Mechanisms Regulating the Concentration and the Conformation of Progesterone Receptor(s) in the Uterus

Abstract

Abstract After administration of estradiol to castrated guinea pigs, a rise in the uterine concentration of specific progesterone binding sites (receptor) was observed as early as at 6 hours, and the peak of concentration (8-fold over basal values) was obtained within approximately 24 hours. The effect of the estrogen was prevented by RNA and protein synthesis inhibitors administered 15 min before estrogen. On the other hand, these compounds had no effect when administered 20 hours after estradiol. These results were obtained by using animals with a stable low concentration of receptor (as observed after castration of the cycling guinea pig at diestrus, a time when the concentration is the lowest). From the rate of the decay of binding site concentration during a period of time when no more synthesis of the receptor occurs, the approximate half-life of the receptor was found to be 5 days. When progesterone was administered 20 hours after the estrogen, it provoked a rapid fall in receptor concentration, so that less than 20% remained 1 day after the injection. This decrease was neither due to masking by unlabeled progesterone nor due to the accumulation of receptor-steroid complexes in the nucleus. The progesterone effect was not prevented by protein synthesis inhibitors. After hormone injection, there were also variations in the sedimentation coefficient of the progesterone receptor. After estradiol, initially only the 4.5 S form increased, but secondarily the 6.7 S receptor became predominant. During the decay in receptor concentration, the 6.7 S binder disappeared faster, so that 7 days after estrogen injection equal amounts of both molecular forms were observed. These data suggest that the progesterone receptor in the guinea pig uterus is under a double control: a positive control by estrogen, requiring RNA and protein synthesis, and a negative control by progesterone, possibly due to an increased inactivation rate. In vitro experiments have indicated that the rate of inactivation of receptor molecules located in the nuclei is faster than that of the cytosol receptor. The relevance of this observation to the physiological situation, however, is still undecided. The effects of estradiol and progesterone on progesterone receptor content in the uterus are compatible with the cyclic changes observed physiologically in intact animals. It is not known whether these changes in the concentration of uterine receptor are due to molecular variations in individual cells or to variations in cell population.