Progesterone (P4) and estradiol (E2) are essential to the maintenance of primate pregnancy and cortisol (F) of fetal adrenal origin is essential to fetal maturation and possibly to the initiation of labor. While the roles of these hormones are relatively well defined the regulation of their production by the fetoplacental unit is poorly understood. Therefore, our consortium study is designed to simultaneously study in vivo the regulation of placental, transuteroplacental and fetal adrenal steroid hormone metabolism (i.e. formation and catabolism) in the baboon, whose endocrinology is similar to that of the human. The role of estrogen, which we have recently shown exerts a common regulatory influence upon fetal-placental steroidogenesis, will be investigated. Specially, we will determine in pregnant baboons: (I) the roles and mechanism of action of the fetus and estrogen in regulating placental P4 production; (II) the roles of the fetus and steroids of placental origin on transuteroplacental F metabolism; and (III) the possible interaction of estrogen and pituitary hormones in regulating fetal-neonatal adrenal maturation and steroidogenesis. Baboons will be: (a) administered antiestrogen between days 130 and 170 of gestation (term=184 days), (b) treated with dehydroepiandrosterone (DHA) or E2 following surgical removal of the fetus at midgestation or (c) injected with E2 early in pregnancy (days 70-100). The transuteroplacental conversion of 3H-pregnenolone to 3H-P4 and interconversion of 14C-P4/ 3H-20 -hydroxy P4 will be assessed in vivo by the constant infusion procedure and placental LDL receptors measured in vitro to elucidate the mechanism by which the fetus and estrogen regulate P4. P4 production by trophoblast cells in culture will also be studied for the latter purpose. The roles of E2, P4 and the fetus on transuteroplacental corticosteroid metabolism will be ascertained in vivo by constant infusion of 14C-F and 3H-cortisone (E) and in vitro by enzymatic analysis of placental 11 -hydroxysteroid dehydrogenase. The regulation of F-E production in the fetus will be determined in utero by constant infusion of 3H/14C-F and -E and by adrenal responsivity to ACTH in the presence or absence of estrogen. To determine whether the differential responses of the developing fetal-neonatal adrenal to pituitary hormones in the formation of F, DHA and DHAS are due to estrogen, the effects of prolactin, growth hormone and ACTH in the presence of absence of estrogen will be examined in the fetus in utero, in neonates in vivo and in fetal adrenal cells in culture. Results obtained from this study will allow us to achieve our overall goal of elucidating the hormonal events resulting in pregnancy maintenance, the initiation of labor and the development of fetal adrenocortical self-sufficiency in the perinatal period. This should eventually enable formulation of methods to reduce the incidence of abnormal human pregnancy and thus neonatal morbidity and mortality.
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