The diverse mechanisms by which functional progesterone withdrawal or antagonism is achieved is an active area of research. These include: (1) changes in the relative expression of the nuclear progesterone-receptor isoforms, PR-A, PR-B, and PR-C; (2) diferential interaction of PR-A and PB-B with enhancers and inhibitors of gene expression; (3) alterations in PR activity through changes in the expression of coactivators or corepressors that directly influence receptor function; (4) local inactivation of progesterone by steroid-metabolizing enzymes or synthesis of a natural antagonist; and (5) microRNA regulation of progesterone-metabolizing enzymes and transcription factors that modulate uterine quiescence (Condon, 2003; Mahendroo, 1999; Mesiano, 2002; Nadeem, 2016; Renthal, 2010; Williams, 2012a). Taken together, these observations support the concept that multiple pathways exist for a functional progesterone withdrawal.
Phase 2 myometrial changes prepare it for labor contractions. his results from a shit in the expression of key proteins that control uterine quiescence to an expression of contraction-associated proteins, described earlier (p. 405) (Renthal, 2015). Of these CAPs, myometrial oxytocin receptors and gap junction proteins, such as connexin-43, markedly rise in number. These CAPs increase uterine irritability and responsiveness to uterotonins.
Another critical change in phase 2 is formation of the lower uterine segment from the isthmus. With this development, the fetal head often descends to or even through the pelvic inletso-called lightening. he abdomen commonly undergoes a shape change, sometimes described by women as "the baby dropped." It is also likely that the lower segment myometrium is unique from that in the upper uterine segment, resulting in distinct roles for each near term and during labor. This is supported by human studies that demonstrate diferential expression of prostaglandin receptors and CAPs within the upper-and lower-segment myometrial regions (Astle, 2005; Blanks, 2003; Sparey, 1999). Near term, elevated expression of the HoA13 gene in the lower myometrial segment compared with the upper segment also induces CAP expression and regionalized contractility of the lower segment (Li, 2016).
Because of its long-standing application for labor induction, it seemed logical that oxytocin must playia central role in spontaneous human labor. Myometrial oxytocin receptor levels do rise during phase 2 of parturition, and the level of oxytocin receptor mRNA in human myometrium at term is greater than that found in preterm myometrium (Wathes, 1999). However, it is unclear whether oxytocin plays a role in the early phases of uterine activation or whether its sole function is in the expulsive phase of labor. Most studies of regulation of myometrial oxytocin receptor synthesis have been performed in rodents. Disruption of the oxytocin receptor gene in the mouse does not afect parturition. This suggests that, at least in this species, multiple systems likely ensure that parturition occurs.
Progesterone and estradiol appear to be the primary regulators of oxytocin receptor expression. Estradiol treatment in vivo or in myometrial explants raises myometrial oxytocin receptor concentrations. This action, however, is prevented by simultaneous treatment with progesterone (Fuchs, 1983). Progesterone also may act within the myometrial cell to enhance oxytocin receptor degradation and inhibit oxytocin activation of its receptor at the cell surface (Bogacki, 2002). hese data indicate that one of the mechanisms whereby progesterone maintains uterine quiescence is through inhibition of a myometrial oxytocin response.
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