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Physiology of Parturition
Labor is the physiologic process by which the products of conception are passed from the uterus to the outside world, and it is common to all mammalian viviparous species. Considerable evidence suggests that the fetoplacental unit primarily controls the timing of physiologic labor in humans, although maternal factors are also involved. This chapter summarizes the current state of knowledge on the biologic mechanisms responsible for the onset of labor at term.
Morphologic Changes in the Reproductive Tract During Pregnancy
Pregnancy is associated with gestational age-dependent morphologic changes in all tissues of the reproductive tract. The most important changes occur in the uterus and cervix.
Uterus
The uterus undergoes a dramatic increase in weight (from 4 to 70 g in the nonpregnant state to 1100 to 1200 g at term) and in volume (from 10 mL to 5 L) during pregnancy. Myometrial smooth muscle cells are highly plastic and transition from quiescent during pregnancy to contractile at term. The number of myometrial cells increases in early pregnancy (myometrial hyperplasia) but thereafter remains stable. Myometrial growth in the latter half of pregnancy results primarily from the increase in cell size (hypertrophy) that occurs under the influence of both endocrine and mechanical signals. This is accompanied by an increase in fibrous connective tissue, blood vessels, and lymphatics. In the latter half of pregnancy, distention leads to gradual thinning of the uterine wall. However, this thinning is not uniform throughout the uterus. The lower portion of the uterus (the isthmus) does not undergo hypertrophy and becomes increasingly thin and distensible as pregnancy progresses, thereby forming the lower uterine segment.
The increase in size of the uterus is accompanied by a 10-fold increase in uterine blood flow—from 2% of cardiac output in the nonpregnant state to 17% at term. , Moreover, pregnancy is associated with a redistribution of blood flow within the uterus. In the nonpregnant state, uterine blood flow is equally divided between myometrium and endometrium. As pregnancy progresses, 80% to 90% of uterine blood flow goes to the placenta, with the remainder distributed equally between endometrium and myometrium. Although the cellular mechanisms responsible for the increase in uteroplacental blood flow in pregnancy are not fully understood, the increase in flow parallels the increase in placental size and decrease in placental vascular resistance, most likely related to the sensitivity of the uterine vasculature to circulating levels of estrogen. However, a number of other biologically active hormones may be involved at the level of the uterine arteries, including vascular endothelial growth factor, angiotensin II, , nitric oxide, and prostacyclin (also known as prostaglandin I 2 [PGI 2 ]). ,
Cervix
The cervix (“neck” of the uterus) is made up of a number of different cell types, including epithelial cells, fibroblasts, smooth muscle cells, and resident immune cells. The smooth muscle cells are circumferentially oriented around the endocervical canal and are more abundant in the upper half of the cervix compared with the lower half. In addition, the cervix contains blood vessels and abundant connective tissue composed of fibrillar collagen I and, to a lesser extent, collagen III, elastin, matricellular proteins, glycosaminoglycans, and proteoglycans. A variety of imaging approaches consistently reveal that the collagen fibers run parallel to the canal in the outer edge and next to the inner canal, whereas collagen fibers in the midstroma run circumferentially around the canal. The load-bearing mechanical response of the tissue is dependent on both collagen fiber directionality and structure and is markedly changed in late pregnancy.
During the first trimester of pregnancy, the cervix begins a progressive remodeling that continues for the remainder of pregnancy. Cervical remodeling can be loosely divided into four overlapping phases: (1) softening during most of pregnancy, (2) ripening during the last 1 to 2 weeks of gestation, (3) dilation during active labor, and (4) postpartum repair after delivery ( Fig. 6.1 ). , Cervical softening begins early in pregnancy and is the longest of all of the phases. It is characterized by a discernible increase in tissue compliance with maintenance of its tensile strength. During the softening phase, there is marked proliferation of epithelial and fibroblast cells. In addition, there are dynamic changes in the extracellular matrix, including changes in the processing and assembly of collagen fibrils that result in collagen fibers with reduced mechanical strength. The connective tissues of the cervix undergo further biochemical modifications that result in a maximal increase in tissue viscoelasticity. These modifications include alterations in water content, collagen, and proteoglycan composition. Advancing gestational age is also associated with an increase in hyaluronan content within the cervix, which leads to increased water content, dispersion of collagen fibers, and maintenance of epithelial barrier function. When biochemical changes that impact the structure and function of the cervical extracellular matrix are misregulated, they can lead to cervical dilation in the absence of significant uterine contractions. This has traditionally been referred to as cervical insufficiency, and recent genetic studies link extracellular matrix dysfunction to cervical insufficiency in women.
Cervical changes throughout gestation are mediated through the coordinated efforts of mechanical signals and endocrine and paracrine factors. Mechanical signals are derived from material properties and geometry of the cervix as well as cervical stretch in response to pressure exerted by the fetal presenting part. Endocrine and paracrine factors include the hormones progesterone, estrogen, oxytocin, and relaxin. With the onset of labor, the factors responsible for the rapid progression of cervical effacement and dilation most likely include a combination of biochemical changes (e.g., increased hyaluronan synthesis, increased local progesterone metabolism), the mechanical forces of traction caused by myometrial contractions, and pressure resulting from descent of the fetal head. After birth, the cervix undergoes a repair phase of remodeling to ensure protection of the reproductive tract from environmental insults and to prepare for subsequent pregnancies.
Diagnosis of Labor
Labor is a clinical diagnosis characterized by evidence of regular, painful uterine contractions increasing in frequency and intensity along with progressive cervical effacement and dilation. Biochemical connective tissue changes in the cervix usually precede uterine contractions and cervical dilation, which occur before rupture of the fetal membranes. The presence of uterine contractions in the absence of cervical change does not meet criteria for the diagnosis of labor.
Timing of Labor
The timely onset of labor and birth is a critical determinant of perinatal outcome. , The mean duration of a human singleton pregnancy is 280 days (40 weeks) from the first day of the last normal menstrual period. Term is defined as the period from 37 weeks to 42 weeks of gestation.
Considerable evidence suggests that the fetus—or, more correctly, the fetoplacental unit—is in control of the timing of labor in all mammalian viviparous species. During the time of Hippocrates, it was believed that the fetus presented head down at the end of pregnancy so that it could kick its legs up against the fundus of the uterus and propel itself through the birth canal. Although we have moved away from this simple and mechanical view of labor, the factors responsible for the initiation and maintenance of labor at term are still not well understood. The past few decades have seen a marked change in the nature of the hypotheses to explain the onset of labor. Initial investigations centered on changes in circulating hormone levels in the maternal and fetal circulations (endocrine events), whereas more recent studies have focused on the ongoing biochemical dialog at the fetal-maternal interface (paracrine and autocrine events).
Genetic Influences on the Timing of Labor
Comparisons in birth timing between 15 inbred strains of mice demonstrate variations in birth timing that can be attributed to genetics. Genome-wide association studies carried out in women of European ancestry identify gene loci associated with gestational duration. , Similarly, familial clustering, , racial disparities, and the high incidence of recurrent preterm birth , all suggest an important role for maternal genetic factors in the timing of labor. For example, Black women in the United States have a significantly higher preterm birth rate compared to the general population. Genetic influences on the onset of parturition among Black women remain to be delineated and will require genome-wide association studies in a large cohort of Black women. Adding to the complexity in identifying genetic influences is the growing understanding that environmental factors also impact genetics. These factors, termed social determinants, include but are not limited to access to quality health care, racial/ethnic disparities, vaginal microbiome, housing inequities, and poor air and water quality. There is growing evidence that social determinants of health can better explain racial and ethnic disparities in perinatal outcomes. In support of the impact of social disparities on preterm birth rates, one study found that quality health care can reduce preterm birth disparities in Black and Hispanic women in an inner-city public hospital.
Hormonal Control of Labor
The hypothesis that the fetus is in control of the timing of labor has been elegantly demonstrated in domestic ruminants such as sheep and cows and involves activation at term of the fetal hypothalamic-pituitary-adrenal (HPA) axis. In such animals, a sharp rise in the concentration of adrenocorticotropic hormone (ACTH) and cortisol in the fetal circulation 15 to 20 days before delivery results in increased expression in the ruminant placenta of the trophoblast cytochrome P-450 (CYP) enzyme 17α-hydroxylase/C 17,20 -lyase (CYP17), which catalyzes the conversion of pregnenolone to 17α-hydroxypregnenolone and dehydroepiandrostenedione. The resultant fall in progesterone and rise in estrone and 17β-estradiol levels in the maternal circulation stimulate the uterus to produce prostaglandin (PG)F 2α , which provides the impetus for labor. , However, human placentas lack the glucocorticoid-inducible CYP17 enzyme. Thus this mechanism does not apply in humans. Despite these observations, recent data suggest that there may be more similarities than differences between species. In both ruminants and humans, fetal adrenal C19 precursors are used to form estrogens. Androstenedione and dehydroepiandrosterone sulfate (DHEAS) are secreted by the fetal adrenal glands under the influence of pituitary ACTH and are metabolized into estrone and 17β-estradiol, respectively. The result is a progressive increase in conjugated estrogens in maternal plasma during the latter part of gestation, which precedes the sharp rise in estrogen that occurs just before delivery in response to cortisol-mediated induction of the placental CYP enzyme in ruminants and other nonprimate species.
It is likely that a parturition cascade ( Fig. 6.2 ) exists in humans that is responsible at term for the removal of mechanisms maintaining uterine quiescence and for the recruitment of factors acting to promote uterine activity. Given its teleological importance, such a cascade is likely to have multiple redundant loops to ensure a fail-safe system of securing pregnancy success and, ultimately, the preservation of the species. In such a model, each element is connected to the next in a sequential fashion, and many of the elements demonstrate positive feed-forward characteristics typical of a cascade mechanism. The sequential recruitment of signals that serve to augment the labor process suggests that it may not be possible to identify any one signaling mechanism as being uniquely responsible for the initiation of labor.
In brief, human labor is a multifactorial physiologic event involving an integrated set of changes within the maternal tissues of the uterus (myometrium, decidua, and uterine cervix) and fetal membranes that occur gradually over a period of days to weeks. Such changes include, but are not limited to, an increase in prostaglandin synthesis and release within the uterus, an increase in myometrial gap junction formation, and upregulation of myometrial oxytocin receptors (i.e., uterine activation). Once the myometrium and cervix are prepared, endocrine and paracrine/autocrine factors from the fetal membranes and placenta bring about a switch in the pattern of myometrial activity from irregular contractures to regular contractions (i.e., uterine stimulation). The fetus may coordinate this switch in myometrial activity through its influence on placental steroid hormone production, through mechanical distention of the uterus, and through secretion of neurohypophyseal hormones and other stimulators of prostaglandin synthesis. The roles of several specific hormones and pathways involved in the timing of labor are discussed in the following sections.
Fetal Hypothalamic-Pituitary-Adrenal Axis
In every animal species studied, there is an increase in the concentration of the major adrenal glucocorticoid product in the fetal circulation during late gestation (cortisol in sheep and humans; corticosterone in rats and mice). As in other mammalian viviparous species, the final common pathway toward parturition in humans appears to be maturation and activation of the fetal HPA axis. The result is a dramatic increase in production of the C19 steroid DHEAS from the intermediate (fetal) zone of the fetal adrenal cortex. DHEAS is directly aromatized in the placenta to estrone and can also be 16-hydroxylated in the fetal liver and converted in the placenta to estriol (16-hydroxy-17β-estradiol) (see Fig. 6.2 ). This occurs because the human placenta is an incomplete steroidogenic organ, and estrogen synthesis by the placenta requires fetal C19 androgens as a steroid precursor. , ,
The cellular and molecular factors responsible for maturation of the fetal HPA axis, although not completely understood, are associated with gestational age–dependent upregulation of a number of critical genes within each compartment of the HPA axis: corticotropin-releasing hormone (CRH) in the fetal hypothalamus, pro-opiomelanocortin in the fetal pituitary, and ACTH receptor and steroidogenic enzymes in the fetal adrenal gland. Animal studies have shown that undernutrition of the mother around the time of conception leads to precocious activation of the fetal HPA and preterm birth. , This suggests that although maturation of the fetal HPA axis is developmentally regulated and the timing of parturition may be determined by a “placental clock” set shortly after implantation, excessive stress may accelerate this clock. Therefore the length of gestation for any individual pregnancy appears to be established early in gestation, but some degree of flexibility may be possible. For example, premature activation of the fetal HPA axis has been demonstrated in the setting of experimentally induced fetal hypoxemia in sheep, probably representing a functional adaptation and an effort by the fetus to trigger labor early and escape a hostile intrauterine environment.
Circulating levels of CRH increase from 10 to 100 pg/mL in nonpregnant women to 500 to 3000 pg/mL in the third trimester of pregnancy and then decrease precipitously after delivery. The source of this excess CRH is the placenta, and—in contrast to the situation in the hypothalamus, where corticosteroids suppress CRH expression in a classic endocrine feedback inhibition loop—the production of CRH by the placenta is upregulated by corticosteroids produced by the fetal adrenal glands at the end of pregnancy. Under the influence of estrogen, hepatic-derived CRH-binding protein (CRH-BP) concentrations also increase in pregnancy. CRH-BP binds and maintains CRH in an inactive form. Importantly, circulating CRH levels increase and CRH-BP levels decrease before the onset of labor, resulting in a marked increase in free (biologically active) CRH. In addition to stimulating production of ACTH by the fetal pituitary, CRH may act directly on the fetal adrenal glands to promote the production of C19 steroid precursor. , For these reasons, some authorities have proposed that CRH may prime the “placental clock” that controls the duration of pregnancy and that measurements of plasma CRH levels in the late second trimester may predict the onset of labor. In support of this hypothesis, circulating levels of CRH have been shown to be increased in pregnant women with anxiety and depression, which may account for the increased incidence of spontaneous preterm birth in such women. However, other studies showed that measurements of maternal CRH are not clinically useful because of substantial intraindividual and interindividual variability that likely reflects the mixed endocrine and paracrine roles of placental, fetal membrane, and decidual CRH in the initiation of parturition.
At a molecular level, CRH acts by binding to specific receptors and affecting the transcription of target genes. A number of CRH receptor isoforms have been described, and all have been identified in the myometrium, placenta, and fetal membranes. During pregnancy, the high-affinity CRH receptor isoforms dominate, and CRH promotes myometrial quiescence by inhibiting the production and increasing the degradation of prostaglandins, increasing intracellular cyclic adenosine monophosphate (cAMP), and stimulating nitric oxide synthase activity. , At term, CRH acts primarily through its low-affinity receptor isoforms, which promote myometrial contractility by stimulating prostaglandin production from the decidua and fetal membranes and potentiating the contractile effects of oxytocin and prostaglandins on the myometrium.
In addition to preparing fetal organ systems for extrauterine life, endogenous glucocorticoids within the fetoplacental unit have a number of important regulatory functions. They regulate the production of prostaglandins at the maternal-fetal interface by affecting the expression of the enzymes responsible for their production and degradation—amniotic prostaglandin H synthase (PGHS) and chorionic 15-hydroxy-prostaglandin dehydrogenase (PGDH), respectively. , They upregulate placental oxytocin expression and interfere with progesterone signaling in the placenta. Finally, they regulate their own levels locally within the placenta and fetal membranes by affecting the expression and activity of 11β-hydroxysteroid dehydrogenase (11β-HSD). This enzyme exists in two isoforms: 11β-HSD-1 acts principally as a reductase enzyme, converting cortisone to cortisol, and is the predominant isoform found in the fetal membranes; 11β-HSD-2, which predominates in the placental syncytiotrophoblast, serves as a dehydrogenase that primarily oxidizes cortisol to inactive cortisone. It has been proposed that placental 11β-HSD-2 protects the fetus from high levels of maternal glucocorticoids. Placental 11β-HSD-2 expression and activity are reduced in the setting of hypoxemia and in placentas from preeclamptic pregnancies, leading to increased passage of maternal cortisol into the fetal compartment, which may contribute to intrauterine growth restriction as well as fetal programming of subsequent adult disease. , ,
Progesterone
Progesterone acts primarily through its nuclear receptor, a member of the family of ligand-activated nuclear transcription regulators. Progesterone produced by the corpus luteum is critical to the maintenance of early pregnancy until the placenta takes over this function at 7 to 9 weeks (hence its name, progest ational st er oidal ket one ). Indeed, surgical removal of the corpus luteum or administration of a progesterone receptor (PR) antagonist such as mifepristone (RU-486) readily induces abortion before 7 weeks (49 days) of gestation.
The role of progesterone in midpregnancy to late pregnancy includes maintaining uterine quiescence in the latter half of pregnancy by limiting the production of stimulatory prostaglandins and inhibiting the expression of contraction-associated protein (CAP) genes (including genes encoding ion channels, oxytocin and prostaglandin receptors, and gap junction proteins) within the myometrium. In the cervix, progesterone plays a key role in structural reorganization of collagen to allow gradual cervical softening.
In most laboratory animals (with the exception of guinea pigs and armadillos), systemic withdrawal of progesterone is a prerequisite for parturition. In humans, however, circulating progesterone levels during labor are similar to those measured 1 week before labor and remain elevated until after delivery of the placenta, suggesting that systemic progesterone withdrawal is not a prerequisite for labor. However, circulating hormone levels do not necessarily reflect tissue levels. In the 1960s, Csapo and Pinto-Dantas first proposed the idea of a progesterone blockage, suggesting that the myometrial quiescence of human pregnancy is maintained by steady tissue levels of progesterone, just as in pregnancies of other species. The earliest studies looking at progesterone levels in labor were done separately in the 1970s by Csapo and colleagues and Cousins and coworkers. Both groups described a relative progesterone deficiency and an increase in the 17β-estradiol-to-progesterone ratio in patients presenting in preterm labor, regardless of etiology. These and other findings have prompted extensive research into the potential mechanisms of progesterone action on the uterus and the possibility of progesterone supplementation to prevent preterm birth.
Although systemic progesterone withdrawal may not correlate directly with the onset of labor in humans, there is increasing evidence to suggest that the onset of labor is preceded by a physiologic (functional) withdrawal of progesterone activity at the level of the uterus. , , Defining mechanisms of progesterone function in normal physiology remains important despite the ongoing debate as to its therapeutic benefit in the prevention of preterm birth. Several studies have evaluated either vaginal progesterone or intramuscular 17α-hydroxyprogesterone caproate for the prevention of preterm birth and reduction in neonatal mortality in asymptomatic women with a singleton pregnancy at high risk of preterm birth , ; this intervention was approved by the US Food and Drug Administration (FDA) in February 2011. Progesterone supplementation has also been shown in some studies to prevent preterm birth in the setting of cervical shortening but not in multiple pregnancies or after preterm premature rupture of membranes. However, more recent investigations fail to support the premise that vaginal progesterone or intramuscular 17α-hydroxyprogesterone caproate is associated with reduced risk of preterm birth or neonatal adverse outcomes. , , Based on these data, the FDA withdrew approval of 17α-hydroxyprogesterone caproate for preventing recurrent preterm birth. , Though the benefits of progestin therapy continues to be debated, the need to identify subtypes of preterm birth for which progestin therapy is or is not effective and the need to identify alternative strategies to prevent preterm birth in women at risk remains a priority.
The molecular mechanisms by which progesterone may be able to maintain uterine quiescence and prevent preterm birth in selected women at high risk are not clear. Potential preventive effects do not appear to be based on genetic variations in the PR gene or prevention of cervical shortening. , Several putative mechanisms have been proposed in the literature to explain the quiescent effect of progesterone on the uterus. These can be summarized briefly as follows:
Functional Progesterone Withdrawal Before Labor May Be Mediated by Changes in PR-A and PR-B Gene Expression With an Increase in the PR-A/PR-B Ratio
The single-copy human PR gene uses separate promoters and translational start sites to produce two distinct isoforms, PR-A (94 kDa) and PR-B (116 kDa), which are identical except for an additional 165 amino acids in the amino terminus of PR-B. , Although PR-B shares many of its structural domains with PR-A, they are two functionally distinct transcripts that mediate their own response genes and physiologic effects with little overlap. Each isoform plays a distinct and critical role in myometrial function. For example, PR-B regulates the oxytocin receptor pathway to suppress contractility, and a shift to PR-A dominance in late pregnancy promotes myometrial gap junction coupling. , The onset of labor at term is purportedly associated with an increase in the myometrial PR-A/PR-B ratio, which results in a functional withdrawal of progesterone action. The factors responsible for this differential expression with the onset of labor are unknown, but they may include prostaglandins (both PGE 2 and PGF 2α ), inflammatory cytokines (e.g., tumor necrosis factor-α [TNF-α]), and estrogen activation. The changes seen in the PR-A/PR-B ratio in the myometrium are also seen in the cervix and putatively in the fetal amniochorion. However, there is no strong evidence that the amniochorion expresses PR; in contrast, there are multiple studies showing PR is confined to the decidual portion of the choriodecidua and not expressed by chorion trophoblast or other cells of the amnion and chorion.
Progesterone Receptor Cofactors Mediate a Functional Withdrawal of Progesterone in the Myometrium
The ability of progesterone to bind its receptor and affect transcription of target genes is reduced in uterine tissues obtained after the onset of labor. Condon and colleagues showed that the PR coactivators cAMP response element–binding protein (CREB) and steroid receptor coactivators 2 and 3 as well as acetylated histone H3 are decreased in the myometrium of women in labor compared with women not in labor. These data suggest that the decline in PR coactivator expression and histone acetylation in the uterus near term and during labor may impair progesterone-PR functioning. Progesterone-PR function may also be antagonized directly through the increased expression of PR corepressors.
Dong and colleagues also identified p54nrb as a PR corepressor in myometrium that modulates PR function during pregnancy. Through in vitro studies they demonstrated that PR suppresses transcription of GJA1 (Cx43), by interacting with AP-1 transcription factors and recruiting p54nrb and the mSin3A/HDAC complex to the proximal AP-1 response element within the Cx43 promoter. They showed that the expression of p54nrb is gestationally regulated in rodents, such that it is highly expressed in quiescent myometrium while it decreases at term, thereby mediating derepression of PR-mediated inhibition of Cx43 transcription. Studies from the same group also showed that PR-B isoform has a higher affinity for p54nrb compared to PR-A, which suggests that the dominance of PR-A over PR-B at term would alleviate the transcriptional repression of CAP genes.
The AP-1 proteins are critical regulators of Cx43 transcription. These transcriptional factors (Juns and Fos proteins) regulate a large number of genes through differential dimerization. Mitchell and colleagues have shown that AP-1 heterodimers are more potent inducers of Cx43 compared to AP-1 homodimers. Specifically, cFOS, FRA2, and JUND proteins are reported to be significantly associated with labor onset in humans. The PR isoforms also display selective interaction with different Jun and Fos proteins; the PR-B isoforms interact with Jun members and PR-A displays interacting ability with both the Jun and Fos proteins, implicating the likely assembly of PRA-Fos/Jun heterodimer complex at Cx43 promoter at term, which in the absence of p54nrb mediates transcriptional activation instead of repression. Therefore modulation of PR function by coactivators, corepressors, and transcriptional factors may explain, at least in part, how it is possible to have a functional withdrawal of progesterone action at the level of the uterus without a significant change in circulating progesterone levels.
Progesterone May Act Also Through Nongenomic Pathways
In addition to its well-described genomic effects, progesterone may act through nongenomic (DNA-independent) pathways. For example, several investigators have shown that selected progesterone metabolites (such as 5β-dihydroprogesterone)—but not progesterone itself—are capable of intercalating themselves into the lipid bilayer of the cell membrane, binding directly to and distorting the heptahelical oxytocin receptor and inhibiting oxytocin binding and downstream signaling. A functional withdrawal of this progesterone metabolite–mediated inhibition of oxytocin action on the myometrium would promote myometrial contractility and labor.
Possible Role for a Cell Membrane–Bound Progesterone Receptor in Myometrium
Recent studies have identified specific membrane-bound PRs in a number of human tissues, including uterine tissues, but the function of this receptor in pregnancy and labor has yet to be fully elucidated. , ,
Effect of Progesterone on Fetal Membranes
Using an in vitro explant model, investigators have shown that progesterone inhibits TNF-α–induced apoptosis (programmed cell death) in human fetal membranes. , Given that one-third of preterm deliveries occur in the setting of preterm premature rupture of the membranes, the observation that exogenous progesterone may prevent or minimize injury to the fetal membranes in the setting of intrauterine infection or inflammation is compelling. In this same model, progesterone was also seen to inhibit basal apoptosis in the fetal membranes, suggesting that this mechanism may also be important for normal labor at term.
Functional Withdrawal of Progesterone Action May Be Mediated by a Decrease in Intracellular Progesterone Concentrations
Recent data suggest that nuclear concentrations of progesterone may fall at the time of labor, enabling the suppressive effects of progesterone on CAP gene expression to be withdrawn. Data from several sources suggest that, in humans, the pregnancy-maintaining action of progesterone may be lost at term as a result of metabolism by 20α-hydroxysteroid dehydrogenase (20α-HSD), the expression of which is increased in uterine myocytes indirectly through the action of the miR200 family of microRNAs or directly through the activation of proinflammatory transcription factors AP-1 and/or NF-kB. Reduced levels of nuclear progesterone result in unliganding of PRs; in the unliganded state, PR-A isoform acts as an activator of CAP gene expression. The intranuclear decline of progesterone and unliganding of progesterone receptors have been found in human myometrium during term and preterm labor, suggesting a local control over progesterone level and action irrespective of the circulating hormone. These data open an avenue for testing synthetic selective progesterone receptor modulators (SPRMs) that are not catabolized by 20α-HSD, such as Promegestone (R5020) for the prevention of preterm birth (PTB).
Estrogens
In the rhesus monkey, infusion of a C19 steroid precursor (androstenedione) leads to preterm delivery. This effect is blocked by concurrent infusion of the aromatase inhibitor Δ 4 -hydroxyandrostenedione, demonstrating that conversion of C19 steroid precursors to estrogen at the level of the fetoplacental unit is important. However, systemic infusion of estrogen failed to induce delivery, , suggesting that the action of estrogen is most likely paracrine or autocrine or both. Levels of estrogen in the maternal circulation are significantly elevated throughout gestation and are derived primarily from the placenta. In contrast to the situation in many animal species (e.g., sheep), the high circulating levels of estrogens in humans are already at the dissociation constant (K d ) for the estrogen receptor (ER), which explains why there is no need for an additional increase in estrogen production at term.
At the cellular level, estrogens exert their effect by binding to specific nuclear receptors to effect transcription of target genes. There are two distinct ERs, ERα and Erβ, each coded by its own gene ( ESR1 and ESR2, respectively). Both require dimerization before binding to their ligands.
At the level of the myometrium, ERα appears to be dominant. The expression of myometrial ERα remains unchanged through gestation; however, it remains insensitive to the presence of estrogen during pregnancy. Prior to labor the sensitivity of ERα to estrogen and its pro-parturition action increases. This activation of ERα results from downregulation of the dominant negative splice variant ERΔ7, which suppresses the action of ERα during myometrial quiescence. Downregulation of ERΔ7 at term results in activation of ERα and induction of CAP genes. Progesterone decreases myometrial estrogen responsiveness by inhibiting ERα gene expression. Thus increased PR-A/PR-B ratio and/or decreased PR activity at term should lead to increased ERα expression and activity. These findings suggest that functional estrogen activation and functional progesterone withdrawal are linked. At term, functional progesterone withdrawal at the level of the uterus removes the suppression of myometrial ERα gene expression, leading to an increase in myometrial estrogen responsiveness. Estrogen can then act to transform the myometrium into a contractile phenotype. This model may explain why disruption of progesterone action is sufficient to trigger the full parturition cascade. The link between functional progesterone withdrawal and functional estrogen activation may be a critical mechanism for the endocrine and paracrine control of human labor at term.
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