The broad goal of this revised application remains to dissect the individual contributions of the neuroendocrine, adrenal, and gonadal components to sexual maturation in the human. Utilizing the model of central precocious puberty (CPP), GnRHa-induced suppression of gonadal steroids, and a longitudinal study design, we will continue to address these broad goals in the next 4 years. However, significant revisions have been incorporated in accord with the Study Section's recommendations. In the final four years of the longitudinal studies in the CPP population, we will bring new tools to bear on pubertal physiology and pathophysiology, including the regulation of FSH secretion, developmental aspects of PCOS, and the underlying mechanisms of autonomous gonadal function in patients with gonadotropin-independent precocity (GIP). SA #1, to determine the relative contributions of gonadal vs. adrenal sex steroids to growth and skeletal maturation in childhood and to use this information to develop robust predictive models of the impact of sex steroid suppression on long- term growth, final height, and bone maturation with broad applicability to a variety of growth disorders, addresses the completion of the ongoing longitudinal studies in CPP with particularly attention to making the valuable data gleaned over 13 years of study a rich resource for investigators and clinicians through the development of predictive models for growth during gonadal suppression. SA #2, to define the association between the development of a polycystic ovarian morphology, insulin resistance, hyperandrogenic disorders, and mature ovulatory function during pubertal maturation will look at the development of PCOS from a developmental spectrum and is driven in large by a mandate to better understand the high prevalence of polycystic ovaries which we have defined in our population. SA #3, To characterize the biologic controls of FSH secretion during sexual maturation by correlating the neuroendocrine pattern of FSH secretion and its biologic activity with the developmental profile of inhibin, inhibin subunits, and follistatin secretion, will advantage of the unique opportunities afforded by the CPP model to chart pubertal physiology with novel tools that will shed light on the developmental regulation of FSH in the human, including an FSH bioassay utilizing the recombinant human FSH receptor, as well as new immunoassays specific for follistatin and inhibin dimers and subunits of varying MW. SA#4, To define the clinical, genetic, biochemical, pathological, and molecular spectrum of defects in children with GIP will combine state of the art molecular techniques with clinical investigations to further understand the signalling pathways of the gonadotropin receptors and the phenotypes that their constitutive activation can yield.
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