas, and GHRP and TRH mainly exert their action through activation of the phosphatidylinositol-protein kinase C pathway, whereas GHRH exe rts its action through the adenylate cyclase-protein kinase A pathway. These three agents seem to release GH sia the arachidonic cascade.