The Specialized Ovulatory Dysfunction Infertility Research Center headed by the University of Michigan Reproductive Sciences Program will conduct, coordinate and integrate a comprehensive program of multidisciplinary research aimed at the problem of human ovulatory dysfunction. A unique aspect of the proposed Center is the combined strength of investigators from reproductive sciences, molecular biology, clinical sciences and behavioral research backgrounds at four major institutions. Building on our well-established contributions to understanding the neuroendocrine regulation of reproduction, we plan to conduct two clinical and five preclinical projects using novel research approaches to address the unifying hypothesis that ovulatory dysfunction and related menstrual cycle defects stem from altered neuroendocrine regulation of pulsatile gonadotropin secretion. In year 01, clinical projects using ethnically diverse populations from multiple sites will be launched which longitudinally assess pulsatile gonadotropin secretion in a) infertility patients with unexplained ovulatory dysfunction (Project I); and b) female college students with well-defined eating behaviors (Project II). Extra- hypothalamic influences such as emotional stress, body weight and age will be examined across projects for effects on neurosecretory patterns in normal volunteers and patient groups. Plasma will be saved from both clinical projects for development of new technologies for assay of critically important hormones such as inhibition by the New Assay Development Core in Years 03-05. To study neuroendocrine mechanisms underlying gonadotropin secretory patterns in patients with ovulatory dysfunction, three preclinical projects will utilize a sheep model to test hypotheses not directly approachable in human beings. These studies will determine if a separate FSH-RF exists (Project III), examine control mechanisms for regulating GnRH receptors (Project IV) and define the likely characteristics of secretory events responsible for normal and abnormal peripheral gonadotropin patterns (Project V). In year 02, two new investigator projects will examine neuroelectric patterns associated with defined GnRH release (Project VI) and estradiol modulation of growth hormone action in human granulosa cells (Project VII). In years 04 and 05, ovulation-induction protocols will be tested in the infertility patient groups that mimic physiologic mechanisms defined from both clinical and preclinical studies. Through consortium arrangements, the Center will take advantage of the outstanding resources and experienced investigators of the University of Michigan Medical School, Wayne State University Medical School, Michigan State University and North Carolina State University. The long term goal is to develop improved diagnostic and treatment strategies based on a testable, explanatory model of human ovulatory failure.
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