Pregnancy in the human lasts about 40 weeks. The process of birth, or parturition, is the expulsion of a viable baby from the uterus at the end of pregnancy and is the culmination of all the processes discussed in this and the previous two chapters. Studying the phenomenon of parturition has revealed a surprising array of strategies that have been adopted by different species, regulate parturition. Humans and the great apes have evolved mechanisms that appear to be unique, and the scarcity of experimental models that employ strategies similar to those of humans has hampered efforts to study underlying mechanisms of timing and initiating parturition in humans. Consequently, our understanding of the processes that bring about this climactic event in human reproductive physiology is still incomplete.

Successful delivery of the baby can take place only after the myometrium acquires the capacity for forceful, coordinated contractions and the cervix softens and becomes distensible (called ripening) so that uterine contractions can drive the baby through the cervical canal. These changes reflect the triumph of the excitatory effects of estrogens over the suppressive effects of progesterone that had prevailed thus far. Indeed, in most animals parturition is heralded by a decline in progesterone production coincident with an increase in estrogen production. Humans and higher primates are unique in the respect that there is neither an abrupt increase in plasma concentrations of estrogens nor a fall in progesterone at the onset of parturition. It is highly likely that multiple gradual changes, gaining momentum over days or weeks, tip the precarious estrogen/progesterone balance in favor of estrogen dominance.

In theory, signals to terminate pregnancy could originate with either the mother or the fetus. Most investigators favor the idea that the fetus, which has essentially controlled events during the rest of pregnancy, signals its readiness to be born. In sheep, the triggering event for parturition is an ACTH-dependent increase in cortisol production by the fetal adrenals. In this species, cortisol stimulates expression of P450c17 in the placenta and thereby shifts production of steroid hormones away from progesterone and toward estrogen. While there is neither a stimulation of P450c17 expression in the human placenta nor a fall in progesterone in humans, the human fetal adrenal may nevertheless have an essential role in orchestrating the events that lead up to parturition.

Role of Corticotropin-Releasing Hormone

Although the ability to secrete 19-carbon androgens is acquired by the fetal zone of the adrenals early in gestation, the definitive and transitional zones mature much later. The capacity to produce significant amounts of cortisol is not acquired until about the 30th week of fetal pituitary o fetal lungs gut

fetal pituitary o

fetal lungs gut

fetal adrenal placenta

FIGURE 9 Effects of cortisol production in late pregnancy. By stimulating placental secretion of CRH (corticotropin-releasing hormone), cortisol initiates direct and indirect (via the fetal pituitary) positive feedback loops that enhance its own secretion and increases secretion of DHEA-S (dehydroepiandrosterone sulfate). In this way cortisol-induced maturation of the fetus occurs simultaneously with increased production of estrogens, which prepare the uterus for parturition. ACTH, adrenocorticotropic hormone.

fetal adrenal

^estrogensy placenta

FIGURE 9 Effects of cortisol production in late pregnancy. By stimulating placental secretion of CRH (corticotropin-releasing hormone), cortisol initiates direct and indirect (via the fetal pituitary) positive feedback loops that enhance its own secretion and increases secretion of DHEA-S (dehydroepiandrosterone sulfate). In this way cortisol-induced maturation of the fetus occurs simultaneously with increased production of estrogens, which prepare the uterus for parturition. ACTH, adrenocorticotropic hormone.

gestation. An abundant supply of cortisol in the final weeks of pregnancy is indispensable for maturation of the lungs, the gastrointestinal tract, and other systems to prepare the fetus for extra-uterine life. Cortisol also antagonizes the suppressive effects of progesterone on CRH production in the placenta and hence increases transcription of the CRH gene. This paradoxical effect of cortisol on placental expression of CRH is opposite to its negative feedback effects on CRH production in the hypothalamus. Instead of suppressing CRH production, fetal production of cortisol initiates a positive feedback loop (Fig. 9). It may be recalled that CRH not only stimulates the fetal pituitary to secrete ACTH but also directly stimulates steroidogenesis in the fetal adrenal cortex; consequently, there is an increasing drive to the adrenal to increase production of cortisol and DHEA-S. Accelerating secretion of DHEA-S accounts for the increasingly steep rise in estrogen concentrations in maternal blood in the last weeks of pregnancy (as shown in Figure 5).

Prostaglandin production is also increased in fetal membranes and the uterus in late pregnancy. Prosta-glandins F2„ and E participate in or initiate events that lead to rupture of the fetal membranes, softening of the uterine cervix, and contraction of the myometrium. CRH stimulates their formation by the fetal membranes. These prostaglandins, in turn, stimulate placental production of CRH and establish a second positive feedback loop. We might expect cortisol to oppose prostaglandin formation in the fetus as it does in extrauterine tissues (Chapter 40); however, in fetal membranes, cortisol paradoxically increases expression of the prostaglandin synthesizing enzyme COX2 and inhibits formation of the principal prostaglandin-degrading enzyme. Prostaglandins also stimulate CRH secretion by the fetal hypothalamus, increasing ACTH secretion and providing further drive for cortisol secretion and consequent stimulation of CRH secretion.

Concentrations of CRH in maternal plasma increase exponentially as pregnancy progresses, but there is only a slight rise in ACTH and free cortisol. Discordance between CRH plasma concentrations and pituitary and adrenal secretory activity is due largely to the presence of a CRH binding protein (CRH-BP) that is present in plasma of pregnant as well as nonpregnant women. Additionally, responsiveness of the maternal pituitary to CRH is decreased during pregnancy possibly because of downregulation of CRH receptors in corticotropes. Despite the somewhat blunted sensitivity to CRH, however, maternal ACTH secretion follows the normal diurnal rhythmic pattern and increases appropriately in response to stress. Until about three weeks before parturition, concentrations of CRH-BP in maternal plasma vastly exceed those of CRH and there is little or no free CRH. For reasons that are not understood, CRH-BP concentrations fall dramatically at the same time that placental production of CRH is increasing most rapidly and exceeds the capacity of CRH-BP. Free CRH in maternal plasma stimulates prostaglandin production in the myometrium and cervix, causing increased contractility and cervical ripening.

In addition to CRH-related positive feedback loops, a large number of genes that encode gap junction proteins, ion channels, oxytocin receptors, prostaglandin receptors, proteases that breakdown cervical collagen fibers, and a host of other proteins are activated to an increasing extent by stretch and probably paracrine and autocrine factors that arise in the placenta or decidua. There is also evidence that progesterone-inactivating enzymes that are induced in the myometrium, the placenta, and the cervix in the final weeks may lower tissue concentrations of progesterone and hence its effectiveness. While there appears to be no single event that precipitates parturition, the various processes that are set in motion weeks earlier gradually build up to overwhelm progesterone dominance and unleash excitatory forces that expel the fetus. CRH and the factors that regulate its production appear to play a crucial but not exclusive, role (Fig. 10).

Role of Oxytocin

Oxytocin is a neurohormone secreted by nerve endings in the posterior lobe of the pituitary gland in uterus

FIGURE 10 Positive feedback cycles that contribute to initiation of parturition. CRH, corticotropin-releasing hormone; + , stimulate; -, inhibit. See text for details.

response to neural stimuli received by cell bodies in the paraventricular and supraoptic nuclei of the hypothalamus (Chapter 38). It produces powerful synchronized contractions of the myometrium at the end of pregnancy, when uterine muscle is highly sensitive to it. Oxytocin is sometimes used clinically to induce labor. As parturition approaches, responsiveness to oxytocin increases in parallel with estrogen-induced increases in oxytocin receptors in both the endometrium and myometrium. Oxytocin is not the physiological trigger for parturition, however, as its concentration in maternal blood normally does not increase until after labor has begun. Oxytocin is secreted in response to stretching of the uterine cervix and hastens expulsion of the fetus and the placenta (as described in Chapter 37), but probably has little to do in initiating parturition. As a consequence of its action on myometrial contraction, oxytocin protects against hemorrhage after expulsion of the placenta. Just prior to delivery, the uterus receives nearly 25% of the cardiac output, most of which flows through the low resistance pathways of the maternal portion of the placenta. Intense contraction of the newly emptied uterus acts as a natural tourniquet to control loss of blood from the massive wound left when the placenta is torn away from the uterine lining.

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