R. L. Schild

Microarray analysis of placental tissue in intrauterine growth restriction

Objective  Besides foetal or maternal disorders, placental dysfunction is a major cause of intrauterine growth restriction (IUGR). Although numerous macro‐ and histopathological changes have been described, little is known about the precise aetiology and the contribution of foetal/placental genes in this disorder.

Thyroid-stimulating hormone is associated with insulin resistance independently of body mass index and age in women with polycystic ovary syndrome

BACKGROUND The aim of this study was to evaluate the association between thyroid function, reflected by thyroid-stimulating hormone (TSH) levels, and insulin resistance (IR) in 337 women suffering from polycystic ovary syndrome (PCOS). METHODS Clinical, metabolic and endocrine parameters were obtained and an oral glucose tolerance test was performed, with calculation of IR indices. The association between thyroid function and IR was evaluated with classification analysis using logistic regression and 10-fold cross-validation to identify a possible TSH threshold for IR. Parameters were then compared between women above and below the TSH threshold using two-sample tests. One-way analyses of covariance were performed to explore whether the impact of TSH on IR is independent of other variables. RESULTS A TSH cut-off value around 2 mIU/l had the best sensitivity and specificity for identifying women with IR. Women with TSH >or= 2 mIU/l were younger, had a higher body mass index (BMI) and were more insulin-resistant compared with women with TSH < 2 mIU/l. This effect of TSH on IR was independent of age and BMI. CONCLUSIONS In women with PCOS, a significant association between thyroid function, as reflected by TSH >or= 2 mIU/l, and IR was found and the association appeared to be independent of age and BMI.

Weight estimation by three‐dimensional ultrasound imaging in the small fetus

To improve birth weight estimation in fetuses weighing ⩽ 1600 g at birth by deriving a new formula including measurements obtained using three‐dimensional (3D) sonography.

Regulation of the human endogenous retroviral Syncytin-1 and cell-cell fusion by the nuclear hormone receptors PPARγ/RXRα in placentogenesis.

Cytotrophoblast (CT) cell fusion into a syncytiotrophoblast is obligatory for placentation and mediated by the human endogenous retrovirus (HERV)‐W envelope gene Syncytin‐1. Abnormal placentation is associated with preeclampsia (PE), HELLP and intrauterine growth restriction (IUGR). In placentogenesis, the MAP‐kinase p38α regulates PPARγ/RXRα signaling and target genes, like leptin, resistin, ABCG2, and hCG. The aim of this study was to analyze PPARγ/RXRα signaling and target gene regulation using primary CT cultures, the trophoblastic cell line BeWo and placental tissues from patients with normal and abnormal placentation. CT from four different human control placentae and BeWo cells demonstrated that Syncytin‐1, other signaling members and CT cell fusions were regulated with PPARγ/RXRα activators troglitazone and 9‐cis retinoic acid, via protein kinase A and p38α inhibition. Significant discordant regulations between CTs and BeWo were found. Two PPARγ/RXRα‐response‐elements from upstream regulatory elements and the 5′LTR of HERV‐W were confirmed with DNA‐protein binding assays using nuclear extracts and recombinant PPARγ/RXRα proteins. These promoter elements were validated with luciferase assays in the presence of PPARγ/RXRα modulators. Furthermore, troglitazone or 9‐cis retinoic acid treatment of siRNA‐PPARγ and siRNA‐RXRα transfected BeWo cells proved the requirement of these proteins for Syncytin‐1 regulation. Thirty primary abnormal placentae from PE, HELLP and IUGR patients compared to 10 controls showed significant deregulation of leptin RNA and protein, p38α, phospho‐p38α, PPARγ, ABCG2, INSL4 and Syncytin‐1. Our study characterized PPARγ/RXRα signaling in human CT and cell fusions identifying Syncytin‐1 as a new target gene. Based on these results, a disturbed PPARγ/RXRα pathway could contribute to pathological human pregnancies. J. Cell. Biochem. 113: 2383–2396, 2012.

Macrosomia: a new formula for optimized fetal weight estimation

To develop and test a specific formula for estimating weight in the macrosomic fetus.

Intrauterine growth restriction (IUGR) is associated with increased leptin synthesis and binding capability in neonates.

Objective  Animal studies suggest pathological foetal programming of hypothalamic circuits regulating food intake in the setting of leptin deficiency and intrauterine growth restriction (IUGR). We aimed to compare placental leptin synthesis and leptin‐binding capability in venous cord blood between IUGR newborns and neonates born appropriate for gestational age (AGA).

Specific weight formula for fetuses with abdominal wall defects

To develop and to evaluate a specific sonographic weight formula for fetuses with abdominal wall defects.

Placental 11β-HSD2 Gene Expression at Birth Is Inversely Correlated With Growth Velocity in the First Year of Life After Intrauterine Growth Restriction

Intrauterine growth restriction (IUGR) is associated with an increased risk for short stature and diseases in adulthood thought to be inflicted by fetal programming. We hypothesized that placental endocrine systems involved in perinatal growth might also play a role in postnatal growth after IUGR. In a prospective controlled multicenter study, placental gene expression of IGF-binding protein-1 (IGFBP-1), leptin and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) were measured in 14 IUGR infants and 15 children born appropriate for gestational age (AGA) proven by serial ultrasound examinations. Postnatally, IUGR infants experienced a significantly higher growth velocity than AGA neonates (at 1 y: p = 0.001). Gene expression of 11β-HSD2 at birth correlated positively with birth length (r = 0.55, p = 0.04) and inversely with growth velocity in the first year of life (r = −0.69, p = 0.01) in the IUGR, but not in the AGA group. There was no correlation between gene expression of placental IGFBP-1, leptin and birth weight, length and growth velocity during the first year of life. AGA infants showed significantly higher concentrations of cortisone in venous cord blood after birth (p = 0.02) as a surrogate of a higher 11β-HSD2 activity in the fetoplacental unit. In conclusion, placental 11β-HSD2 gene expression might predict postnatal growth in IUGR.

Increased uterine arterial pressure and contractility of perfused swine uterus after treatment with serum from pre-eclamptic women and endothelin-1

The present study was designed to examine the effects of ET-1 (endothelin-1) and serum from PE (pre-eclamptic), HP (healthy pregnant) and HNP (healthy non-pregnant) women on uterine arterial perfusion pressure and uterine contractility. Swine uteri (n = 25) were perfused for a period of up to 11 h, with the aim being to preserve a viable organ. Various concentrations of ET-1 as well as serum from PE, HP and HNP women (n = 10 per group) were administered to the perfused swine uteri and IUP (intrauterine pressure) and IAP (intra-arterial pressure) were recorded. ET-1 produced dose-dependent increases in IUP and IAP. The ET-1 concentration in serum was higher in serum from PE women than in HP and HNP women (P > 0.05). Administration of all serum samples had a contractile effect on the swine uterus, with the greatest effect being seen in HNP women (12.8 +/- 5.3 mmHg), followed by PE (9.06 +/- 4.2 mmHg) and HP (6.1 +/- 4.1 mmHg) women. Statistically significant differences were observed between HNP and PE women (P = 0.048), and PE and HP women (P = 0.021). Increases in IAP following administration of serum from PE women (48.8 +/- 20.0 mmHg) were significantly higher (P = 0.024) compared with the effect of serum from HP women (28.4 +/- 13.7 mmHg). In conclusion, the findings show that serum from PE women has significant vasoconstrictive and oxytocic effects compared with serum from HP women. In pre-eclampsia, the balance between vasorelaxing and vasoactive substances is disturbed.

Gene expression of placental hormones regulating energy balance in small for gestational age neonates

OBJECTIVE Fetal growth restriction is associated with an increased risk for metabolic and cardiovascular disease in later life. To further elucidate mechanisms that might be involved in the process of prenatal programming, we measured the adipokines leptin, resistin, and adiponectin and the GH-releasing hormone ghrelin in the placenta of small for gestational age (SGA) neonates. STUDY DESIGN The control group included 24 placentas of appropriate for gestational age (AGA) newborns, in the study group were 16 placentas of SGA neonates. Gene expression of leptin, resistin, adiponectin, and ghrelin was examined. For hormones showing alterations in gene regulation placental protein expression was measured by Western blot. RESULTS Placental mRNA expression of leptin was significantly increased in SGA placentas (p=0.0035, related to beta-actin). Protein concentration was increased, as well. There were no differences in placental resistin, adiponectin, or ghrelin gene expressions between SGA neonates and controls. Leptin was the only hormone to demonstrate a significant inverse correlation with birth weight (r=-0.44, p=0.01). Adiponectin correlated significantly with leptin (r=0.53, p=0.0023) and ghrelin (r=0.50, p=0.0045). CONCLUSIONS Placental leptin gene expression and protein concentration showed the expected increase in the SGA group. Leptin was inversely correlated with birth weight. Positive correlation of adiponectin with leptin and ghrelin expression suggests an interaction between these hormones in the placenta. However, the unchanged expression of resistin, adiponectin, and ghrelin in SGA placentas and the absence of correlation with birth weight cast doubt whether these hormones produced in the placenta play a key role in fetal programming.