The effect of low dose continuous exposure to estradiol on the estrogen receptor (type I) and nuclear type II sites

These studies were done to evaluate the temporal relationships between cytoplasmic and nuclear estrogen receptors (type I sites), nuclear type II estrogen binding sites, and uterotropic response (true uterine growth; DNA content) after low dose estrogen administration to adult-ovariectomized rats by beeswax pellet implant. Administration of low dose (2.5 micrograms estradiol-17 beta/pellet) estrogen pellets resulted in a slight accumulation of nuclear type I sites (approximately 1700 sites per cell above ovariectomized controls) and a 2-fold stimulation of nuclear type II estrogen binding sites (approximately 5,000 sites per cell) at short times (1-24 h) after estrogen treatment. By 96 h, nuclear levels of type I sites were not different from control even though nuclear type II sites remained elevated and uterotropic response was maintained. Similar temporal responses were observed after treatment with a higher dose estradiol (20 micrograms/pellet) except that early response (1-24 h) to the hormone was accompanied by a more pronounced accumulation (approximately 3,000 sites per cell above control) of type I sites in the nucleus. By 96 h after the administration of the 20-micrograms estradiol pellet, nuclear type I sites declined to control, however nuclear type II sites continued to increase (approximately 30,000 sites per cell) and maximum uterotropic response was observed. Comparison of the results obtained with these two dose levels of estradiol suggested that at early times (1-24 h) after treatment only a very small quantity (approximately 1,700 sites per cell) of nuclear type I sites is required for uterine growth. Likewise, although nuclear type II sites can be maximally stimulated (approximately 30,000 sites per cell) by higher doses of estrogen (20 micrograms) only 5,000 sites per cell may be necessary for maximal response. Surprisingly, uterine growth was sustained by very low to non-measurable quantities of type I sites in the nucleus (96 h). Regardless of the initial numbers of type I sites translocated to the nucleus (approximately 1,700 sites per cell, 2.5 micrograms estradiol; approximately 3,000 sites per cell, 20 micrograms estradiol), at early times (1-24 h), these levels decline to control approximately 96 h after treatment. These results are not due to a decreased rate of estrogen release from the beeswax pellet implant and the data suggest a down-regulation of nuclear type I sites is a normal response to the hormone under these experimental conditions, even though maximum uterine growth is maintained.