The physiological roles of placental corticotropin releasing hormone in pregnancy and childbirth

In response to stress, the hypothalamus releases cortiticotropin releasing hormone (CRH) that travels to the anterior pituitary, where it stimulates the release of adrenocorticotropic hormone (ACTH). ACTH travels to the adrenal cortex, where it stimulates the release of cortisol and other steroids that liberate energy stores to cope with the stress. During pregnancy, the placenta synthesises CRH and releases it into the bloodstream at increasing levels to reach concentrations 1,000 to 10, 000 times of that found in the non-pregnant individual. Urocortins, which are CRH analogues are also secreted by the placenta. Desensitisation of the maternal pituitary to CRH and resetting after birth may be a factor in post-partum depression. Recently, CRH has been found to modulate glucose transporter (GLUT) proteins in placental tissue, and therefore there may be a link between CRH levels and foetal growth. Evidence suggests CRH is involved in the timing of birth by modulating signalling systems that control the contractile properties of the myometrium. In the placenta, cortisol stimulates CRH synthesis via activation of nuclear factor kappa B (NF-κB), a component in a cellular messenger system that may also be triggered by stressors such as hypoxia and infection, indicating that intrauterine stress could bring forward childbirth and cause low birth weight infants. Such infants could suffer health issues into their adult life as a result of foetal programming. Future treatment of these problems with CRH antagonists is an exciting possibility.     

Elevated maternal cortisol early in pregnancy predicts third trimester levels of placental corticotropin releasing hormone (CRH): priming the placental clock

The purposes of this study were to determine the intervals when placental corticotrophic-releasing hormone (CRH) was most responsive to maternal cortisol. A sample of 203 women each were evaluated at 15, 19, 25 and 31 weeks gestation and followed to term. Placental CRH and maternal adrenocorticotropin hormone (ACTH), B-endorphin and cortisol were determined from plasma. CRH levels increased faster and were higher in women who delivered preterm compared with women who delivered at term (F3,603 = 5.73, p < .001). Simple effects indicated that CRH levels only at 31 weeks predicted preterm birth (F1,201 = 5.53, p = .02). Levels of cortisol were higher in women who delivered preterm at 15 weeks gestation (F1,201 = 4.45, p = .03) with a similar trend at 19 weeks gestation. Hierarchical regression suggested that the influence on birth outcome of maternal cortisol early in pregnancy was mediated by its influence on placental CRH at 31 weeks. Elevated cortisol at 15 weeks predicted the surge in placental CRH at 31 weeks (R = .49, d.f. = 1,199, Fchange = 61.78, p < .0001). Every unit of change in cortisol (microg/dl) at 15 weeks was associated with a 34 unit change of CRH (pg/ml) at 31 weeks. These findings suggested that early detection of stress signals by the placenta stimulated the subsequent release of CRH and resulted in increased risk for preterm delivery.     

Effects of restricting uteroplacental blood flow on concentrations of corticotrophin-releasing hormone, adrenocorticotrophin, cortisol, and prostaglandin E2 in the sheep fetus during late pregnancy.

We have examined the effects of reduced uterine blood flow and prolonged fetal hypoxemia on the temporal relationship between changes in hormones associated with the activity of the pituitary-adrenal axis (corticotrophin-releasing hormone (CRH), adrenocorticotrophin (ACTH), cortisol, and prostaglandin E2 (PGE2) in the ovine fetus at 120-125 days of pregnancy, and we sought evidence for placental secretion of CRH and ACTH during prolonged hypoxemia. Uterine blood flow was reduced by placing an adjustable Teflon clamp around the maternal common internal iliac artery to decrease fetal arterial oxygen saturation from mean values of 59.1 +/- 3.3 to 25.7 +/- 4.6% (+/- SEM, n = 10). There was a transient peak in immunoreactive (IR-) CRH at 1-2 h after reducing uterine blood flow. IR-ACTH rose to peak values at +2 h, then gradually decreased to control level by +12 h. Fetal plasma cortisol and PGE2 concentrations were elevated significantly by +2 and +4 h, respectively, and at 20-24 h. The identity of IR-CRH in fetal plasma and in ovine placental extracts was confirmed by HPLC, but there was no consistent umbilical vein--femoral arterial concentration difference for either IR-CRH or IR-ACTH during normoxemia or hypoxemia. We conclude that a sequence of endocrine changes involving CRH, ACTH, PGE2, and cortisol occurs in the fetus during a prolonged reduction in uterine blood flow. However, we did not obtain evidence, for placental secretion of either CRH or ACTH in response to this manipulation.     

Pattern of maternal serum corticotropin-releasing hormone concentration during pregnancy in the common marmoset (Callithrix jacchus)

Corticotropin-releasing hormone (CRH), a potent neuropeptide, is produced by the placenta of anthropoid primates. No other mammals, including prosimian primates, are known to produce placental CRH. In humans, placental CRH appears to play an important role in the progression of pregnancy to parturition. Maternal circulating CRH begins to rise early in pregnancy and increases until parturition. Gorillas and chimpanzees share this pattern of increasing maternal CRH during pregnancy with humans. In humans, chimpanzees, and gorillas, maternal CRH and estradiol concentrations are correlated, consistent with the hypothesis that CRH is involved in the biosynthetic pathway for placental estrogen production. In contrast, in baboons, maternal circulating CRH rises precipitously early in pregnancy and then declines, though CRH is detectable until birth. This research was designed to investigate the pattern of maternal circulating CRH in the common marmoset during pregnancy. Blood samples were taken across gestation from nine subjects over 11 pregnancies, and the plasma was assayed for CRH. The pattern of maternal circulating CRH in the common marmoset was similar to that of the baboon, with a rapid rise starting at about 50 days postconception and a peak at approximately 70 days postconception. By 110 days postconception, CRH concentration had plateaued at a significantly lower value. The peak and mean values for CRH were associated with fetal number (e.g., females gestating triplets had higher values than females gestating twins). Urinary estradiol showed no association with plasma CRH concentration. Marmosets appear to differ from the great apes in this regard, and to share a pattern of maternal CRH during pregnancy with the baboon, indicating that the baboon and marmoset pattern may be ancestral. The function of the early rapid rise of CRH in baboons and marmosets, and the significance of this difference between monkeys and apes, are not known.     

Production of corticotrophin releasing hormone by the sheep placenta in vivo

Corticotrophin-releasing hormone (CRH)-like activity has been reported in placental tissue and to rise sharply in maternal and fetal plasma during the third trimester of human pregnancy. It is unclear whether this applies to other species, if the placental secretes CRH, and if so what factors regulate its production. The present experiments were conducted on sheep 123-144 days pregnant. CRH-like activity was detected in the plasma of the uterine and umbilical vein at modest concentrations. These concentrations rose in the final days before delivery. Reduction of uterine blood flow, particularly caused by an elevation of maternal adrenaline, had the capacity to sharply increase placental output. The CRH-like activity on separation by hplc had the characteristics of 41CRH. The results are discussed in relation to the potential role of placentally-derived CRH.     

Ethnic differences in adrenocorticotropic hormone, cortisol and corticotropin-releasing hormone during pregnancy

Significant ethnic disparities exist in reproductive outcomes. A potential contributing factor may be the functioning of the hypothalamic-pituitary-adrenal (HPA) axis and placenta during pregnancy. In the present study, levels of cortisol, ACTH and CRH were determined longitudinally from the plasma of 310 African American, Hispanic and non-Hispanic White women at 18-20, 24-26 and 30-32 weeks' gestation. During pregnancy, African American women exhibited lower levels of cortisol than non-Hispanic women and higher levels of ACTH than Hispanic women. The trajectory of CRH increase also differed by ethnicity, with African Americans exhibiting the lowest levels both early and late in pregnancy. Higher levels of cortisol at 18-20 weeks were associated with higher levels of CRH at 30-32 weeks among the African American and Hispanic women, but not among non-Hispanic women. Ethnic differences persisted when adjusting statistically for sociodemographic and biomedical factors. The findings are consistent with the possibility that ethnic disparities in adverse birth outcomes may be due, in part, to differences in HPA axis and placental function.     

Corticotropin-releasing hormone stimulates estrogen biosynthesis in cultured human placental trophoblasts

Estrogens and corticotrophin-releasing hormone (CRH) produced by the placenta play pivotal roles in the control of parturition in human and other primates. There is a strong correlation between maternal CRH and estrogen concentrations throughout gestation. To investigate whether CRH produced locally in the placenta could modulate estrogen production, we obtained human placental trophoblasts from uncomplicated term pregnancies and cultured them for 72 h. Cells were then treated with CRH and with a CRH receptor antagonist, alpha-helical CRH9-41. The results showed that CRH stimulated, but alpha-helical CRH9-41 inhibited, the production of estradiol in a time- and dose-dependent manner. Consistent with this thesis, CRH increased whereas alpha-helical CRH decreased the mRNA levels of STS, CYP19A1, and HSD17B1, the key enzymes for estrogen synthesis. These results suggest that, in the placenta, endogenously produced CRH exhibits a tonic stimulatory effect on estrogen production.     

Induction of parturition by cortisol: effects on negative feedback sensitivity and plasma CRF.

In fetal sheep, plasma concentrations of both adrenocorticotropic hormone (ACTH) and cortisol increase at the end of gestation. The increase in fetal plasma cortisol concentration induces placental 17 alpha-hydroxylase and 17, 20 lyase activities and therefore stimulates the placenta to secrete relatively more estrogen and relatively less progesterone. The resultant increase in the estrogen-to-progesterone ratio is thought to increase uterine contractility and initiate labour. We had previously demonstrated that the efficacy of cortisol-induced suppression of ACTH secretion at the end of gestation was reduced. We hypothesized that cortisol-induced stimulation of placental steroidogenesis promoted the secretion of a steroid hormone which reduced negative feedback efficacy, and therefore allowed both ACTH and cortisol secretion to increase simultaneously. Others had proposed that cortisol stimulates the placental secretion of corticotrophin releasing factor, which might also stimulate fetal ACTH secretion. This study was designed to test the hypotheses that cortisol reduces its own feedback efficacy or stimulates CRF secretion. Five pregnant ewes with twin pregnancies were studied after chronic catheterization. One fetus was subjected to infusion of hydrocortisone sodium succinate (10 micrograms/min, iv) and the other to infusion of saline. After 5 and 53 h of infusion, each fetus was subjected to a period of hypotension produced by infusion of sodium nitroprusside. The infusion of hydrocortisone sodium succinate decreased plasma progesterone concentrations in the fetal circulation into which the steroid was infused, and in the maternal circulation. Fetal plasma CRF concentrations were increased on the third day of infusion, the day in which the fetuses went into labour.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glucocorticoid regulation of human and ovine parturition: the relationship between fetal hypothalamic-pituitary-adrenal axis activation and intrauterine prostaglandin production

Birth in many animal species and in humans is associated with activation of hypothalamic-pituitary-adrenal function in the fetus and the increased influence of glucocorticoids on trophoblast cells of the placenta and fetal membranes. We suggest that in ovine pregnancy glucocorticoids directly increase fetal placental prostaglandin production, and indirectly increase prostaglandin production by maternal uterine tissues through the stimulation of placental estradiol synthesis. The events of ovine parturition are compared with those of human parturition. In the latter, we suggest similar direct effects of glucocorticoids on prostaglandin synthesis and metabolism in fetal membranes and similar indirect effects mediated by glucocorticoid-stimulated increases in intrauterine corticotropin-releasing hormone expression.     

Pattern of maternal circulating CRH in laboratory‐housed squirrel and owl monkeys

The anthropoid primate placenta appears to be unique in producing corticotropin‐releasing hormone (CRH). Placental CRH is involved in an endocrine circuit key to the production of estrogens during pregnancy. CRH induces cortisol production by the maternal and fetal adrenal glands, leading to further placental CRH production. CRH also stimulates the fetal adrenal glands to produce dehydroepiandrostendione sulfate (DHEAS), which the placenta converts into estrogens. There are at least two patterns of maternal circulating CRH across gestation among anthropoids. Monkeys examined to date (Papio and Callithrix) have an early‐to‐mid gestational peak of circulating CRH, followed by a steady decline to a plateau level, with a possible rise near parturition. In contrast, humans and great apes have an exponential rise in circulating CRH peaking at parturition. To further document and compare patterns of maternal circulating CRH in anthropoid primates, we collected monthly blood samples from 14 squirrel monkeys (Saimiri boliviensis) and ten owl monkeys (Aotus nancymaae) during pregnancy. CRH immunoreactivity was measured from extracted plasma by using solid‐phase radioimmunoassay. Both squirrel and owl monkeys displayed a mid‐gestational peak in circulating CRH: days 45–65 of the 152‐day gestation for squirrel monkeys (mean±SEM CRH=2,694±276 pg/ml) and days 60–80 of the 133‐day gestation for owl monkeys (9,871±974 pg/ml). In squirrel monkeys, circulating CRH declined to 36% of mean peak value by 2 weeks before parturition and then appeared to increase; the best model for circulating CRH over gestation in squirrel monkeys was a cubic function, similar to previous results for baboons and marmosets. In owl monkeys, circulating CRH appeared to reach plateau with no subsequent significant decline approaching parturition, although a cubic function was the best fit. This study provides additional evidence for a mid‐gestational peak of maternal circulating CRH in ancestral anthropoids that has been lost in the hominoid lineage. Am. J. Primatol. 72:1004–1012, 2010. © 2010 Wiley‐Liss, Inc.     

High and Low Protein∶ Carbohydrate Dietary Ratios during Gestation Alter Maternal-Fetal Cortisol Regulation in Pigs

Imbalanced maternal nutrition during gestation can cause alterations of the hypothalamic-pituitary-adrenal (HPA) system in offspring. The present study investigated the effects of maternal low- and high-protein diets during gestation in pigs on the maternal-fetal HPA regulation and expression of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), 11β-hydroxysteroid dehydrogenase 1 and 2 (11β-HSD1 and 11β-HSD2) and c-fos mRNAs in the placenta and fetal brain. Twenty-seven German Landrace sows were fed diets with high (HP, 30%), low (LP, 6.5%) or adequate (AP, 12.1%) protein levels made isoenergetic by varying the carbohydrate levels. On gestational day 94, fetuses were recovered under general anesthesia for the collection of blood, brain and placenta samples. The LP diet in sows increased salivary cortisol levels during gestation compared to the HP and AP sows and caused an increase of placental GR and c-fos mRNA expression. However, the diurnal rhythm of plasma cortisol was disturbed in both LP and HP sows. Total plasma cortisol concentrations in the umbilical cord vessels were elevated in fetuses from HP sows, whereas corticosteroid-binding globulin levels were decreased in LP fetuses. In the hypothalamus, LP fetuses displayed an enhanced mRNA expression of 11β-HSD1 and a reduced expression of c-fos. Additionally, the 11β-HSD2 mRNA expression was decreased in both LP and HP fetuses. The present results suggest that both low and high protein∶carbohydrate dietary ratios during gestation may alter the expression of genes encoding key determinants of glucocorticoid hormone action in the fetus with potential long-lasting consequences for stress adaptation and health.     

The corticotropin releasing hormone gene is expressed in human placenta

Maternal plasma immunoreactive corticotropin-releasing hormone (IR-CRH) increases progressively with pregnancy. This elevated plasma IR-CRH is presumably secreted by the placenta. To investigate further this hypothesis, we searched for the CRH mRNA and its peptide product in full term human placentae. Using a radiolabelled 48-mer oligonucleotide probe complementary to a portion of human CRH mRNA, we identified a 1300 nucleotide RNA from human placenta and rat hypothalami. We next examined the chromatographic characteristics of the placental IR-CRH. The bulk of the IR-CRH extracted from placenta and the IR-CRH secreted in vitro by placental fragments had the same chromatographic profiles as synthetic CRH. These findings indicate that the CRH gene is expressed in human placenta and imply that this organ is a site of CRH biosynthesis during pregnancy.     

Brief communication: Fecal androgen excretion and fetal sex effects during gestation in wild Assamese macaques (Macaca assamensis)

In placental mammals, pregnancy usually is associated with an increase in maternal androgens, which may significantly impact fetal growth and differentiation, and affect postnatal development and behavior. Owing to their slow life histories and challenging social conditions, determination of maternal androgens and potential interference effects of fetal androgen production are of particular interest in wild primates. However, androgen production has been rarely investigated in wild female primates, and studies on maternal androgens during gestation in particular often do not span the entire pregnancy. Here, we characterize fecal androgen production throughout gestation in wild Assamese macaques (Macaca assamensis) using noninvasive hormone analysis and, furthermore, examine fetal sex effects on maternal androgen excretion. A total of 207 fecal samples were analyzed from seven females for concentrations of immunoreactive epiandrosterone (iEA). Fecal iEA concentrations, as predicted based on cercopithecine blood-serum patterns, increased during early gestation and were significantly higher during the first trimester compared with preconception concentrations and those recorded during later stages of gestation. Further, during the third trimester, male-carrying mothers showed significantly higher iEA concentrations compared with female-carrying mothers. This first characterization of fecal androgen excretion during gestation in Assamese macaques indicates both a maternal and fetal effect on androgen production. Although our sample size is small, our results, nevertheless, provide the basis for assessing potential influences of maternal androgens on postnatal offspring development and behavior.     

Expression of the corticotropin-releasing hormone (CRH) gene in human placenta and amniotic membrane

Immunoreactive corticotropin-releasing hormone (IR-CRH) in maternal plasma increases progressively during pregnancy and decreases rapidly after delivery, suggesting that IR-CRH is produced in the placenta. We studied the expression of the CRH gene in developing human chorionic tissue, the amniotic membrane, the uterine myometrium and a fresh surgical specimen of hydatidiform mole by Northern blot analysis. Our results were as follows: (1) CRH mRNA was demonstrated in the placenta in the third trimester and at term, but under detectable level in the first and second trimesters. (2) CRH mRNA expression was observed in the amniotic membrane, but its expression in the myometrium in normal pregnancy was under detectable level at term. (3) CRH mRNA was also under detectable level in trophoblasts of a hydatidiform mole. These results suggest that the sources of the increased level of IR-CRH in human plasma and amniotic fluid during pregnancy are the placenta and amniotic membrane, and that gene expression of placental CRH increases during pregnancy.     

Steroid hormone metabolism by the chorioallantoic placenta of the mountain spiny lizard Sceloporus jarrovi as a possible mechanism for buffering maternal-fetal hormone exchange

The placenta provides a maternal-fetal exchange interface that maximizes the diffusion of gases, nutrients, and wastes. However, the placenta also may permit diffusion of lipid-soluble steroid hormones that influence processes such as sex-specific fetal development and maternal pregnancy maintenance. In mammals, placental steroid metabolism contributes to regulation of maternal and fetal hormone levels. Such mechanisms may be less highly developed in species that have recently evolved placentation, such as many reptiles. We therefore chose to investigate placental metabolism of steroids in the viviparous lizard Sceloporus jarrovi. In vitro tissue incubations tested the abilities of the chorioallantoic placenta to clear progesterone and corticosterone by converting them to other metabolites and to synthesize progesterone. Placental tissue rapidly cleared progesterone and corticosterone added to the incubation media, indicating that the tissue had converted the steroids to other products. Placental tissue also synthesized substantial concentrations of progesterone from the prohormone pregnenolone. Thus, even in a species with a simple, recently evolved placenta, steroid metabolism appears to be highly developed and could be critical for regulation of maternal and fetal hormone levels. This finding suggests that placental hormone metabolism may be critical to the successful evolution of placentation.     

Steroid hormones: their physiological role and diagnostic value during pregnancy

Steroid hormones play a key role in the beginning, development and termination of gestation. This reveiw is devoted for physiological effects of estrogens, progesterone, cortisole, ACTH, CRH in various pregnancy events: implantation, fetus development, maternal adaptation and birth initiation. Priority is fixed for estrogens--steroids that vastly increase maternal circulating blood value, induce progesterone action on uterus, regulate fetal "hypothalamic-pituitary-adrenocortical" axis, control free cortisole level in feminine blood. Diagnostic criterions of steroid hormone determination durijng pregnancy are presented. To day unconjugated estriol is the only steroid hormone that implicated in total pregnancy screening programs. Its concentration reduction has been noted in pregnancies with Dawn syndrome, some child enzyme defetcs, intrauterine growth retardation and fetal death incidents.     

Calcitriol affects hCG gene transcription in cultured human syncytiotrophoblasts

Background  

In pregnancy, maternal serum concentrations of calcitriol significantly rise as a result of increased renal and placental contribution in order to assure calcium supply for the developing fetus. Considering that placenta is a site for vitamin D activation, and the versatility and potency of calcitriol, it is feasible that this hormone participates in fetal/placental development and physiology. In the present work we studied calcitriol actions upon human chorionic gonadotropin (hCG) secretion and expression in cultured trophoblasts, as well as vitamin D receptor (VDR) and CYP27B1 immunolocalization in placental villi.     

Adrenocorticotrophin responses to hypoxaemia in fetal sheep are sustained in the presence of naloxone.

We have examined the effects of fetal hypoxaemia, produced by reducing the percent oxygen in maternal inspired air, on fetal plasma concentrations of corticotrophin releasing hormone (CRH), adrenocorticotrophin (ACTH) and cortisol and determined the effects of an opioid receptor antagonist, naloxone on these responses. Hypoxaemia (fetal PO2, 15-18 mmHg) for 60 min provoked a significant (P < 0.05) increase in fetal plasma ACTH and cortisol concentrations at days 125-130 of pregnancy, but did not affect circulating CRH. There was no effect of naloxone administered either intravenously (1.25 mg bolus followed by a 2.5 mg/h continuous infusion for one hour; fetal body weight approximately 2.5 Kg) or via the lateral cerebral ventricle (50 micrograms bolus followed by a 100 micrograms/h infusion for one hour) on this pattern of ACTH and cortisol change nor on the lack of CRH response to hypoxaemia. We conclude that the increase in fetal ACTH and cortisol in response to acute hypoxaemia is not accompanied by an increase in systemic CRH concentrations, nor is the response dependent on short-term opioid regulation.     

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.     

Human placenta metabolizes fatty acids: implications for fetal fatty acid oxidation disorders and maternal liver diseases

The role of fat metabolism during human pregnancy and in placental growth and function is poorly understood. Mitochondrial fatty acid oxidation disorders in an affected fetus are associated with maternal diseases of pregnancy, including preeclampsia, acute fatty liver of pregnancy, and the hemolysis, elevated liver enzymes, and low platelets syndrome called HELLP. We have investigated the developmental expression and activity of six fatty acid beta-oxidation enzymes at various gestational-age human placentas. Placental specimens exhibited abundant expression of all six enzymes, as assessed by immunohistochemical and immunoblot analyses, with greater staining in syncytiotrophoblasts compared with other placental cell types. beta-Oxidation enzyme activities in placental tissues were higher early in gestation and lower near term. Trophoblast cells in culture oxidized tritium-labeled palmitate and myristate in substantial amounts, indicating that the human placenta utilizes fatty acids as a significant metabolic fuel. Thus human placenta derives energy from fatty acid oxidation, providing a potential explanation for the association of fetal fatty acid oxidation disorders with maternal liver diseases in pregnancy.