(Scanned from the applicant's description): Fetal glucocorticoid (GC) induces premature labor in pregnant sheep in studies conducted in several laboratories throughout the world. However, pathways by which fetal cortisol triggers the subsequent interactive evolution of maternal and fetal endocrine changes are not clear. In particular, mechanisms that enhance uterine prostaglandin (PG) synthesis and output, and result in increased uterine activity and birth remain to be determined. While it has long been accepted that cortisol influences progesterone to estrogen conversion with resultant changes in uterine PG production (indirect pathway), we hypothesize that cortisol also acts by an important additional pathway stimulating PG production directly (direct pathway). We propose studies to examine both the direction and indirect pathways of GC regulation of key enzymes of PG synthesis- PGH synthase (PGHS) and the critical post PGHS enzymes that determine the exact mix of POE2 and PGF2F2a produced. HYPOTHESIS: cortisol, both 1) directly and 2) indirectly (through estrogen) regulates activity of four key enzymes in PG synthesis: PGHS, POE2, isomerase (POES), PGF2a synthase (PGFS), and PG 9-keto reductase (PG9KR) in ovine fetal and maternal placenta, endometrium, myometrium, and cervix in a tissue- and regional- specific manner to initiate and maintain the several critical processes involved in labor. Nothing is known of regulation of PGES, PGFS or PG9KR.
SPECIFIC AIMS : our two specific aims relate to the two component parts of our central hypothesis: We will use chronically instrumented adrenalectomized fetal sheep to evaluate the respective roles of cortisol acting (i) directly and (ii) indirectly through estrogen, in regulation of activity of PGHS, PGES, PGFS, and PG9KR in ovine fetal and maternal placenta, endometrium, myometrium and cervix in a tissue- and regional- specific manner. The chronically instrumented pregnant sheep and fetus have been studied extensively as a major model of parturition. To maximize information obtained, we have developed systems to interrogate the model at both the in vivo and in vitro levels. Our approach is to investigate time-related and tissue-specific events in pregnant animals undergoing specific experimental perturbations to determine critical steps in the direct and indirect pathways. For example, use of the estrogen receptor antagonist ICI 182780 addresses estrogen's role via the indirect pathway. The pathways whereby PG production is altered by cortisol and by estrogen are likely to operate in both sheep and primates. There is considerable evidence for both increased fetal adrenal function and increased estrogen in late gestation in primates including pregnant women. Simultaneous study of both pathways provides information critical to understanding of parturition across species. Premature labor is the major cause of perinatal mortality and morbidity. Better understanding of the mechanisms of term and preterm labor will provide evidence based, rational diagnosis and management.
