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Estrogen action in the rat uterus can be arbitrarily considered as occurring in three steps. The first step is the interaction of the estrogen with the target tissue. This appears to be of stereospecific interaction with a receptor that is sensitive to proteinases and extremes of pH and insensitive to ribonuclease and deoxyribonuclease. The second step involves a change in the biological activity of this receptor protein due to the interaction with estrogen, a mechanism about which we have no definitive information at present. Eventually, this primary function does bring about an increase in glucose metabolism and an increase in lipid and RNA synthesis, as well as a number of other responses. The fact that these responses are all blocked by inhibitors of RNA and protein synthesis at a time when no effect on overall protein synthesis is noted suggests that the synthesis of specific enzymes may be involved. Certain complications in this interpretation are discussed. The events of the third, or amplification, step of estrogen action arise as a consequence of the first two events, and appear to include a number of metabolic changes which contribute to the increase in overall protein synthesis occurring between 2 and 4 hours after estrogen administration.The molecular action of a hormone in a target tissue necessarily involves a sequence of steps. First, there must be a n interaction of the hormone with some preexisting receptor molecule i n or on the cells of the target tissues. Second, this interaction must influence the receptor molecule's biological function, i.e., to initiate the primary response to the hormone. Finally, the third step involves the amplification of the primary response by secondary effects on other metabolic machinery.Studies of the mechanisms of action of estrogenic hormones have been aimed at describing this whole sequence of events, but one finds that, as with most hormone action studies, most of the literature iii this area are descriptions of various events associated with the third or amplification step. The mechanisms of estrogen interaction with the uterus and its primary response remain, as with other endocrine systems, an unsolved problem.In this paper we discuss early estrogen effects on RNA and protein synthesis and their possible roles in the primary response and amplification steps. We also discuss our recent work on the binding of estrogenic molecules in the rat uterus and the significance of this work in respect to step one of estrogen action. In the past, studies of the interaction of estrogens with target tissues have been limited by lack of techniques which would be sensitive enough to detect the very small levels of hormone in the target tissue. In their studies of the fate of injected estrogen, Jensen and Jacobson ('62) made elegant use of new procedures for catalytic reduction of unsaturated steroids with tritium gas and for counting low-energy beta particles. In contrast to earlier work with lower specific activity estrogen labeled with i4C, they showed that in the ...