Ovulation is triggered one every four or five days in female rate by a mid-cycle surge of luteinizing hormone (LH). Generation of the preovulatory LH surge depends upon two important neuroendocrine events: an appropriately timed discharge of luteinizing hormone-releasing hormone (LHRH) into the hypophysial portal vessels, and an acute increase in responsiveness of the anterior pituitary gland to this neurosecretory signal. Both processes are, in turn, dependent upon exposure of the hypothalamus and pituitary gland to preovulatory estrogen (E2) and progesterone (P) secretions. The goal of the proposed studies is to characterize cellular mechanisms by which ovarian steroids evoke preovulatory gonadotropin surges. We have hypothesized that one important positive feedback action of steroids is to increase gene expression of receptors for endogenous neuromodulators which facilitate LHRH and/or LHRH-induced LH secretion. In work completed during the previous funding period, we identified the 36-amino acid peptide, neuropeptide Y (NPY), as one such modulator, and determined that the preovulatory steroid milieu acutely enhances responsiveness to NPY's facilitory effects at both hypothalamic and pituitary levels. The proposed studies will therefore test the hypothesis that ovarian steroids regulate both hypothalamic and pituitary NPY receptor gene expression, and NPY signal transduction, as requisite components of the gonadotropin surge-generating process. We will first determine the identities and functional properties of NPY receptors which mediate NPY's actions on pituitary LH secretions and hypothalamic LHRH surges (Aims 1 & 2). We will then attempt to determine if NPY receptor gene expression is stimulated in association with gonadotropin surge generation (Aim 3), assess the specific roles that the E2 and P4 play in regulating NPY receptor function (Aim 4), and ascertain whether steroids may exert their effects on NPY receptors expressed in LHRH neurons (Aim 5). These studies will provide a more detailed understanding of the basic, neuroendocrine mechanisms controlling gonadotropin surge generation and ovulatory cyclicity. Information on cellular and molecular routes of steroid positive feedback may also be of particular significance in the diagnosis and treatment of certain infertility syndromes, such as hypothalamic amenorrhea. The present studies may also provide important new avenues for development of """"""""once- per-month"""""""" contraceptive strategies based on progesterone receptor antagonism or transient pharmacological blockade of hypothalamic- and pituitary-specific NPY receptor isoforms.
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