Relationship between the Quantity of Progesterone Receptor and the Antagonism of Estrogen-Induced Uterotropic Response*

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Abstract
The ability of the uterus to respond to progesterone was examined as a function of cytosol progesterone receptor levels. The response was assessed by measuring the capacity of progesterone to antagonize estradiol-induced uterine fluid accumulation in uteri containing either high or low levels of progesterone receptor. High receptor levels (4-12 pmol/uterus) were induced by estradiol treatment (1.0 μg/rat/day for 2 days) in ovariectomized rats. Low levels (≤2 pmol/uterus) were obtained by injecting estrogen-primed rats with 0.5 mg progesterone and waiting 24 h before subsequent treatment. Progesterone (0.5 mg) was very effective in inhibiting estradiol-induced uterine fluid accumulation in uteri with high levels of receptor, whereas the same dose of progesterone was without effect in uteri with low levels of receptor. These data demonstrate that the level of cytosol progesterone receptors is correlated with the ability of the uterus to respond to progesterone. The reduction in progesterone receptors observed 24 h after an injection of 0.5 mg progesterone was not due to a shift in ligand specificity, a change in dissociation constant, or increased in vitro Ca++-dependent proteolysis of receptor. Instead, we conclude that the reduction is due to an actual decrease in the number of progesterone receptor sites. This receptor reduction after progesterone treatment is preceded by complete replenishment of uterine cytosol receptor within 12 h of injection in the adrenalectomized-ovariectomized rat. Therefore, the mechanism by which cytosol progesterone receptors are decreased at 24 h must operate between 12–24 h. In conclusion, the reduction of progesterone receptors in uterine cytosol 24 h after progesterone treatment results from an actual decrease in receptor numbers which occurs during the period 12–24 h after injection. This loss of receptors reduces the ability of the uterus to respond to subsequent progesterone administration.