Estrogen receptors: how do they control reproductive and nonreproductive functions?

Three aspects of recent development in estrogen receptor research will be discussed in this review. First, since the discovery of the second estrogen receptor, ERbeta, a new era has begun in this field. The presence of another receptor for estrogen having different tissue distribution and molecular specificity has posed a question as to the authenticity of the hitherto believed interpretation of the diverse actions of estrogen in different organs of both sexes. Ongoing studies, however, seem on the way of clarifying these new complex puzzles caused by the appearance of the new actor. Recent data with knockout mice for these genes are analyzed and discussed. Second, the mechanism of estrogen receptor action as a ligand-dependent transcription factor has been much more clarified these several years since the discovery of coactivators of steroid receptors which transmit the effect of ER to the transcription initiation complex. This may also open a way to understand the remodeling of chromatin to an active form which has long been sought. Third, the downstream genes of ER are now being isolated and characterized, which is mandatory for the global understanding of the estrogen action during the development and function of an individual animal. This approach, which has been most difficult, will now become more popular in future as newer technologies for this develop.