Putative Role of Placental Corticotropin-Releasing Factor in the Mechanisms of Human Parturition

Abstract

Corticotropin-releasing factor is a 41-amino-aic neuropeptide synthesized in the paraventicular 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 gland. In addition, corticotropin-releasing factor modulates behavioral, vascular, and immune responses to stress. Corticotropin-releasing factor was first detected in the extracts of human placentas obtained at full term from spontaneous deliveries. Placental corticotropin-releasing factor content and messenger RNA expression progressively increase during normal pregnancy, and corticotropin-releasing factor levels in maternal plasma have a similar time course. The addition of corticotropin-releasing factor to primary trophoblast cell cultures stimulates ACTH secretion in a dose-dependent manner, and its action is mediated by cyclic adenosine monophosphate as second messenger. In addition, corticotropin-releasing factor is a potent local regulator of myometrial contractility and of membrane prostaglandin release. The effects of corticotropin-releasing factor in these various tissues are mediated by specific receptors. Placental corticotropin-releasing factor is also secreted into the fetal circulation and the stimulation of fetal pituitary ACTH and fetal adrend gland dehydroepiandrosterone sulfate release in vitro has been shown. Recently, urocortin, 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-molecular-weight corticotropin-releasing factor-binding protein modulates the activity of both these peptides. Plasma corticotropin-releasing factor levels are low in nonpregnant women and become higher during the second trimester of pregnancy, rising steadily until about 35 weeks, and then increasing more rapidly until term. Vaginal delivery is a condition associated with the highest values of maternal corticotropin-releasing factor levels. Corticotropin-releasing factor is also measurable in fetal plasma (20-fold lower than in maternal circulation) and in amniotic fluid. Increased maternal plasma corticotropin-releasing factor levels characterize some gestational diseases. Women with chronic hypertension and preeclampsia have high corticotropin-releasing factor levels, and intrauterine growth retardation is associated with an activation of the hypothalamus-pituitary-adrenal axis, reflected by increased fetal plasma concentrations of ACTH, cortisol, and corticotropin-releasing factor. The role of corticotropin-releasing factor in preterm labor is uncertain, but midgestational plasma corticotropin-releasing factor levels may be higher in women delivering preterm. In these various pathologic states, maternal plasma corticotropin-releasing factor-binding proten levels undergo opposite changes, decreasing to very low levels. The endocrine-paracrine corticotropin-releasing factor/corticotropin-releasing factor-binding protein pathways may play a major role in the mechanism of human parturition.