Estradiol Is Less Potent than Ethinyl Estradiol for in Vivo Translocation of the Mammalian Liver Estrogen Receptor to the Nucleus*

Estradiol (E2) or ethinyl estradiol (EE2) was administered to adult female rats, and the distribution of the mammalian liver estrogen receptor between the cytosol and the nucleus was examined 30 min later. The levels of total and occupied liver estrogen receptor (ER) in 30% ammonium sulfateprecipitated liver cytosol and purified nuclei were determined in vitro by exchange assays using [3H]E2. The redistribution of the ER from the cytosol to the nucleus was dose dependent for E2 as well as for EE2. E2 was less potent than EE2, and maximal translocation required relatively high doses. The dose necessary for a half-maximal increase in the total ER of purified nuclei was about 15 μg for EE2 and more than 100 fig for E2. In vitro, EE2 and E2 were equally effective in competing with [3H]E2 for binding to ammonium sulfate-precipitated liver cytosol ER. The redistribution of the ER by E2 and EE2 has also been examined in rats treated with drugs that may inhibit estrogen metabolism. When SKF525A (2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride) and testosterone were coadministered with E2, the dose of E2 required for half-maximal nuclear ER levels was reduced approximately 8-fold (15 μg). Both SKF525A and testosterone were required. When SKF525A was coadministered with EE2, the dose of EE2 required for half-maximal nuclear ER levels was reduced approximately 6-fold (2.5 μg). To examine some effects of SKF525A on estrogen metabolism, the concentration of [3H]EE2 was measured in liver homogenate, liver cytosol, and plasma 15 min after the administration of 5 fig [6,7-3H]EE2. The concentration of [3H]EE2 is increased 2-fold in liver homogenate and 3-fold in liver cytosol with SKF525A treatment. The in vivo results strengthen the possibility that E2 administration, especially by routes other than those dependent on intestinal absorption, may produce fewer liver ER-mediated side effects than the current contraceptive estrogen, EE2. The administration of E2 together with a progestin by an alternate route might improve the safety of contraceptives while maintaining efficacy.