GROWTH-HORMONE (GH)-RELEASING HORMONE TONICALLY INHIBITS IN-VITRO ENDOGENOUS SOMATOSTATIN IN HUMAN GH-SECRETING TUMORS

We have previously shown that the somatostatin (SRIH) precursor (pro-S RIH) and SRIH are present in the normal human pituitary, whereas matur e SRIH is never detected in GH-secreting adenomas associated with high plasma GH levels, and pro-SRIH is absent in 50% of them. Considering the fact that GHRH is present and released in vitro in higher amounts from GH adenomas than from normal. human pituitaries, the possibility of a negative control exerted by GHRH on pituitary SRIH was investigat ed. When GH-secreting adenomas were incubated for 4 h in the presence of GHRH (10(-8) mol/L), the amount of pro-SRIH, quantified after Sepha dex G-50 filtration of the acetic acid extracts, was significantly dec reased. The percent inhibition was negatively correlated to the amount of endogenously released GHRH measured in the control incubation medi um, suggesting a local negative feedback control exerted by pituitary GHRH on pituitary SRIH. This was further demonstrated when adenomas we re incubated with a GHRH antibody. Indeed, the presence of the GHRH an tibody resulted in a significant increase in the content of pro-SRIH i n the adenoma. Similar results were obtained for in vitro SRIH release ; exogenous GHRH induced an inhibition of SRIH release from GH-secreti ng adenomas, and the GHRH antibody had the opposite effect. Using a pe rifusion system, we showed the concomitance between the increase in GH release and the decrease in SRIH release after GHRH stimulation. Toge ther, these results show in vitro a negative control exerted by GHRH ( both exogenous and locally released) on adenomatous pituitary SRIH. Th is further amplifies the importance of autocrine or paracrine controls in these tumors.