Putative role of placental corticotropin-releasing factor in the mechanisms of human parturition

Corticotropin-releasing factor is a 41-amino-acid neuropeptide synthesized in the paraventricular nucleus of the hypothalamus and released in response to stress. Its major role is the regulation of the hypothalamus-pituitary- adrenal axis by stimulation of ACTH release from the anterior pituitary gla ns. Corticotropin-releasing factor was first detected in the extracts of hu man placentas obtained at full term from spontaneous deliveries. Placental corticotropin-releasing factor content and messenger RNA expression progres sively increase during normal pregnancy, and corticotropin-releasing factor levels in maternal plasma have a similar time course. The addition of cort icotropin-releasing factor to primary trophoblast cell cultures stimulated ACTH secretion in a dose-dependent manner, and its action is mediated by cy clic adenosine monophosphate as second messenger. In addition, corticotropi n-releasing factor is a potent local regulator of myometrial contractility and of membrane prostaglandin release. The effects of corticotropin-releasi ng factor in these various tissues are mediated by specific receptors. Plac ental corticotropin-releasing factor is also secreted into the fetal circul ation and the stimulation of fetal pituitary ACTH and fetal adrenal gland d ehydroepiandrosterone sulfate release in vitro has been shown. Recently, ur ocortin, a new peptide related to corticotropin-releasing factor, has been found in human placenta. Corticotropin-releasing factor and urocortin share some of their biologic effects, acting on the same receptors. A large-mole cular-weight corticotropin-releasing factor-binding protein modulates the a ctivity of both these peptides. Plasma corticotropin-releasing factor level s are low in nonpregnant women and become higher during the second trimeste r of pregnancy, rising steadily until about 35 weeks, and then increasing m ore rapidly until term. Vaginal delivery is a condition associated with the highest values of maternal corticotropin-releasing factor levels. Corticot ropin-releasing factor is also measurable in fetal plasma (20-fold lower th an in maternal circulation) and in amniotic fluid. Increased maternal plasm a corticotropin-releasing factor levels characterize some gestational disea ses. Women with chronic hypertension and preeclampsia have high corticotrop in-releasing factor levels, and intrauterine growth retardation is associat ed with an activation of the hypothalamus-pituitary-adrenal axis, reflected by increased fetal plasma concentrations of ACTH, cortisol, and corticotro pin-releasing factor. The role of corticotropin-releasing factor in preterm labor is uncertain, but midgestational plasma corticotropin-releasing fact or levels may be higher in women delivering preterm. In these various patho logic states, maternal plasma corticotropin-releasing factor-binding protei n levels undergo opposite changes, decreasing to very low levels. The endoc rine-paracrine corticotropin-releasing factor/corticotropin-releasing facto r-binding protein pathways may play a major role in the mechanism of human parturition. Copyright (C) 1999 by the Society for Gynecologic Investigatio n.