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that are less stabilizing. Estrogen stimulates collagen degradation in vitro, and intravenous administration of 17β-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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