Placental Corticotropin-releasing Hormone Research Articles

Placental corticotrophin-releasing hormone trajectories in pregnancy: Associations with postpartum depressive symptoms

ObjectiveDepressive symptoms following birth are common and can have adverse effects for mothers, children, and families. Changes in hypothalamic-pituitary-adrenal (HPA) axis regulation during pregnancy may be implicated in the development of postpartum depressive symptoms, particularly changes in placental corticotropinreleasing hormone (pCRH). However, few studies have tested how dynamic pCRH changes over pregnancy relate to postpartum depressive symptoms. This preregistered investigation tests associations of both pCRH levels and changes from early to late pregnancy with postpartum depressive symptoms. Methods: The sample consists of 173 women studied in early, mid, and late pregnancy who later reported on depressive symptoms with the Edinburgh Postpartum Depression Scale during interviews at 1, 6 and 12 months postpartum. Blood samples were collected at each prenatal timepoint and assayed for pCRH using radioimmunoassay. Latent growth curve analysis was employed to identify distinct trajectories of pCRH during pregnancy.Results: We identified three prenatal pCRH trajectories labeled as typical, flat, and accelerated. Each trajectory showed exponential increases in pCRH levels over the course of gestation but differed in overall levels and rates of change. pCRH levels were not associated with postpartum depressive symptoms. However, women with accelerated pCRH trajectories reported marginally higher depressive symptoms one month postpartum. Primary analysis models adjusted for marital status, income, prepregnancy BMI, parity, prenatal depressive symptoms, and gestational age.Conclusions: These findings add to our understanding of dynamic changes to maternal HPA axis regulation during pregnancy and contribute to growing evidence on how pCRH changes relate to the development of postpartum depressive symptoms

Sex-specific associations between placental corticotropin releasing hormone and problem behaviors in childhood

Placental corticotropin-releasing hormone (pCRH) is a neuroactive peptide produced in high concentrations in mid-late pregnancy, during key periods of fetal brain development. Some evidence suggests that higher pCRH exposure during gestation is associated with adverse neurodevelopment, particularly in female offspring. In 858 mother-child dyads from the sociodemographically diverse CANDLE cohort (Memphis, TN), we examined: (1) the slope of pCRH rise in mid-late pregnancy and (2) estimated pCRH at delivery as a measure of cumulative prenatal exposure. When children were 4 years-old, mothers reported on problem behaviors using the Child Behavior Checklist (CBCL) and cognitive performance was assessed by trained psychologists using the Stanford-Binet Intelligence Scales. We fitted linear regression models examining pCRH in relation to behavioral and cognitive performance measures, adjusting for covariates. Using interaction models, we evaluated whether associations differed by fetal sex, breastfeeding, and postnatal neighborhood opportunity. In the full cohort, log-transformed pCRH measures were not associated with outcomes; however, we observed sex differences in some models (interaction p-values≤0.01). In male offspring, an interquartile (IQR) increase in pCRH slope (but not estimated pCRH at delivery), was positively associated with raw Total (β=3.06, 95%CI: 0.40, 5.72), Internalizing (β=0.89, 95%CI: 0.03, 1.76), and Externalizing (β=1.25, 95%CI: 0.27, 2.22) Problem scores, whereas, in females, all associations were negative (Total Problems: β=−1.99, 95%CI: −3.89, −0.09; Internalizing: β=−0.82, 95%CI: −1.42, −0.23; Externalizing: β=−0.56, 95%CI: −1.34, 0.22). No associations with cognitive performance were observed nor did we observe moderation by breastfeeding or postnatal neighborhood opportunity. Our results provide further evidence that prenatal pCRH exposure may impact subsequent child behavior in sex-specific ways, however in contrast to prior studies suggesting adverse impacts in females, steeper mid-gestation pCRH rise was associated with more problem behaviors in males, but fewer in females.

Stress-responsive Psychobiological Markers During Pregnancy and Fetal and Infant Outcomes Across Countries

The prenatal period is a sensitive window of development that is open to both opportunity and risk for predicting later developmental outcomes. There are multiple stress-responsive physiological systems during pregnancy that may mediate the link between stress exposure and physical and mental health. Alterations in these systems during gestation due to elevated stress exposure can lead to poorer health in both the gestational parent and the offspring. In this symposium, we examine stress-responsive psychobiological systems during pregnancy and their association with differential developmental outcomes during gestation, at birth, and in infancy by a multinational group of researchers. The first presentation by the symposium chair, Özlü Aran (University of Denver, USA), will focus on the trajectories of placental corticotropin-releasing hormone (pCRH), a stress-responsive hormone released by placenta, and their association with birth outcomes as well as infant socioemotional development at 6 months postpartum. In the second presentation, Dr. Elif Aysimi Duman (Boğaziçi University, Turkey) will highlight intergenerational associations of parental early life stress and gestational parent prenatal cortisol awakening response with infant development at 4 months postpartum. This study underscores psychosocial risk (i.e., pregnancy-related worries) and protective factors (i.e., fetal bonding) in addition to prenatal HPA activity during gestation. In the third presentation, Dr. Sameera Abuaish (Princess Nourah bint Abdulrahman University, Saudi Arabia) will extend research findings beyond HPA axis by demonstrating the association between gestational parent body mass index (BMI) and prenatal mood and immune functioning, while also linking BMI to both fetal and infant outcomes. Consistent with the ISPNE’s 2023 symposium translational psychoneuroendocrinology themes, these presentations apply basic scientific methods to understand better health outcomes for gestational parents and their offspring with a focus on stress-responsive physiological systems during pregnancy. Together, they underscore the importance of early life stressors as well as prenatal stressors and their potential impact over generations among individuals across countries and cultures. Finally, these presentations will be discussed by a leading investigator, Dr. Jenalee Doom (University of Denver, USA), who has expertise on early life stress and the biological embedding of early experiences across development with a special focus on mental and physical health.

Human placenta releases extracellular vesicles carrying corticotrophin releasing hormone mRNA into the maternal blood

The human placenta releases diverse extracellular vesicles (EVs), including microvesicles (100–1000 nm) and exosomes (30–150 nm), into the maternal blood for feto-maternal communication. Exosomes and microvesicles contribute to normal pregnancy physiology and major pregnancy pathologies. Differences in miRNA expressions and protein content in placental exosomes have been reported in complicated pregnancies. During human pregnancy, Corticotropin-Releasing Hormone (CRH) is produced and released by the placenta into the maternal blood. CRH is involved in regulating gestational length and the initiation of labour. CRH mRNA levels in the maternal plasma rise with gestation. High levels of CRH mRNA are reported to be associated with preeclamptic and preterm pregnancies. However, the underlying mechanism of placental CRH mRNA secretion remains to be elucidated. We hypothesise that the placenta releases CRH mRNA packaged within extracellular vesicles (EVs) into the maternal blood. In this study, placental EVs (microvesicles and exosomes) were isolated from human term healthy placentas via villus washes and from explant culture media by differential centrifugation and purified by density gradient ultracentrifugation using a continuous sucrose gradient (0.25–2.5 M). Western blotting using placenta- and exosome-specific markers and electron microscopy confirmed exosomes and microvesicles in the placental wash and explant media samples. Real-time quantitative RT-PCR data detected CRH mRNA in placenta-derived EVs from placental washes and explants. We also sorted placenta-secreted EVs in maternal plasma samples (≥37 weeks) by high-resolution flow cytometry using a fluorescent-labelled PLAP antibody. CRH mRNA was demonstrated in placental EVs obtained from maternal blood plasma. We therefore show that human placental EVs carry CRH mRNA into the maternal blood. Our study implies that measuring CRH mRNA in placental EVs in the maternal plasma could beused for monitoring pregnancy.

Testing the Benefits of Reducing Prenatal Maternal Depression for Maternal and Infant outcomes: A randomized controlled trial

Depression is one of the most common prenatal complications affecting 13 to 40 percent of pregnant individuals. Prenatal depression has far-reaching implications for both the mother and for the next generation, including premature birth, dysregulation of stress physiology, developmental delays, and vulnerability to psychopathology. Despite this clear need, there is a dearth of available and efficacious prenatal interventions. Further, few studies have evaluated physiological pathways by which reducing maternal depression may benefit the fetus. The Care Project uses a randomized controlled trial design (RCT) to test a culturally sensitive psychotherapy intervention (brief interpersonal therapy) designed for pregnant individuals (MomCare). Effects of the intervention on both psychological well-being and neurobiological processes will be assessed. This RCT included 234 pregnant participants [119 enhanced usual care (EUC) and 115 active treatment (MomCare)]. Depression symptoms were assessed at baseline and throughout gestation; Symptom Checklist-20. Prenatal maternal cortisol and placental corticotropin releasing hormone and infant brain and behavioral markers also were assessed. Analyses were conducted using an intent to treat design by a biostatistician blind to group condition. Employing hierarchical linear modeling, analyses revealed a significantly faster rate of decrease in depression symptoms over pregnancy between the MomCare (8.9 pts) and EUC (3.1 pts) groups, t(229)=3.77, p=.0002; medium effect size (D=0.50, 95%CI 0.16-0.84). The prenatal intervention, MomCare, resulted in a meaningful reduction in prenatal maternal depression symptoms. Next steps include testing the hypothesis that reducing maternal prenatal depression will influence both prenatal biological pathways and infant neurodevelopment assessed through age 4.

Corticotropin releasing hormone is present in the feline placenta and maternal serum.

In women, placental corticotropin releasing hormone (CRH) can be detected in maternal blood throughout pregnancy and is important in the regulation of the timing of parturition. However, its role in other mammalian species is unclear. In fact, very little is known about the presence and localization of CRH in placentas other than human. In this study we report for the first time the presence of CRH in feline placenta and maternal serum. Presence of CRH mRNA and protein was assessed using RT-PCR and Western blot, respectively, in at term domestic cat placentas opportunistically obtained at a local animal shelter and spay clinic. In addition, CRH localization within the placenta was demonstrated via immunohistochemistry. Finally, presence of CRH in maternal blood from early (¾21 days) and mid (25-35 days) stages of pregnancy was investigated by ELISA. CRH mRNA and protein were detected in feline placentas, and localized to larger decidual cells and fetal trophoblast cells, including the binucleate cells. CRH was detectable in maternal blood collected from early-stage pregnancies, and amounts significantly increased in mid-gestation samples. This is the first report on the presence and localization of CRH in the feline placenta, and its increase in maternal serum during the first half of pregnancy. These data lay the foundation for future studies to determine if CRH can be used as potential novel marker for early pregnancy diagnosis, determination, and monitoring in felids, and could greatly increase efficiency and success in zoo breeding programs utilizing artificial reproductive technologies for endangered feline species.

Prenatal polycyclic aromatic hydrocarbon (PAH) exposure in relation to placental corticotropin releasing hormone (pCRH) in the CANDLE pregnancy cohort.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous endocrine-disrupting combustion by-products that have been linked to preterm birth. One possible mechanism is through disruption of placental corticotropin releasing hormone (pCRH), a key hormone implicated in parturition. As an extension of recent research identifying pCRH as a potential target of endocrine disruption, we examined maternal PAH exposure in relation to pCRH in a large, diverse sample. Participants, drawn from the CANDLE cohort, part of the ECHO-PATHWAYS Consortium, completed study visits at 16-29 weeks (V1) and 22-39 weeks (V2) gestation (n=812). Seven urinary mono-hydroxylated PAH metabolites (OH-PAHs) were measured at V1 and serum pCRH at V1 and V2. Associations between individual log-transformed OH-PAHs (as well as two summed PAH measures) and log(pCRH) concentrations across visits were estimated using mixed effects models. Minimally-adjusted models included gestational age and urinary specific gravity, while fully-adjusted models also included sociodemographic characteristics. We additionally evaluated effect modification by pregnancy complications, fetal sex, and maternal childhood trauma history. We observed associations between 2-OH-Phenanthrene (2-OH-PHEN) and rate of pCRH change that persisted in fully adjusted models (β=0.0009, 0.00006, 0.0017), however, positive associations with other metabolites (most notably 3-OH-Phenanthrene and 1-Hydroxypyrene) were attenuated after adjustment for sociodemographic characteristics. Associations tended to be stronger at V1 compared to V2 and we observed no evidence of effect modification by pregnancy complications, fetal sex, or maternal childhood trauma history. In conclusion, we observed modest evidence of association between OH-PAHs, most notably 2-OH-PHEN, and pCRH in this sample. Additional research using serial measures of PAH exposure is warranted, as is investigation of alternative mechanisms that may link PAHs and timing of birth, such as inflammatory, epigenetic, or oxidative stress pathways.

Cohort profile: the ECHO prenatal and early childhood pathways to health consortium (ECHO-PATHWAYS)

PurposeExposures early in life, beginning in utero, have long-term impacts on mental and physical health. The ECHO prenatal and early childhood pathways to health consortium (ECHO-PATHWAYS) was established to examine...

Prenatal polycyclic aromatic hydrocarbon (PAH) exposure in relation to placental corticotropin releasing hormone (pCRH) in a sociodemographically diverse U.S. cohort

Prenatal polycyclic aromatic hydrocarbon (PAH) exposure in relation to placental corticotropin releasing hormone (pCRH) in a sociodemographically diverse U.S. cohort

Increases in maternal depressive symptoms during pregnancy and infant cortisol reactivity: Mediation by placental corticotropin-releasing hormone.

Maternal depressive symptoms in pregnancy may affect offspring health through prenatal programming of the hypothalamic-pituitary-adrenal (HPA) axis. The biological mechanisms that explain the associations between maternal prenatal depressive symptoms and offspring HPA axis regulation are not yet clear. This pre-registered investigation examines whether patterns of maternal depressive symptoms in pregnancy are associated with infant cortisol reactivity and whether this association is mediated by changes in placental corticotropin-releasing hormone (pCRH). A sample of 174 pregnant women completed assessments in early, mid, and late pregnancy that included standardized measures of depressive symptoms and blood samples for pCRH. Infant cortisol reactivity was assessed at 1 and 6 months of age. Greater increases in maternal depressive symptoms in pregnancy were associated with higher cortisol infant cortisol reactivity at 1 and 6 months. Greater increases in maternal depressive symptoms in pregnancy were associated with greater increases in pCRH from early to late pregnancy which in turn were associated with higher infant cortisol reactivity. Increases in maternal depressive symptoms and pCRH over pregnancy may contribute to higher infant cortisol reactivity. These findings help to elucidate the prenatal biopsychosocial processes contributing to offspring HPA axis regulation early in development.

Pregnancy anxiety, placental corticotropin-releasing hormone and length of gestation

ObjectiveHigh pregnancy anxiety is a consistent predictor of earlier labor and delivery. Placental corticotropin-releasing hormone (pCRH) predicts earlier delivery consistently and it has been identified as a biological mediator of the association between pregnancy anxiety and gestational length. However, studies have not examined whether changes in pregnancy anxiety are associated with earlier birth as mediated by changes in pCRH during pregnancy. Accordingly, this study tests whether linear changes in pregnancy anxiety are associated with length of gestation indirectly through nonlinear increases in pCRH over pregnancy. MethodsA sample of pregnant women (n=233) completed prenatal assessments in early pregnancy, second trimester, and third trimester that included a 4-item assessment of pregnancy anxiety and collection of blood samples assayed for pCRH using radioimmunoassay. Length of gestation was abstracted from medical records after birth. ResultsIncreases in pregnancy anxiety from early pregnancy to third trimester predicted shorted length of gestation, as did nonlinear increases in pCRH over pregnancy. However, there was no evidence of an indirect effect of changes in pregnancy anxiety on length of gestation via changes in pCRH. ConclusionsThese results indicate that linear changes in pregnancy anxiety and nonlinear changes in pCRH during pregnancy are independent risk factors for shortened gestational length. This study adds to a small but growing body of work on biopsychological processes in pregnancy and length of gestation. Modeling changes in psychological and biological processes during pregnancy could provide more insight into understanding risk for adverse pregnancy outcomes.

Prenatal phthalate exposure in relation to placental corticotropin releasing hormone (pCRH) in the CANDLE cohort.

Phthalates may disrupt maternal-fetal-placental endocrine pathways, affecting pregnancy outcomes and child development. Placental corticotropin releasing hormone (pCRH) is critical for healthy pregnancy and child development, but understudied as a target of endocrine disruption. To examine phthalate metabolite concentrations (as mixtures and individually) in relation to pCRH. Secondary data analysis from a prospective cohort study. Prenatal clinics in Tennessee, USA. 1018 pregnant women (61.4% non-Hispanic Black, 32% non-Hispanic White, 6.6% other) participated in the CANDLE study and provided data. Inclusion criteria included: low-medical-risk singleton pregnancy, age 16-40, and gestational weeks 16-29. None. Plasma pCRH at two visits (mean gestational ages 23.0 and 31.8weeks) and change in pCRH between visits (ΔpCRH). In weighted quantile sums (WQS) regression models, phthalate mixtures were associated with higher pCRH at Visit 1 (β=0.07, 95%CI: 0.02, 0.11) but lower pCRH at Visit 2 (β=-0.08, 95%CI: -0.14, -0.02). In stratified analyses, among women with gestational diabetes (n=59), phthalate mixtures were associated with lower pCRH at Visit 1 (β=-0.17, 95%CI: -0.35, 0.0006) and Visit 2 (β=-0.35, 95%CI: -0.50, -0.19), as well as greater ΔpCRH (β=0.16, 95%CI: 0.07, 0.25). Among women with gestational hypertension (n=102), phthalate mixtures were associated with higher pCRH at Visit 1 (β=0.20, 95%CI: 0.03, 0.36) and Visit 2 (β=0.42; 95%CI: 0.19, 0.64) and lower ΔpCRH (β=-0.17, 95%CI: -0.29, -0.06). Significant interactions between individual phthalate metabolites and pregnancy complications were observed. Phthalates may impact placental CRH secretion, with differing effects across pregnancy. Differences in results between women with and without gestational diabetes and gestational hypertension suggest a need for further research examining whether women with pregnancy complications may be more vulnerable to endocrine-disrupting effects of phthalates.

A COMPARATIVE STUDY OF FETAL ADRENAL GLAND BIOMETRY AND CERVICAL LENGTH AS A PREDICTOR OF PRETERM BIRTH

Background: Preterm birth is an important challenge in obstetrics and contemporary perinatology in India. Timely recognition, intervention and appropriate management is integral in curbing the upsurge in its incidence and consequent poor perinatal outcome. This study was conducted taking into account the potential mechanism of preterm labor: premature activation of the placental-adrenal endocrine axis wherein elevation of maternal cortisol leads to an increased production of placental corticotrophin releasing hormone which causes an increase in dehydroepiandrosterone produced by the fetal zone of the adrenal gland and its enlargement. This activates a cascade leading to early loss of uterine quiescence, consequently causing cervical modelling, ripening and preterm birth.
 Aim and Objectives: To assess fetal adrenal gland volume, fetal zone enlargement and cervical length on ultrasound and compare their efficacy in the prediction of preterm birth. 
 Methods: This was a hospital based prospective study in which pregnant women with an uncomplicated live singleton pregnancy between 28 to 34 weeks of gestation were subjected to obstetric ultrasonography wherein fetal adrenal gland volume, fetal zone enlargement and cervical length was measured. They were then followed up until their delivery, whether term or preterm and its correlation with fetal adrenal gland parameters and cervical length was assessed. 
 Result: Corrected fetal adrenal gland volume showed the highest sensitivity of 90.0% and a specificity of 96.7% with a cut off value of 632.50 mm3/kg while fetal zone enlargement showed a sensitivity and specificity of 72.7% and 60.9% respectively. Cervical length was found to be the least important marker for predicting the preterm birth as having the least AUC as 0.209, sensitivity as 36.4 % and specificity as 76.1%.
 Conclusion: This study concludes that fetal adrenal gland biometry can be used as a noninvasive, cost effective and potential new marker for the prediction of preterm birth and is a better predictor than cervical length.
 Keywords: Preterm, Cervical length, Adrenal biometry.

FETAL ADRENAL GLAND BIOMETRY: A POTENTIAL PREDICTOR OF PRETERM BIRTH

Background: Preterm birth is an important challenge in obstetrics and contemporary perinatology in India. Timely recognition, intervention and appropriate management is integral in curbing the upsurge in its incidence and consequent poor perinatal outcome. This study was conducted taking into account the potential mechanism of preterm labor: premature activation of the placental-adrenal endocrine axis wherein elevation of maternal cortisol leads to an increased production of placental corticotrophin releasing hormone which causes an increase in dehydroepiandrosterone produced by the fetal zone of the adrenal gland and its enlargement. This activates a cascade leading to early loss of uterine quiescence, consequently causing cervical modelling, ripening and preterm birth.
 Aim and Objectives: To assess fetal adrenal gland volume and fetal zone enlargement on ultrasound and evaluate its efficacy in the prediction of preterm birth. 
 Methods: This was a hospital based prospective study in which pregnant women with an uncomplicated live singleton pregnancy between 28 to 34 weeks of gestation were subjected to obstetric ultrasonography wherein fetal adrenal gland volume and fetal zone enlargement was measured. They were then followed up until their delivery, whether term or preterm and its correlation with fetal adrenal gland parameters was assessed. 
 Result: Corrected fetal adrenal gland volume showed the highest sensitivity of 90.0% and a specificity of 96.7% with a cut off value of 632.50 mm3/kg while fetal zone enlargement showed a sensitivity and specificity of 72.7% and 60.9% respectively. 
 Conclusion: This study concludes that fetal adrenal gland biometry can be used as a noninvasive, cost effective and potential new marker for the prediction of preterm birth.

Prenatal phthalate exposure in relation to placental corticotropin releasing hormone (pCRH) concentrations in the CANDLE study

BACKGROUND AND AIM: Studies suggest that prenatal phthalate exposure may contribute to preterm birth. Placental corticotropin releasing hormone (pCRH) may be a “placental clock” whereby levels rise in late pregnancy, triggering parturition. To explore a possible mechanism linking phthalates to preterm birth, the ECHO-PATHWAYS Consortium examined associations between phthalate exposure and pCRH concentrations in mid-late pregnancy. METHODS: We measured urinary phthalate metabolites and serum pCRH in the 2nd(T2: mean 23.0 weeks) and 3rd(T3: mean 31.8 weeks) trimesters in CANDLE study participants (n=1018). We fit covariate adjusted models associating log(pCRH) (at each timepoint) with 15 log-transformed phthalate metabolites and Σdi(2-ethylhexyl)phthalate(ΣDEHP), in individual regression models and as mixtures using weighted quantile sums (WQS) regression. We evaluated effect modification by gestational diabetes (GDM) and gestational hypertension (GHTN). RESULTS:Median pCRH was 37.6±75.0 and 235.2±429.0 pg/mL in T2 and T3, respectively. In WQS models, phthalate mixtures were not associated with CRH at either timepoint. Monobutyl phthalate was associated with higher T2 pCRH (β=0.07, 95%CI:0.004, 0.13). Monoethyl phthalate was associated with lower pCRH at both visits, while monomethyl phthalate was associated with higher T3 pCRH (β=0.04, 95%CI:0.01, 0.08). In interaction models, positive associations were observed between each phthalate metabolite and T3 pCRH among women with GHTN (n=102), whereas each association was negative for women without GHTN (p0.05 for interaction in 9 of 15 models). By contrast, among women with GDM (n=59), most individual phthalate metabolites were associated with lower pCRH at T3, with associations being strongest for the DEHP metabolites. CONCLUSIONS:In the whole cohort, we observed few associations between phthalate metabolites and CRH. However associations between phthalate exposure and pCRH in late pregnancy may differ among women with or without GDM or GHTN. More research is needed to understand whether women with pregnancy complications may be more vulnerable to reproductive effects of phthalates. KEYWORDS: phthalates, pregnancy, CRH, preterm birth, pregnancy complications, endocrine disruption

Placental CRH as a Signal of Pregnancy Adversity and Impact on Fetal Neurodevelopment.

Early life is a period of considerable plasticity and vulnerability and insults during that period can disrupt the homeostatic equilibrium of the developing organism, resulting in adverse developmental programming and enhanced susceptibility to disease. Fetal exposure to prenatal stress can impede optimum brain development and deranged mother’s hypothalamic–pituitary–adrenal axis (HPA axis) stress responses can alter the neurodevelopmental trajectories of the offspring. Corticotropin-releasing hormone (CRH) and glucocorticoids, regulate fetal neurogenesis and while CRH exerts neuroprotective actions, increased levels of stress hormones have been associated with fetal brain structural alterations such as reduced cortical volume, impoverishment of neuronal density in the limbic brain areas and alterations in neuronal circuitry, synaptic plasticity, neurotransmission and G-protein coupled receptor (GPCR) signalling. Emerging evidence highlight the role of epigenetic changes in fetal brain programming, as stress-induced methylation of genes encoding molecules that are implicated in HPA axis and major neurodevelopmental processes. These serve as molecular memories and have been associated with long term modifications of the offspring’s stress regulatory system and increased susceptibility to psychosomatic disorders later in life. This review summarises our current understanding on the roles of CRH and other mediators of stress responses on fetal neurodevelopment.

Placental Corticotrophin-Releasing Hormone is a Modulator of Fetal Liver Blood Perfusion.

Variation in fetal liver blood flow influences fetal growth and postnatal body composition. Placental corticotrophin-releasing hormone has been implicated as a key mediator of placental-fetal perfusion. To determine whether circulating levels of placental corticotrophin-releasing hormone across gestation are associated with variations in fetal liver blood flow. Prospective cohort study. Fetal ultrasonography was performed at 30 weeks' gestation to characterize fetal liver blood flow (quantified by subtracting ductus venosus flow from umbilical vein flow). Placental corticotrophin-releasing hormone was measured in maternal circulation at approximately 12, 20, and 30 weeks' gestation. Multiple regression analysis was used to determine the proportion of variation in fetal liver blood flow explained by placental corticotrophin-releasing hormone. Covariates included maternal age, parity, pre-pregnancy body mass index, gestational weight gain, and fetal sex. A total of 79 uncomplicated singleton pregnancies were analyzed. Fetal liver blood flow was 68.4 ± 36.0 mL/min (mean ± SD). Placental corticotrophin-releasing hormone concentrations at 12, 20, and 30 weeks were 12.5 ± 8.1, 35.7 ± 24.5, and 247.9 ± 167.8 pg/mL, respectively. Placental corticotrophin-releasing hormone at 30 weeks, but not at 12 and 20 weeks, was significantly and positively associated with fetal liver blood flow at 30 weeks (r = 0.319; P = 0.004) and explained 10.4% of the variance in fetal liver blood flow. Placental corticotrophin-releasing hormone in late gestation is a possible modulator of fetal liver blood flow and may constitute a biochemical marker in clinical investigations of fetal growth and body composition.

Maternal exposure to childhood traumatic events, but not multi-domain psychosocial stressors, predict placental corticotrophin releasing hormone across pregnancy.

Maternal psychosocial stress increases the risk of adverse birth and postnatal outcomes for the mother and child, but the role of maternal exposure to childhood traumatic events (CTE) and multi-domain psychosocial stressors for the level and rise of placental Corticotrophin-Releasing Hormone (pCRH) across pregnancy has been understudied. In a sociodemographically and racially diverse sample of 1303 women (64% Black, 36% White/others) with low-medical risk pregnancies at enrollment from Shelby County, Tennessee, USA, blood samples were drawn twice, corresponding roughly to second and third trimester, and extracted prior to conducting radioimmune assays for pCRH. Mothers reported CTE (physical abuse, sexual abuse, or family violence, in childhood), adulthood traumatic events, and interpersonal violence during pregnancy. Neighborhood crime/deprivation was derived using geospatially-linked objective databases. General linear and mixed models tested associations between stress exposure variables and pCRH levels and rate of rise, adjusting for obstetric/clinical/health related factors. Maternal CTE did not predict pCRH levels at time 1, but positively predicted levels at time 2, and the rate of rise in pCRH across pregnancy. Race did not moderate this association. No additional maternal stress exposures across adulthood or during pregnancy predicted pCRH outcomes. Findings indicate that childhood violence or abuse exposure can become biologically embedded in a manner predicting later prenatal physiology relevant for maternal and offspring health, and that such embedding may be specific to childhood, but not adulthood, stress. Findings also highlight the placental-fetal unit as a mechanistic pathway through which intergenerational transmission of the adverse effects of childhood adversities may occur.

Influence of labor on direct and indirect determinants of placental 11beta-hydroxysteroid dehydrogenase activity

PurposeLabor is a complex process involving multiple para-, auto- and endocrine cascades. The interaction of cortisol, corticotropin-releasing hormone (CRH) and progesterone is essential. The action of cortisol on the human feto-placental unit is regulated by 11beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2/HSD11B2) that converts cortisol into inactive cortisone. The majority of studies on the assessment of placental 11β-HSD2 function determined indirect activity parameters. It remains elusive if indirect measurements correlate with enzymatic function and if these parameters are affected by potential confounders (e.g., mode of delivery). Thus, we compared determinants of indirect 11β-HSD2 tissue activity with its direct enzymatic turnover rate in placental samples from spontaneous births and cesarean (C)-sections.MethodsUsing LC–MS/MS, we determined CRH, cortisol, cortisone, progesterone and 17-hydroxy(OH)-progesterone in human term placentas (spontaneous birth vs. C-section, n = 5 each) and measured the enzymatic glucocorticoid conversion rates in placental microsomes. Expression of HSD11B1, 2 and CRH was determined via qRT-PCR in the same samples.ResultsCortisol–cortisone ratio correlated with direct microsomal enzymatic turnover. While this observation seemed independent of sampling site, a strong influence of mode of delivery on tissue steroids was observed. The mRNA expression of HSD11B2 correlated with indirect and direct cortisol turnover rates in C-section placentas only. In contrast to C-sections, CRH, cortisol and cortisone levels were significantly increased in placental samples following spontaneous birth.ConclusionLabor involves a series of complex hormonal processes including activation of placental CRH and glucocorticoid metabolism. This has to be taken into account when selecting human cohorts for comparative analysis of placental steroids.

Inhibition of expression of glucocorticoids receptors may contribute to postpartum depression

Although postpartum depression (PPD) is the leading cause of disability worldwide, its molecular mechanisms are poorly understood. Recent evidence has suggested that impaired glucocorticoid receptor (GR), the signaling of key molecules of the HPA axis, plays a key role in the behavioral and neuroendorcrine alterations of major depression. However, the role of GR in postpartum period, which following with the abrupt withdrawal of placental corticotropin releasing hormone (CRH) and resulting in a re-equilibration of the maternal HPA axis in the days of post-delivery, is still not entirely clear. Previously, a hormone-simulated pregnancy (HSP), and the subsequent ‘postpartum’ withdrawal in estrogen has been employed to mimic the fluctuations in estradiol associated with pregnancy and postpartum. Using the HSP model, we investigated here the effect of ‘postpartum’ withdrawal in estrogen as well as depression- and anxiety-like behavior by intra-hippocampal infusion with GR inhibitor-RU486. Following the successful acquisition of PPD model by withdrawal in estrogen, reduced GR expression was observed in hippocampus. Further, HSP-rats suffered intra-hippocampal RU486 infusion presented depression- and anxiety-like behavior as postpartum depression. Together, these results suggest an important, though complex, role for GR in the behavioral regulation of postpartum depression.