Comparison of mechanisms of action of luteinizing hormone-releasing hormone (LHRH) antagonist cetrorelix and LHRH agonist triptorelin on the gene expression of pituitary LHRH receptors in rats

The mechanisms through which luteinizing hormone (LH)-releasing hormone (LH RH) antagonists suppress pituitary gonadotroph functions and LHRH-receptor expression are incompletely understood. Consequently, we investigated the d irect effect of LHRH antagonist cetrorelix in vitro on the expression of th e pituitary LHRH-R gene and its ability to counteract the exogenous LHRH an d the agonist triptorelin in the regulation of this gene. We also compared the effects of chronic administration of cetrorelix and triptorelin on the LHRH-R mRNA level and gonadotropin secretion in ovariectomized (OVX) and no rmal female rats. The exposure of pituitary cells in vitro to 3-min pulses of 1 nM LHRH or 0.1 nM triptorelin for 5 h increased the LHRH-R mRNA level by 77-88%. Continuous perfusion of the cells with 50 nM cetrorelix did not cause any significant changes, but prevented the stimulatory effect of LHRH pulses on the receptor mRNA expression. In OVX rats, 10 days after adminis tration of a depot formulation of cetrorelix, releasing 100 mug of peptide daily, the elevated LHRH-R mRNA level was decreased by 73%, whereas daily i njection of 100 mug of triptorelin caused a 41% suppression. In normal fema le rats, cetrorelix treatment suppressed the LHRH-R mRNA level by 33%, but triptorelin increased it by 150%. The highly elevated serum LH levels in OV X rats and the normal LH concentration of cycling rats were rapidly and com pletely suppressed by cetrorelix. Triptorelin decreased the serum LH in OVX rats to the precastration level, but had no effect on basal LH in normal r ats. Our results confirm that LHRH antagonists, such as cetrorelix, inhibit the gene expression of pituitary LHRH-R indirectly, by counteracting the s timulatory effect of LHRH. A rapid suppression of serum LH by LHRH antagoni sts would be advantageous in the treatment of sex hormone-dependent tumors and other conditions.