MOLECULAR NEUROENDOCRINOLOGY OF THE FETAL HYPOTHALAMUS

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INTRODUCTION: Prostaglandins (PGs) are key mediators involved at several fetal and maternal levels in the promotion and completion of parturition, the fetal hypothalamic-pituitary-adrenal-placental loop (HPAPL) and maternal uterine issues. The proposed studies will determine the role of PGs as activators and/or as stimulators of labor in pregnant sheep. Two forms of prostaglandin H synthase (PGHS), constitutive isozyme PGHS-1 and inducible isozyme PGHS-2, have been characterized. We will examine the precise role of PG and the separate and distinct function of both PGHS isozymes in association with the promotion of parturition. HYPOTHESES: Hypotheses 1: The placenta is the major source of the increased PGs in fetal and maternal circulation in the last 40 days gestation (dGA) of ovine pregnancy: the two isoforms of PGHS-1 PGHS-2 play separate, clearly defined roles for placental PG's production; Hypothesis 2: Placental PGs play central and distinct roles in maturation of fetal hypothalamic-pituitary-adrenal axis (HPAA); Hypothesis 3: Placental PGs play a central role in placental steroidogenesis, specifically the function of 17alpha hydroxylase (17alphaOH); Hypothesis 4: PGs play a central role in regulation of the switch of myometrial contractures to contractions both as direct stimulators and as activators of myometrial contraction associated proteins (CAPs). OUR FOUR SPECIFIC AIMS relate directly to our hypotheses and use chronically instrumented pregnant sheep to evaluate effects of altered PG function by inhibition of PGHS and/or infusion of PGE/2 in the last 40 days gestation (dGA) in relation to the fetal HPAA, placental steroidogenesis and myometrial activity. METHODS: PGHS inhibition and PGE/2 infusion will be performed at two critical stages of gestation, 110 and 140 dGA, and at labor. To differentiate direct PG function on uterine tissue from secondary PG effects mediated through fetal HPAA, adrenalectomized fetal sheep will be studied with or without PGE/2 infusion. The following endpoints will be analyzed at mRNA and/or protein, and/or enzyme activity levels: 1) placental, myometrial, endometrial, fetal hypothalamic and pituitary PGHS- 1 and PGHS-2; 2) fetal hypothalamic CRH pituitary POMC and circulating ACTH, adrenal steroidogenic enzymes and circulating cortisol; 3) placental 17alphaOH; 4) myometrial contraction activity and CAPs. SUMMARY AND RATIONALE: The proposed studies will provide a better understanding of the importance of PGs in processes that promote and stimulate parturition and their intersection with maternal and fetal HPAA and help to develop strategies for prevention and management of pre-term and post-term birth.