The Relevance of Interaction Kinetics in Determining Biological Response to Estrogens

Abstract

The study of the kinetics of the interaction between two ethynyl estradiol derivatives (llβ-methoxy-17-ethynyl-l,3,5(10)-estratriene-3,17β-diol and llα-methoxy-17-ethynyl-l,3,5(10)-estratriene-3,17β-diol), differing in the configuration of the 11-methoxy substituent, and the cytoplasmic estrogen receptor in mouse uterus and the study of their ability to induce short and long term estrogen responses (uterine weight increase, estrogen receptor replenishment, and progestin receptor induction) in the mouse have led to the following conclusions. Potent agonists are compounds which form slowly dissociating cytoplasmic receptor complexes. Low doses of weak agonists are able to induce short term responses to the same extent as potent agonists but are unable to maintain these responses; higher doses or frequent administration are required to maintain an effect. The degree of agonist activity is related to the nuclear estrogen receptor concentration, which is in turn related to the ability of the ligand to form a stable cytoplasmic receptor complex. Low doses of weak agonists can effectively compete with endogenous hormone for cytoplasmic receptor sites and thus prevent the endogenous hormone from inducing its full biological response. Since they are themselves unable to induce a full response, this competition results in antihormonal activity.