Fundamental differences in the action of estrogens and antiestrogens on the uterus: comparison between compounds with similar duration of action.

In order to understand differences in the mechanism of action of estrogens and antiestrogens, it is essential to make comparisons between compounds with similar duration of action. Hence, in these studies, we compare the action of a long-acting estrogen (17alpha-ethinyl estriol-3-cyclopentyl ether, EE3CPE) and a long-acting antiestrogen (U-11,100AUA) on the immature rat uterus and analyze different dosage regimens (single and multiple injections) in studying the effects of these compounds on the uterine estrogen receptor and on uterine growth and sensitivity to estradiol. During the first 24 h, UA (50 microng) and EE3CPE (5 microng) evoke remarkably similar receptor distribution patterns and uterine wet weight increase; however, pronounced differences are seen with long-term, multiple injection regimens (every 12 or 24 h for 72 h). Such treatment with UA results in maintenance of high nuclear receptor levels and very low cytoplasmic receptor levels (ca. 10% of total), but no further increase in uterine weight, DNA or protein content, or total receptor content beyond 24-48 h. In contrast, multiple injections of EE3CPE produce not only a prolonged nuclear retention of receptor, but a progressive increase in total receptor content in the tissue and 35-50% of total receptor is cytoplasmic; uterine weight and DNA and protein content also continue to increase markedly above the 24 h level, and responsiveness to estradiol is maintained. However, regardless of whether the uterus continues to grow (as the EE3CPE) or stops growing after 24-48 h (as with UA), the receptor content on a cell basis is similar. Hence, uterine responsiveness to estradiol and continued uterine growth appear not to be related to the total content of receptor per cell, but rather are correlated with the cytoplasmic receptor level within the cell. As there is a continuous translocation of cytoplasmic receptor to the necleus in the growing uterus, the antagonistic action of antiestrogens appears to derive from their ability to effect a marked perturbation in the subcellular distribution of receptor, whereby very little of receptor (ca. 10%) is cytoplasmic, and further estrogen receptor accumulation (most likely synthesis) is blocked.