Estradiol Down-Regulation of the Rat Uterine Estrogen Receptor

Abstract

We have previously shown that neonatal exposure of rats to pharmacologic doses of diethylstilbestrol via daily injections resulted in a significant decrease in the estrogen-binding capacity of the uterine estrogen receptor (ER). In this study, we examined the effects of physiologic and pharmacologic doses of estradiol (E2) administered to adult ovariectomized rats via Silastic implants. Two days after implantation, uteri were removed, weighted, and homogenized, and ER levels were determined in the supernatant (hydroxylapatite assay) and low-speed pellet (nuclear exchange assay). Implants containing E2 concentrations of 0.005 or 0.05 mg/ml increased cytosolic but not total ER-binding capacity, whereas 0.5 or 5.0 mg of E2/ml implants decreased the binding capacity of cytosol ER to 40% and total ER to 50% of control values. The 0.005-mg/ml dose increased cytosol ER without increasing uterine weight; all higher doses significantly increased uterine weight. Determination of ER protein by an ER radioimmunoassay showed the same extent of reduction of ER concentration as the binding assays, demonstrating that the loss in E2 binding capacity is homologous down-regulation. The down-regulation of ER was maximal at 24 hr and was completely reversible after implant removal, although the time required to recover from down-regulation was dose dependent. Uterine weight also returned to control levels slowly after implant removal. Neither the sedimentation rate of the down-regulated ER nor the Kd of the cytosolic ER changed following long-term implantation; however, the Kd of the nuclear ER decreased significantly. This is the first demonstration of in vivo homologous down-regulation of uterine ER. ER down-regulation may play a role in several biologic processes.

A biphasic action of estradiol on estrogen and progesterone receptor expression in the lamb uterus

“…Since a loss of immunoreactive ER was found in the present study, we suggest that the initial decrease in receptor concentration after E2 treatment is due to a loss of the protein itself, instead of a reduction in the binding capacity for the steroid (receptor inactivation). This receptor processing was reported in rodents [20,39], and could be the result of an increase in the action of specific proteases or inhibition of receptor synthesis [8,13]. The latter cannot be explained by the ER mRNA levels since mRNA no further increases were observed with a double challenge with E2 [40], supporting the findings in this study.…”

“…The initial suppression on the binding capacity of ER and PR is different from the reported receptor up-regulation induced by estrogen in cyclic and ovariectomized ewes [25,31,32]. It has been suggested that E2 regulation of uterine ER in rat is dose dependent, as demonstrated by the positive and negative effects of low and high doses of E2 on ER concentrations, respectively [20]. The dose used in the present study (1 µg .…”

“…Inhibition of receptor synthesis was shown in rat uteri and MCF-7 cells, where E2 induced suppression of ER mRNA a few hours after treatment [1,39]. Furthermore, the apparent decrease in the total number of measurable binding sites after a hormone challenge in rat uteri is due to degradation of the protein [20,39]. This "processing" found in the regulatory action of E2 on its receptor was also reported in the same specie by other authors [3,13,33], but no data as such has been reported for sheep.…”

Estrogen receptor (ER) and its messenger ribonucleic acid expression in the genital tract of female mice exposed neonatally to tamoxifen and diethylstilbestrol

“…And the injection of DES or Tx to 50-day-old ovariectomized mice significantly stimulated the cell division in uterine and vaginal epithelial cells. Shupnik et al (1989) and Medlock et al (1991) showed that ER mRNA level in the uterus of ovariectomized adult rats is reduced by E,. Our results, however, indicate that both DES and Tx act as ER inducer in the uterus and vagina in both neonatal and ovariectomized adult mice, although ER mRNA induction time of Tx is slower than that of DES in neonatal mice.…”

“…However, in the uterus of adult ovariectomized rats, ER mRNA levels were decreased by E, (Shupnik et al, 1989;Medlock et al, 1991).…”