Estradiol stimulates protein, RNA, and ultimately DNA synthesis in the uterus. The earliest uterine responses seen after estrogen administration occur within minutes. Some of these responses are incorporation of labelled uridine into RNA, histone acetylation, eosinophil infiltration into the uterus, synthesis of mRNA for induced protein, RNA polymerase activity, a decrease in arginine-rich histone content, an increase in glucose uptake, and an increase in amino acid uptake. Among later uterine responses to estrogen requiring 6 hours or more are generalized protein synthesis, and the increase in the activity of the hexose monophosphate shunt enzymes.
The classical model of induction of the response of the uterus to estradiol is the two-site model proposed by Gorski et al. (11) and Jensen et al. (12). This model is based on studies of the binding of radioactive estradiol to receptor in various cell fractions. According to this model, estradiol enters the cytoplasm and binds to the receptor. The receptor upon estradiol binding has a sedimentation coefficent which changes from 4S to 5S and is then translocated to the nucleus. Once in the nucleus, the receptor-estradiol complex binds to chromatin. It is through this interaction that estradiol induces changes in cellular activity. This model, however, is inconsistent with the findings of Welshons et al. who showed that cytoplasts (cells enucleated with cytochalasin B) showed little estrogen binding activity while the nucleoplasts showed considerable estrogen binding activity. In addition, the studies of King and Greene, using a monoclonal antibody against the estrogen receptor and immunochemical staining, showed that specific staining was confined to the nucleus. These last two studies support the conclusion that the estradiol receptor resides in the nucleus and not in the cytoplasm and that the cytoplasmic receptor may be an artifact of the fractionation procedures.