EFFECTS OF PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE ON HORMONE-SECRETION BY HUMAN PITUITARY-ADENOMAS IN-VITRO

Hormone release in culture in response to pituitary adenylate cyclase- activating polypeptide (PACAP) was examined in 28 human pituitary aden omas: 10 null cell adenomas, 4 gonadotropin-, 6 GH-, 6 ACTH-, and 2 PR L-producing adenomas. The effects of PACAP38 were compared with those of the classical hypothalamic releasing hormones and other activators of intracellular signaling pathways. PACAP38 significantly stimulated GH release from 1 somatotrope tumor (125 +/- 3% of control; P < 0.05) and ACTH release from 3 corticotrope tumors (134 +/- 6%, 136 +/- 7%, a nd 137 +/- 9% of control; P < 0.05). The effects of PACAP38 were less potent than either GHRH on GH release in the somatotrope tumor or CRH on ACTH release in the corticotrope tumors but similar to the response s seen with the cAMP analog 8-bromo-cAMP (8-Br-cAMP). No detectable ef fects of PACAP38 on hormone release from null cell, gonadotropin-, or PRL-producing adenomas were observed. Of the 5 somatotrope tumors that failed to respond to PACAP38, all also failed to respond to either 8- Br-cAMP, TRH, or GHRH. Of the corticotrope tumors that failed to respo nd, 2 of the 5 also failed to respond to CRH. In addition to eliciting hormone release appropriate to the tumor type, PACAP38 also stimulate d glycoprotein hormone cu-subunit (alpha SU) release from one somatotr ope tumor (229 +/- 35% of control, P < 0.01) and one corticotrope tumo r (149 +/- 4% of control; P < 0.01). This response was not mimicked by 8-Br-cAMP in the somatotrope tumor, but in the corticotrope tumor a s ignificant alpha SU release was also seen after stimulation with the p rotein kinase C activator 12-0-tetradecanoyl-phorbol-13-acetate and 8- Br-cAMP. These results suggest that the novel hypothalamic peptide PAC AP38 has a modest role in the regulation of GH, ACTH, and alpha SU sec retion from some human tumorous pituitary corticotropes and somatotrop es. Further studies ate needed to elucidate the intracellular signalin g pathways that mediate the effects of PACAP on hormone secretion by t hese tumor types.