The placental lactogen receptor in maternal and fetal sheep liver: regulation by glucose and role in the pathogenesis of fasting during pregnancy.

To clarify the roles of glucose and insulin in the regulation of the PL receptor in fetal and maternal sheep liver, we administered iv glucose to pregnant ewes during a 72-h fast. The binding of ovine PL (oPL) to hepatic membranes from glucose-infused ewes and their fetuses was compared with the binding of oPL to tissues of fasted, saline-infused sheep and sheep fed normally ad libitum. Fasting of pregnant ewes caused a 58-70% reduction in the number of PL receptors in fetal and maternal liver. Intravenous administration of glucose during fasting increased the number of PL receptors in fetal liver by 137.4%. In contrast, glucose administration during fasting had no effect on the number of PL receptors in maternal liver. The number of PL binding sites in fetal liver correlated positively with fetal weight (r = 0.59) and length (r = 0.54) and with fetal plasma glucose (r = 0.69) and insulin (r = 0.55) concentrations. In contrast, PL binding was inversely related to fetal plasma oPL concentrations (r = -0.70). These findings suggested that glucose, insulin, and/or oPL may regulate PL binding in the ovine fetus. To determine whether glucose or insulin exert direct effects on the PL receptor in ovine fetal tissues, we examined the binding of radiolabeled oPL to ovine fetal hepatocytes and fibroblasts in culture. The specific binding of oPL to fetal hepatocytes was low and variable (1.0 +/- 0.5%) and it was not possible to assess reliably the effects of glucose or insulin supplementation. The specific binding of oPL to fetal fibroblasts (5.4 +/- 0.6%/mg) was unaffected by variations in media glucose concentrations (5.5-16.5 mM) or by pretreatment with insulin (10-1000 ng/ml). The results of these studies demonstrate that glucose and other nutritional factors regulate the expression of the PL receptor in fetal and maternal sheep liver. Alterations in PL binding play roles in the metabolic adaptation of the mother and fetus to nutritional deprivation and stress.

Placental lactogen receptors in maternal sheep liver: effects of fasting and refeeding.

In a recent study we demonstrated that fasting of the pregnant ewe reduces the number of placental lactogen (PL) receptors in fetal sheep liver. In the present study we examined the effects of a 72-h fast on the number and affinity of PL receptors in maternal sheep liver. Fasting caused a 57% reduction in the number of hepatic ovine PL receptors; this effect was reversed by refeeding. There were no changes in the affinity of the PL receptor, the subunit structure of the receptor, or the extent of occupancy of the receptor by endogenous circulating maternal hormones. The number of hepatic PL receptors was correlated positively with the maternal plasma concentrations of glucose and insulin, suggesting that these factors may regulate PL binding to maternal tissues during pregnancy. In addition, PL receptor number was correlated positively with maternal plasma insulin-like growth factor I (IGF-I) concentrations, suggesting that a reduction in hepatic ovine PL binding may contribute to the reduction in maternal IGF-I during fasting. Fasting produced a 72% reduction in the number of ovine growth hormone receptors in maternal liver and an 83% increase in hepatic insulin binding. These findings indicate that fasting of the pregnant ewe reduces the number of PL receptors in maternal and fetal liver. The reduction in PL binding may contribute to maternal and fetal hyposomatomedinemia and may play a role in the pathogenesis of the intrauterine growth retardation that accompanies maternal nutritional deprivation.

Nutritional regulation of the placental lactogen receptor in fetal liver: implications for fetal metabolism and growth.

We have recently identified and purified from fetal liver a distinct receptor that mediates the effects of placental lactogen (PL) on amino acid transport, glycogen synthesis, and somatomedin production in fetal tissues. At present, the factors that regulate the number and affinity of PL receptors in the fetus are unknown. Since maternal nutrition plays a critical role in fetal metabolism and growth, we have examined the role of nutrition in the regulation of the PL receptor in fetal lambs. Pregnant ewes at 123-126 days gestation were fed ad libitum (FED), fasted for 3 days (FASTED), or fasted for 3 days and then refed for an additional 3 days (REFED). The ewes were then killed, and the binding of [125I]ovine (o) PL to hepatic microsomes from the fetal lambs was examined. Maternal fasting caused a 60-75% reduction in the specific binding of oPL to fetal liver; the effect of fasting was reversed in part by refeeding [specific binding per mg protein: FED, 11.8 +/- 2.2% (n = 8); FASTED, 2.8 +/- 0.4% (n = 7); REFED, 7.2 +/- 2.6% (n = 3)]. The decrease in oPL binding resulted from an 80% reduction in the number of fetal oPL-binding sites (Scatchard analysis); there were no changes in the affinity of the oPL receptor (Kd, 0.6 nM), the subunit structure of the receptor, or the degree of occupancy of the receptor in vivo by endogenous fetal hormones. The specific bindings of GH (0.6%), PRL (0.3%), and insulin (35%) to fetal liver were not affected by maternal fasting, indicating that caloric restriction exerted a specific effect on oPL binding in the fetus. The number of fetal oPL-binding sites was positively correlated with the fetal liver glycogen content (r = 0.69; P less than 0.01) and the fetal plasma concentrations of glucose (r = 0.68; P less than 0.01) and insulin-like growth factor-I (r = 0.74; P less than 0.001), suggesting a role for the PL receptor in the regulation of fetal carbohydrate metabolism and growth. The number of fetal PL receptors was inversely correlated with the fetal plasma oPL concentration (r = 0.47; P less than 0.05). These studies demonstrate that fasting of the pregnant ewe reduces the number of PL receptors in ovine fetal liver. The reduction in fetal hepatic PL receptors may contribute to the mobilization and depletion of fetal liver glycogen stores and may play a role in the pathogenesis of the fetal growth retardation that accompanies maternal caloric deprivation.

High-density lipoproteins (HDL) stimulate placental lactogen secretion in pregnant ewes: further evidence for a role of HDL in placental lactogen secretion during pregnancy.

Previous studies from our laboratory showed that high-density lipoproteins (HDL) stimulate the release of human placental lactogen (PL) from cultured trophoblast cells from normal pregnant women. To determine whether HDL stimulates PL secretion in vivo, ovine HDL was infused over 2-5 min into 11 pregnant ewes (22 separate experiments) at 86-130 days of gestation via an indwelling catheter into the maternal jugular vein. The HDL, freshly prepared from the plasma of pregnant ewes by differential flotation ultracentrifugation, was greater than 99% purified as judged by SDS-PAGE. Plasma samples were obtained from the ewes before and at 0.5-h intervals for 6 h following the infusions and were assayed for PL by a specific homologous radioimmunoassay. The maternal infusion of HDL at doses of 302-784 mg (5.3-13.8 mg/kg body weight) stimulated significant increases in maternal plasma PL concentrations in six out of eight experiments (six ewes), and the infusion of 108-264 mg (1.9-4.6 mg/kg) stimulated plasma PL concentrations in two out of six experiments. In contrast, HDL at doses less than 100 mg were without effect in eight experiments. The response to the HDL infusions was characterized by a sustained increase in plasma PL concentrations beginning 1.5-2.5 h after the infusions, reaching a maximum 274.2 +/- 21.9% of the baseline value (P less than 0.001). In contrast, the maternal infusion of lipoprotein-free plasma proteins or saline had no effect on maternal plasma PL concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

A modified biophysical profile for antenatal fetal surveillance.

Three hundred thirty-seven high-risk pregnancies were screened using a modified biophysical profile consisting of nonstress testing (NST) and ultrasound evaluation of amniotic fluid volume. Ultrasound assessment of fetal breathing and body movements was performed only to evaluate the nonreactive NST. Decreased amniotic fluid volume and spontaneous fetal heart rate (FHR) decelerations were considered abnormal findings during antenatal testing, and served as indications for delivery regardless of FHR reactivity. Despite intervention, decreased amniotic fluid volume and spontaneous decelerations were associated with an increased incidence of meconium staining, decelerations during labor, cesarean section for fetal distress, and small for gestational age infants. Perinatal morbidity also occurred in patients with spontaneous decelerations and normal amniotic fluid volume. The search for spontaneous FHR decelerations by electronic fetal monitoring should continue during antepartum testing because FHR decelerations cannot be identified by conventional ultrasound assessment. The modified profile seems practical for routine assessment of fetal well-being in high-risk pregnancy, and affords insights unavailable with ultrasound surveillance alone.

Intrauterine hypercarbia and lamb lung surfactant synthesis.

Prenatal asphyxia resulting in hypoxia, hypercarbia and amniotic fluid aspiration reduces the synthesis of the pulmonary surfactant. Using 135-day fetal lambs we studied the in utero effects of hypercarbic acidosis alone on fetal breathing activity, excised lung pressure-volume relationships and lamellar body (LB) surfactant disaturated phosphatidylcholine (DSPC) pool size and specific activity for [14C]palmitate. Fetal PaCO2 levels greater than 125 mm Hg for 30 min were associated with pH values less than 7.0 and very vigorous breathing activity. Analysis 22 h after the period of hypercarbic acidosis demonstrated no differences in pressure-volume relationships or the quantity of lamellar body surfactant DSPC. The specific activity of lamellar body DSPC also was not different although total label (dpm) per gram dry weight was higher and label was detected in the lavage fluid earlier in the acidotic lambs than controls. We conclude from these data that hypercarbic acidosis does not influence the synthesis or function of the pulmonary surfactant as assessed in this system. From these results and prior work from our laboratory we can infer that hypoxia remains the most probable cause for reduced surfactant synthesis in the asphyxiated fetus.

Accuracy of ultrasonic fetal weight prediction in preterm infants.

We analyzed the accuracy of four previously reported ultrasound formulas by means of abdominal circumference and/or biparietal diameter measurement for the prediction of fetal weight in the preterm infant (less than 2,000 gm). The birth weights of 25 preterm infants delivered within 72 hours of ultrasound measurement were compared to the weights calculated by formulas derived from the ultrasound measurements, and the accuracy of each formula was determined. A high degree of correlation was found or the logarithmic formulas with the use of both biparietal diameter and abdominal circumference measurement. Our data suggest that the present ultrasound methodology is of sufficient accuracy to warrant the use of ultrasonic measurement to predict fetal weight prospectively before delivery of the very low-birth weight infant. We also retrospectively reviewed the previous 4-year neonatal mortality rate for infant weighing between 500 and 2,000 gm at birth at Duke University.