Studies dealing with the biochemical and molecular mechanism of gonadotropin releasing hormone (GnRH) action have served to: (a) identify new clinical and veterinary uses for GnRH and its analogs, (b) bring these uses to fruition through a rational process based on understanding of the mechanism of hormone action, and (c) provide the means for anticipating, understanding, and ameliorating side-effects of the agents. FDA approvals of GnRH agonists for the treatment of prostate cancer, endometriosis, and precocious puberty, as well as for the use of natural sequence GnRH to induce ovulation, and to test the hypothalamic-pituitary-gonadal axis, are examples of the clinical usefulness derived from these fundamental observations. There are multiple advantages to the study of GnRH- stimulation of the gonadotrope that make it facile to collect interpretable data: (a) GnRH stimulation of the gonadotrope cell has clearly defined, specific and measurable endpoints: release of endocrine (and potentially endocrine) substances (LH, FSH, secretogranin II, alpha- subunit of gonadotropin), regulation of target cell sensitivity, regulation of the GnRH receptor, and biosynthesis of released substances. (b)The releasing hormone itself (as well as its agonists and antagonists) can be radioiodinated to high specific activity. (c) Many (>3,000) analogs exist that can be chemically derivatized without loss of biological activity. Antagonists and agonists which bind the receptor with greater affinities than the natural sequence GnRH are available. (d) Virtually all known agonists and antagonists are """"""""pure"""""""" in action and metabolically stable agonists are available. The present project is divided into three areas of focus that are detailed in the """"""""Specific Aims"""""""" section and form the basis of organization of the """"""""Research Design and Methods"""""""" section. The first area will provide information on the structure of the GnRH receptor and early actions following the interaction of the receptor with GnRH and its analogs. At the present time, due to technical difficulties in dealing with the receptor itself, it has not been possible to use standard techniques to purify or even solubilize the receptor for a protracted period. Accordingly, these studies should advance our understanding of the receptor in the mechanism of GnRH action. The second area will provide information on the relationship between the multiple effector mechanisms already implicated in GnRH action with the multiple actions stimulated by the releasing hormone (release of multiple endocrine substances, regulation of target cell responsiveness, biosynthesis, and regulation of receptor number). This is important since considerable confusion remains regarding these relationships. The third area involves understanding the molecular sites of action of activin and inhibin in relation to GnRH action and are significant to understand the actions of these agent in vivo.
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