Effects of progesterone (P) and antiprogestin RU486 on LH and FSH release by incubated pituitaries from rats treated with the SERM LY117018-HCl and/or recombinant human FSH

The aim of the present study was to investigate the role of the estrogen (ES) background on the effects of P or its antagonist RU486 on basal and LHRH-stimulated LH and FSH secretion. To do this, pituitaries collected from: intact rats in proestrus; rats injected with the ES antagonist LY117018-HCl; rats injected with recombinant-human FSH (r-hFSH) to stimulate ovarian hormonogenesis; and rats injected with both LY117018-HCl and r-hFSH were incubated with or without LHRH (10 nM) in the presence of P (100 nM) or RU486 (110 nM). RU486 decreased basal and LHRH-stimulated release of LH and FSH and LHRH self-priming in pituitaries from control rats, while P increased both pituitary responsiveness and LHRH self-priming. These effects were absent in pituitaries from rats treated either with the ES antagonist or r-hFSH, which, in the absence of P or RU486 in the incubation medium, reduced gonadotropin release. Because r-hFSH did not increase E2 serum concentration significantly, the putative FSH-dependent ovarian non-steroidal gonadotropin surge inhibiting factor (GnSIF) might be the hormonal cause of the reduced secretion of LH and FSH. Combined treatment with LY117018-HCl and r-hFSH had additive inhibitory effects on gonadotropin release. These results indicate that ES-inducible P receptor (PR) in the pituitary can be activated in a ligand-independent manner by intracellular messengers giving rise to enhanced basal and LHRH-stimulated gonadotropin secretion. The results also suggested that the r-hFSH-stimulated ovarian bioactive entity GnSIF and RU486 may share a similar mechanism of action involving pituitary PR.