Progesterone modulation of estrogen-stimulated uterine biosynthetic events and estrogen receptor levels

The effect of progesterone on estrogen-stimulated biosynthetic events - namely, glucose metabolism, fluid imbibition, DNA synthesis, and replenishment of estrogen receptor - is studied in uteri of immature (22-24-day-old) rats and immature estrogen-primed rats. Pretreatment with progesterone alone (2 mg s.c./rat) for up to 48 h does not markedly influence the subsequent uterine response to estrogen in terms of 2-h deoxyglucose metabolism, 3-h uterine wet weight or 24-h DNA synthesis rate. Moreover, progesterone alone increases uterine glucose metabolism and the rate of DNA synthesis, as does estradiol (5 Mg), although the magnitude of the responses obtained is lower with progesterone. However, simultaneous exposure to progesterone plus estradiol (E + P) for over 12 h results in a decreased uterine responsiveness to subsequent estrogen as monitored by glucose metabolism and uterine wet weight stimulation. This decreased responsiveness to estrogen after exposure to E + P correlates with a decreased content of uterine cytosol estrogen receptor. After treatment with E (5 Mg) plus P (0.5 or 2 mg), or E alone, the initial movement of the estrogen receptor into the nucleus is similar, but by 12 h after E + P the rate of reappearance of the cytosol receptor is slower and the levels of cytosol receptor are depressed, reaching only 50-60% of that seen after E alone. This depression of cytosol receptor replenishment is most marked with the steroid progesterone, although exposure to estradiol (5 μg) plus high doses of dihydrotestosterone or testosterone (2 mg), but not low doses (0.5 mg), results in slightly depressed levels of cytosol receptor at 12-48 h. Cortisol (0.5 or 2 mg) is without any effect. Administration of either progesterone or the inhibitor cycloheximide or actinomycin D at zero time (along with the estradiol) or up to 4-6 h following estradiol injection is markedly effective in decreasing the levels of estradiol cytoplasmic receptor (to approx. 40-50% of the control, E alone, level by 12 h) in 3-day estrogen-primed rat uteri. The striking similarity in the time course and extent of the cycloheximide-, actinomycin D-, and progesterone-sensitive inhibition of estrogen receptor replenishment suggests that progesterone may influence uterine sensitivity to estrogen by interfering with the de novo synthesis of new estrogen receptors.