Evaluation of disordered human growth consumes a large portion of the effort expended in any pediatric endocrinology clinic. Consequently, intensive investigative efforts are underway to increase knowledge in this area, particularly with regard to the physiology and pathophysiology of endogenous growth hormone (GH) secretion. An outstanding, multi- departmental faculty of neuroendocrinologists at the University of Virginia is actively contributing to such knowledge with ongoing research which spans the spectrum from purely clinical to purely basic at the cellular, subcellular and molecular levels. Although the mechanisms governing GH secretion are complex, a central role is clearly subserved by circulating gonadal steroid hormones, particularly the androgens. The principal investigator has initiated both clinical and basic laboratory studies designed to carefully probe this relationship between GH secretion and the androgen environment. As a fully trained clinical pediatric endocrinologist he now seeks support to pursue further this line of investigation with specific members of the neuroendocrine faculty providing guidance. Several highly qualified independent investigators have expressed their enthusiastic commitment to provide such guidance with the goal of facilitating the transition of the principal investigator to an independent biomedical investigator. We intend to combine studies in humans and an animal model (the rat) using current investigative techniques to examine in depth the role of androgens in controlling GH secretion. In particular, we will employ the in vivo technique of frequent venous sampling with subsequent computer assisted pulse detection analysis to evaluate GH secretion in humans. Using the vitro techniques of primary cell culture and reverse hemolytic plaque assay of anterior pituitary cells as well as in situ hybridization in hypothalamic neurons we will further explore the hypothalamic- pituitary component of GH secretion in the rat. These tools will be utilized to address the following specific aims: 1) To characterize the GH secretory response to physiologic and non-physiologic alterations in the androgen environment; 2) To delineate specific androgen-dependent GH secretory characteristics of individual somatotropes and demonstrate their dependence on androgen receptors; 3) To establish the presence or absence of a direct effect of androgens at the pituitary level; and 4) To quantitate androgen-dependent variations in specific messenger RNA signal for somatostatin in the hypothalamus.
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