Antagonizing diestrous progesterone actions in cyclic rats by s.c. injections of the antiprogesterone RU486 (2 mg twice a day from metestrus through proestrus) increased LH and decreased FSH basal serum concentrations. Ovariectomy at metestrus (0800 h) increased serum levels of both gonadotropins in controls and reversed the RU486-induced dissociation of basal gonadotropin secretion. RU486-dissociated gonadotropin secretion is also dependent upon LHRH, since treatment (s.c.) with 1 mg GnRH antagonist (ORG 30276) twice a day on metestrus and diestrus completely prevented both the RU486-induced increase in LH and the decrease in FSH serum concentrations. The LHRH content in the medial basal hypothalamus and median eminence increased on proestrous morning in RU486-treated rats. The LH pituitary response to an exogenous i.v. bolus of 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-injected rats. The pituitary content of both gonadotropins decreased in RU486-treated rats on proestrous morning. All these effects due to RU486 in cyclic rats were reversed by ovariectomy. Testosterone serum levels increased significantly from diestrus onward, and the estradiol concentration increased on proestrous morning in RU486-treated rats. Ovariectomy as well as LHRH antagonist treatment eliminated the effects of RU486 on ovarian steroid production. Moreover, antiestrogen tamoxifen treatment reversed RU486-dissociated gonadotropin secretion, while antiandrogen flutamide treatment had no effect. The results of this experiment have confirmed previous findings that RU486 treatment dissociates basal gonadotropin secretion in cyclic rats. In addition, the present 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 secretion 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 treated with RU486 seems to be exerted by inhibin and estradiol at the pituitary level by reducing FSH synthesis and secretion; and (4) the hypersecretion of LH in rats treated with RU486, as compared to that resulting from ovariectomy, seems to be the consequence of, first, a lack of progesterone inhibitory action on LH secretion, and, second, an inappropriate feedback system involving increased hypothalamic LHRH activity and pituitary sensitivity to LHRH of moderately high levels of estradiol in the presence of abnormally high levels of testosterone.
The antiprogesterone RU486 injected on the morning of pro-oestrus blunts the preovulatory secretion of LH and FSH and abolishes the secondary secretion of FSH during oestrus without affecting ovulation in the rat. To ascertain whether the secretion of LHRH is involved in these effects, we studied the effects of RU486 (4 mg/0.2 ml oil), given s.c. at 0800 h on pro-oestrus, on LHRH secretion into the pituitary stalk blood vessels and on peripheral plasma concentrations of LH and FSH at 1800 h on pro-oestrus and 0200 h on oestrus. Furthermore, we determined the effects of an s.c. injection of 1 mg of an LHRH antagonist (LHRH-A; ORG30276) at 2000 h on pro-oestrus and those of an i.p. injection of 100 ng LHRH (Peninsula 7201) at 0100 h on oestrus on serum concentrations of LH, FSH and oestradiol at 0200 h on oestrus in oil- and RU486-treated rats. RU486 decreased LHRH secretion at 1800 h on pro-oestrus while this was increased at 0200 h on oestrus. While the reduction of preovulatory LHRH secretion in RU486-treated rats coincided with a reduction in both LH and FSH surges during the evening of pro-oestrus, the increased LHRH secretion during the early hours of oestrus was only accompanied by an increased concentration of LH. An injection of LHRH stimulated, while that of LHRH-A inhibited serum concentrations of LH at 0200 h on oestrus in both oil- and RU486-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration of antiprogesterone RU486 to female cyclic rats results in blockade of ovulation associated with both a decreased ovulatory release of LH and an increased rate of follicular atresia. These rats also exhibit increased LH:FSH and testosterone:oestradiol ratios in serum during the period of follicular development as well as an increase in serum concentrations of prolactin that can be suppressed by a dopamine agonist. The increase in either prolactin or testosterone concentrations as well as the relative deficiency in FSH might be responsible for the increase in follicular atresia. The present work evaluated the involvement of LH, FSH, prolactin and testosterone in follicular atresia and in blockade of ovulation induced by RU486 in the cyclic rat. Although bromocriptine treatment did not modify the blockade of ovulation induced by RU486, unilateral ovariectomy at metoestrus and anti-androgen flutamide treatment reversed, in part, the effects of RU486 on both follicular development and ovulation. The combined increase in FSH serum concentration during dioestrus induced by unilateral ovariectomy and the treatment with flutamide had no additive effects. Furthermore, treatment with a superovulatory amount of hFSH did not reverse the effects of RU486. Moreover, unilateral ovariectomy halved testosterone serum concentrations and flutamide treatment had no effect on LH and FSH concentrations in RU486-treated rats. It was therefore concluded that androgens play a role, at least in part, in the process of follicular atresia induced by RU486.
Administration of 4 mg of the antisteroid RU486 over 8 consecutive days to adult male rats dissociated in vivo and in vitro gonadotrophin secretion, increasing FSH and decreasing LH secretion. In subsequent experiments we evaluated the involvement of testicular or adrenal secretory products, as well as hypothalamic LHRH, in the effects of 4 consecutive days of RU486 treatment on the secretion of gonadotrophins. The first day of RU486 injection was designated day 1, subsequent days being numbered consecutively. Groups of rats injected with oil (0·2 ml) or RU486 (4 mg) were: (i) injected s.c. from day 1 to day 4 with the antiandrogen flutamide (10 mg/kg); (ii) bilateral orchidectomized (ORCH) on day 1; and (iii) bilateral adrenalectomized (ADX) on day 1. Controls were given flutamide vehicle or were sham operated. To ascertain whether the secretion of LHRH is involved in the effects of RU486 on gonadotrophin secretion, we measured the LHRH secretion into the pituitary stalk blood vessels at 1100 h on day 5 in oil-or RU486-treated rats. Additional oil-and RU486-treated rats were injected i.p. with 100 ng LHRH at 1000 h on day 5, or s.c. with 1 mg LHRH antagonist (LHRH-ANT) at 1000 h on days 2 and 4. Controls were given saline. All animals were decapitated at 1100 h on day 5, trunk blood collected and serum stored frozen until FSH, LH and testosterone assays.While ADX had no effect on FSH and LH secretion in either oil-or RU486-treated rats, the removal of androgen negative feedback with flutamide treatment or by ORCH substantially increased serum levels of FSH and LH in both oil-and RU486-treated rats, and thus annulled the effects of RU486. No differences in pituitary stalk plasma LHRH concentrations were found between oil-and RU486-treated rats. Injection of LHRH increased serum FSH and LH concentrations in oil-treated rats but only, and to a lesser extent, LH concentrations in RU486-treated rats. Treatment with LHRH-ANT decreased serum concentrations of FSH and LH in both oil-and RU486-treated rats. These results suggest that RU486 inhibited LHRHstimulated LH secretion at the pituitary level, and that FSH secretion increased in response to a reduction in the negative feedback of androgen.
Administration of the antiprogestagen RU486 in the morning of proestrus abolishes the secondary surge of FSH during early estrus in the rat without preventing the drop in serum inhibin. In addition, the injection of an ovulatory dose of LH to RU486-injected rats does not restore the secondary surge of FSH. Since RU486 is a potent antiprogesterone with antiglucocorticoid activity, in the first experiment we compared the effects of RU486 and a specific antiprogesterone serum (APS), administered on proestrus, on the secretion of FSH during early estrus. While RU486 and APS reduced the primary surge of LH and FSH, only RU486 abolished the secondary secretion of FSH. In the second experiment, rats injected with LHRH antagonist (LHRHa) and ovine LH (oLH) were adrenalectomized (ADX) or sham-ADX in the morning and injected with corticosterone (B) or oil in the afternoon of proestrus. LHRHa completely eliminated, and oLH restored, the secretion of FSH at 0200 h in estrus. ADX reduced FSH serum concentration at 0200 h in estrus, and B reversed this effect in rats injected with LHRHa and oLH. The results of these experiments indicate that, in the rat, the LHRH-independent secretion of FSH during early estrus is evoked by the combined effects of the preovulatory surge of LH and the rise in serum B on proestrous afternoon.
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