Placental Corticotropin-releasing Hormone Research Articles

Mechanisms of Term and Preterm Birth

Labour at term and preterm results from activation and then stimulation of the myometrium. Activation can occur through mechanical stretch of the uterus, and by endocrine pathways resulting from increased activity of the fetal hypothalamic-pituitary-adrenal axis. In women and in experimental animals, cortisol likely contributes to increased prostaglandin production in fetal tissues through up-regulation of the type 2 prostaglandin H2, synthase-2 (PGHS-2) and down-regulation of 15-OH prostaglandin dehydrogenase. Cortisol increases expression of prostaglandin dehydrogenase in the chorion by reversing the stimulatory effect of progesterone, and may represent “progesterone withdrawal” in the primate. By competing with progesterone inhibition, cortisol also increases expression of placental corticotropin-releasing hormone. Other agents, such as pro-inflammatory cytokines, similarly up-regulate PGHS-2 and decrease expression of prostaglandin dehydrogenase. Oxytocin, produced locally within the intrauterine tissues, is also thought to be involved in parturition, and there is a marked increase in oxytocin receptor expression at term. There are thus several mechanisms by which labour at term or preterm may be initiated. These different mechanisms need to be considered in the development of strategies for the detection and management of women in preterm labour. Ongoing studies are investigating the use of oxytocin receptor antagonists, PGHS-2 inhibitors, and nitric oxide to prevent or regulate preterm labour. The presence of fibronectin in vaginal secretions and elevated maternal serum levels of corticotropin-releasing hormone estro ens and cytokines have been examined as possible markers of preterm labour. However, at the present time we do not have the ability to accurately predict or diagnose preterm labour, nor do we have specific or efficient methods to inhibit labour once it has started.

Behavioral perinatology: biobehavioral processes in human fetal development.

Behavioral perinatology is as an interdisciplinary area of research that involves conceptualization of theoretical models and conduct of empirical studies of the dynamic time-, place-, and context-dependent interplay between biological and behavioral processes in fetal, neonatal, and infant life using an epigenetic framework of development. The biobehavioral processes of particular interest to our research group relate to the effects of maternal pre- and perinatal stress and maternal-placental-fetal stress physiology. We propose that behavioral perinatology research may have important implications for a better understanding of the processes that underlie or contribute to the risk of three sets of outcomes: prematurity, adverse neurodevelopment, and chronic degenerative diseases in adulthood. Based on our understanding of the ontogeny of human fetal development and the physiology of pregnancy and fetal development, we have articulated a neurobiological model of pre- and perinatal stress. Our model proposes that chronic maternal stress may exert a significant influence on fetal developmental outcomes. Maternal stress may act via one or more of three major physiological pathways: neuroendocrine, immune/inflammatory, and vascular. We further suggest that placental corticotropin-releasing hormone (CRH) may play a central role in coordinating the effects of endocrine, immune/inflammatory, and vascular processes on fetal developmental outcomes. Finally, we hypothesize that the effects of maternal stress are modulated by the nature, duration, and timing of occurrence of stress during gestation. In this paper, we elaborate on the conceptual and empirical basis for this model, highlight some relevant issues and questions, and make recommendations for future research in this area.

Role of stress peptides during human pregnancy and labour.

Premature birth is the major source of perinatal death and disability. Furthermore, the intrauterine health of the baby is important for preventing certain adult diseases. However, the molecular mechanisms driving the onset of human labour remain uncertain, although several key players have been identified. It is becoming clear that there are many pathways to parturition in humans. Stress peptides, in particular placental corticotrophin releasing hormone (CRH) and possibly the related peptide urocortin, appear to play important roles throughout pregnancy. Plasma CRH is a predictor of the duration of human gestation. During most of pregnancy, CRH, acting via specific CRH receptor subtypes, plays a 'protective' role by promoting myometrial quiescence via the generation of cAMP and cGMP, and upregulation of nitric oxide synthase expression. At term, myometrial contractility is enhanced by a complex series of molecular switches, involving the upregulation of oxytocin receptor expression and crosstalk between the oxytocin and CRH receptors. This results in protein kinase C-induced phosphorylation of specific CRH receptor subtypes, with subsequent desensitization and a shift in the intracellular microenvironment to enhance contractility. CRH/urocortin, via specific receptor isoforms, is now able to activate Gq and potentially enhance the oxytocin-driven generation of inositol triphosphate. In addition, CRH/urocortin, via specific CRH receptor subtypes, may generate prostaglandins from the fetal membranes and decidua, play a role in placental vasodilatation and participate in fetal adrenal function and organ maturation. These peptides and receptors are phylogenetically ancient and well preserved across species. They may have evolved as a mechanism to protect against the 'stress' of premature birth.

Role of stress peptides during human pregnancy and labour

Premature birth is the major source of perinatal death and disability. Furthermore, the intrauterine health of the baby is important for preventing certain adult diseases. However, the molecular mechanisms driving the onset of human labour remain uncertain, although several key players have been identified. It is becoming clear that there are many pathways to parturition in humans. Stress peptides, in particular placental corticotrophin releasing hormone (CRH) and possibly the related peptide urocortin, appear to play important roles throughout pregnancy. Plasma CRH is a predictor of the duration of human gestation. During most of pregnancy, CRH, acting via specific CRH receptor subtypes, plays a 'protective' role by promoting myometrial quiescence via the generation of cAMP and cGMP, and upregulation of nitric oxide synthase expression. At term, myometrial contractility is enhanced by a complex series of molecular switches, involving the upregulation of oxytocin receptor expression and crosstalk between the oxytocin and CRH receptors. This results in protein kinase C-induced phosphorylation of specific CRH receptor subtypes, with subsequent desensitization and a shift in the intracellular microenvironment to enhance contractility. CRH/urocortin, via specific receptor isoforms, is now able to activate Gq and potentially enhance the oxytocin-driven generation of inositol triphosphate. In addition, CRH/urocortin, via specific CRH receptor subtypes, may generate prostaglandins from the fetal membranes and decidua, play a role in placental vasodilatation and participate in fetal adrenal function and organ maturation. These peptides and receptors are phylogenetically ancient and well preserved across species. They may have evolved as a mechanism to protect against the 'stress' of premature birth.

Maternal plasma corticotropin-releasing hormone trajectories vary depending on the cause of preterm delivery

Objective: Although second trimester maternal plasma corticotropin-releasing hormone concentrations are elevated in women who are destined to deliver preterm, the sensitivity and positive predictive value of an individual test of corticotropin-releasing hormone concentration is low. This poor screening performance may be due in part to the observation that the causes of preterm delivery are heterogenous, with potentially different effects on corticotropin-releasing hormone production. We have reanalyzed data from a previous cohort of women with multiple samplings to determine whether the trajectory of increase of placental corticotropin-releasing hormone provided more information than did a single sample. Study Design: In this cohort, where 2 to 4 samples that had been assayed for corticotropin-releasing hormone were available on 305 women, the general form of the exponential equation y = aebt was fitted to the corticotropin-releasing hormone data of each individual by the Gauss-Newton nonlinear least squares method, which generated the parameters, y-intercept and rate of rise, in corticotropin-releasing hormone concentration for each woman. Nonparametric statistical techniques, including bootstrapping, were applied to compare the results for the group of women who delivered at term with the group of women who delivered spontaneously preterm and the group of women who were delivered preterm by induction or cesarean delivery because of obstetric indication. Results: The 3 clinically defined groups have significantly different parameters, y-intercept and rate of rise, which describe the corticotropin-releasing hormone trajectory. The group that delivered preterm because of obstetric indications had a similar mean y-intercept but significantly greater mean rate of rise in corticotropin-releasing hormone concentration than the term group (0.3491 vs 0.1788; 95% CI, 0.2331-0.4615 vs 0.1394-0.2330). The group that delivered spontaneously preterm had a significantly greater mean y-intercept than the group that delivered preterm because of obstetric indication (17.08 vs 1.83; 95% CI, 5.89-28.43 vs 0.03-5.19) but a similar mean rate of rise to the group that delivered at term. Conclusion: These data suggest that spontaneous preterm delivery is associated with an abnormal setting of the production of corticotropin-releasing hormone that is present from very early in pregnancy, although women who experience an induced preterm delivery are characterized by rapidly rising placental corticotropin-releasing hormone concentrations. These data further suggest that clinical abnormalities that are associated with preterm delivery by induction or cesarean delivery are associated with abnormalities that lead to a rapidly increasing corticotropin-releasing hormone concentrations. Trajectories for corticotropin-releasing hormone provide information beyond that obtained from a single sample. (Am J Obstet Gynecol 2002;186:257-60.)

Stress, infection and preterm birth: a biobehavioural perspective.

Preterm birth is currently the most important problem in maternal-child health in the United States. Epidemiological studies have suggested that two factors, maternal stress and maternal urogenital tract infection, are significantly and independently associated with an increased risk of spontaneous preterm birth. These factors are also more prevalent in the population of sociodemographically disadvantaged women who are at increased risk for preterm birth. Studies of the physiology of parturition suggest that neuroendocrine and immune processes play important roles in the physiology and pathophysiology of normal and preterm parturition. However, not all women with high levels of stress and/or infection deliver preterm, and little is understood about factors that modulate susceptibility to pathophysiological events of the endocrine and immune systems in pregnancy. We present here a comprehensive, biobehavioural model of maternal stress and spontaneous preterm delivery. According to this model, chronic maternal stress is a significant and independent risk factor for preterm birth. The effects of maternal stress on preterm birth may be mediated through biological and/or behavioural mechanisms. We propose that maternal stress may act via one or both of two physiological pathways: (a) a neuroendocrine pathway, wherein maternal stress may ultimately result in premature and/or greater degree of activation of the maternal-placental-fetal endocrine systems that promote parturition; and (b) an immune/inflammatory pathway, wherein maternal stress may modulate characteristics of systemic and local (placental-decidual) immunity to increase susceptibility to intrauterine and fetal infectious-inflammatory processes and thereby promote parturition through pro-inflammatory mechanisms. We suggest that placental corticotropin-releasing hormone may play a key role in orchestrating the effects of endocrine and inflammatory/immune processes on preterm birth. Moreover, because neuroendocrine and immune processes extensively cross-regulate one another, we further posit that exposure to both high levels of chronic stress and infectious pathogens in pregnancy may produce an interaction and multiplicative effect in terms of their combined risk for preterm birth. Finally, we hypothesise that the effects of maternal stress are modulated by the nature, duration and timing of occurrence of stress during gestation. A discussion of the components of this model, including a theoretical rationale and review of the available empirical evidence, is presented. A major strength of this biobehavioural perspective is the ability to explore new questions and to do so in a manner that is more comprehensive than has been previously attempted. We expect findings from this line of proposed research to improve our present state of knowledge about obstetric risk assessment for preterm birth by determining the characteristics of pregnant women who are especially susceptible to stress and/or infection, and to broaden our understanding of biological (endocrine, immune, and endocrine-immune interactions) mechanisms that may translate social adversity during pregnancy into pathophysiology, thereby suggesting intervention strategies.

Socio-economic disparities in preterm birth: causal pathways and mechanisms.

Preterm birth is the leading cause of infant mortality in industrialised societies. Its incidence is greatly increased among the socially disadvantaged, but the reasons for this excess are unclear and have been relatively unexplored. We hypothesise two distinct sets of causal pathways and mechanisms that may explain social disparities in preterm birth. The first set involves chronic and acute psychosocial stressors, psychological distress caused by those stressors, increased secretion of placental corticotropin releasing hormone (CRH), changes in sexual behaviours or enhanced susceptibility to bacterial vaginosis and chorioamnionitis, cigarette smoking or cocaine use, and decidual vasculopathy. The second hypothesised pathway is a gene-environment interaction based on a highly prevalent mutation in the gene for methylenetetrahydrofolate reductase (MTHFR), combined with low folate intake from the diet and from prenatal vitamin supplements, consequent hyperhomocysteinemia, and decidual vasculopathy. We propose to test these hypothesised pathways and mechanisms in a nested case-control study within a prospectively recruited and followed cohort of pregnant women with singleton pregnancies who deliver at one of four Montreal hospitals that serve an ethnically and socio-economically diverse population. Following recruitment during the late first or early second trimester, participating women are seen at 24-26 weeks, when a research nurse obtains a detailed medical and obstetric history; administers several scales to assess chronic and acute stressors and psychological function; obtains blood samples for CRH, red blood cell and plasma folate, homocysteine, and DNA for the MTHFR mutation; and performs a digital and speculum examination to measure cervical length and vaginal pH and to obtain swabs for bacterial vaginosis and fetal fibronectin. After delivery, each case (delivery at < 37 completed weeks following spontaneous onset of labour or prelabour rupture of membranes) and two controls are selected for placental pathological examination, hair analysis of cotinine, cocaine, and benzoylecgonine, and analysis of stored blood and vaginal specimens. Statistical analysis will be based on multiple logistic regression and structural equation modelling, with sequential construction of models of potential aetiological determinants and covariates to test the hypothesised causal pathways and mechanisms. The research we propose should improve understanding of the factors and processes that mediate social disparities in preterm birth. This improved understanding should help not only in developing strategies to reduce the disparities but also in suggesting preventive interventions applicable across the entire socio-economic spectrum.

Maternal experiences of racism and violence as predictors of preterm birth: rationale and study design.

Chronic psychological stress may raise the risk of preterm delivery by raising levels of placental corticotropin-releasing hormone (CRH). Women who have been the targets of racism or personal violence may be at particularly high risk of preterm delivery. The aims of this study are to examine the extent to which: (1) maternal experiences of racism or violence in childhood, adulthood, or pregnancy are associated with the risk of preterm birth; (2) CRH levels are prospectively associated with risk of preterm birth; and (3) CRH levels are associated with past and current maternal experiences of racism or violence. We have begun to examine these questions among women enrolled in Project Viva, a Boston-based longitudinal study of 6000 pregnant women and their children.

Second Trimester Corticotropin-Releasing Hormone Levels in Relation to Preterm Delivery and Ethnicity

In Brief Objective To assess the relationship between maternal corticotropin-releasing hormone (CRH) levels in second trimester sera, and the risk of preterm delivery in an ethnically heterogeneous sample of pregnant women. Methods This nested case-control study included two case groups (97 women who delivered before 35 weeks' gestation, 144 who delivered at 35–36 weeks' gestation), and a control group (244 women who delivered at or after 37 weeks' gestation) frequency matched by ethnicity (black, white) and by alpha-fetoprotein levels (normal, unexplained high). Corticotropin-releasing hormone was evaluated in stored maternal sera collected at 15–19 weeks' gestation from cases and controls. Results Delivery before 35 weeks' gestation was associated positively with a second trimester, ethnic-specific CRH above 1.5 multiples of the median in white women [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.1, 5.1] and black women (OR 5.0, 95% CI 1.8, 13.3). Sensitivity was 29% in whites and 41% in blacks; specificity was 84% in whites and 80% in blacks. We estimated the positive and negative predictive values to be 6% and 97%, respectively, in white women, and 16% and 93%, respectively, in black women. It was also noted that, within case and control groups, black women had consistently lower CRH levels than white women. Conclusion Factors that lead to a premature increase in placental CRH production and are associated with an increased risk of preterm birth are evident as early as 15–19 weeks' pregnancy. When considering potential links between stressors, placental changes, CRH levels, and preterm birth, it might be important to stratify or adjust for ethnicity. Second trimester maternal corticotropin-releasing hormone levels are elevated among women who deliver before 35 weeks' gestation, and are lower in blacks than whites.

Second trimester corticotropin-releasing hormone levels in relation to preterm delivery and ethnicity

%Objective: To assess the relationship between maternal corticotropin-releasing hormone (CRH) levels in second trimester sera, and the risk of preterm delivery in an ethnically heterogeneous sample of pregnant women. Methods: This nested case-control study included two case groups (97 women who delivered before 35 weeks’ gestation, 144 who delivered at 35–36 weeks’ gestation), and a control group (244 women who delivered at or after 37 weeks’ gestation) frequency matched by ethnicity (black, white) and by alpha-fetoprotein levels (normal, unexplained high). Corticotropin-releasing hormone was evaluated in stored maternal sera collected at 15–19 weeks’ gestation from cases and controls. Results: Delivery before 35 weeks’ gestation was associated positively with a second trimester, ethnic-specific CRH above 1.5 multiples of the median in white women [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.1, 5.1] and black women (OR 5.0, 95% CI 1.8, 13.3). Sensitivity was 29% in whites and 41% in blacks; specificity was 84% in whites and 80% in blacks. We estimated the positive and negative predictive values to be 6% and 97%, respectively, in white women, and 16% and 93%, respectively, in black women. It was also noted that, within case and control groups, black women had consistently lower CRH levels than white women. Conclusion: Factors that lead to a premature increase in placental CRH production and are associated with an increased risk of preterm birth are evident as early as 15–19 weeks’ pregnancy. When considering potential links between stressors, placental changes, CRH levels, and preterm birth, it might be important to stratify or adjust for ethnicity.

The regulation of human corticotrophin-releasing hormone gene expression in the placenta

Corticotrophin-releasing hormone (CRH) is a 41 amino acid neuropeptide that is expressed in the hypothalamus and the human placenta. Placental CRH production has been linked to the determination of gestational length in the human. Although encoded by a single copy gene, CRH expression in the placenta is regulated differently to the hypothalamus. Glucocorticoids stimulate CRH promoter activity in the placenta but inhibit it’s activity in the hypothalamus, via mechanisms involving different regions of the CRH promoter. We discuss how various stimuli alter CRH promoter activity and why these responses are unique to the placenta.

The Role of Corticotropin-Releasing Hormone Receptors in Placenta and Fetal Membranes during Human Pregnancy

Corticotropin-releasing hormone (CRH) is a 41 amino acid polypeptide that exerts a wide spectrum of hypothalamic and extrahypothalamic functions. Moreover, the placenta and other intrauterine tissues produce and secrete immunoreactive CRH. It has been demonstrated that placental CRH is secreted into the maternal circulation in large amounts during the third trimester of human pregnancy and may play an important role in the onset of labor. CRH exerts a number of functions within the intratuterine environment like induction of prostaglandin production and maintenance of the placental blood flow. Here we present an overview of current knowledge about the CRH receptor subtypes and their signaling properties within the feto-placental unit.

Corticotrophin-releasing hormone and human parturition

Corticotrophin-releasing hormone (CRH), the hypothalamic peptide that controls function of the pituitary-adrenal axis in response to stress, is expressed in abundance in the human placenta and is present in high concentrations in maternal and fetal plasma during late pregnancy. A number of lines of evidence now imply a role for this hormone in the control of parturition and fetal maturation in humans. It has been proposed that CRH, through interactions with oestrogen, adrenal steroids, prostaglandins and oxytocin, establishes positive-feedback loops that initiate parturition and labour. Excessive production of placental CRH has also been linked to preterm labour. However, there are a number of significant gaps in our knowledge of the function of this peptide in pregnancy. This review examines current evidence regarding the putative role of CRH in human parturition.

Fetal Endocrine Signals and Preterm Labor

Increased uterine contractility at term and preterm results from activation and then stimulation of the myometrium. Activation can be provoked by mechanical stretch of the uterus and by an endocrine pathway resulting from increased activity of the fetal hypothalamic-pituitary-adrenal axis. Cortisol, derived from the fetal adrenal in cases of intrauterine compromise or from the maternal adrenal in response to stress, or generated locally from cortisone in choriodecidual trophoblasts, provides a crucial link to uterine stimulation. Cortisol contributes to the increased production of prostaglandins (PGs) by fetal membranes and the decidua through the upregulation of PG synthase and the downregulation of PG dehydrogenase enzymes. Cortisol also stimulates placental corticotropin-releasing hormone (CRH) output, although CRH may both relax and stimulate uterine activity depending on the distribution and affinity of its receptor subtypes. Other agents such as cytokines may intercede in this sequence to stimulate PGs and/or CRH, giving rise to a cascade phenomenon that results in preterm birth.

Involvement of Central, but Not Placental Corticotropin Releasing Hormone (CRH) in Heat Stress Induced Immunosuppression during Pregnancy

To clarify whether corticotropin releasing hormone (CRH) and β-endorphin (βEP) system mediate maternal immunosuppression in pregnant rats exposed to heat through central or placental pathway, we examined the effects of intravenous (iv) (100 or 500 μg) or intracerebroventricular (icv) (5μg) administration of CRH receptor antagonist α-helical CRH (9–41) on splenic natural killer cell activity (NKCA) as well as βEP in blood, pituitary lobes, and placenta in pregnant rats at 15 to 16 days gestation. Two-way ANOVA revealed that heat reduced NKCA and elevated blood and pituitary βEP but did not change placental βEP. Iv administered 500 μg and icv administered α-helical CRH reversed the reduced NKCA and the elevated pituitary βEP, while iv administration of 100 μg α-helical CRH did not. The increased blood βEP was reversed by iv 100 and 500 μg α-helical CRH and icv administration. Both iv and icv administrations reduced placental βEP independent of heat exposure. Thus, the response of placental βEP to iv administration of α-helical CRH seemed to be stronger than that of pituitary βEP. These results indicate that α-helical CRH which acts on pituitary βEP antagonizes heat-induced immunosuppression during pregnancy, suggesting that immunosuppression produced by heat stress during pregnancy is mediated by the central CRH system. The placental CRH-βEP system seems unlikely to be involved in the immunosuppression. Physiologic roles of placental CRH and opioid system should be clarified by future in vitro experiments using placenta specimen including placental immunocyte.

Corticotropin-releasing hormone-binding protein in primates.

In humans, placental corticotropin-releasing hormone (CRH) production has been linked to the determination of gestational length, and a late gestational fall in CRH-binding protein (CRH-BP) has been linked to the onset of parturition. Expression of placental CRH mRNA is limited to primates, and only in man has a circulating CRH-BP been described. As the fall in CRH-BP in late gestation has been associated with parturition in humans, we sought to determine whether a CRH-BP circulated in the plasma of other primates. It is unclear whether maternal plasma CRH concentrations are elevated in New World monkeys and prosimians. We have therefore performed CRH plasma measurements in the blood of pregnant marmosets, in several species of lemur, and in pregnant and fetal rhesus monkeys as a positive control. Using gel chromatography, CRH-BP was detected in the human, gorilla, chimpanzee, orangutan, gibbon, macaque, squirrel monkey, and marmoset, but was absent in the mandrill, spider monkey, and lemur. CRH was detected in the plasma of pregnant marmosets and rhesus monkeys. CRH was also detected in the fetal rhesus monkey, but at lower concentrations than in maternal plasma. CRH immunoreactivity was not detectable in the plasma of pregnant lemurs or in extracts of lemur placenta. In conclusion, a circulating binding protein for CRH exists in all species of apes but occurs variably among New World and Old World monkeys and is absent in lemurs. The variable occurrence of the CRH-BP does not support a role for this protein in the mechanism of parturition in primates. Maternal CRH is elevated in the pregnant marmoset and rhesus, and may play a role in the pregnancy of New and Old World monkeys.

Chapter 9 The neurobiology of stress in human pregnancy: implications for prematurity and development of the fetal central nervous system

Adverse early experience, including prenatal maternal psychosocial stress, has the potential to negatively influence developmental processes through both physiological and behavioral mechanisms. This in turn may have adverse consequences for the mental and physical health, well-being and aging of the individual throughout the entire life-span. We have initiated a program of research on humans to examine the consequences of maternal stress and related factors in pregnancy on the length of gestation, fetal growth, and brain development. We have also investigated the physiological mechanisms that are involved. In this chapter we outline the theoretical rationale for this work and give an overview of our findings to date. These findings support a significant and independent role for behavioral processes such as maternal prenatal stress in the etiology of prematurity-related outcomes, and suggest that these effects are mediated, in part, by the maternal-placental-fetal neuroendocrine axis; specifically by placental corticotropin-releasing hormone. Using a fetal challenge paradigm as a novel method for quantifying fetal neurologic maturity in utero, we have found that the maternal environment exerts a significant influence on the fetal autonomic nervous system and on central nervous system processes related to recognition, memory and habituation. Finally, our findings provide preliminary evidence to support the notion that the influence of prenatal stress and maternal-placental hormones on the developing fetus may persist after birth, as assessed by measures of temperament and behavioral reactivity in the first 3 years of postnatal life. The implications of these studies for life-span development and health are discussed.

Effect of antenatal betamethasone administration on placental vascular resistance

High placental vascular resistance is an important cause of fetal growth restriction and subsequent perinatal mortality. Identification of affected pregnancies allows appropriate fetal surveillance and delivery, but there are no known therapeutic strategies to decrease resistance and improve blood flow. However, placental corticotropin-releasing hormone (CRH) is thought to be a potent fetoplacental vasodilator, and exogenous corticosteroids can increase placental CRH secretion. Therefore, we examined whether corticosteroids could improve fetoplacental blood flow in pregnancies with increased vascular resistance. A retrospective review of umbilical-artery flow-velocity waveforms (FVWs) before and after betamethasone administration was undertaken in pregnancies with increased placental vascular resistance, as shown by umbilical-artery absent end-diastolic flow (AEDF). FVWs were obtained by pulsed-wave doppler ultrasonography. We studied all 28 pregnancies monitored at the maternal-fetal medicine unit of a university teaching hospital since 1995. The median duration of gestation at presentation with AEDF was 27 weeks (range 23-33). In 19 (68% [95% CI 49-86]) pregnancies, umbilical-artery diastolic flow returned within 24 h after betamethasone administration, consistent with decreased resistance. The median duration of this effect was 3 days (range 2-7). There were no differences in duration of gestation at diagnosis or delivery, or in birthweight between fetuses showing a return of flow after betamethasone and those not showing a return of flow. In pregnancies with umbilical-artery AEDF, betamethasone treatment is associated with decreased placental vascular resistance, possibly induced via increased placental CRH secretion. This study does not provide insights into whether this effect would be beneficial or harmful to the fetus.

Reproductive placental corticotropin-releasing hormone and its clinical implications

The hypothalamic-pituitary-adrenal axis and the reproductive system exhibit a complex relationship in both nonpregnant and pregnant women.1,2 The hypothalamic-pituitary-adrenal axis exerts profound, mostly inhibitory, effects on the reproductive axis, with corticotropin-releasing hormone and corticotropin-releasing hormone–induced pro-opiomelanocortin peptides inhibiting hypothalamic gonadotropin-releasing hormone secretion and with glucocorticoids inhibiting pituitary luteinizing hormone and ovarian estrogen and progesterone secretion and rendering estrogen-target tissues, such as the endometrium, resistant to the gonadal steroid. Conversely, estrogen directly stimulates the hypothalamic corticotropin-releasing hormone gene, which may explain the slight hypercortisolism seen in women and the preponderance of depression, anxiety disorders, and anorexia nervosa among women.3 Interestingly, several components of the hypothalamicpituitary-adrenal axis and their receptors are present in reproductive tissues as autacoid regulators of their various functions2, 4-7 (Table I). These include ovarian and endometrial corticotropin-releasing hormone, which may participate in the regulation of steroidogenesis and the inflammatory processes of the ovary (ovulation and luteolysis) and of the endometrium (blastocyst implantation and menstruation), and placental corticotropin-releasing hormone, which is secreted mostly in the latter half of pregnancy and is responsible for the physiologic hypercortisolism seen during this period (Fig 1). Most circulating corticotropin-releasing hormone is neutralized by corticotropin-releasing hormone binding protein produced by the liver. Between weeks 34 and 35 of gestation, however, the concentrations of this protein fall by about 60%, leading to elevations of free corticotropin-releasing hormone. Subsequently plasma free corticotropin-releasing hormone concentrations rise further, to peak at labor and delivery. In addition to the hypercortisolism of pregnancy, placental corticotropin-releasing hormone causes vasodilation of the fetoplacental circulation by activating nitric oxide synthase and participates in labor by stimulating secretion of prostaglandin F2α and prostaglandin E2 by the fetal membranes and by promoting constriction of myometrial cells. Placental corticotropin-releasing hormone secretion is stimulated by glucocorticoids, inflammatory cytokines, and anoxic conditions and therefore by noninflammatory or inflammatory stress, including the stress of preeclampsia or eclampsia.2,6 Premature elevation of placental corticotropin-releasing hormone level has been associated with premature labor and birth. Potent corticotropin-releasing hormone antagonists are in the making and could be tested as labor retardants. The hypercortisolism of pregnancy is followed by a transient suppression of hypothalamic corticotropin-releasing hormone secretion in the postpartum period, which may explain the blues or depression and autoimmune phenomena seen during this period.2,7 Estrogen administration has been shown to ameliorate postpartum depression, probably by returning to normal the secretion of the suppressed corticotropin-releasing hormone neuron. From Section on Pediatric Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Development, National Institutes of Health. Reprint requests: G. P. Chrousos, MD, Section on Pediatric Endocrinology, National Institutes of Health, Bethesda, MD 20892-1862. Am J Obstet Gynecol 1999;180:S249-50. 0002-9378/99 $8.00 + 0 6/0/90865 Table I. Reproductive corticotropin-releasing hormone and its potential physiologic functions

Placental corticotropin-releasing hormone: Function and regulation

Corticotropin-releasing hormone is a neuropeptide placentally expressed among mammals only in primates. Its expression increases as much as 100 times during the last 6 to 8 weeks of pregnancy and is paradoxically stimulated by glucocorticoids. Increasing evidence suggests that placental corticotropin-releasing hormone may have evolved in primates to stimulate fetal adrenocorticotropin release and adrenal steroidogenesis, thus satisfying the high demand for synthesis of dehydroepiandrosterone, the predominant source of placental estradiol. Concomitant stimulation by placental corticotropin-releasing hormone of fetal cortisol and dehydroepiandrosterone would couple the glucocorticoid effects on fetal organ maturation with the timing of parturition, an obvious benefit in postnatal survival. (Am J Obstet Gynecol 1999;180:S242-6.)