Estrogen is an essential hormone that controls reproduction and is also important for an adequate functioning of many organs in the body, including the brain and pituitary where it regulates at least in part a variety of neuroendocrine circuits, behaviors and certain aspects of cognition. While most of the effects of estradiol on the brain and pituitary are beneficial, a general therapy using estradiol is often not appropriate since estradiol is also a potent factor that can induce tumor formation. The development of Selective Estrogen Receptor Modulators (SERMs), such as Raloxifene that act either as an estradiol agonist or antagonist, depending upon the target cell was a major breakthrough in steroid therapy, however, very few data are known about the effects on the brain and pituitary gland. The central hypotheses to be tested in this proposal is that Raloxifene acts through estrogen receptor (ER) alpha and/or beta to produce both agonist and antagonist effects in the brain and pituitary gland in a target cell-specific manner. Aim 1 will determine the effects of Raloxifene on the endocrine hypothalamus and basal forebrain. Aim 2 will determine if the effects of Raloxifene in the brain are mediated by ERalpha and/or ERbeta. Aim 3 will determine if Raloxifene acts as an estrogen receptor antagonist in vivo on pituitary hormone gene expression and secretion. Aim 4 will determine if Raloxifene alters pituitary cell responsiveness by hypothalamic releasing and inhibiting hormones. Together, the proposed studies will provide comprehensive information on the effects of estradiol and Raloxifene on the brain-pituitary axis and will unravel some of the mechanisms that mediate these effects. A detailed knowledge of the effects on the brain and pituitary will have important implications for t he use of these drugs in the treatment of various disorders or conditions that are caused by inadequate endogenous levels of estrogen.