Corticotropin-releasing hormone (CRH) is synthesized in the placenta and hypothalamus. Discussed on page 410, CRH plasma levels rise dramatically during the inal 6 to 8 weeks of normal pregnancy and are implicated in mechanisms that control the timing of human parturition (Smith, 2007; Wadhwa, 1998). CRH appears to promote myometrial quiescence during most of pregnancy but then aids myometrial contractions with parturition onset. Studies suggest that these opposing actions are achieved by diferential actions of CRH via its receptor CRHR1. In nonlaboring myometrium at term, the interaction of CRH with its CRHR1 receptor activates the Gs-adenylate cyclasecAMP signaling pathway. his results in inhibition of inositol triphosphate (IP3) and stabilization of (Ca2+)j levels (You, 2012). However, in term laboring myometrium, (Ca2+)j concentrations are augmented by CRH activation of G proteins Gq and Gi and prompts stimulation ofIP3 production and greater contractility.
As just described, cAvIP is an important mediator of myometrial relaxation. However, activation of guanylyl cyclase raises
Physiology of Labor 407 intracellular cyclic guanosine monophosphate (cGMP) levels. This also promotes smooth muscle relaxation (Word, 1993). Intracellular cGMP levels are increased in the pregnant myometrium and can be stimulated by atrial natriuretic peptide (ANP) , brain natriuretic peptide (BNP) receptors, and nitric oxide (Telfer, 2001). All of these factors and their receptors are expressed in the pregnant uterus.
In addition to pregnancy-induced compounds that promote myometrial cell refractoriness, the activity of enzymes that degrade or inactivate endogenously produced uterotonins are strikingly increased in phase 1. Some of these degrading enzymes and their respective targets include PGDH and prostaglandins; enkephalinase and endothelins; oxytocinase and oxytocin; diamine oxidase and histamine; catechol O-methyltransferase and catecholamines; angiotensinases and angiotensin-II; and platelet-activating factor (P AF) and P AF acetylhydrolase. Levels of several of these enzymes decrease late in gestation (Germain, 1994).
To ensure uterine quiescence, the synthesis in the decidua of prostaglandins, in particular PGF2', is markedly suppressed.
Suppression of prostaglandin production here persists through out most of pregnancy, and suppression withdrawal is a prereq uisite for parturition (Norwitz, 2015).
Phase 1 of parturition also promotes an environment of immune tolerance to protect the fetus. Namely, decidual stromal cells proactively ensure that fetal antigens do not elicit a maternal immune response. his stems from a reduced capacity to attract T cells. This limited ability derives in part from epigenetic silencing of T cell-attracting inlammatory chemokine genes (Erlebacher, 2013; Nancy, 2012; PrabhuDas, 2015).
The initial stage of cervical remodeling-termed soteningbegins in phase 1 of parturition. It is characterized by greater tissue compliance, yet the cervix remains irm and unyielding. Hegar (1895) irst described palpable softening of the lower uterine segment at 4 to 6 weeks' gestation, and this sign was once used to diagnose pregnancy. Clinically, the maintenance of cervical anatomical and structural integrity is essential for pregnancy to continue to term. Preterm cervical dilation, structural insuiciency, or both may forecast delivery.