We will use pregnant rhesus monkeys to continue studies of critical events in maturation of the fetal hypothalamo- hypophyseal-adrenocortical-placental aids (HHAPA), decidual, myometrial, and cervical function. We will combine whole animal in vivo, molecular biology, enzyme kinetic, in vitro muscle contraction and receptor techniques to study critical fetal neuroendocrine and uterine mechanisms that regulate myometrial contractility and cervical function in relation to parturition. We propose five hypotheses and five related specific aims. We hypothesize that: 1. Androgens are key initiators of the reversible switch from myometrial contractures to contractions that occurs at night time a few days before term delivery and recurs and augments each night until delivery eventually occurs. 2. Androgens must be aromatized to estrogens to initiate the switch from myometrial contractures to contractions that occurs at night time a few days before term delivery and recurs and augments each night until delivery. 3. The reversible switch from contractures to contractions that occurs at term involves changes at seven functional levels:: a) changes in arachidonic acid metabolite, specifically prostaglandin synthase, function, corticotropin releasing hormone, and proopiomelanocortin function in intrauterine tissues; b) changes in fundal dominance and myometrial electrical conduction and sensitivity to electrical stimulation; c) changes in myometrial and mesometrial responsiveness to key agonists measured in vitro; d) increased decidual, myometrial and mesometrial oxytocin receptors;e) increased intrauterine oxytocin synthesis especially in decidua and fetal membranes; f) increased permeability in myometrial and mesometrial cell ion channels; g) increased prostanoid production and distensibility in the cervix. 4. Estrogen induced change in myometrial contractility (following androgen infusion to the mother) is associated with the same preparturitional changes in the tissues at the seven functional levels predicted in Specific Aim 3. 5. In the pregnant rhesus monkey increased fetal hypothalamic and pituitary function regulates the exponential rise in fetal adrenal androgen production that occurs over the final thirty days of gestation. Labor is a multifactorial process with interconnected positive and negative feedback loops. Most studies on control of the fetal adrenal, parturition, and myometrial function have been performed in sheep. Differences in fetal and maternal endocrinology and myometrial contractility between sheep and primates dictate that a clear understanding of control of parturition awaits firm comparative experimental data from both sheep and nonhuman primates. Prevention and management of preterm labor and preterm birth both require a better understanding of these processes.
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