Biphasic Effect of Gonadotropin-Releasing Hormone and Its Agonist Analog (HOE766) on in Vitro Testosterone Production by Purified Rat Leydig Cells

Abstract

GnRH [gonadotropin-releasing hormone] and GnRH agonists have stimulatory and inhibitory effects on testicular testosterone secretion both in vivo and in vitro. To determine whether they are exerted directly on the Leydig cells and to explore the temporal relationships, the effects of acute (3 h) and chronic (24-72 h) exposure of purified (.gtoreq. 80%) rat Leydig cells to GnRH and its agonist analog HOE766 (D-Ser-t-BU6, des-Gly-NH210LHRH ethylamide; on testosterone production were examined. GnRH and HOE766 enhanced basal testosterone secretion by freshly isolated or cultured Leydig cells. HOE766 was at least 100 times more potent than GnRH. However, exposure of Leydig cells to HOE766 for 24 h or longer lead to a significant reduction in hCG [human chorionic gonadotropin] responsiveness without altering basal testosterone secretion. Both the stimulatory and inhibitory effects were dose related, with a maximal response elicited by 10-9 M HOE766. HOE766 reduced Leydig cell sensitivity to hCG (ED50) stimulation, but did not alter the slope of the dose-response curves. GnRH and its agonist appear to have a dual and biphasic effect on the Leydig cells. Acute exposure stimulates basal testosterone secretion (and occasionally the hCG response), while chronic exposure decreases the response to hCG stimulation. These data provide additional evidence that GnRH has a direct effect on Leydig cell steroidogenesis.