HYPOTHALAMUS-PITUITARY-OVARIAN AXIS IN CYCLIC RATS LACKING PROGESTERONE ACTIONS

Antagonizing diestrous progesterone actions in cyclic rats by s.c. inj ections of the antiprogesterone RU486 (2 mg twice a day from metestrus through proestrus) increased LH and decreased FSH basal serum concent rations. Ovariectomy at metestrus (0800 h) increased serum levels of b oth gonadotropins in controls and reversed the RU486-induced dissociat ion of basal gonadotropin secretion. RU486-dissociated gonadotropin se cretion is also dependent upon LHRH, since treatment (s.c.) with 1 mg GnRH antagonist (ORG 30276) twice a day on metestrus and diestrus comp letely prevented both the RU486-induced increase in LH and the decreas e in FSH serum concentrations. The LHRH content in the medial basal hy pothalamus and median eminence increased on proestrous morning in RU48 6-treated rats. The LH pituitary response to an exogenous i.v. bolus o f 25 ng LHRH (Peninsula 7201; Peninsula Laboratory, inc., Merseyside, UK) at 1700 h on diestrus was enhanced in rats treated with RU486. No differences in pituitary FSH response were noted with respect to oil-i njected rats. The pituitary content of both gonadotropins decreased in RU486-treated rats on proestrous morning. All these effects due to RU 486 in cyclic rats were reversed by ovariectomy. Testosterone serum le vels increased significantly from diestrus onward, and the estradiol c oncentration increased on proestrous morning in RU486-treated rats. Ov ariectomy as well as LHRH antagonist treatment eliminated the effects of RU486 on ovarian steroid production. Moreover, antiestrogen tamoxif en treatment reversed RU486-dissociated gonadotropin secretion, while antiandrogen flutamide treatment had no effect. The results of this ex periment have confirmed previous findings that RU486 treatment dissoci ates basal gonadotropin secretion in cyclic rats. In addition, the pre sent results show that (1) this effect of RU486 is not due to a direct effect of this compound or to the blockade of progesterone action at a central level; (2) the effect of RU486 on pituitary gonadotropin sec retion depends on ovarian substances other than progesterone and LHRH, since it is reversed by ovariectomy and completely abolished by LHRH antagonist treatment; (3) the reduction in FSH serum levels in rats tr eated with RU486 seems to be exerted by inhibin and estradiol at the p ituitary level by reducing FSH synthesis and secretion; and (4) the hy persecretion of LH in rats treated with RU486, as compared to that res ulting from ovariectomy, seems to be the consequence of, first, a lack of progesterone inhibitory action on LH secretion, and, second, an in appropriate feedback system involving increased hypothalamic LHRH acti vity and pituitary sensitivity to LHRH of moderately high levels of es tradiol in the presence of abnormally high levels of testosterone.