title: Prostaglandins and mechanisms of preterm birth.
abstract: Increased uterine contractility at term and preterm results first from activation and then stimulation of the myometrium. Activation can be provoked by mechanical stretch of the uterus, and by an endocrine pathway resulting from increased activity of the fetal hypothalamic-pituitary-adrenal axis. In sheep fetuses, increased cortisol output during pregnancy regulates expression of prostaglandin synthase type 2 (PGHS-2) in the placenta in an oestrogen-independent manner, resulting in increased concentrations of prostaglandin E2 (PGE2) in the fetal circulation. Later increases in maternal uterine expression of PGHS-2 require increases in oestrogen and lead to increased concentrations of PGF(2alpha) in the maternal circulation. Thus, regulation of PGHS-2 at term is differentially controlled in fetal (trophoblast) and maternal (uterine epithelium) tissue. This difference may reflect expression of glucocorticoid receptor but not oestrogen receptor (ER) in placental trophoblast cells. In women, cortisol also contributes to increased prostaglandin production in fetal tissues through upregulation of PGHS-2 (amnion and chorion) and downregulation of 15-OH prostaglandin dehydrogenase (PGDH; chorion trophoblasts). The effect of cortisol on expression of PGDH in the chorion reverses a tonic stimulatory effect of progesterone, potentially through a paracrine or autocrine action. In membranes, cortisol may be derived from cortisone through activity of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1, in addition to secretion from the maternal or fetal adrenal glands. In placenta, 11beta-HSD-2 oxidase activity predominates and expression of this enzyme is reduced with hypoxaemia and in placentae from pre-eclamptic pregnancies. In these circumstances, increased concentrations of maternal cortisol may cross into the fetal compartment, contributing to growth restriction and programming later life disease.
authors.affiliation: Department of Physiology, CIHR Group in Fetal and Neonatal Health and Development, CIHR Institute of Human Development, Child and Youth Health, University of Toronto, Medical Sciences Building, Suite 3368, Toronto M5S 1A8, Canada. j.challis@utoronto.ca
authors.forename: John R G
authors.initials: JR
authors.lastname: Challis
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Sloboda
authors.forename: Nadia
authors.initials: N
authors.lastname: Alfaidy
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Lye
authors.forename: William
authors.initials: W
authors.lastname: Gibb
authors.forename: Fal A
authors.initials: FA
authors.lastname: Patel
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Whittle
authors.forename: John P
authors.initials: JP
authors.lastname: Newnham
mesh_terms: D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000502:physiology; D005260:Female; D005333:Fetus / Q000378:metabolism*; D005938:Glucocorticoids / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007231:Infant, Newborn; D007752:Obstetric Labor, Premature / Q000378:metabolism*; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000502:physiology*; D014590:Uterine Contraction / Q000502:physiology*
chemical_list: D005938:Glucocorticoids; D011453:Prostaglandins; D003346:Corticotropin-Releasing Hormone; D011451:Prostaglandin-Endoperoxide Synthases; D006854:Hydrocortisone