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 influ ence adult behaviors, endocrine state, and a host of other physiologic al functions. Given the recent cloning of a second estrogen receptor ( ER) cDNA (the ER beta), work on alternate spliced forms of ER alpha, a nd the potential for membrane estrogen receptors, an animal with a nul l background for ER alpha function is invaluable for distinguishing bi ological responses of estrogens working via the ER alpha protein and t hose working via another ER protein. Data generated to date, and revie wed here, indicate that there are profound ramifications of the ER alp ha disruption on behavior and neuroendocrine function. First, data on plasma levels of estradiol (E-2), testosterone (T), and luteinizing ho rmone (LH) in wild-type (WT) versus ER alpha(-) mice confirm that ER a lpha is essential in females for normal regulation of the hypothalamic -pituitary gonadal axis. Second, ovariectomized female ER alpha(-) mic e do not display sexual receptivity when treated with a hormonal regim e of estrogen and progesterone that induces receptivity in WT litterma tes. Finally, male sexual behaviors are disrupted in ER alpha(-) anima ls. Given decades of data on these topics our findings may seem self-e vident. However, these data represent the most direct test currently p ossible of the specific role of the ER alpha protein on behavior and n euroendocrinology. The ER alpha(-) mouse can be used to ascertain the specific functions of ER alpha, to suggest functions for the other est rogen receptors, and to study indirect effects of ER alpha on behavior via actions on other receptors, neurotransmitters, and neuropeptides. (C) 1997 Academic Press.