Estradiol (E2) regulation of estrogen receptor (ER) concentrations has been shown to be both time- and dose-dependent. E2 concentrations of 0.5 mg/ml or greater contained in Silastic capsules suppressed uterine ER concentrations after one day's exposure. In this study, we looked at the effects of physiological (1.0 and 10.0 micrograms subcutaneous injections) and pharmacological (5.0 mg/ml implants) doses of E2 on ER concentrations at times less than 24 hours. The implanted rats had maximum E2 plasma levels of approximately 2000 pg/ml for at least six hours which fell to around 800 pg/ml by 12 hours where they remained up to 24 hours. The physiological doses resulted in plasma levels at one hour of 2000 pg/ml (10 micrograms dose) and 250 pg/ml (1 microgram dose) both of which fell to less than 60 pg/ml by six hours. All treatments caused maximal ER suppression by six hours; however, the implants caused a greater reduction in ER levels than either of the physiological doses. The reduction of ER levels was due primarily to a decrease in the "cytosolic" receptor. Despite the decrease in ER, all doses caused a significant and equivalent increase in uterine weight at six hours, however, only the implanted animals maintained the maximal uterine weight gain through 24 hours. This maintenance of uterine weight appears to be correlated with a small but significant increase in the nuclear ER level over this same time period. Thus, while E2 can cause a short-term suppression of its receptor concentration with no effect on short-term uterine weight gain, uterine growth is positively correlated with the level of nuclear ER.

Autologous down-regulation of hormone receptors has been shown for several steroid hormones. We have previously shown estradiol (E2) regulates estrogen receptor (ER) in ovariectomized (OVX) rats. These studies have been extended to investigate the interaction between progesterone (P) and E2 in the regulation of ER and uterine weight. We implanted Silastic capsules containing varying concentrations of E2 (0.0005 mg E2/ml to 5.0 mg E2/ml of sesame oil) into adult female Sprague-Dawley rats one week after OVX. Simultaneously with implantation, P injections were started (sc in sesame oil) at doses of 1-40 mg/day for three days. In the absence of P, the 0.05 mg E2/ml implant significantly increased total ER levels (measured by cytosol and nuclear exchange assays) by 25%, while the two highest concentrations of E2 (0.5 and 5.0 mg E2/ml) significantly decreased cytosol and total ER levels by at least 40%. No P dose altered ER levels in OVX rats or in rats given E2 implants of 0.01 mg E2/ml or lower. At E2 implant concentrations of 0.05 mg E2/ml and higher, P decreased total ER levels 30%-50% compared to the appropriate E2-only controls. P increased uterine weight by 25% in OVX controls and in rats treated with E2 implants of 0.01 mg E2/ml and below. In contrast, P inhibited uterine weight gain induced by 0.05-5.0 mg/E2 ml implants by 20%-30%; maximal inhibition occurred at 5 mg/day of P and above. These data demonstrate that P increases uterine weight but does not alter ER concentration in rats with low E2 levels (OVX or low E2 concentration implants) but decreases uterine weight and down-regulates ER at higher E2 levels, regardless of whether ER is up-regulated or down-regulated by E2.

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