rity has been reached (as determined by as yet unknown mechanisms), the fetal hypothalamus and/or the placenta (see below) increase the level of CRH secretion, which in turn stimulates adrenocorticotropic hormone (ACTH) expression by the fetal pituitary and cortisol and androgen production by the fetal adrenals. Fetal androgens are then aromatized into estrogens by the placenta. Ultimately, this initiates a biological cascade that leads to a common pathway of parturition characterized by uterine contractility, cervical ripening and decidual/fetal membrane activation seen in Phase 2 of parturition.
Phase 2 involves a progressive cascade of events that lead to a common pathway of parturition involving uterine contractility, cervical ripening, and decidual and fetal membrane activation. These events are characterized by fetal HPA activation, functional progesterone withdrawal, increasing maternal and fetal estrogens, and rising prostaglandins. The cascade may begin with the placental production of CRH and eventually leads to a functional progesterone withdrawal in the myometrium. The progesterone withdrawal causes increased levels of expression of estrogen receptors and promotes estrogen activity. The increased action of estrogen leads to the formation of many estrogen-dependent CAPs, such as CX-43, oxytocin receptors, and prostaglandins, that promote uterine contractility.
CRH and the “placental clock.” Corticotropin-releasing hormone (CRH) is thought to play a central role in fetal maturation and human parturition (McLean et al., 1999; reviewed by Smith R et al. ). CRH, a neuropeptide of predominantly hypothalamic origin, is also expressed in the human placenta and membranes and is released into maternal and fetal compartments in exponentially increasing amounts over the course of gestation. The trajectory of the rise in CRH levels has been associated with the length of gestation (Hobel et al., 1999; Leung et al., 1999; McLean and Smith, 1999). Specifically, women destined to preterm delivery have higher concentrations of maternal CRH in plasma as early as 16 weeks of gestation and a more rapid rise in CRH levels than women who deliver at term. These findings have led some researchers to suggest that placental CRH may act as a “placental clock” that regulates the length of gestation (McLean and Smith, 1999).
Placental CRH synthesis is stimulated by glucocorticoids, in contrast to the inhibitory effect of glucocorticoids on hypothalamic CRH synthesis. Placental CRH, in turn, promotes fetal cortisol and DHEA-S production, and this positive-feedback loop is progressively amplified, thereby driving the process forward from fetal HPA activation to parturition. Placental