Progesterone receptor replenishment during sustained progesterone treatment in the hamster uterus

Previous studies have demonstrated that uterine progesterone (P) receptor is under dual hormonal control; estradiol (E2) induces the synthesis of cytosolic P receptor, and P induces the loss of its own receptor and antagonizes E2-induced P receptor replenishment. The objective of this study was to examine the contributions of E2 and P in the replenishment of uterine P receptor during sustained P exposure. Silastic implants of varying length (0.4, 0.8, 1.5, 2.5, and 5.0 cm) were packed with crystalline P and placed sc in the flank region of ovariectomized adult female hamsters. The serum P levels obtained with these implants (2-22 ng/ml) were within the physiological range observed previously during the estrous cycle, pregnancy, and lactation in the Syrian hamster. Control animals received a blank implant (1.5 cm). Three, 5, and 7 days after placement of the implants, uterine cytosolic and nuclear P receptor levels were decreased as serum P level was increased by the P implants. Total cellular P receptor level was inversely correlated with serum P level at 3 days (r = -0.996), 5 days (r = -0.98), and 7 days (r = -0.99). To distinguish the effect of E2 and P, ovariectomized animals were maintained on Silastic implants of P (1.5 cm) or P plus E2 (1.0 cm). After 3 days, cytosolic P receptor was determined 0, 8, 16, 24, and 48 h after removal of P implants. No difference was observed in cytosolic P receptor between P and P plus E2 groups before P withdrawal. E2-maintained animals showed a significant rise of cytosolic P receptor at all time points after P withdrawal. Although P withdrawal in the absence of E2 showed no significant change in P receptor at 8 or 16 h, a significant increase in P receptor (equivalent to that of ovariectomized control animals) was observed at 24 and 48 h. Treatment of ovariectomized animals with cycloheximide significantly reduced uterine cytosolic P receptor levels 8, 18, and 24 h after treatment. These results suggest that 1) an active receptor replenishment process occurs in the absence of E2; 2) this replenishment process does not appear to be P dependent, but, rather, constitutively expressed; and 3) the rate of constitutive P receptor replenishment is slower and of lower magnitude than that promoted by E2. Because P antagonizes E2-induced P receptor, a constitutive P receptor replenishment mechanism may play an important role in the maintenance of P action during sustained P exposure, such as in pregnancy.