Estrogen Receptor Function as Revealed by Knockout Studies: Neuroendocrine and Behavioral Aspects

Estrogens are an important class of steroid hormones, involved in the development of brain, skeletal, and soft tissues. These hormones influence adult behaviors, endocrine state, and a host of other physiological functions. Given the recent cloning of a second estrogen receptor (ER) cDNA (the ERβ), work on alternate spliced forms of ERα, and the potential for membrane estrogen receptors, an animal with a null background for ERα function is invaluable for distinguishing biological responses of estrogens working via the ERα protein and those working via another ER protein. Data generated to date, and reviewed here, indicate that there are profound ramifications of the ERα disruption on behavior and neuroendocrine function. First, data on plasma levels of estradiol (E₂), testosterone (T), and luteinizing hormone (LH) in wild-type (WT) versus ERα⁻mice confirm that ERα is essential in females for normal regulation of the hypothalamic–pituitary gonadal axis. Second, ovariectomized female ERα⁻mice do not display sexual receptivity when treated with a hormonal regime of estrogen and progesterone that induces receptivity in WT littermates. Finally, male sexual behaviors are disrupted in ERα⁻animals. Given decades of data on these topics our findings may seem self-evident. However, these data represent the most direct test currently possible of the specific role of the ERα protein on behavior and neuroendocrinology. The ERα⁻mouse can be used to ascertain the specific functions of ERα, to suggest functions for the other estrogen receptors, and to study indirect effects of ERα on behavior via actions on other receptors, neurotransmitters, and neuropeptides.