Cervical softening results from increased vascularity, cellular hypertrophy and hyperplasia, and slow, progressive compositional and structural changes in the extracellular matrix (Mahendroo, 2012; Myers, 2015; Word, 2007). Key to matrix changes, collagen, which is the main structural protein in the cervix, undergoes conformational changes that alter tissue stifness and flexibility (Zhang, 2012). Speciically, collagen processing and the number or type of stable covalent cross-links between collagen triple helices is altered. Mature cross-links between newly synthesized collagen monomers are reduced due to diminished expression and activity of the cross-link-forming enzymes beginning in early pregnancy (Akins, 2011; Drewes, 2007; Yoshida, 2014). hese enzymes are lysyl hydroxylase and lysyl oxidase. Together, these early pregnancy changes contribute to greater tissue compliance.
Clinical evidence for the importance of matrix changes to cervical sotening is supported by in vivo mechanical evaluation of the cervix (Badir, 2013; Parra-Saavedra, 2011). he prevalence of cervical insuiciency is also higher in those with inherited defects in the synthesis or assembly of collagen or elastic ibers (Anum, 2009; Hermanns-Le, 2005; Rahman, 2003; Wang, 2006). Examples are Ehlers-Danlos and Marfan syndromes, discussed in Chapter 59 (p. 1151). Concurrent with matrix remodeling in the sotening period, genes involved in cervical dilation and parturition are actively repressed (Hari Kishore, 2012).
PHASE 2: PREPARATION FOR LABOR
To prepare for labor, the myometrial tranquility of phase 1 of parturition must be suspended-so-called uterine awakening or activation. This phase 2 of parturition is a progression of uterine changes during the last few weeks of pregnancy. Importantly, shifting events associated with phase 2 can cause either preterm or delayed labor.
Key factors in uterine activation are depicted in Figure 21-5. In species that exhibit progesterone withdrawal, parturition progression to labor can be blocked by administering progesterone to the mother. Whether progesterone administration in the absence of classic progesterone withdrawal in pregnant women can delay the timely onset of parturition or prevent preterm labor continues to be investigated. he possibility that progesterone-containing injections or vaginal suppositories may prevent preterm labor has been studied in several randomized trials conducted during the past 15 years. hese are discussed in Chapter 42 (p. 816), and their use in preventing recurrent preterm birth continues to be debated (Norman, 2016).
Classic progesterone withdrawal resulting from decreased secretion does not occur in human parturition. However, a mechanism for progesterone inactivation, whereby the myometrium and cervix become refractory to progesterone's inhibitory actions, is supported by studies using progesterone-receptor antagonists. Mifepristone is a classic steroid antagonist, acting at the level of the progesterone receptor. Although less efective in inducing abortion or labor in women later in pregnancy, mifepristone appears to have some efect on cervical ripening and on increasing myometrial sensitivity to uterotonins (Berkane, 2005; Chwalisz, 1994a).