Progesterone (P4) is essential to the maintenance of primate pregnancy and fetal adrenal cortisol (F) and androgens to fetal development and placental estrogen formation. While the roles of these hormones are known, regulation of their production is not, although studies by the applicants indicate a role for estrogen. Therefore, the proposed consortium study utilizing pregnant baboons is designed to: (I) elucidate the mechanism of action of estrogen and the fetus on placental P4 formation via the LDL and de novo cholesterol pathways; (II) test the hypothesis that the change in placental F metabolism normally induced by estrogen near term regulates maturation of the fetal pituitary-adrenal axis; (III) determine the mechanisms by which estrogen modulates responsivity of the fetal adrenal to ACTH and the fetal pituitary to corticotropin releasing factor (CRF). Pregnant baboons will be: (a) administered antiestrogen daily between days 140-170 (term=184) to block estrogen action; (b) treated with androstenedione (delta 4 A) between days 70-100 to increase E2 production prematurely, and (c) fetectomized (placenta in situ) on day 100 to ascertain the role of the fetus. Placental LDL uptake/conversion to P4 in utero will be quantitated by constant infusion of (3H) cholesterl linoleate-LDL. LDL receptors, the activities of P450 cholesterol side chain cleavage and 3-hydroxy, 3-methyl glutaryl coenzyme A, and de novo cholesterol production will be determined in the placentas and fetal adrenals of baboons exposed to antiestrogen or elevated estrogen and in human trophoblast cells cultured with/without estrogen. Fetal adrenal maturation will be determined by quantitating de novo fetal F production in utero by maternal infusion of (3H)F/(14C)E and in vitro by measuring fetal adrenal 3 beta-hydroxysteroid dehydrogenase activity, F/DHA production by isolated cells, and tissue histology. Activity of 11 beta-hydroxysteroid dehydrogenase in baboon placental homogenates and human trophoblast cells cultured with/without estrogen will be measured to determine mechanism of action. Fetal adrenal 17- hydroxylase/17-20 lyase activity and ACTH receptor content and pituitary ACTH responsivity to infusion in utero of CRF will also be quantitated to determine mechanism of action of estrogen on fetal adrenal maturation. 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.
Showing the most recent 10 out of 99 publications
