ROLE AND REGULATION OF GALANIN IN PITUITARY ADENOMAS

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This proposal tests the hypothesis that the peptide galanin plays a significant role in pituitary adenoma formation. The majority of pituitary adenomas in humans secrete copious amounts of prolactin. Hyperprolactinemia is the leading cause of neuroendocrine-related infertility in women and impotence in men. Estrogen has a profound stimulatory effect on prolactin synthesis and release. and induces prolactinoma formation in the rat. In addition to its effects on prolactin, estrogen markedly increases the synthesis of galanin in the anterior pituitary gland. Galanin is stored with prolactin in the same secretory granules of estrogen-treated pituitary cells, and its secretion is regulated by the same hypothalamic hormones. Galanin is the first anterior pituitary peptide, in addition to the "classic" pituitary hormones, whose secretion is controlled by hypothalamic factors. In Specific Aim 1 the direct effects of galanin on pituitary cell proliferation will be examined in vitro and in vivo. The effects of galanin on 3H-thymidine incorporation into DNA will be assessed in conjunction with immunocytochemistry to identify which pituitary cell types are proliferating. Moreover, galanin antiserum will be administered in vivo to determine if estrogen-induced pituitary tumor formation is inhibited by passive immunization. Specific Aim 2 will address the hypothesis that galanin is one of the factors which contributes to the heterogeneity of prolactin secretion from hyperplastic lactotrophs. These studies will utilize adenomatous pituitary cells and combine the reverse hemolytic plaque assay for prolactin release with immunocytochemistry for galanin to assess if lactotrophs which colocalize galanin hypersecrete prolactin. Specific Aim 3 is designed to determine if estrogen and selected growth factors directly regulate galanin within pituitary cells. First, double-labeling immunocytochemistry for estrogen receptors and galanin will used to determine if galanin-containing pituitary cells are direct targets of estrogen. Second, the effects of estrogen and other growth factors on galanin release and mRNA levels will be tested in vitro. Specific Aim 4 will examine if galanin synthesis and release are increased in pituitary adenomas which are induced by factors other than estrogen. Specifically, animal models of mammosomatotroph and thyrotroph adenomas will be studied. Overall, these studies will determine the role of galanin in tumorigenesis in the pituitary gland, and provide insight to the physiology and pathophysiology of galanin.