Replenishment and Properties of Cytosol Progesterone Receptor in Rabbit Uterus after Multiple Progesterone Administrations*

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Abstract
To clarify the role of progesterone in the regulation of its own uterine receptors, nuclear and cytosol progesterone receptors in uteri of 5-day-progesterone-treated rabbits were investigated before and after an acute challenge with progesterone. Properties of the cytosol receptor present after the progesterone administration were also compared with those of the receptor induced by estradiol. All receptor assays were carried out using the synthetic progestin ORG 2058 (16α-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione) as the labeled ligand. The physicochemical characteristics of the cytosol progesterone receptors in the rabbit uterus (equilibrium dissociation constant for ligand binding, density gradient sedimentation properties, and binding to and elution from DNA-Sepharose column) were indistinguishable after long term progesterone or estradiol administration. When iv progesterone (5 mg/kg BW) was given to rabbits exposed to this steroid during the preceding 5 days, the osol receptor content rapidly declined and reached a nadir within 0.5-1 h. The decrease in the cytosol receptor content was accompanied by a small and temporary nuclear progesterone receptor accumulation that did not, however, account for all of the receptor sites lost from cytosol. A relatively rapid and almost complete cytosol receptor replenishment occurred within 4 h of progesterone administration in rabbits pretreated with progesterone, in contrast to previous findings of a defective progesterone receptor replenishment in estrogen-primed rabbits. The short-lived receptor accumulation in the nuclei was followed by a decrease in the nuclear receptor content to a level that was 70% of the pretreatment value. Acute administration of progesterone brought about changes in the sedimentation velocity of the cytosol receptor. At times of receptor decline and during the early replenishment phase, a 4.6S receptor form was found, in contrast to the 6.2S receptor entity present after a chronic progesterone exposure or during later phases of the replenishment phenomenon. Ligand-binding affinity, degree of receptor activation, or binding to and elution from the DNA-column were not acutely modified by the iv progesterone administration. Collectively, these data suggest that regulation of progesterone receptor dynamics by the homologous steroid is different in animals previously exposed to progesterone compared to those primed with estradiol. An active replenishment of the cytosol receptor content under these conditions may be the mechanism by which continuation of the biological responsiveness to progesterone is ensured. (Endocrinology108: 868, 1981)