Inhibitory effects of the antiprogestin, RU 486, on progesterone actions and luteinizing hormone secretion in pituitary gonadotrophs

Abstract

The effects of RU486 on the modulation of LH release by progesterone were investigated in cultured anterior pituitary cells from ovariectomized adult female rats. The inhibitory effect of progesterone on LH secretion was demonstrable in estrogen-treated pituitary cells, in which addition of 10 −6M progesterone to cells cultured in the presence of 10 −9M estradiol for 52 h reduced the LH response to GnRH (10 −11 to 10 −7 M). When RU 486 was superimposed upon such combined treatment with estradiol and progesterone, the suppressive effect of progesterone on GnRH-induced LH release was completely abolished. The converse (facilitatory) effect of progesterone on LH secretion was observed in pituitary cells pretreated with 10 −9 M estradiol for 48 h and then with 10 −6M progesterone for 4h. When RU486 was added together with progesterone during the 4 h treatment period, the facilitatory effect of progesterone was blocked and LH release fell to below the corresponding control value. The direct effect of RU 486 on LH secretion in the absence of exogenous progesterone was evaluated in cells cultured in the absence or presence of 10 −9M estradiol and then treated for 4 to 24 h with increasing concentrations of RU486 (10 −12 to 10 −5M) and stimulated with GnRH (10 −9M) during the last 3 h of incubation. In estrogendeficient cultures, 4 h exposure to RU486 concentrations of 10 −6M and above decreased the LH response to GnRH by up to 50%. In cultures pretreated with 10 −9 M estradiol, GnRH-stimulated LH responses was inhibited by much lower RU486 concentrations, of 10 −9M and above. After 24 h of incubation the effects of RU 486 were similar in control and estradiol-pretreated pituitary cell cultures. Thus, RU 486 alone has a significant inhibitory effect on LH secretion that is enhanced in the presence of estrogen. The antiprogestin is also a potent antagonist of both the inhibitory and the facilitatory actions of progesterone upon pituitary gonadotropin release in vitro.