GnRH Antagonist-induced Down-regulation of the mRNA Expression of Pituitary Receptors: Comparisons with GnRH Agonist Effects

Abstract

Abstract. In order to compare the mechanism for the down regulation of the mRNA expression of pituitary receptors induced by GnRH antagonist (GnRHant) to that by GnRH agonist (GnRHa), we examined the effects of GnRHant (Cetrorelix, 333 mg/kg/day), GnRHa (leuprolide depot, 333 mg/kg), and GnRHant combined with GnRHa on LH response to exogenous GnRH, pituitary LH content, LHb subunit mRNA, and GnRH receptor (GnRH-R) mRNA levels at 2, 5, 24, 72 hours, and 7 days after the treatment in ovariectomized rats. GnRHant significantly decreased serum LH, the LH response of the pituitary to exogenous GnRH, and the pituitary LH content compared to the control treatment, though GnRHa significantly increased serum LH. GnRHant with GnRHa significantly diminished the GnRHa-induced flare-up phenomenon. GnRHant significantly decreased LHb mRNA and GnRH-R mRNA levels, but the magnitude of the decrease in these mRNA levels by GnRHant was significantly less than those by GnRHa until 72 hours following treatment. Prolonged treatment of GnRHant caused a marked inhibition of LHb mRNA and GnRH-R mRNA expression, similar to that caused by GnRHa. Combination treatment with GnRHa and GnRHant was demonstrated to decrease LHb mRNA and GnRH-R mRNA levels as much as GnRHa alone and GnRHant alone over 7 days of the treatment. The present study showed differences between GnRHant and GnRHa treatment in the reduction of GnRH-R mRNA levels up to 72 hours after the treatment, and indicated that the suppression of GnRH-R mRNA by GnRHant was the maximal by GnRHa 7 days after the treatment because more profound suppression was not observed upon additional treatment with GnRHa. The findings in the present study support the hypothesis that the mechanism by which GnRHant leads to downregulation of the mRNA expression of pituitary receptors is similar to that of GnRHa.

Actions of gonadotropin-releasing hormone analogues in pituitary gonadotrophs and their modulation by ovarian steroids

“…In contrast, cetrorelix decreased FSH-beta mRNA [42]. Treatment of female rats for 7 days with GnRHag, GnRHant or their combination lead to a marked decrease in pituitary LH content [43]. This is contradictory to our finding that high concentrations of cetrorelix (100 nM) increased, whereas lower concentrations of cetrorelix did not affect the LH pool.…”

Sustained treatment with a GnRH agonist (leuprorelin) affects the ultrastructural characteristics of membranous organelles in male rat pituitary gonadotropes

“…Bars: 500 nm events downstream of the GnRH receptor, by mechanisms referred to as receptor/post-receptor desensitization (McArdle et al, 2002;Millar et al, 2004;Naor 2009). The present study further confirmed long-lasting suppressive effects of the depot formulation of leuprorelin on biosynthesis and release of gonadotropins (Okada et al, 1991;Murase et al, 2005), by demonstrating the chronic changes in the ultrastructure of the Golgi apparatus and ER within pituitary gonadotropes. By using the chronic effects of the leuprorelin depot formulation, we further examined whether the GnRH agonist could also suppress the hypertrophic state of gonadotropes long after castration.…”

Effect of immunization against GnRH on hypothalamic and testicular function in rams

“…Suppression of hypothalamic GnRH input, either by passive anti-GnRH immunization [26] or GnRH antagonist administration [27], also reduced GnRH receptor mRNA and its protein concentrations in the pituitary, suggesting the need for sustained GnRH stimulation to maintain pituitary GnRH receptors. Reduced pituitary GnRH receptor mRNA expressions after anti-GnRH immunization indicated decreased pituitary responsiveness to GnRH stimulation.…”