|HOME SCHEDULE AUTHOR INDEX SUBJECT INDEX|
ENDOCRINE AND PARACRINE REGULATION OF BIRTH.
Challis, J1, Alfaidy, N, Lye, S, Gibb, W, Patel, F, Gupta, S, Martin, R, Giannoulias, D, Whittle, W, Xu, P, 1
ABSTRACT- Studies in sheep show clearly that birth is associated with increased fetal hypothalamic-pituitary-adrenal (HPA) activity and that elevations in fetal cortisol during late pregnancy lead to upregulation of prostaglandin (PG) synthesis in placental trophoblast cells. Regulation of placental PGHS-2 occurs in the absence of changes in circulating estrogens, consistent with the presence of GR, and absence of ER in the trophoblast cells. The progressive increase in placental PGHS-2 during pregnancy and with cortisol treatment correlates with the appearance of PGE synthase and GR expression in the placenta. Maternal (endometrial) PGHS-2 expression, in contrast, is prevented in animals treated with an aromatase inhibitor, during intra-fetal cortisol infusion. In human pregnancy, glucocorticoids simulate PG synthesis and decrease expression of PG metabolizing enzymes in trophoblast and trophoblast-derived cells of the fetal membranes, leading to increased PG output. The PG synthetic cascade is also activated by pro-inflammatory cytokines and these effects are modulated by anti-inflammatory cytokines. The effects of glucocorticoids on chorionic PGDH are modified by local 11-HSD-1 (reductase activity), and by paracrine interactions with locally generated progesterone (P4). P4 maintains PGDH activity in chorion during pregnancy, in part by interaction with glucocorticoid receptor (GR). Displacement of progesterone by cortisol at term within intrauterine tissues may be the equivalent to functional progesterone withdrawal. In turn, PGE2 and PGF2a increase expression of 11 HSD-1 in chorion trophoblasts, through a calcium dependent mechanism, and decrease 11 HSD-2 (dehydrogenase activity) in placental syncytiotrophoblast, thereby augmenting bioactive glucocorticoid levels locally at both sites. Thus, in membranes a feed forward loop is established that predisposes to (preterm) labor. In the placenta, local cortisol may contribute to apoptosis (for example, with preeclampsia), and eventually fetal compromise. Cortisol also upregulates placental CRH gene expression; placental CRH output is higher in threatened preterm labor, preeclampsia and with intrauterine growth restriction. Thus, in both the sheep and human glucocorticoids contribute to mechanisms of labor at term and the effects of glucocorticoids are modulated in a local, intrauterine fashion. Eventually these give rise to a series of feed forward cascades which culminate in membrane rupture (through increased MMP9 activity), myometrial activation, cervical dilatation and effacement, and birth.
KEY WORDS: glucocorticoids, prostaglandins, 11 HSD, PGHS-2
Internet Services provided by|
Allen Press, Inc. | 810 E. 10th St. | Lawrence, Kansas 66044 USA
e-mail email@example.com | Web www.allenpress.com
All material is copyright © 2001 SSR