Benign pituitary neoplasms are typically characterized by hormone hypersecretion. Patients with these tumors manifest the metabolic consequences of hormone excess. Insights into the regulation of PRL or GH biosynthesis and secretion have been critical in the development of medical therapies for these tumors. In contrast, approximately 25% of pituitary tumors present as large macroadenomas with visual loss and hypopituitarism in the absence of clinical stigmata of hormone excess. Although these tumors cause considerable morbidity because of their large size, there are currently no effective medical therapies. Because investigation of hormone regulation in other endocrine neoplasms has led to the development of therapeutic modalities, studies are needed to investigate hormone production and regulation in these tumors. We have shown that the majority of these tumors secrete intact glycoprotein hormones (GPH) or free subunits. This important observation has enabled the study of hormone regulation of these tumors in vitro. The long-term objective of this application will be to investigate the regulation of hormone biosynthesis and secretion in GPH producing tumors and to assess the mechanisms for benign neoplastic growth in pituitary tissue. Our first specific aim will be to characterize defects in GPH subunit biosynthesis and secretion in human pituitary adenomas by assessing GPH subunit mRNAs and protein characterization in vitro. FSH secretion will be further characterized by assessment of both its bioactivity and immunoactivity. The second specific aim will be to study the regulation of GPH biosynthesis and secretion by the hypothalamic factors dopamine, somatostatin, and LHRH, and the gonadal protein inhibin by determining their effects on mRNAs and hormone produc- tion. The third specific aim will be to investigate the pathogenesis of benign pituitary tumors by analyzing the clonal origins of these neoplastic tissues. Clonality of pituitary tumors will be studied using the novel technique of x-chromosome inactivation analysis in women with heterogeneity for screened HPRT polymorphisms to establish single cell versus polyclonal tumor origins. Prior studies have suggested a role for oncogenes in the pathogenesis of neoplasia. The fourth specific aim will be the investigation of oncogene expression in human pituitary tumors. The expression of oncogene mRNAs will be studied and tumors will be screened for transforming genes by transfecting DNA into 3T3 fibroblasts. The studies outlined in this application should provide information about hormone regulation and pathogenesis of these common pituitary-tumors.
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