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.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR015592-03
Application #
6646701
Study Section
Special Emphasis Panel (ZRR1)
Project Start
2002-09-01
Project End
2003-08-31
Budget Start
Budget End
Support Year
3
Fiscal Year
2002
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Type
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Cerny, Katheryn L; Ribeiro, Rosanne A C; Jeoung, Myoungkun et al. (2016) Estrogen Receptor Alpha (ESR1)-Dependent Regulation of the Mouse Oviductal Transcriptome. PLoS One 11:e0147685
Pushkarskaya, Helen; Smithson, Michael; Joseph, Jane E et al. (2015) Neural Correlates of Decision-Making Under Ambiguity and Conflict. Front Behav Neurosci 9:325
Zhu, Xun; Kelly, Thomas H; Curry Jr, Thomas E et al. (2015) Altered functional brain asymmetry for mental rotation: effect of estradiol changes across the menstrual cycle. Neuroreport 26:814-9
Huang, Wen; Chen, Lei; Zhang, Bei et al. (2014) PPAR agonist-mediated protection against HIV Tat-induced cerebrovascular toxicity is enhanced in MMP-9-deficient mice. J Cereb Blood Flow Metab 34:646-53
Martin, Catherine Anne; Lile, Joshua; Guenthner, Greg et al. (2014) Behavioral effects of modafinil and nicotine, alone and in combination, in tobacco-deprived young adult smokers. J Clin Psychopharmacol 34:278-81
Rosewell, Katherine L; Li, Feixue; Puttabyatappa, Muraly et al. (2013) Ovarian expression, localization, and function of tissue inhibitor of metalloproteinase 3 (TIMP3) during the periovulatory period of the human menstrual cycle. Biol Reprod 89:121
Garabedian, Matthew J; Hansen, Wendy F; McCord, Lauren A et al. (2013) Up-regulation of oxytocin receptor expression at term is related to maternal body mass index. Am J Perinatol 30:491-7
Wilson, Melinda E; Sengoku, Tomoko (2013) Developmental regulation of neuronal genes by DNA methylation: environmental influences. Int J Dev Neurosci 31:448-51
Lile, Joshua A; Kelly, Thomas H; Charnigo, Richard J et al. (2013) Pharmacokinetic and pharmacodynamic profile of supratherapeutic oral doses of ?(9) -THC in cannabis users. J Clin Pharmacol 53:680-90
Akundi, Ravi S; Zhi, Lianteng; Sullivan, Patrick G et al. (2013) Shared and cell type-specific mitochondrial defects and metabolic adaptations in primary cells from PINK1-deficient mice. Neurodegener Dis 12:136-49

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