The process of normal spontaneous parturition can be divided into four stages (see the reviews of Challis  and Challis et al. ). During most of pregnancy, the uterus remains relatively quiescent, and this corresponds to Phase 0 (quiescence) of parturition. Phase 1 (activation) involves uterine stretch and fetal hypothalamic-pituitary-adrenal (HPA) activation. Phase 2 (stimulation) refers to stimulation of the activated uterus by various substances, including corti-cotropin-releasing hormone (CRH), oxytocin, and prostaglandins. These different processes lead to a common pathway to parturition involving increased uterine contractility, cervical ripening, and decidual and fetal membrane activation (Romero et al., 2004a). Phase 3 (involution) corre-
sponds to postpartum involution of the uterus. These unique phases are described below and are summarized in Figure 6-1.
FIGURE 6-1. The stages of parturition. Following implantation, more than 95 percent of gestation is spent in Phase 0, uterine quiescence. During quiescence, myometrial contractility is inhibited by a variety of biological substances, including progesterone. Phase 1, myometrial activation, is characterized by increased expression of contraction-associated proteins, receptors for oxytocin, and prostaglandins, and increased placental estrogen biosynthesis. The signal for myometrial activation is controlled by the fetal HPA axis, which, in turn, is up-regulated by endogenous placental CRH production. Phase 2, myometrial stimulation, involves a progressive cascade of events, beginning with myometrial activation, which results in myometrial contractility, cervical ripening, and decidua and membrane activation. It is likely initiated by the same events of fetal HPA activation that initiate Phase 1. Phase 3, involution, involves placental separation and contraction of the uterus. It is primarily effected by maternal oxytocin.
Phase 0: Quiescence
Throughout most of pregnancy the uterus remains relatively quiescent. Myometrial activity is inhibited during pregnancy by various substances, including progesterone, prostacyclin (PGI2), nitric oxide, relaxin, and parathyroid hormone-related peptide. These substances function by different mechanisms, but in general they increase intracellular levels of cyclic nucleotides (cyclic adenosine monophosphate [cAMP] or cyclic guanosine monophosphate), which in turn inhibit the release of calcium from intracellular stores or reduce the activity of the enzyme myosin light-chain kinase (MLCK). Calcium and MLCK are central to uterine contractility. Calcium is required to activate calmodulin, which in turn induces a conformational change in MLCK, allowing the enzyme to phosphorylate myosin and initiate the coupling of actin and myosin, which leads to myometrial contraction.
Phase 0: Uterine Quiescence
Phase 1: Ph Phase 3:
Activation Sti Involu tion
Rare uterine contractions that occur during the quiescent phase are of low frequency and amplitude and are poorly coordinated; these are commonly referred to as contractures in animals and Braxton-Hicks contractions in women. The poor coordination of these contractions is primarily due to an absence of gap junctions in the pregnant myometrium (Garfield, 1988). Gap junctions (and their associated proteins, called connexins) allow cell-to-cell coupling. With the onset of labor, there is a massive increase in the numbers of gap junctions, resulting in significantly enhanced electrical coupling and synchronized high-amplitude contractions throughout the myometrium.
Phase 1: Activation
Phase 1 myometrial activation is characterized by increased levels of expression of contraction-associated proteins (CAPs), including connexin-43 (CX-43; the major protein of myometrial gap junctions), and receptors for oxytocin and stimulatory prostaglandins (Lye et al., 1998). Normally, the signals for myometrial activation can come from uterine stretch as a result of fetal growth or from activation of the fetal HPA axis as a result of fetal maturation, or both.
Uterine stretch has been shown in animal models to increase CAP and oxytocin receptor gene expression in the myometrium, but the ability to do so is highly dependent on the endocrine environment. Progesterone blocks stretch-induced increases in the levels of CX-43 expression. However, with progesterone withdrawal at term (see below), uterine stretch is associated with significant increases in the levels of CX-43 expression.
Signals for myometrial activation also come from the fetal HPA axis (Liggins and Thor-burn, 1994). It is currently thought that once fetal maturity 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 an-drogens 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: Stimulation
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 et al. [2002b]). 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; McClean 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 CRH, in turn, enhances prostaglandin production by increasing the levels of expression of prostaglandin H2 synthase (PGHS) chorion and amnion cells, creating yet another positive-feedback loop that drives the process of parturition. Paradoxically, during uterine quiescence CRH may act as a myometrial relaxant rather than as a promoter of parturition. Throughout most of pregnancy, the myometrium expresses CRH type 1 receptors that are linked by Gsa regulatory proteins to adenylate cyclase and cAMP, which would promote myometrial relaxation when they are stimulated. At the end of pregnancy, however, an alternative splice variant of the CRH receptor is expressed and the level of expression of GsD subunits declines, which may promote a contractile phenotype (reviewed by Challis et al. ).
Functional progesterone withdrawal. For most of pregnancy, uterine quiescence is maintained by the action of progesterone. It does so by blocking CAP gene expression and gap junction formation within the myometrium; inhibiting placental CRH secretion; opposing the activity of estrogen (see below); up-regulating systems (e.g., nitric oxide) that promote myometrial relaxation; and suppressing the expression of cytokines and prostaglandins. At the end of pregnancy in most mammals, maternal progesterone levels fall and estrogen levels rise. In women, however, progesterone and estrogen concentrations continue to rise throughout pregnancy until delivery of the placenta. Recent data suggest that functional progesterone withdrawal may occur in women and nonhuman primates by alterations in the levels of progesterone receptor (PR) isoforms (Smith et al., 2002b). In women, the PR-B receptor isoform functions predominantly as an activator of progesterone-responsive genes, whereas the PR-A receptor isoform acts as a repressor of PR-B function and other nuclear receptors. In the term myometrium, the onset of labor is associated with increased levels of PR-A expression relative to the levels of PR-B expression. Because PR-A suppresses the action of progesterone, the increased level of PR-A expression relative to that of PR-B decreases the responsiveness of the myometrium to progesterone, resulting in a functional progesterone withdrawal that enables parturition to proceed.
Estrogens. Unlike the placentas of most other species, the human placenta cannot convert progesterone to estrogen because it is deficient in 17-hydroxylase, which is required for this conversion. Estrogen production in the placenta depends largely on precursor androgens synthesized in the fetal zone of the fetal adrenal; approximately 50 percent of circulating maternal estrone and estradiol are derived from placental aromatization of the fetal androgen, DHEA-S. Placental CRH directly and indirectly (via fetal pituitary secretion of ACTH) stimulates the fetal zone of the fetal adrenals to produce DHEA-S, thereby supplying the precursors needed for estrogen synthesis in the placenta.
Estrogens, in turn, enhance the expression of many estrogen-dependent CAPs, including CX-43 (gap junctions), oxytocin receptor, prostaglandin receptors, cyclooxygenase-2 (COX-2; which results in prostaglandin production), and MLCK (which stimulates myometrial contractility and labor) (Challis, 2000).
Prostaglandins. Extensive evidence supports a central role for prostaglandins in promoting uterine contractiity (Challis et al., 2000). The actions of prostaglandin are effected through specific receptors. PGE2 induces myometrial contractions by binding to EP-1 and EP-3 receptors, which mediate contractions through mechanisms that lead to increased calcium mobilization and reduced levels of production of inhibition of intracellular cAMP. Prostaglandins also enhance the production of matrix metalloproteinases (MMP) in the cervix and decidua to promote cervical ripening and decidual and fetal membrane activation. PGF2a binds to FP receptors to induce myometrial contractions. In contrast, in the lower uterine segment PGE2 induces myometrial relaxation by binding to EP-2 and EP-4 receptors that increase the level of cAMP formation.
Prostaglandins are formed from arachidonic acid by PGHS. In turn, prostaglandins are metabolized to inactive forms by the actions of PGDH. Cortisol, CRH, and estrogens stimulate PGHS activity and cortisone and CRH also inhib PGDH expression. Thus, increases in fetal steroid hormone production following fetal HPA activation leads to a net increase in prostaglandin levels. Similarly, proinflammatory cytokines such as IL-1 and tumor necrosis factor alpha (TNF-a) up-regulate PGHS expression and down-regulate PGDH expression leading to prostaglandin synthesis associated with preterm delivery in the setting of infection.
In summary, these events initiated by fetal HPA activation and resulting in increased fetal and placental steroid biosynthesis result in a progressive cascade of biological processes lead to a common pathway of parturition involving cervical ripening, uterine contractility and decidual and fetal membrane activation.
Cervical Ripening. Cervical changes precede the onset of labor, are gradual, and develop over several weeks. Cervical ripening is characterized by a decrease in the total collagen content, an increase in collagen solubility, and an increase in collagenolytic activity that results in the remodeling of the extracellular matrix of the cervix (Romero et al., 2004a). Prostaglandins, estrogens, progesterones, and inflammatory cytokines (e.g., IL-8) effect the metabolism of the extracellular matrix. PGE2 stimulates collagenolytic activity and the synthesis of subtypes of proteoaminoglycans that are less stabilizing. Estrogen stimulates collagen degradation in vitro, and intravenous administration of 17P-estradiol induces cervical ripening. Progesterone blocks estrogen-induced collagenolysis in vitro and down-regulates IL-8 production by the uterine cervix. In addition to these hormones, nitric oxide may play a role in cervical ripening in some circumstances. Nitric oxide accumulates at sites of inflammation and can act as an inflammatory mediator at high concentrations. Nitric oxide donors (e.g., sodium nitroprusside) have been
shown to induce cervical ripening, whereas nitric oxide inhibitors (e.g., L-nitro-arginine methylester) block cervical ripening.
Uterine contractility. Uterine contraction results from the coupling of actin and myosin, which depends on the phosphorylation of myosin by MLCK. MLCK is activated by calcium-calmodulin after an increase in intracellular calcium levels. This increase in generated by the actions of various uterotonins, including oxytocin and prostaglandins. Cell-to-cell coupling, which allows the myometrium to develop synchronous high-amplitude contractions during labor, is facilitated by the formation of gap junctions and their associated proteins (e.g., connexins) (Lye et al., 1998). Their formation is highly dependent on estrogen; estrogen activation, in turn, is induced by a functional progesterone withdrawal at term.
Decidual and fetal membrane activation. Decidual and fetal membrane activation refers to a complex set of anatomical and biochemical events that result in the separation of the lower pole of the membranes from the deciduas of the lower uterine segment and, eventually, in the spontaneous rupture of membranes. The precise mechanism of membrane and decidual membrane activation remains to be elucidated, but extracellular matrix-degrading enzymes such as MMP type 1 (MMP-1), interstitial collagenase, MMP-8 (neutrophil collagenase), MMP-9 (gelatinase B), neutrophil elastase, and plasmin have been implicated. These enzymes degrade extracellular matrix proteins (e.g., collagens and fibronectins), thereby weakening the membranes, which eventually leads to the rupture of membranes. Some MMPs, such as MMP-9, may induce apoptosis in the amnion.
Phase 3: Involution
Phase 3 begins with the third stage of labor and involves placental separation and uterine contraction. Placental separation occurs by cleavage along the plane of the decidua basalis. Uterine contraction is essential to prevent bleeding from the large venous sinuses that are exposed after delivery of the placenta and is primarily affected by oxytocin.
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