Physiology of Labor
BS. Nguyễn Hồng Anh
Labor is characterized by forceful and painful uterine contractions that effect cervical dilation and cause the fetus to descend through the birth canal. However, extensive preparations take place in both the uterus and cervix long before this. During the first 36 to 38 weeks of normal gestation, the myometrium is in a preparatory yet unresponsive state. Concurrently, the cervix begins an early stage of remodeling yet maintains structural integrity. Following uterine quiescence, a transitional phase begins during which myometrial unresponsiveness is suspended and the cervix undergoes ripening, effacement, and loss of structural cohesion.
The physiological processes that regulate parturition and the onset of labor continue to be defined. Tree theories describe labor initiation. Viewed simplistically, the first is the functional loss of pregnancy maintenance factors. The second focuses on synthesis of factors that induce parturition. The third suggests that the mature fetus is the source of the initial signal for parturition commencement. Research supports a model that draws from all three themes. Thus, labor onset represents the culmination of a series of biochemical changes in the uterus and cervix.
These result from endocrine and paracrine signals emanating from both mother and fetus. Their relative contributions vary between species, and it is these differences that complicate elucidation of the exact factors that regulate human parturition. When parturition is abnormal, preterm labor, dystocia, or postterm pregnancy may result.
MATERNAL AND FETAL COMPARTMENTS
■ Uterus and Cervix
The myometrial layer of the uterus is composed of bundles of smooth muscle cells surrounded by connective tissue. In contrast to skeletal or cardiac muscle, the smooth muscle cell is not terminally differentiated and therefore is readily adaptable to environmental changes. Varied stimuli such as mechanical stretch, inflammation, and endocrine and paracrine signals modulate the transition of the smooth muscle cell into phenotypes that provide cell growth, proliferation, secretion, and contractility.
Additionally, several smooth muscle qualities confer advantages for uterine contraction effciency and fetal delivery. First, the degree of smooth muscle cell shortening with contractions may be one order of magnitude greater than that attained in striated muscle cells. Second, forces can be exerted in smooth muscle cells in multiple directions. This differs from the contraction force generated by skeletal muscle, which is always aligned with the axis of the muscle fibers. Third, the thick and thin filaments of smooth muscle are found in long, random bundles throughout the cells. This plexiform arrangement aids augmented shortening and force-generating capacity. Last, greater multidirectional force generation in the uterine fundus compared with that of the lower uterine segment helps optimize expulsive force vectors.
Lining the thick muscular uterine walls, the endometrium is transformed by pregnancy hormones and is then termed decidua. Composed of stromal cells and maternal immune cells, the decidua serves to maintain the pregnancy via unique immunoregulatory functions that suppress inflammatory signals during gestation. However, at the end of pregnancy, the decidua transitions to induce inflammatory signals and withdraw active immunosuppression, contributing to parturition initiation.
During pregnancy, the cervix has multiple functions that include: (1) maintaining the epithelial barrier to protect the reproductive tract from infection, (2) sustaining cervical competence despite greater gravitational forces as the fetus grows, and (3) orchestrating extracellular matrix (ECM) changes that allow progressively greater tissue compliance.
In nonpregnant women, the cervix is closed and firm, and its consistency is similar to nasal cartilage. By the end of pregnancy, the cervix is easily distensible, and its consistency is similar to the lips of the oral cavity. The cervix has a high ratio of fibroblasts to smooth muscle cells, and ECM contributes significantly to overall tissue mass. Vink and colleagues (2016) showed that the smooth muscle cells in the cervix have a spatial gradient. Specifically, smooth muscle cells make up approximately 50 percent of stromal cells at the internal os but only 10 percent at the external os. Also, three-dimensional sonography and magnetic resonance imaging show increases in the cross-sectional area of the cervical canal and changes in ECM structure from early to late pregnancy (House, 2009; Lang, 2010; Pizzella, 2020). Concurrent with expansion of the stroma, the cervical epithelia proliferate and exert a pregnancy-specific immunoprotection.
■ Placenta
In addition to providing the exchange of nutrients and waste between mother and fetus, the placenta is a key source of steroid hormones, growth factors, and other mediators that maintain pregnancy and potentially aid the transition to parturition. The fetal membranes—amnion and chorion—and adjacent decidua serve as a physiologic, immunologic, and metabolic shield to protect against untimely parturition initiation.
The amnion provides virtually all of the fetal membranes’ tensile strength to resist membrane tearing and rupture (Chap. 5, p. 94). This avascular tissue is highly resistant to penetration by leukocytes, microorganisms, and neoplastic cells (Fig. 21-1). It also constitutes a selective filter to prevent fetal particulate-bound lung and skin secretions from reaching the maternal compartment. In this manner, maternal tissues are protected from amnionic fluid constituents that could prematurely accelerate decidual or myometrial activation or could promote adverse events such as amnionic fluid embolism.
The chorion is a primarily protective tissue layer and provides immunological acceptance. It is also enriched with enzymes that inactivate uterotonins, which are agents that stimulate contractions. Inactivating enzymes include prostaglandin dehydrogenase, oxytocinase, and enkephalinase (Cheung, 1990; Germain, 1994; Mizutani, 2011).
SEX STEROID HORMONE ROLE
In many species, the role of sex steroid hormones is clear— estrogen promotes and progesterone inhibits the events leading to parturition. The removal of progesterone, that is, progesterone withdrawal, directly precedes progression of parturition.
In addition, providing progesterone to some species will delay parturition via a decline in myometrial activity and continued cervical competency (Challis, 1994). In humans, however, both estrogen and progesterone are components of a broader molecular system that maintains uterine quiescence.
Plasma levels of estrogen and progesterone in normal pregnancy are enormous and in great excess of the anity constants for their receptors. For this reason, it is difficult to comprehend how relatively subtle changes in the ratio of their concentrations could modulate physiological processes during pregnancy. The evidence, however, for an increased progesterone-to- estrogen ratio in the maintenance of pregnancy and a decline in this ratio for parturition is overwhelming. In all species studied, including humans, administration of the progesterone-receptor antagonists mifepristone (RU-486) or onapristone will promote some or all key features of parturition. These include cervical ripening, greater cervical distensibility, and augmented uterine sensitivity to uterotonins (Bygdeman, 1994; Chwalisz, 1994b; Wolf, 1993). The exact role of estrogen in regulation of human uterine quiescence and cervical competency is less well understood. That said, estrogen can advance progesterone responsiveness and, at the end of pregnancy, aid in processes that mediate uterine activation and cervical ripening.
Both progesterone and estrogen bind to nuclear receptors that regulate gene transcription. Two nuclear receptors for estrogen are estrogen receptor α (ERα) and estrogen receptor β (ERβ). Nuclear receptor isoforms of the progesterone receptor (PR-A and PR-B) are encoded by differing transcripts from a single gene (Patel, 2015).
PROSTAGLANDINS ROLE
Prostaglandins are lipid molecules with varied hormone-like actions. In parturition, they play a prominent role in myometrial contractility, relaxation, and inflammation. Prostaglandins interact with a family of eight different G protein–coupled receptors (p. 403), several of which are expressed in the myometrium and the cervix (Konopka, 2015; Myatt, 2004).
The major synthetic pathway involved in prostaglandin biosynthesis is shown in Figure 21-2. Prostaglandins are produced using plasma membrane–derived arachidonic acid, which usually is released by the action of phospholipase A2 or C. The enzymes type 1 and 2 prostaglandin H synthase (PGHS-1 and -2), also known as cyclooxygenase 1 and 2 (COX-1 and -2), convert arachidonic acid to prostaglandin H2 (PGH2). These enzymes are the target of many nonsteroidal antiinflammatory drugs (NSAIDs). The tocolytic actions of specific COX inhibitors, as discussed in Chapter 45 (p. 806), were considered promising until they were shown to have adverse fetal effects (Loudon, 2003; Olson, 2007).
Through prostaglandin isomerases, PGH2 is converted to active prostaglandins. These include prostaglandins E2 (PGE2), F2α (PGF2α), and I2 (PGI2). Isomerase expression is tissue-specific and thereby controls the relative production of various prostaglandins. Another important control point for prostaglandin activity is its metabolism, which most often is through the action of 15-hydroxyprostaglandin dehydrogenase (PGDH). Expression of this enzyme is upregulated during pregnancy in the uterus and cervix, which provides the important ability to rapidly inactivate prostaglandins (Giannoulias, 2002; Kishore, 2017). Thus, myometrial responses to prostaglandins stem from a balance between prostaglandin synthesis versus metabolism, from the relative expression of various prostaglandin receptors, or from a switch in receptor-signaling pathways (Kandola, 2014; Lyall, 2002; Olson, 2007; Smith, 2001). It is possible that prostanoids contribute to myometrial relaxation at one stage of pregnancy and to myometrial contractions after parturition initiation (Myatt, 2004).
In addition to the myometrium, the amnion synthesizes several bioactive peptides and prostaglandins that cause myometrial relaxation or contraction (see Fig. 21-1). Late in pregnancy, amnionic prostaglandin biosynthesis of PGE2 and PGF2α is increased, and phospholipase A2 and PGHS-2 show greater activity (Peiris, 2020). The amnion is likely the major source for amnionic fluid prostaglandins, and their role in the activation of cascades that promote membrane rupture is clear. However, the influence of amnion-derived prostaglandins on uterine quiescence and activation is less clear because their access to maternal tissues is limited by expression of PGDH.
PHASE 1: UTERINE QUIESCENCE AND CERVICAL SOFTENING
Parturition can be arbitrarily divided into four overlapping phases that correspond to the major physiological transitions of the myometrium and cervix during pregnancy (Fig. 21-3) (Casey, 1997; Shynlova, 2020; Vink, 2018). These include: (1) the prelude, (2) the preparation, (3) the process itself, and (4) the recovery. Importantly, the phases of parturition should not be confused with the clinical stages of labor. The first, second, and third stages of labor make up phase 3 of parturition (Fig. 21-4).
Beginning even before implantation, a remarkably effective period of myometrial quiescence is imposed. This phase 1 normally constitutes 95 percent of pregnancy and is characterized by uterine smooth muscle tranquility with maintenance of cervical structural integrity (Fig. 21-5). All manner of molecular systems—neural, endocrine, paracrine, and autocrine—are likely called to implement and coordinate a state of relative uterine unresponsiveness. Moreover, a complementary “fail-safe” system that protects the uterus against agents that could perturb the tranquility of phase 1 also must be in place.
During phase 1, the uterus must initiate extensive changes in its size and vascularity to accommodate fetal growth. Concurrently, myometrial cells undergo a phenotypic modification to a noncontractile state, and uterine muscle is rendered unresponsive to natural stimuli. Although this unresponsiveness continues until near the end of pregnancy, some low-intensity myometrial contractions are felt during the quiescent phase. These contractions do not normally cause cervical dilation, and they are common toward the end of pregnancy, especially in multiparas. They are referred to as Braxton Hicks contractions or false labor (Chap. 4, p. 52).
The quiescence of phase 1 likely stems from: (1) actions of estrogen and progesterone via intracellular receptors, (2) myometrial-cell plasma membrane receptor–mediated increases in cyclic adenosine monophosphate (cAMP), (3) generation of cyclic guanosine monophosphate, and (4) other systems, including modification of myometrial-cell ion channels.
■ Myometrial Relaxation and Contraction
The balance between myometrial relaxation and contraction is controlled by steroid- and peptide-hormone transcriptional regulation of key genes and their protein products (Wray, 2019). Quiescence is achieved in part by: (1) diminished intracellular crosstalk and reduced intracellular Ca2+ ([Ca2+]i) levels, (2) ion-channel regulation of cell membrane potential, (3) activation of the stress– unfolded protein response by the uterine endoplasmic reticulum, and (4) uterotonin degradation. In contrast, contractility results from: (1) enhanced interactions between the actin and myosin proteins, (2) heightened excitability of individual myometrial cells, and (3) promotion of intracellular crosstalk that allows synchronous contractions to develop.
Actin–Myosin Interactions
Actin and myosin proteins are essential to muscle contraction. For this, actin must be converted from a globular to a flamentous form. Indeed, a potential mechanism for maintenance of relaxation is the promotion of actin into a globular form rather than into fibrils, which are required for contraction. Moreover, actin must be attached to the cytoskeleton at focal points in the cell membrane to allow tension to develop.
Actin must partner with myosin, which is composed of multiple light and heavy chains (Fig. 21-6). This interaction is brought about by enzymatic phosphorylation of the 20-kDa light chain of myosin (Stull, 1998). This is catalyzed by the enzyme myosin light-chain kinase, which is activated by calcium (Ca2+).
Thus, logically, uterine relaxation ordinarily is promoted by conditions that lower concentrations of (Ca2+)i. In contrast, agents that prompt contraction act on myometrial cells to augment (Ca2+)i levels. Or, they allow an influx of extracellular calcium through ligand- or voltage-regulated calcium channels (see Fig. 21-6). For example, PGF2α and oxytocin bind their respective receptors during labor to open ligand-activated calcium channels. Activation of these receptors also releases calcium from the sarcoplasmic reticulum. Additionally, greater localization of nonselective cation channels on the cell membrane promotes Ca2+ entry (Ying, 2015). The rise in (Ca2+)i levels is often transient. But, contractions can be prolonged by inhibition of myosin phosphatase, an enzyme that dephosphorylates myosin (Woodcock, 2004).
Regulation of Membrane Potentials
As just noted, myocyte excitability is regulated in part by changes in the electrochemical potential gradient across the plasma membrane. Before labor, myocytes maintain a relatively high interior electronegativity. Maintenance of a hyperpolarized membrane potential attenuates smooth muscle cell excitation and is regulated by ion channels.
Numerous ion channels control sodium (Na+) and calcium (Ca2+) influx and potassium (K+) efux to collectively regulate membrane potential. Sodium leak channels (NALCN) are important to normal uterine function (Reinl, 2018).
Another key regulator is the large-conductance voltage- and Ca2+-activated K+ channel (BKCa) (Pérez, 1993). The BKCa channel is abundantly expressed in the myometrium and plays dual promoting and opposing roles to maintain a balance between uterine quiescence and contractility. Opening the BKCa channel allows potassium to leave the cell to maintain interior electronegativity, thus preventing voltage-gated Ca2+ influx and contraction. Inhibition of the BKCa channel augments myometrial contractility. Regulation of uterine contractility from early to late gestation may result from temporal changes in expression of the BKCa channel and/or BKCa interacting partners (Wakle-Prabagaran, 2016).
Myometrial Gap Junctions
Cellular signals that control myometrial contraction and relaxation can be effectively transferred between cells through intercellular junctional channels. Communication is established between myocytes by gap junctions, which aid the passage of electrical or ionic coupling currents as well as metabolite coupling. The connexin family of proteins form cell-type specific gap junctions (Solan, 2018). Connexin-43 is expressed in the myometrium, and concentrations rise near labor onset. Six connexin subunits form a connexon, and two adjacent connexons establish a conduit between communicating cells. This permits exchange of small molecules that can be nutrients, waste, metabolites, second messengers, or ions. Optimal numbers and types of gap junctions are believed to be important for electrical myometrial synchrony.
Progesterone promotes uterine quiescence in part by lowering expression of contraction-associated proteins (CAPs) and maintaining expression of anticontractile agents such as caspase 3 (Ingles, 2018; Kyathanahalli, 2015). CAPs include the oxytocin receptor, prostaglandin F receptor, and connexin-43. Also, at the end of pregnancy, increased stretch, metabolism of progesterone by the enzyme 20α-hydroxysteroid dehydrogenase (20α-HSD), loss of progesterone-mediated repression of CAP genes, and greater estrogen dominance raise CAP levels. Integration of diverse regulatory pathways culminates in released inhibition of connexin-43 and oxytocin receptor levels to promote greater uterine contractility
(Anamthathmakula, 2019; Mendelson, 2019; Peavey, 2021).
G Protein–Coupled Receptors
In addition to ion-channel linked receptors, G protein–coupled receptors regulate myocyte contractility. These receptors together with appropriate ligands may act with sex steroid hormones to maintain uterine quiescence (Price, 2000; Sanborn, 1998). Examples are the luteinizing hormone (LH) receptor and corticotropin-releasing hormone receptor 1 (CRHR1), both described in this section (Fig. 21-7). Other G protein–coupled myometrial receptors, instead, are associated with uterine contractility. G protein–mediated activation of phospholipase C, which releases arachidonic acid, is one example. Ligands for the G protein–coupled receptors include numerous neuropeptides, hormones, and autacoids. Many of these are available to the myometrium during pregnancy in high concentration via endocrine or autocrine mechanisms.
LH and human chorionic gonadotropin (hCG) hormones share the same LH-hCG receptor. This G protein–coupled receptor is found in myometrial smooth muscle and blood vessels, and levels during pregnancy are greater before labor (Ziecik, 1992). hCG acts to activate adenylyl cyclase by way of a plasma membrane receptor Gαs-linked system. This lessens contraction frequency and force and lowers the number of tissue-specific myometrial cell gap junctions (Ambrus, 1994; Eta, 1994). Thus, high circulating levels of hCG may be one mechanism of uterine quiescence. β-Adrenergic receptors mediate G αs-stimulated myometrial cell relaxation. Agents binding to these receptors have been used for tocolysis of preterm labor and include ritodrine and terbutaline (Chap. 45, p. 805). The rate-limiting factor is likely the number of receptors expressed and the level of adenylyl cyclase expression.
Prostaglandin E2 mediates its diverse cellular effects through four G protein–coupled receptors. Specifically, prostaglandin E receptors 1 through 4 (EP1-EP4) are expressed in the myometrium during pregnancy and with labor onset (Astle, 2005; Leonhardt, 2003). EP2 and EP4 act through Gαs to maintain myometrial cell quiescence but switch to a Gαq/11 calcium-activating pathway during labor (Kandola, 2014). EP1 and EP3 receptors act through Gαq and Gαi to augment intracellular Ca2+ and contractility.
The peptide hormone relaxin binds to the G protein–coupled receptor named relaxin family peptide receptor 1 (RXFP1). Binding activates adenylyl cyclase, which in turn prevents increased intracellular Ca2+, and thus promotes uterine quiescence (Downing, 1993; Meera, 1995). The H1 relaxin gene is primarily expressed in the decidua, trophoblast, and prostate, whereas the H2 gene is primarily expressed in the corpus luteum. Relaxin plasma levels peak at approximately 1 ng/mL between 8 and 12 weeks’ gestation. Thereafter, they decline until term. Corticotropin-releasing hormone (CRH) is synthesized in the placenta and hypothalamus. Discussed on page 408, CRH plasma levels rise dramatically during the final 6 to 8 weeks of normal pregnancy and are implicated in mechanisms that control the timing of human parturition (Smith, 2007; Wadhwa, 1998; Wang, 2019). CRH appears to promote myometrial quiescence during most of pregnancy but then aids contractions with parturition onset. Studies suggest that these opposing actions are achieved by differential actions of CRH via its receptor CRHR1. In nonlaboring myometrium at term, the interaction of CRH with CRHR1 activates the Gs-adenylate cyclase-cAMP signaling pathway. This results in inhibition of inositol triphosphate (IP3) and stabilization of (Ca2+)i levels (You, 2012). However, in term laboring myometrium, (Ca2+)i concentrations are augmented by CRH activation of G proteins Gq and Gi and prompts stimulation of IP3 production and greater contractility.
Cyclic Guanosine Monophosphate
As noted, cAMP is an important mediator of myometrial relaxation. However, activation of guanylyl cyclase raises 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, brain natriuretic peptide, and nitric oxide (Guerra, 2019; eler, 2001). All of these factors and their receptors are expressed in the pregnant uterus.
Accelerated Uterotonin
Degradation
The activity of enzymes that degrade or inactivate endogenously produced ute rotonins also is strikingly increased in phase
1. Pairs of some 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 (PAF) and PAF acetylhydrolase. Levels of several of these enzymes decline late in gestation (Germain, 1994).
■ Decidua
To ensure uterine quiescence, the synthesis in the decidua of prostaglandins, in particular PGF2α, is markedly suppressed. Suppression of prostaglandin production here persists throughout most of pregnancy, and suppression withdrawal is a prerequisite for parturition (Norwitz, 2015).
The mother and fetus come in direct contact at the decidua basalis and decidua parietalis. At this interface, myeloid and lymphoid immune cells such as natural killer cells, macrophages, dendritic cells, and T cells undergo dynamic changes in number and phenotype to achieve a balanced microenvironment (Ander, 2019; Solano, 2019; van der Zwan, 2020). This is a critical site for immune tolerance in phase 1 and for decidual activation in phase 2 of parturition (see Fig. 21-5). In phase 1 of parturition, these cells, in collaboration with decidual cells, promote an environment of immune tolerance to protect the fetus. Immune cells with innate and adaptive immune responses support vascular and tissue remodeling, immune surveillance and defense, and trophoblast invasion in phase 1 (Fig. 21-8).
During phase 2, decidual stromal cells and fetal membranes undergo an aging process termed cellular senescence. Noninflammatory signals precipitate senescence, which in turn leads to synthesis of proinflammatory cytokines, augmented prostaglandin production, and increased protease expression. These proteins and hormones break down fetal membranes.
■ Cervical Softening
The initial stage of cervical remodeling—termed softening— begins in phase 1 of parturition. It is characterized by greater tissue compliance, yet the cervix remains firm and unyielding. Hegar (1895) first 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 insufficiency, or both may forecast delivery.
■ Cervical Connective Tissue
Cervical softening is an active molecular process that balances tissue competence against slow, progressive compositional and structural changes in the extracellular matrix (ECM) to increase compliance (Myers, 2015; Nallasamy, 2017; Vink, 2018). Constituents of the ECM include type I and III fibrillar collagens, matricellular proteins, glycosaminoglycans, proteoglycans, and elastic fibers. Key to matrix changes, collagen, which is the main structural protein in the cervix, undergoes conformational changes that alter tissue stiffness and flexibility (Zhang, 2012). Specifically, collagen processing and the number or type of stable covalent cross-links between collagen's triple helices are altered. Beginning in early pregnancy, mature cross-links between newly synthesized collagen monomers are reduced due to diminished expression and activity of the cross-link-forming enzymes (Akins, 2011; Yoshida, 2014). These enzymes are lysyl hydroxylase and lysyl oxidase. Gradual turnover of collagen during pregnancy replaces mature cross-linked collagen fibrils with poorly linked fibrils. The result is a collagen with reduced stiffness. The collagen-binding proteoglycans—decorin and biglycan—ensure the new, poorly cross-linked collagen is appropriately assembled and deposited in the ECM. Data from human and mouse studies support the theory that a balance in the synthesis and breakdown of collagen, rather than loss of collagen, achieves cervical remodeling (Fig. 21-9) (Akins, 2011; Myers, 2008; Read, 2007; Yoshida, 2014).
Clinical evidence for the importance of matrix changes to cervical softening is supported by in vivo mechanical evaluation of the cervix (Badir, 2013; Parra-Saavedra, 2011). The prevalence of cervical insufficiency is also higher in those with inherited defects in the synthesis or assembly of collagen or elastic fibers (Anum, 2009; Hermanns-Le, 2005; Volozonoka, 2020) Examples are Ehlers-Danlos and Marfan syndromes, discussed in Chapter 62 (p. 1121). Concurrent with matrix remodeling in the softening period, genes involved in cervical dilation and parturition are actively repressed (Kishore, 2012).
PHASE 2: PREPARATION FOR LABOR
To prepare for labor, the myometrial tranquility of phase 1 of parturition must be suspended. This so-called uterine awakening or activation in 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.
■ Progesterone Withdrawal
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 can delay the timely onset of parturition or prevent preterm labor remains unclear. The possibility that progesterone may prevent preterm labor has been studied, but its use in preventing preterm birth continues to be debated (Chap. 45, p. 795).
Classic progesterone withdrawal 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 effective in inducing abortion or labor later in pregnancy, mifepristone appears to have some effect on cervical ripening and on increasing myometrial sensitivity to uterotonins (Berkane, 2005; Chwalisz, 1994a).
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 (PR) isoforms, (2) differential interaction of PR isoforms A and B with enhancers and inhibitors of gene expression, (3) altered PR activity through changes in the expression of coactivators or corepressors of receptor function, (4) local progesterone inactivation 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 (Chen, 2017; Condon, 2003; Mahendroo, 1999; Mesiano, 2002; Nadeem, 2016; Peavey, 2021; Renthal, 2010; Williams, 2012). Thus, multiple pathways exist to create functional progesterone withdrawal.
■ Myometrial Changes
Phase 2 changes in the myometrium prepare it for labor contractions. Changes result from a shift in the expression of proteins that control uterine quiescence to an expression of CAPs, described earlier (p. 403) (Mendelson, 2019; Renthal, 2015; Stanfield, 2019). These CAPs increase uterine 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 inlet— lightening. The 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, and leads to distinct roles for each near term and during labor. This is supported by human studies that demonstrate differential 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 HoxA13 gene in the lower myometrial segment compared with the upper segment also induces CAP expression and regionalized contractility of the lower segment (Li, 2016).
Oxytocin Receptors
Because of its long-standing application for labor induction, it seemed logical that oxytocin must play a 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 affect parturition. This suggests that, at least in this species, multiple systems likely ensure that parturition occurs.
Progesterone inhibits and estradiol induces oxytocin receptor expression. Through interaction with PR-B, progesterone regulates numerous genes in the oxytocin signaling pathway (Peavey, 2021). Progesterone may also act within the myometrial cell to enhance oxytocin receptor degradation (Bogacki, 2002). These data indicate that one of the mechanisms whereby progesterone maintains uterine quiescence is through inhibition of a myometrial oxytocin signaling pathway.
■ Cervical Ripening
Before contractions begin, the cervix must shift from a state of competence to one of compliance. This eventually leads to the cervix yielding and dilating from forceful uterine contractions. Cervical modifications during phase 2 principally involve connective tissue changes—termed cervical ripening. The transition from the softening to the ripening phase begins weeks or days before labor. The understanding of this cervical matrix trans- formation remains incomplete. However, it is clear that levels of glycosaminoglycans, which are large linear polysaccharides, are uniquely increased in phase 2.
Glycosaminoglycans and Proteoglycans
Hyaluronan is a high-molecular-weight polysaccharide that functions alone, but most other glycosaminoglycans (GAGs) complex with proteins to form proteoglycans. Hyaluronan is a hydrophilic, space-filling molecule, and thus greater hyaluronan production during cervical ripening is thought to increase viscoelasticity, hydration, and matrix disorganization. Hyaluronan synthesis is carried out by hyaluronan synthase isoenzymes, and expression of these enzymes is elevated in the cervix during ripening (Akgul, 2012; Straach, 2005).
Inflammatory Changes
In phase 2, resident immune cells are localized to the cervical stroma, although a functional role for them in this phase has not been demonstrated. For example, studies of gene expression patterns at term both before and after cervical ripening show little rise in proinflammatory gene expression. However, once labor is underway, activation of neutrophils, proinflammatory M1 macrophages, and tissue repair M2 macrophages in the cervix is augmented. Moreover, proinflammatory and immunosuppressive gene expression in the cervix increases markedly after delivery (Bollapragada, 2009; Hassan, 2006, 2009). Tis suggests a role for inflammatory cells in postpartum cervical remodeling and repair (Mahendroo, 2012).
Induction of Cervical Ripening
No therapies prevent premature cervical ripening. In contrast, treatment to promote cervical ripening for labor induction includes direct application of PGE2 and PGF2α (Chap. 26, p. 489). Prostaglandins likely modify ECM structure to aid ripening, although their role in the normal physiology of cervical ripening remains unclear. In some nonhuman species, events that allow cervical ripening are induced by dropping serum progesterone concentrations. And in humans, administration of progesterone antagonists causes cervical ripening.
Endocervical Epithelia
In addition to matrix changes during pregnancy, endocervical epithelial cells proliferate such that endocervical glands account for a significant percentage of cervical mass. The endocervical canal is lined with mucus-secreting columnar and stratified squamous epithelia. These cells form both a mucosal barrier and a tight junctional barrier that protect against microbial invasion (Akgul, 2014; Blaskewicz, 2011; Timmons, 2007).
The mucosal epithelium recognizes and deters pathogen invasion via expression of toll-like receptors that identify pathogens and via antimicrobial peptides and protease inhibitors. These epithelia also express signals to underlying immune cells when a pathogenic challenge exceeds their protective capacity (Wira, 2005).
■ Fetal Contributions to Parturition
It is intriguing to envision that the mature human fetus provides the signal to initiate parturition, and evidence for fetal signaling is mounting (Mendelson, 2017). The fetus may give signals through blood-borne agents that act on the placenta or through secretion into the amnionic fluid.
Uterine Stretch
Fetal growth is an important component of uterine activation in phase 2 of parturition. With uterine activation, stretch is required for induction of specific CAPs. Namely, stretch increases expression of connexin-43 and oxytocin receptors. Levels of gastrin-releasing peptide, a stimulatory agonist for smooth muscle, also are augmented by stretch in the myometrium (attersall, 2012). Clinical clues for a role of stretch come from the observation that multifetal pregnancies carry a much greater risk for preterm labor than singleton ones. Preterm labor is also more common in pregnancies complicated by hydramnios. Although the mechanisms causing preterm birth in these two are debated, a role for uterine stretch must be considered.
Cell signaling systems are influenced by stretch to regulate the myometrial cell. This process—mechanotransduction—may include activation of cell-surface receptors or ion channels, transmission of signals through ECM, or release of autocrine molecules that act directly on myometrium (Shynlova, 2007; Young, 2011).
Fetal Endocrine Cascades
The ability of the fetus to provide endocrine signals that initiate parturition has been demonstrated in several species. However, evidence suggests that it is not regulated in the same manner in humans. That said, the human fetal hypothalamic-pituitaryadrenal-placental axis is considered a critical component of normal parturition. Moreover, premature activation of this axis is considered to prompt many cases of preterm labor (Challis, 2000, 2001). Steroid products of the human fetal adrenal gland are believed to have effects on the placenta and membranes that eventually transform the myometrium from a quiescent to a contractile state.
A key component in the human may be the unique ability of the placenta to produce large amounts of CRH that is identical to maternal and fetal hypothalamic CRH (Grino, 1987; Saijonmaa, 1988) (Fig. 21-10). However, unlike hypothalamic CRH, which is under glucocorticoid negative feedback, cortisol instead stimulates placental CRH production. This ability makes it possible to create a feed-forward endocrine cascade that does not end until delivery.
Maternal plasma CRH levels are low in the first trimester and rise from midgestation to term. In the last 12 weeks, CRH plasma levels rise exponentially, peak during labor, and then fall precipitously after delivery (Frim, 1988; Sasaki, 1987). Amnionic fluid CRH concentrations similarly increase in late gestation. CRH is the only trophic hormone-releasing factor to have a specific serum binding protein. During most of pregnancy, CRH-binding protein (CRH-BP) binds most maternal circulating CRH, and this inactivates it (Lowry, 1993). During later pregnancy, however, CRH-BP levels in both maternal plasma and amnionic fluid decline, leading to markedly greater levels of bioavailable CRH (Perkins, 1995; Petraglia, 1997).
In pregnancies in which the fetus can be considered “stressed” from various complications, concentrations of CRH in fetal plasma, amnionic fluid, and maternal plasma are greater than those seen in normal gestation (Berkowitz, 1996; McGrath, 2002). The placenta is the likely source of this elevated CRH concentration. For example, placental CRH content is four- fold higher in placentas from women with preeclampsia than in those from normal pregnancies (Perkins, 1995).
Placental CRH is thought to play several roles in parturition regulation. It may enhance fetal cortisol production to provide positive feedback so that the placenta produces more CRH. Late in pregnancy—phase 2 or 3 of parturition—modification in the CRH receptor favors a switch from cAMP formation instead to increased myometrial cell calcium levels via protein kinase C activation (You, 2012). Oxytocin acts to attenuate
CRH-stimulated accumulation of cAMP in myometrial tissue. CRH acts to augment myometrial contractile force in response to PGF2α (Benedetto, 1994). Last, CRH stimulates fetal adrenal C19-steroid synthesis, thereby increasing substrate for placental aromatization. Some have proposed that the rising CRH level at the end of gestation reflects a fetal-placental clock (McLean, 1995).
CRH concentrations vary greatly among women, and the rate of rise in maternal CRH levels is a more accurate predictor of pregnancy outcome than is a single measurement (Leung, 2001; McGrath, 2002). In this regard, the placenta and fetus, through endocrinological events, influence parturition timing at the end of normal gestation.
Fetal Lung Surfactant and Platelet-activating Factor
Surfactant protein A (SP-A) produced by the fetal lung is required for lung maturation. SP-A is expressed by the human amnion and decidua, is present in the amnionic fluid, and prompts signaling pathways in human myometrial cells (Garcia-Verdugo, 2008; Lee, 2010; Snegovskikh, 2011). The exact mechanisms by which SP-A activates myometrial contractility in women, however, remain to be clarified. One mode may be its effects on prostaglandins. Namely, SP-A selectively inhibits PGF2α in the term decidua, but SP-A levels drop in the amnionic fluid at term (Chaiworapongsa, 2008). The fetal lung also makes the uterotonic agent platelet-activating factor (Frenkel, 1996; oyoshima, 1995). This factor and SP-A play a role in fetal–maternal signaling for parturition (Gao, 2015).
Fetal Membrane Senescence
Toward the end o pregnancy, etal membranes undergo cellular senescence (Menon, 2016). In human and animal etal membranes, stretch and oxidative stress induce senescent etal membrane to maniest a orm o sterile inammation termed senescent-associated secretory phenotype (SASP). Tis in turn propagates inammatory signals that urther weaken the etal membrane and activate signals in the decidua and myometrium to initiate parturition. Tus, as the unctional necessity o etal membranes declines at term, they are able to promote signals that contribute to parturition initiation.
Fetal Anomalies and Delayed Parturition
Some evidence shows that pregnancies with markedly diminished estrogen production may be associated with prolonged gestation. Tese include women with inherited placental sulatase deciency and etal anencephaly with adrenal hypoplasia. Te broad range o gestational length seen with these disorders, however, calls into question the exact role o estrogen in human parturition initiation. Some brain anomalies o the etal cal, etal lamb, and sometimes the human etus delay the normal timing o parturition. In particular, the association between etal anencephaly and prolonged gestation is well described (Rea, 1898; Malpas, 1933). Malpas concluded that the prolonged gestation was attributable to anomalous etal brain-pituitary-adrenal unction. Indeed, the adrenal glands o the anencephalic etus are very small and, at term, may be only 5 to 10 percent as large as those o a normal etus. Tis is caused by developmental ailure o the etal zone that normally accounts or most o etal adrenal mass and production o C19-steroid hormones (Chap. 5, p. 101). Such pregnancies are associated with delayed labor and suggest that the etal adrenal glands are important or the timely onset o parturition.
Other etal abnormalities that prevent or severely reduce the entry o etal urine or lung secretions into amnionic uid do not prolong human pregnancy. Examples are renal agenesis and pulmonary hypoplasia, respectively. Tus, a etal signal through the paracrine arm o the etal–maternal communication system does not appear to be mandated or parturition initiation.
PHASE 3: LABOR
This phase is synonymous with active labor, which is customarily divided into three stages (see Figure 21-4). The first stage begins when spaced uterine contractions of sufficient frequency, intensity, and duration are attained to bring about cervical thinning, termed effacement. Several uterotonins may be important to the success of this stage of active labor (see Fig. 21-5). These have been shown to stimulate smooth muscle contraction through G-protein coupling. This labor stage ends when the cervix is fully dilated—about 10 cm—to allow passage of the term-sized fetus. The first stage of labor, therefore, is the stage of cervical effacement and dilation. The second stage begins when cervical dilation is complete and ends with delivery. Thus, the second stage of labor is the stage of fetal expulsion.
Last, the third stage begins immediately after delivery of the fetus and ends with the delivery of the placenta. This stage of labor is the stage of placental separation and expulsion.
■ First Stage: Clinical Onset of Labor
Uterine Labor Contractions
In some women, orceul uterine contractions that eect delivery begin suddenly. In others, labor initiation is heralded by spontaneous release o a small amount o blood-tinged mucus rom the vagina. Tis extrusion o the mucus plug that had previously lled the cervical canal during pregnancy is reerred to as “bloody show.” Its passage indicates that labor is already in progress or likely will ensue in hours to days.
Unique among physiological muscular contractions, those o uterine smooth muscle during labor are painul. Suggested causes are: (1) hypoxia o the contracted myometrium—such as that with angina pectoris; (2) compression o nerve ganglia in the cervix and lower uterus by contracted interlocking muscle bundles; (3) cervical stretching during dilation; and (4) stretching o the peritoneum overlying the undus
O these, compression o nerve ganglia in the cervix and lower uterine segment by the contracting myometrium is an especially attractive hypothesis. Paracervical inltration with local anesthetic usually produces appreciable pain relie with contractions (Chap. 25, p. 472). Uterine contractions are involuntary and, or the most part, independent o extrauterine control. Neural blockade rom epidural analgesia does not diminish their requency or intensity. In other examples, myometrial contractions in paraplegic women and in women ater bilateral lumbar sympathectomy are normal but painless.
Mechanical stretching o the cervix enhances uterine activity in several species, including humans. Tis phenomenon is the Ferguson refex (Ferguson, 1941). Its exact mechanism is unclear, and release o oxytocin has been suggested but not proven. Manipulation o the cervix and “stripping” the etal membranes are associated with a rise in blood levels o prostaglandin F2α metabolites.
Te interval between contractions narrows gradually rom approximately 10 minutes at the onset o rst-stage labor to as little as 1 minute or less in the second stage. Periods o relaxation between contractions, however, are essential or etal welare. Unremitting contractions compromise uteroplacental blood ow suciently to cause etal hypoxemia. In activephase labor, the duration o each contraction ranges rom 30 to 90 seconds and averages 1 minute. Contraction intensity varies appreciably during normal labor. Specically, amnionic uid pressures generated by contractions during spontaneous labor average 40 mm Hg, but vary rom 20 to 60 mm Hg (Chap. 24, p. 462).
Distinct Lower and Upper Uterine Segments
During active labor, the anatomical uterine divisions that were initiated in phase 2 o parturition become increasingly evident (Figs. 21-11 and 21-12). By abdominal palpation, even beore membrane rupture, the two segments can sometimes be dierentiated. Te upper segment is rm during contractions, whereas the lower segment is soter, distended, and more passive. Tis mechanism is imperative because i the entire myometrium, including the lower uterine segment and cervix, were to contract simultaneously and with equal intensity, the net expulsive orce would markedly decline. Tus, the upper segment contracts, retracts, and expels the etus. In response to these contractions, the sotened lower uterine segment and cervix dilate and thereby orm a greatly expanded, thinned-out tube through which the etus can pass. Te myometrium o the upper segment does not relax to its original length ater contractions. Instead, it becomes relatively xed at a shorter length. Te upper active uterine segment contracts down on its diminishing contents, but myometrial tension remains constant. Te net eect is to take up slack, thus maintaining the advantage gained in expulsion o the etus. Concurrently, the uterine musculature is kept in rm contact with the uterine contents. As the consequence o retraction, each successive contraction commences where its predecessor let o. Tus, the upper part o the uterine cavity becomes slightly smaller with each successive contraction. Because o the successive shortening o the muscular bers, the upper active segment becomes progressively thickened throughout rst- and second-stage labor (see Fig. 21-11). Tis process continues and results in a tremendously thickened upper uterine segment immediately ater delivery.
Clinically, it is important to understand that the phenomenon o upper segment retraction is contingent on a decrease in the volume o its contents. For this to happen, particularly early in labor when the entire uterus is virtually a closed sac with only minimal cervical dilation, the musculature o the lower segment must stretch. Tis permits a greater portion o the uterine contents to occupy the lower segment. Te upper segment retracts only to the extent that the lower segment distends and the cervix dilates. Relaxation o the lower uterine segment mirrors the same gradual progression o retraction. In the lower segment, successive lengthening o the bers with labor is accompanied by thinning, normally to only a ew millimeters in the thinnest part. With lower segment thinning and concomitant upper segment thickening, a boundary between the two is marked by a ridge on the inner uterine surace—the physiological retraction ring. When the thinning o the lower uterine segment is extreme, as in obstructed labor, the ring is prominent and orms a pathological retraction ring. Tis abnormal condition is also known as the Bandl ring, which is discussed urther in Chapter 23 (p. 442).
Changes in Uterine Shape
Each contraction gradually elongates the ovoid uterine shape an estimated 5 to 10 cm and thereby narrows the horizontal diameter. This fetal axis pressure straightens the fetal vertebral column. It also presses the upper pole of the fetus firmly against the fundus, whereas the lower pole is thrust farther downward. With uterine lengthening, the longitudinal muscle fibers are drawn taut. As a result, the lower segment and cervix are the only parts of the uterus that are flexible, and these are pulled upward and around the lower pole of the fetus.
Ancillary Forces
After the cervix is dilated fully, the most important force in fetal expulsion is produced by maternal intraabdominal pressure. Contraction of the abdominal muscles simultaneously with forced respiratory efforts with the glottis closed is referred to as pushing. The force is similar to that with defecation, but the intensity usually is much greater. The importance of intraabdominal pressure is shown by the prolonged descent during labor in paraplegic women and in those with a dense epidural block.
Cervical Changes
As the result of contraction forces, two fundamental changes— effacement and dilation—occur in the ripened cervix. For an average-sized fetal head to pass through the cervix, it must completely or fully dilate to a diameter of approximately 10 cm. The fetus may not descend during cervical effacement. However, as the cervix dilates, the presenting fetal part typically does descend somewhat.
Cervical effacement is “obliteration” or “taking up” of the cervix. It is manifest clinically by shortening of the cervical canal from a length of approximately 3 cm to a mere circular orifice with almost paper-thin edges. The muscular fibers at the level of the internal cervical os are pulled upward, or “taken up,” into the lower uterine segment. The condition of the external os remains temporarily unchanged (Fig. 21-13). Because of growing myometrial activity during uterine preparedness for labor, appreciable effacement of a softened cervix sometimes is accomplished before active labor begins. Effacement causes expulsion of the mucous plug as the cervical canal is shortened.
Because the lower segment and cervix have less resistance during a contraction, a centriugal pull is exerted on the cervix and creates cervical dilation (Fig. 21-14). As uterine contractions cause pressure on the membranes, the hydrostatic action of the amnionic sac in turn dilates the cervical canal like a wedge. Te process o cervical eacement and dilation causes formation o the forebag o amnionic uid. Tis is the leading portion o uid and amnionic sac located in ront o the presenting part. In the absence o intact membranes, the pressure o the presenting etal part against the cervix and lower uterine segment is a similar wedge. Early rupture o the membranes does not retard cervical dilation so long as the presenting etal part is positioned to exert pressure against the cervix and lower segment.
Reerring back to Figure 21-4, recall that cervical dilation is divided into latent and active phases. Te duration o the latent phase is more variable and sensitive to extraneous actors. For example, sedation may prolong the latent phase, and myometrial stimulation shortens it. Te latent phase duration has little bearing on the subsequent course o labor, whereas the characteristics o the active phase are usually predictive o labor outcome. Normal and abnormal labor curves are ully described in Chapters 22 and 23.
■ Second Stage: Fetal Descent
In many nulliparas, engagement o the head is accomplished beore labor begins. Tat said, the head may not descend urther until late in labor. In the descent pattern o normal labor, a typical hyperbolic curve is ormed when the station o the etal head is plotted as a unction o labor duration (see Fig. 21-4). Station describes descent o the etal biparietal diameter in relation to a line drawn between maternal ischial spines (Chap. 22, p. 427). Active descent usually takes place ater dilation has progressed or some time. During second-stage labor, the speed o descent is maximal and is maintained until the presenting part reaches the perineal oor (Friedman, 1978). In nulliparas, the presenting part typically descends slowly and steadily. In multiparas, however, descent may be rapid.
■ Pelvic Floor Changes
The birth canal is supported and functionally closed by the pelvic oor (Chap. 2, p. 19). Te most important component o the oor is the levator ani muscle and the bromuscular connective tissue that covers its upper and lower suraces. Te biomechanical properties o these structures and o the vaginal wall change markedly during parturition. Tese result rom altered ECM structure or composition (Alperin, 2015; Lowder, 2007; Rahn, 2008).
In the rst stage o labor, the membranes, when intact, and the etal presenting part serve to dilate the upper vagina. Te most marked change consists o stretching levator ani muscle bers. Tis is accompanied by thinning o the central portion o the perineum, which becomes transormed rom a wedgeshaped, 5-cm-thick tissue mass to a thin, almost transparent membranous structure less than 1 cm thick. When the perineum is distended maximally, the anus becomes markedly dilated and presents an opening that varies rom 2 to 3 cm in diameter and through which the anterior wall o the rectum bulges.
■ Third Stage: Delivery of Placenta and Membranes
Tis stage begins immediately ater etal delivery and involves separation and expulsion o the placenta and membranes. Normally, by the time the newborn is delivered, the uterine cavity is nearly obliterated and is an almost solid mass o muscle, several centimeters thick, above the thinner lower segment. Te uterine undus now lies just below the level o the umbilicus.
This sudden diminution in uterine size is inevitably accompanied by a decrease in the area of the placental implantation site (Fig. 21-15). For the placenta to accommodate itself to this reduced area, it thickens, but because of limited placental elasticity, it buckles. The resulting tension pulls the weakest layer—decidua spongiosa—from that site. Thus, placental separation follows the disproportion created between the relatively unchanged placental size and the reduced implantation site size.
Cleavage of the placenta is aided greatly by the loose structure of the spongy decidua. As detachment proceeds, a
Amnion
Chorion
Decidua vera
Myometrium
FIGURE 21-16 Postpartum, membranes are thrown up into folds as the uterine cavity decreases in size. (Reproduced with permission from Dr. Kelley S. Carrick.) hematoma forms between the separating placenta and the adjacent decidua, which remains attached to the myometrium. The hematoma is usually the result rather than the cause of the separation, because in some cases bleeding is negligible.
The great decline in uterine cavity surface area simultaneously throws the fetal membranes—the amniochorion and the parietal decidua—into innumerable folds (Fig. 21-16). Membranes usually remain in situ until placental separation is nearly completed. These are then peeled of the uterine wall, partly by further contraction of the myometrium and partly by traction that is exerted by the separated placenta as it descends during expulsion.
After the placenta has detached, it can be expelled by increased abdominal pressure. Completion of the third stage is also accomplished by alternately compressing and elevating the fundus, while exerting minimal traction on the umbilical cord.
The retroplacental hematoma either follows the placenta or is found within the inverted sac formed by the membranes. In this process, known as the Schultze mechanism of placental expulsion, blood from the placental site pours into the membrane sac and does not escape externally until after extrusion of the placenta. In the other form of placental extrusion, known as the Duncan mechanism, the placenta separates first at the periphery and blood collects between the membranes and the uterine wall and escapes from the vagina. In this circumstance, the placenta descends sideways, and its maternal surface appears first.
UTEROTONINS IN PARTURITION PHASE 3
■ Oxytocin
This nanopeptide is synthesized in the magnocellular neurons of the supraoptic and paraventricular neurons. The prohormone is transported with its carrier protein, neurophysin, along the axons to the neural lobe of the posterior pituitary gland in membrane-bound vesicles for storage and later release.
The prohormone is converted enzymatically to oxytocin during transport (Gainer, 1988; Leake, 1990). Oxytocin—literally, quick birth—was the first uterotonin to be implicated in parturition initiation. Support for this role includes: (1) oxytocin receptor numbers strikingly rising in myometrial and decidual tissues near the end of gestation; (2) oxytocin acting on decidual tissue to promote prostaglandin release; and (3) oxytocin synthesis directly in decidual and extraembryonic fetal tissues and in the placenta (Chibbar, 1993; Zingg, 1995). Moreover, abundant data support oxytocin's important role during second-stage labor and in the puerperium, which is phase 4 of parturition. Specifically, maternal serum oxytocin levels are elevated: (1) during secondstage labor, which is the end of phase 3 of parturition; (2) in the early puerperium; and (3) during breastfeeding (Nissen, 1995). Immediately after delivery of the fetus and placenta, which completes parturition phase 3, firm and persistent uterine contractions induced by oxytocin are essential to prevent postpartum hemorrhage.
■ Prostaglandins
Prostaglandins play a critical role in phase 3 of parturition (MacDonald, 1993). First, levels of prostaglandins—or their metabolites—in amnionic fluid, maternal plasma, and maternal urine are increased during labor. Second, receptors for PGE2 and PGF2α are expressed in the uterus and cervix. Thus, if these tissues are exposed to prostaglandins, they will respond. Third, treatment of pregnant women with prostaglandins, by any of several administration routes, causes abortion or labor at all gestational ages. Moreover, administration of prostaglandin H synthase type 2 inhibitors to pregnant women will delay spontaneous labor onset and sometimes arrest preterm labor (Loudon, 2003).
During labor, prostaglandin production within the myometrium and decidua is an efficient mechanism of activating contractions. For example, prostaglandin synthesis is high and unchanging in the decidua during phase 2 and 3 of parturition. Moreover, the receptor level for PGF2α is augmented in the decidua at term, and this increase most likely is the regulatory step in prostaglandin action in the uterus.
The fetal membranes and placenta also produce prostaglandins. Primarily PGE2, but also PGF2α, are detected in amnionic fluid at all gestational ages. As the fetus grows, prostaglandin levels in the amnionic fluid rise gradually. Their greatest elevation in concentration within amnionic fluid, however, is demonstrable after labor begins. These higher levels likely result as the cervix dilates and exposes decidual tissue (Fig. 21-17). These higher levels in the forebag, compared with those in the upper compartment, are believed to follow an inflammatory response that signals the events leading to active labor. Together, the rise in cytokine and prostaglandin concentrations further degrade the ECM, thus weakening fetal membranes.
■ Endothelin 1
Te endothelins are a family o 21-amino-acid peptides that powerully induce myometrial contraction (Word, 1990). Te endothelin A receptor is preerentially expressed in smooth muscle, and when activated, it eects a rise in intracellular calcium. Endothelin 1 is produced in myometrium o term gestations and is able to induce synthesis o other contractile actors such as prostaglandins and inammatory mediators (Momohara, 2004; Sutclie, 2009). Te requirement o endothelin 1 in normal parturition physiology remains to be established.
■ Angiotensin II
Modulation o uteroplacental blood ow is regulated by angiotensin II, a potent vasoconstrictor. Although, in pregnancy, circulating levels o angiotensin II are increased, vascular resistance is reduced and vasodilation is enhanced. wo angiotensin II receptors are expressed in the uterus—A1R and A2R. In nonpregnant women, the A1R receptor predominates, but the A2R receptor is preerentially expressed in gravidas (Cox, 1993). During normotensive pregnancy, A2R-mediated eects on vascular smooth muscle lead to vasodilation, which contributes to the pregnancy-associated rise in uterine arterial blood ow. Decreased A2R expression is associated with preeclamptic pregnancies (Mishra, 2018; Roseneld, 2012) (Chap. 4, p. 65).
PHASE 4: THE PUERPERIUM
Immediately and for about an hour after delivery, the myometrium remains persistently contracted. This directly compresses large uterine vessels and allows thrombosis of their lumens to prevent hemorrhage. This is typically augmented by endogenous and pharmacological uterotonic agents (Chap. 27, p. 507).
Uterine involution and cervical repair are prompt remodeling processes that restore these organs to the nonpregnant state. These protect the reproductive tract from invasion by commensal microorganisms and restore endometrial responsiveness to normal hormonal cyclicity.
During the early puerperium, lactogenesis and milk let-down begin in mammary glands (Chap. 36, p. 639). Reinstitution of ovulation signals preparation for the next pregnancy. Ovulation generally occurs within 4 to 6 weeks after birth. However, it is dependent on the duration of breastfeeding and lactationinduced, prolactin-mediated anovulation and amenorrhea
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