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

Abstract

GnRH 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, we examined the effects of acute (3 h) and chronic (24-72 h) exposure of purified (greater than or equal to 80%) rat Leydig cells to GnRH and its agonist analog HOE766 (D-Ser-t-BU6,des-Gly-NH2 10LHRH ethylamide; Hoechst, Frankfurt, Germany) on testosterone production. 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 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. Thus, 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), whereas chronic exposure decreases the response to hCG stimulation. These data provide additional evidence that GnRH has a direct effect on Leydig cell steroidogenesis.

Dose and time effects of treatment with low doses of a LRH agonist on testicular axis and accessory sex organs in rats

“…The doses of the 'agonist' used are relatively low. When given for a short time such doses have been shown to exert no inhibitory effects on the weights of sex organs and steroido¬ genesis (Sandow et al 1978;Huhtaniemi et al 1983;Sharpe et al 1983a;Browning et al 1983). Our data show that at the pituitary level these doses of the 'agonist' disclose only a stimulatory effect on LH and FSH secretion for the 15 days of treatment, the gonadotropin responses to the 'agonist' being, however, more marked during the first days of treatment than during the following days.…”

“…A short-term exposure to LRH or to LRH agonist indirectly enhances testicular function by stimulation of the release of the gonadotropins and a long-term exposure para¬ doxically inhibits testicular function as a conse¬ quence of elevated gonadotropin levels and down regulation of the LH/hCG receptors (Sandow et al 1980;Seguin et al 1982). However, LRH and its agonists can also act directly on the testes to reduce gonadotropin and Prl receptors (Auclair et al 1977) and inhibit testicular steroidogenesis and spermatogenesis (Hsueh et al 1983;Belanger et al 1980a,b;Browning et al 1983;Rivier et al 1979;Pelletier et al 1980). These direct actions are mediated by specific high affinity membrane receptors for LRH on the interstitial cells (Clayton et al 1980;Clayton & Catt 1981).…”

A remarkable Activity of Steroid Biosynthesis in Captopril Preserved Leydig Cells of Mice Implicated Leukotriene B4 and Gonadotropin Releasing Hormones in vitro

“…Furthermore, it is known that short-term in vitro treatment of GnRH stimulates testosterone production by adult rat Leydig cells (27), whereas, long-term incubation decreases the response to LH (28). In addition, GnRH or its agonist induced paradoxical effects on testosterone secretion in adult hypophysectomized rats (29) by inhibiting basal and LHdependent steroidogenesis in rat fetuses in vivo.…”

Transcripts of testicular gonadotropin-releasing hormone, steroidogenic enzymes, and intratesticular testosterone levels in infertile men

“…Short-term treatment of adult rat Leydig cells with GnRH resulted in increased T production (10,11), while long-term incubation decreased the response to hCG stimulation (12). Administration of GnRH or its agonist induced paradoxical inhibitory effects on the T secretion and reproduction function in adult hypophysectomized rats (13,14) and inhibited the basal and LH-dependent steroidogenesis in rat fetus (15,16).…”