This research proposal focuses on maturational changes in pituitary function as a possible determinant of growth hormone (GH) release in the developing rat. The factors which regualte GH secretion in immature animals are not understood. In vivo studies by the PI and others suggest indirectly that there may be maturational changes in pituitary responisiveness to physiologic regulators of GH release. In order to directly evaluate this question, the current proposal examines GH release from cultured pituitary cells of developing rats. Rats will be studied at key developmental stages which coincide with major changes in circulating GH levels: fetus (day 20 of gestation), postnatal days 2 and 15, and adults (3-4 mo). The project will determine 1) the relative sensitivity of the developing somatotroph to growth hormone-releasing factor (GHRF), 2) the relative effectiveness of somatostatin (SRIF) in inhibiting GH release during early development, 3) the susceptibility of the immature pituitary to the desensitizing effectis of continuous exposure to GHRF and somatostatin, 4) the influence of prostaglandins E1 and E2 (PGE1, PGE2) on GH release during early development and their interaction with GHRF, 5) the development of the negative feedback effect of Insulin-like Growth Factors on pituitary GH release. Preliminary results indicate marked age-dependency in the effects of GHRF and SRIF on GH release. To further define the mechanisms underlying these developmental alterations in pituitary function, it is also planned to determine 6) the relative capacity of the immature pituitary to generate cAMP in response to GHRF and 7) the relative sensitivity of the developing somatotroph to GH secretogogues which increase intracellular cAMP content independent of the GHRF receptor. Preliminary results indicate quantitative ontogenic differences in the release of GH by (Bu)2cAMP and forskolin, suggesting the possibility of maturational changes in somatotroph function distal to cAMP formation. The long term goal is to identify those factors which contribute to the maturation of normal neuroendocrine control of GH secretion in order to understand both physiologic determinants of GH release in growing animals and the pathophysiology of GH secretory disorders. Maturational changes in pituitary function are of potential importance as A) a possible explanation for developmental changes in plasma GH levels, B) a concept in neuroendocrine ontogeny, and C) a possible site of dysfunction which may contribute to neurosecretory disorders of GH in childhood.
