Taxonomy of SERM activity in vivo

The limited success, in terms of prevention of diseases associated to menopause, of hormone replacement therapies imposes further research aimed at better defining the risks and real advantages. SERMs (Selective Estrogen Receptor Modulators) are a class of estrogen mimetics prescribed for the treatment of the menopause. SERMs do not fall into distinct categories of agonists and antagonists, since their action is regulated by tissue-specific expression of a number of auxiliary proteins called coactivators or corepressors. This complexity limits the systemic analysis of their activities, and SERMs development may fail in the late stages of drug development as a result of unforeseen toxicity. The recent description of reporter mice (ERE-luc) for in vivo analysis of hormone receptor activity opens new horizons for drug discovery. The aim of the present thesis was to obtain a taxonomy of drug activity in vivo by developing a method to profile the interaction of SERMs on the transcriptional activity of the ER in ovarectomized ERE-luc female mice as a model of menopause. These novel animal models, in association with in vivo imaging technologies, provided a global view of the target tissues allowing to discover specific signatures of SERM action following acute and repeated drug treatment. This new knowledge lead to propose a new ontology for hormone replacement therapy regimens based on their closeness with the physiological ER activity picture observed in intact cycling females.