Inhibitory Effects of GHRH Antagonists on Human GH-Secreting Adenoma Tissue

Abstract

Experimental data indicate that antagonists of growth hormone-releasing hormone (GHRH) could be used clinically in disorders characterized by excessive GHRH/growth hormone (GH) secretion, but direct evidence for the effectiveness of GHRH antagonists on human pituitary tissue is still lacking. In this study, we investigated the inhibitory effect of our GHRH antagonists MZ-4-71 and JV-1-36 and the somatostatin (SST) analog RC-160 on superfused pituitary cells obtained from a human GH-secreting adenoma. Using Western blot analysis and immunohistochemistry, we demonstrated profuse expression of the GHRH receptor and its major splice variant SV1 and an increase in the expression of Gsa protein in the adenoma tissue. Exposure of the tumor cells to exogenous pulses of GHRH induced definite GH responses, causing a 3- to 5-fold elevation of the basal GH level. The antagonists MZ-4-71 and JV-1-36 did not alter basal GH secretion, indicating that the adenoma cells did not secrete GHRH in an autocrine manner. However, both antagonists prevented the stimulatory effect of exogenous GHRH. Similarly to the GHRH antagonists, neither SST-14 nor the SST analog RC-160 had an effect on the basal GH secretion of the tumor cells, but both peptides inhibited the stimulatory effect of exogenous GHRH, with RC-160 being more potent than SST. Our study provides direct evidence for the effectiveness of potent GHRH antagonists such as MZ-4-71 and JV-1-36 on human pituitary GH-secreting adenoma tissue and strongly suggests that these drugs could be used for therapy of GHRH-associated forms of acromegaly, particularly for those patients in whom surgery fails or is not an option.