Medical Physiology, 3rd Edition

Parturition

Human birth usually occurs at around the 40th week of gestation

As we will see in Chapter 57, after birth, the fetus—now a neonate—must maintain physiological homeostasis even though it has lost its placenta and been thrust into a markedly altered environment. Therefore, birth should occur only after organ systems have matured sufficiently to allow the neonate to survive outside the uterus. At the ~40th week of gestation, critical organ systems, especially those that interface with the environment (e.g., lungs, gut, and immune system) and those that maintain homeostasis (e.g., the hypothalamic-pituitary-adrenal axis, kidneys, liver, and pancreas), are functionally competent, and with maternal nurturing, the neonate has a high probability of survival. However, birth prior to 40 weeks is associated with neonatal morbidity and mortality, the severity of which increases the earlier birth occurs.

Parturition—the process of birth—is an integral and pivotal event in the reproductive cycle of all viviparous species. The process involves (1) transformation of the myometrium (smooth-muscle component of the uterine wall) from a quiescent to a highly contractile state to become the engine for birth, (2) remodeling of the uterine cervix such that it softens (effacement) and dilates to open the gateway for birth, (3) rupture of the fetal membranes, (4) expulsion of the uterine contents, and (5) return of the uterus to its prepregnant state.

Parturition occurs in distinct stages, numbered 0 to 3

Stage 0—Quiescence

Throughout most of pregnancy the uterus is relaxed, quiescent, and relatively insensitive to uterotonins—hormones that stimulate contractions, such as prostaglandins (PGs) and oxytocin (OT)—and the uterine cervix remains closed and rigid. The quiescent uterus grows and distends to accommodate the developing conceptus (fetus, placenta, and amniotic fluid), and myometrial cells undergo significant hypertrophy. Weak and irregular contractions, known as Braxton Hicks contractions, occur toward the end of pregnancy and may increase in frequency and intensity near term. These contractions are not powerful enough to induce labor, however, and are thought to prepare the uterus for parturition.

Stage 1—Transformation/Activation

Before labor, the myometrium transforms to a more contractile state. This awakening of myometrial cells involves increased expression of genes that encode factors collectively referred to as contraction-associated proteins (CAPs). Some important CAPs are receptors for uterotonic hormones (e.g., prostaglandin F2 [PGF] receptor and OT receptor), enzymes involved in PG synthesis (e.g., cyclooxygenase 2), and components of gap junction complexes (e.g., connexin-43). Gap junctions are especially important because they form electrochemical connections between myometrial cells to synchronize contractions over the entire uterus (see pp. 243–244). The cervix also begins to express genes encoding enzymes that break down the collagen matrix to facilitate effacement and dilation.

Stage 2—Active Labor

Three major factors induce the forceful and rhythmic contractions that, in association with effacement and dilation of the cervix, constitute the obstetrical definition of labor: (1) increased levels of PGs (especially PGF) produced by the myometrium and fetal membranes, (2) increased myometrial cell interconnectivity, and (3) increased myometrial responsiveness to PGs and OT. Each contraction forces the fetal head against the cervix, which becomes progressively more compliant as its extracellular matrix remodels. Eventually, the cervix dilates enough to allow the contractions of labor to force the fetus and then the placenta through the birth canal. Labor may last for several hours, a day, or even longer and eventually results in the expulsion of the fetus, placenta, and membranes through the vaginal canal.

Stage 3—Involution

Immediately after expulsion of the uterine contents, it is mainly OT that causes the sustained and forceful myometrial contraction that helps constrict the spiral arterioles and thereby facilitates postpartum uterine hemostasis. This contraction is critical to avoid a potentially lethal postpartum hemorrhage through the vascular lakes once occupied by the placental villi. The maternal endocrine milieu changes dramatically after birth. Estrogens produced by the placenta during pregnancy are uterotrophic; that is, they stimulate growth of the uterus, imageN56-8 primarily hypertrophy of the myometrium. Estrogens also increase the vascularity of the uterus. The decline in estrogen levels after birth causes myometrial atrophy. As the organ reverts to its nonpregnant size during the first 3 to 6 weeks after birth, uterine vasculature regresses, which curtails blood flow and leads to further involution. At the same time, the cervix remodels and reverts to the closed and rigid state. Within 3 to 5 months, the endometrium re-establishes cyclic activity as the menstrual cycle resumes.

Reciprocal decreases in progesterone receptors and increases in estrogen receptors are critical for the onset of labor

Although not all of the factors leading to the initiation of labor are known, endocrine and paracrine interactions, signals elicited in response to inflammation (e.g., in response to intrauterine infection), and mechanical stretching of the uterus appear to play key roles. Once labor is initiated, it is sustained by a series of positive-feedback mechanisms involving inflammation within the gestational tissues—myometrium, cervix, decidua, placenta, nonplacental chorion, and amnion—until the uterine contents are expelled.

The principal hormones that affect parturition are progesterone and estrogens (a mix of estradiol, estrone, and estriol).

Progesterone promotes pregnancy mainly by inducing myometrial relaxation and blocking the contractions of labor. Treatment of women with nuclear progesterone receptor antagonists, such as mifepristone (RU486), increases myometrial contractility and excitability and in most cases induces labor at any stage of pregnancy.

Estrogens augment myometrial contractility and thus cervical dilation. They are thought to oppose the actions of progesterone by increasing the responsiveness of myometrial cells to OT and PGs and by stimulating the formation of gap junctions between myometrial cells. Estrogens also increase the production and release of PGs by the fetal membranes, and in the cervix, estrogens stimulate expression of proteolytic enzymes (e.g., collagenase), which degrade the extracellular matrix to facilitate effacement and dilation.

In most viviparous species, the onset of labor is triggered by a coordinated decrease in circulating progesterone levels (progesterone withdrawal) and an increase in circulating estrogen levels (estrogen activation). In women, however, uterine cells are exposed to high levels of progesterone and estrogens for most of pregnancy, and progesterone level remains elevated during labor and delivery, declining only when the placenta is expelled. Thus, human parturition is not associated with systemic progesterone withdrawal. Instead, labor in women is thought to be initiated by desensitization of uterine cells to the progestational actions of progesterone (i.e., functional progesterone withdrawal). Because progesterone inhibits estrogen receptor expression, the functional desensitization to progesterone leads to increased expression of estrogen receptors. The result is an increased responsiveness to circulating estrogens, which induces genes encoding CAPs that augment contractility and transform the myometrium from a quiescent to a laboring phenotype. The shift from progesterone to estrogen dominance is thought to be the pivotal trigger event for human parturition and is mediated by reciprocal changes in progesterone and estrogen receptor levels in myometrial and cervical cells.

Signals from the fetus may initiate labor

Studies in sheep demonstrate the importance of the fetal hypothalamic-pituitary-adrenal axis in the preparation for, or initiation of, parturition. In the fetal lamb, transection of the hypothalamic portal vessels—or removal of the fetal pituitary—prolongs gestation. Infusing adrenocorticotropic hormone (ACTH; see pp. 1023–1025) into fetal lambs with intact adrenal glands, or directly infusing cortisol into the fetus, causes premature maturation of fetal organ systems (especially the lungs) and premature parturition. Indeed, a surge in fetal adrenal cortisol production triggers normal parturition in sheep. Cortisol, in turn, induces the expression of placental enzymes that convert progesterone to estrogens (see Fig. 56-9), triggering a shift from progesterone to estrogen dominance and thereby inducing labor and delivery. imageN56-9 In humans, the fetal hypothalamic-pituitary-adrenal axis does not play as critical a role in controlling the timing of birth. In fact, the maternal and fetal/placental signals that initiate labor in women are not clearly understood.

N56-9

Fetal Hypothalamic-Pituitary-Adrenal Axis near the End of Pregnancy in Sheep

Contributed by Sam Mesiano

In sheep, the timing of birth is determined by the activity of the fetal hypothalamic-pituitary-adrenal axis, which not only triggers labor but also stimulates the functional maturation of key fetal organ systems, so that the fetus is prepared for life as a neonate. These studies in sheep led directly to the development of synthetic glucocorticoid therapy to promote fetal lung maturation in women experiencing preterm labor and threatened preterm birth.

PGs initiate uterine contractions, and both PGs and OT sustain labor

Whereas OT, produced by the maternal posterior pituitary, and PGs, produced locally within the gestational tissues, play an important role in stimulating the contractions that sustain labor, only PGs are believed to have a key role in initiating labor.

Prostaglandins

The uterus, the placenta, and the fetal membranes synthesize and release PGs (see p. 64). Arachidonic acid, the precursor of PG production, is present in very high concentrations in the fetal membranes near term. PGF and PGE2 from the uterine decidual cells act by a paracrine mechanism on adjacent myometrial cells. OT stimulates uterine decidual cells to increase PGF synthesis. Thus, PGs and OT act synergistically to augment uterine contractility.

PGs have three major effects. First, PGs strongly stimulate myometrial contraction. Second, PGF potentiates OT-induced contractions by promoting formation of gap junctions (see pp. 158–159) between uterine smooth-muscle cells. Third, PGs also cause effacement of the cervix, which occurs early during labor. This softening is akin to an inflammatory reaction in that it is associated with an invasion by polymorphonuclear leukocytes (see p. 435). Because of these effects, PGs are used to induce labor and delivery in certain clinical settings.

PGs may physiologically initiate labor. Both PGF and PGE2 evoke myometrial contractions at any stage of gestation, regardless of the route of administration. The levels of PGs or their metabolic products naturally increase in the blood and amniotic fluid just before and during labor. Arachidonic acid instilled into the amniotic cavity causes the uterus to contract and to expel its contents. Aspirin, which inhibits the enzyme cyclooxygenases (see pp. 62–64), reduces the formation of PGF and PGE2, thus inhibiting labor and prolonging gestation.

Oxytocin

The nonapeptide OT is closely related to AVP (Fig. 56-10), imageN56-10 and both are synthesized in the cell bodies of the neurons in the supraoptic and paraventricular nuclei of the hypothalamus of the fetus and mother. Both OT and AVP then move by fast axonal transport to the posterior pituitary gland, where they are stored in the nerve terminals until released—along with neurophysins (see pp. 845 and 981)—in response to the appropriate stimuli.

image

FIGURE 56-10 Comparison of the structures of OT and AVP. DDAVP (desmopressin acetate) is a synthetic AVP in which the N-terminal cysteine is deaminated and L-arginine at position 8 is replaced with D-arginine (see Box 38-1).

N56-10

Vasotocin, Oxytocin, and Arginine Vasopressin

Contributed by Ervin Jones

OT and AVP apparently evolved from vasotocin, the single neurohypophyseal hormone in nonmammalian vertebrates. OT and AVP, which both differ from vasotocin by a single amino acid, are synthesized in the cell bodies of the neurons in the supraoptic and paraventricular nuclei of the hypothalamus.

Circulating OT binds to Gαq-coupled OT receptors (OTRs) on the plasma membrane of myometrial cells, triggering the phospholipase C cascade (see p. 58). Presumably, formation of IP3 leads to Ca2+ release from internal stores and to an increase in [Ca2+]i. The rise in [Ca2+]i activates calmodulin, which stimulates myosin light-chain kinase to phosphorylate the regulatory light chain; the result is contraction of uterine smooth muscle (see pp. 247–248) and increased intrauterine pressure. OT also binds to a receptor on decidual cells, thereby stimulating PGF production, as discussed above.

Estrogen increases the number of OTRs in the myometrium and decidua during pregnancy. The uterus actually remains insensitive to OT until ~20 weeks' gestation, at which time the number of OTRs increases progressively to 80-fold higher than baseline values by ~36 weeks, plateaus just before labor, and then rises again to 200-fold higher than baseline values during early labor. The time course of the expression of OTRs may account for the increase in spontaneous myometrial contractions even in the absence of increased plasma OT levels. Whereas the uterus is sensitive to OT only at the end of pregnancy, it is susceptible to PGs throughout pregnancy.

Maternal plasma OT levels rise gradually during the 40 weeks of pregnancy and then rise further with active labor (stage 2), with maternal OT being released in bursts and the frequency of these bursts increasing as labor progresses. The primary stimulus for the release of maternal OT appears to be distention of the cervix; this effect is known as the Ferguson reflex. OT is an important stimulator of myometrial contraction late in labor. During the second stage of labor, OT release may play a synergistic role in the expulsion of the fetus by virtue of its ability to stimulate PG release.

During the third stage of labor, uterine contractions induced by OT are also important for constricting uterine blood vessels at the site where the placenta used to be, which promotes hemostasis (i.e., blood coagulation). At about 60 minutes after delivery, maternal plasma OT levels return to prepartum levels.

Relaxin

Relaxin is a polypeptide hormone of 48 amino acids, structurally related to insulin, that is produced by the corpus luteum, the placenta, and the decidua. Relaxin may play a role in keeping the uterus in a quiet state during pregnancy. Production and release of relaxin increase during labor, when relaxin may soften and thus help dilate the cervix.

Mechanical Factors

Mechanical stretch placed on the uterine muscle may lead to the rhythmic contractions of labor. Thus, the increase in the size of the uterine contents to a critical level may stimulate uterine contractions and thereby lead to initiation of labor.

Positive Feedback

Once labor is initiated, several positive-feedback loops involving PGs and OT help to sustain it. First, uterine contractions stimulate PG release, which itself increases the intensity of uterine contractions. Second, uterine activity stretches the cervix, which stimulates OT release via the Ferguson reflex. Because OT stimulates further uterine contractions, these contractions become self-perpetuating.

LESION

REFLEXOGENIC ERECTION

PSYCHOGENIC ERECTION

EFFECT ON EJACULATION

Upper motor neuron

Present

Absent

Significantly impaired

Lower motor neuron

Absent

Present

Less impaired