Progesterone antagonism of estradiol-stimulated uterine 'induced protein' synthesis

Modulation of estrogen-stimulated uterine induced protein (IP) synthesis by progestins is studied in immature, immature estrogen-primed, and ovariectomized rats. Pretreatment with either high (2 mg) or low (0.5 mg) doses of progesterone (P) or the synthetic progestins, norgestrel or chlormadinone acetate, results in a significant inhibition of subsequent estradiol induction of IP synthesis as measured by the relative rate of IP synthesis. The inhibitory effect of the progestins is progressive with time, and is maximal (approx. 50% inhibition) by 12-24 h of in vivo exposure. The inducibility of IP synthesis then returns to the control level by 48 h. Dose-response studies in immature (day 21) rats indicate that 0.5 mg of P is as effective as 2 mg but that lower (0.1 or 0.2 mg) doses have only a slight effect on the inhibition of IP synthesis. This inhibitory effect was found to be specific to progestins and could not be obtained by pretreatment with different steroidal hormones (0.2 0.5 or 2 mg of testosterone, dihydrotestosterone, or hydrocortisone for 12 or 24 h). The antagonistic effect of P appears to be preferentially on the relative rate of synthesis of IP, and not on total uterine protein synthesis which is actually increased to approx. 150% of the control by 24 h of progestin treatment. This effect of P appears to be on the rate of synthesis of IP and not on its turnover, as IP turnover either with or without P pretreatment of uteri appears to be the same (half-life of over 24 h). The relative rate of IP synthesis in the immature rat uterus is shown to be related to the level of nuclear-bound estrogen receptor. The depressive effect of progestins on IP induction by subsequent estradiol appears to be accounted for, at least in large part, by their ability to decrease the amount of receptor sites moved to and/or retained in the nucleus by subsequent estradiol in vivo. These findings suggest that the reduced rate of synthesis of the induced protein during the estrus phase of the estrous cycle in rats, and the low inducibility of IP synthesis by exogenously administered estrogen at estrus, may be due, at least in part, to the action of progesterone.