The hypothalamus-pituitary-adrenal axis in fetal sheep plays an important role in fetal maturation, in the timing of parturition, and in homeostatic responses to stress. Elucidation of the physiological mechanisms controlling this axis will improve our understanding of essential processes that direct the transition from fetal to adult fife. A major focus of experiments in this laboratory has been the study of developmental changes in the sensitivity of the ACTH secretory activity of the hypothalamopituitary unit to negative feedback inhibition by cortisol. Previous experiments in this laboratory have demonstrated that the sensitivity of stimulated ACTH secretion to negative feedback inhibition is high in fetal sheep between 117 and 131 days' gestation, but is very low in fetal sheep at term. The experiments proposed in the continuation of this project will investigate the mechanism of this decreased negative feedback sensitivity. Specifically, these experiments are designed to test: a) the possible role of estrogens, androgens, or progesterone in the reduction of sensitivity to negative feedback sensitivity; b) the possibility that increases in fetal brain levels of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) at the end of gestation desensitizes negative feedback; c) whether changes in hypothalamic or hippocampal glucocorticoid receptor number or synthesis (reflected by changes in the level of glucocorticoid receptor mRNA) mediate changes in negative feedback sensitivity; d) whether estrogen, androgen, or progesterone alter cortisol negative feedback sensitivity by altering glucocorticoid receptor number or mRNA concentration or 11beta-HSD activity in the fetal brain; and 5) the possibility that blockade of 11beta-HSD or blockade of estrogen action in the brain prolongs gestation. Chronically catheterized, unanesthetized fetal sheep will be studied. The fetal sheep will be subjected to intracerebroventricular infusions of estrogen, androgen, progesterone, or blockers of 11beta-HSD or of estrogen. In experiments designed to investigate negative feedback sensitivity, nitroprusside-induced hypotension as a stimulus to ACTH secretion. Blood samples will be analyzed for plasma concentrations of ACTH, and cortisol using specific radioimmunoassays. Fetal blood pressure and heart rate will be monitored using a microcomputer on-line. These experiments represent an extension of the work initiated in the first three years of this project. The goal of the experiments is, to investigate the mechanism of the change in feedback sensitivity at term and to investigate the effect of the alterations in feedback sensitivity on the length of gestation.
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