Antiprogestins RU486 and ZK299 suppress basal and LHRH-stimulated FSH and LH secretion at pituitary level in the rat in an oestrous cycle stage-dependent manner

We have previously shown that administration of antiprogestin (AP) type II RU486 to ovariectomized (OVX) rats on the morning of pro-oestrus decreases the magnitude of the preovulatory gonadotrophin surge. This suggests that t he effect of RU486 on LHRH-dependent gonadotrophin release may be independe nt of its ability to block progesterone actions. The aim of the present res earch was to study the possible site of RU486 action and to determine wh et her the gonadotrophin-suppressive effect of APs RU486 and ZK299 is dependen t on the oestrogen background, Intact or OVX rats in the morning of pro-oestrus were injected s.c. with 4 mg RU486 or ZK299 (AP type I) at 0900 h on pro-oestrus. At 1830 h, serum co ncentrations of FSH and LH and median eminence (ME) content of LHRH were de termined. In the second experiment, the effect of RU486 and ZK299 on pituit ary responsiveness to LHRH (100 ng, i.p.) and ME content of LHRH at 1830 h in pentobarbital (PB)-blocked intact or OVX rats was evaluated. In the last study, the anterior pituitary release of FSH and LH from pro-oestrous or m etoestrous donors incubated with or without LHRH (1, 10 or 100 nM) in the p resence or absence of APs (20 nM) was evaluated. Both APs reduced serum FSH and LH levels at 1830 h on pro-oestrus in intact and OVX rats. The suppressive effect on gonadotrophin release brought abou t by AP treatment was also evidenced in PB-blocked intact and OVX rats. Thi s suggested that the inhibitory effect of APs occurred, at least in part, a t the pituitary level. Furthermore, in the absence of the natural ligand, A Ps significantly reduced basal and LHRH-stimulated FSH and LH release from pro-oestrous but not metoestrous pituitaries. In conclusion, these experiments have shown, both in vivo and ill vitro, th at APs RU486 and ZK299 have suppressive effects at the pituitary level on b asal and LHRH-stimulated FSH and LH secretion, regardless of their antiprog estagenic activity, in pro-oestrus but not in metoestrus.