Studies of oxytocin in the baboon during pregnancy and delivery.

Oxytocin was determined by radioimmunoassay in pregnant baboons throughout gestation, in the foetus at caesarean section, and after oxytocin infusion into the mother and foetus. Serial maternal plasma oxytocin in 6 baboons during pregnancy showed a significant correlation between the gestational age and maternal plasma oxytocin concentrations with a correlation coefficient of r = 0.3185 and P less than 0.005. Seventy-one out of 75 plasma samples (94.7%) during pregnancy had detectable levels of oxytocin. Uterine vein plasma had higher oxytocin concentrations than maternal plasma and amniotic fluid (18.6 +/- 4.6 pg/ml; mean +/0 SE) but lower than umbilical, jugular vein and cardiac blood from the foetus. Foetal pituitary gland contained 5.4--26.1 micrograms oxytocin/g. Regular uterine contractions were established with iv oxytocin of 4--20 mU/min and the plasma oxytocin measured showed a significant correlation with the uterine activity achieved (r = 0.64, P less than 0.001). The disappearance of plasma oxytocin at 179 days gestation gave an apparent half-life of 1.1 and 1.7 min in 2 baboons with a late half-life of 9.9 and 17.3 min, respectively. In one baboon at 171 days gestation, the apparent half-life of oxytocin was 9.9 min. The metabolic clearance rates were calculated to be 3.1, 3.2 and 11.7 ml/kg/min, respectively. The production rates were 97, 74, 390 pg/kg/min, respectively. Oxytocin injected into the umbilical vessel near term showed an increase in oxytocin concentration in maternal and uterine vein plasma and amniotic fluid, suggesting that oxytocin can cross the placenta from the foetal to the maternal side. Our findings indicate that in the baboon (1) oxytocin is present throughout pregnancy, (2) uterine activity can be correlated with plasma oxytocin during oxytocin infusion, (3) foetal circulation has higher oxytocin concentration than maternal blood and (4) oxytocin probably can cross the placenta from the foetus to the mother.     

Oxytocin in maternal circulation and amniotic fluid during pregnancy.

Oxytocin (OT) was measured by a specific and sensitive RIA in plasma and amniotic fluid throughout pregnancy. OT was detectable in 84.5% of 362 maternal plasma samples and showed a slow and fluctuating increase towards term with a significant sharp peak at 39 weeks of gestation. There was a highly significant correlation between mean plasma OT and the week of gestation (r = 0.5419, P less than 0.005). The minute to minute variability in plasma OT during pregnancy and labor in 7 subjects showed episodic release of OT with two or three spurts per 10 min, with the amplitude of the spurts being greater during labor. Serial maternal plasma OT throughout pregnancy in 10 patients revealed good concentrations of OT (greater than 10 pg/ml) in patients who subsequently had spontaneous labor and no intrapartum uterine dysfunction. Poor (less than 10 pg/ml) or undetectable OT levels were found in patients who subsequently developed intrapartum uterine dysfunction which necessitated cesarean section. OT was detectable in 89.7% or 87 amniotic fluid samples, with a mean +/- SE of 7.8 +/- 3.6 pg/ml at 14--15 weeks, 43.9 +/- 14.7 pg/ml at 40 weeks, and 30.8 +/- 10.5 pg/ml at 41--42 weeks. The significance of these findings is discussed in relation to the role and origin of OT in pregnancy and parturition.     

Thrombopoietin levels in cord blood plasma and amniotic fluid in fetuses with alloimmune thrombocytopenia and healthy controls

To extend our knowledge of the kinetics of fetal thrombopoietin (TPO), we studied TPO levels in cord blood plasma and amniotic fluid collected from 15 fetuses considered to be at risk of fetomaternal alloimmune thrombocytopenia and also from 10 healthy controls at caesarean delivery. In the plasma of all 25 fetuses and newborn infants studied, TPO was detected above the lower limit of detection (7 pg/ml) and correlated inversely with platelet counts (r = -0.53, P = 0.006). At term, TPO detected in amniotic fluid was at significantly lower levels (7 pg/ml; range 0-22 pg/ml) than simultaneously obtained cord plasma TPO (114 pg/ml; range 43-201 pg/ml; P < 0.001). There was no correlation between levels of TPO in amniotic fluid and cord plasma or platelet counts. In the serial samples collected from the five fetuses with HPA-1a alloimmunization before 37 weeks' gestation, the TPO levels in amniotic fluid were significantly higher than at term (P = 0.013): from 22 to 28 weeks' gestation, 42 pg/ml (30-78 pg/ml); from 32 weeks', 24 pg/ml (17-33 pg/ml); at term, 8 pg/ml (4-13 pg/ml), correlating inversely with gestational age (r = -0.81, P = 0.003). Thus, TPO is present in amniotic fluid at levels apparently inversely related to gestational age. Whether these high levels seen early in pregnancy are normal or are associated with the HPA-1 alloimmunization remains to be shown.     

High levels of corticotropin-releasing hormone immunoactivity in maternal and fetal plasma during pregnancy

Corticotropin-releasing hormone immunoactivity (CRHi) was measured in the plasma of 31 pregnant women and 6 nonpregnant women as well as in the umbilical cord plasma of 40 term fetuses. CRHi was not detectable (less than 44 pg/ml) in the plasma of 6 nonpregnant women or in 6 women in the first trimester of pregnancy. Mean plasma CRHi rose progressively to 58 +/- 18 and 270 +/- 68 pg/ml during the second and third trimesters, respectively, and again became undetectable within 24 h after delivery. Mean CRHi in 40 umbilical cord plasma samples was 136 +/- 16 pg/ml. Gel filtration of both fetal and maternal plasma showed that the majority of the CRHi eluted in the same position as synthetic human CRH. There was no significant correlation between CRHi and either beta-endorphin or ACTH in umbilical cord plasma, suggesting that this CRHi may not be primarily responsible for the release of beta-endorphin and ACTH into fetal plasma at delivery. A close correlation (r = 0.82) was found between simultaneously obtained maternal and umbilical cord plasma CRHi in 10 maternal-fetal pairs, supporting a common source for this peptide in maternal and fetal circulation. A placental source for fetal and maternal CRHi was suggested by the finding of a higher CRHi concentration in the umbilical vein than in the umbilical artery and by the disappearance of this peptide from maternal plasma after delivery. We conclude that a large amount of CRHi is secreted by the placenta into both the maternal and fetal circulation during pregnancy and suggest that this may be an important modulator of the maternal and fetal hypothalamic-pituitary-adrenal axis during gestation.     

Increased human placental growth hormone at midtrimester pregnancies may be an index of intrauterine growth retardation related to preeclampsia

OBJECTIVE: To evaluate the relationship between maternal serum and amniotic fluid levels of human Placental Growth Hormone (hPGH) with the fetal intrauterine growth retardation (IUGR) related to preeclampsia. DESIGN: We analyzed samples in pairs of serum and amniotic fluid retrospectively from 25 women, who manifested preeclampsia and IUGR in the late second or the third trimester of gestation. The samples were obtained at 16-22 weeks' gestation during amniocentesis for fetal karyotyping. At this time, there was no clinical or sonographic evidence of preeclampsia or IUGR, respectively. Sixty-two serum samples were used as controls which were obtained at 16-22 weeks' gestation from women with singleton, uncomplicated pregnancies, with normal outcome, and appropriate for gestational age neonatal birth weight. Forty-seven amniotic fluid samples were also used as controls which were obtained at 16-22 weeks' gestation from the women that were included in the control group who underwent an amniocentesis. hPGH levels were measured by a solid phase immunoradiometric assay. RESULTS: The mean hPGH values in the serum and the amniotic fluid of the IUGR related to preeclampsia affected pregnancies were significantly higher (P<0.05) than those of the normal pregnancies at 16-22 weeks' gestation: mean+/-SD in the serum was 13.16+/-10.52 ng/ml vs. 4.39+/-2.23 ng/ml; mean+/-SD in the amniotic fluid 2.49+/-1.6 ng/ml vs. 0.82+/-0.67 ng/ml. CONCLUSION: hPGH levels in maternal serum and amniotic fluid were found to be higher at 16-22 weeks' gestation in pregnancies that will be complicated subsequently by IUGR related to preeclampsia. Our findings suggest that the evaluation of the changes of hPGH levels at midtrimester should be further investigated for the possibility to provide a potential predictive index of IUGR and preeclampsia.     

Ontogeny of foetal exposure to maternal cortisol using midtrimester amniotic fluid as a biomarker

OBJECTIVE: There is increasing evidence that antenatal stress has long-lasting effects on child development, but there is less accord on the mechanisms and the gestational window of susceptibility. One possible mechanism is by foetal exposure to maternal cortisol. To explore this, we investigated the relationship between cortisol in maternal plasma and amniotic fluid, and any moderating influence of gestational age. PATIENTS AND MEASUREMENTS: Two hundred and sixty-seven women awaiting amniocentesis for karyotyping were studied. Samples were collected between 0900 and 1730 h. Gestational age was determined to the nearest day by ultrasound biometry and time of collection noted to the nearest 15 min. Total cortisol was measured by radioimmunoassay in paired amniotic fluid and maternal blood samples (n = 267) [gestation range 15-37 weeks, median 17 weeks (119 days)]. RESULTS: Both maternal and amniotic fluid cortisol levels increased with gestation (r = 0.25, P < 0.001; r = 0.33 P < 0.001, respectively). Amniotic fluid cortisol was positively correlated with time of collection (r = 0.22, P < 0.001) and negatively with maternal age (r =-0.24, P < 0.001). There was a positive correlation between amniotic fluid cortisol with maternal plasma levels (r = 0.32, P < 0.001), which persisted after multivariate analysis controlling for gestation, time of collection and maternal age. The association appeared to be dependent on gestational age, being nonsignificant at 15-16 weeks' gestation and increasing in strength thereafter. CONCLUSION: This study shows a positive correlation between maternal and amniotic fluid cortisol levels, which becomes robust from 17 to 18 weeks onwards. The results provide support for the hypothesis that alterations in maternal cortisol may be reflected in amniotic fluid levels from this gestation.     

Amniotic fluid testosterone: relationship with cortisol and gestational age

INTRODUCTION: Foetal exposure to testosterone is increasingly implicated in the programming of future reproductive and non-reproductive behaviour. Some outcomes associated with prenatal exposure to testosterone may be predicted from exposure to prenatal stress, suggesting a link between them. The peak serum levels of testosterone in the foetus are thought to be around 14-18 weeks' gestation, and we explored testosterone levels at different gestations. Although best investigated in foetal plasma, this is now difficult because of the decline in frequency of foetal blood sampling; in this study, we used amniotic fluid as a biomarker to investigate foetal exposure. AIMS: To investigate the relationship between amniotic fluid testosterone, amniotic fluid cortisol, foetal gender, and gestational age. METHODS: Paired amniotic fluid and maternal plasma samples were collected from 264 pregnant women undergoing amniocentesis between 15 and 37 weeks' gestation (median 17 weeks [119 days]). Total testosterone and cortisol in amniotic fluid, and total plasma testosterone (maternal) were measured by radioimmunoassay. RESULTS: Amniotic fluid testosterone levels were higher in male than in female foetuses, with a median (interquartile range) of 0.85 nmol/l (0.60-1.17 nmol/l) and 0.28 nmol/l (0.175-0.45 nmol/l), respectively. No relationship between amniotic fluid testosterone and gestational age was detected in either sex. Amniotic fluid testosterone correlated positively with amniotic fluid cortisol in both sexes (r = 0.30 male foetuses, r = 0.33 female foetuses, P < 0.001 for both), and remained significant in multivariate analysis. CONCLUSION: Testosterone in amniotic fluid did not change with gestation in the second and third trimester, raising questions about the timing of the reported early peak in the male foetus. The positive correlation between cortisol and testosterone in amniotic fluid suggests that increased foetal exposure to cortisol may also be associated with increased exposure to testosterone.     

Plasma corticotropin-releasing hormone concentrations during pregnancy and parturition

Plasma CRH was measured in maternal plasma throughout the third trimester of pregnancy, during labor, and postpartum. CRH levels were also measured in arterial and venous umbilical cord plasma samples. In normal pregnant women, plasma CRH increased from 50 +/- 15 (+/- SEM) pg/mL at 28 weeks gestation (n = 41) to 1462 +/- 182 pg/mL at 40 weeks (n = 55) and 1680 +/- 101 pg/mL (n = 65) in labor. Women with pregnancy-induced hypertension (n = 49) had plasma CRH levels significantly elevated above this normal range. Similarly, women who subsequently went into premature labor had raised levels several weeks before the onset of labor. After delivery, plasma CRH returned to normal within 15 h. Total plasma cortisol levels varied little throughout the third trimester, but increased during labor and remained elevated 2-3 days postpartum. There was, therefore, no correlation between plasma cortisol and CRH, implying that this placental CRH is not primarily involved in the control of the maternal hypothalamo-pituitary adrenal axis during pregnancy. The concentrations of CRH in umbilical cord plasma samples were considerably lower than those in the maternal circulation and were close to those in normal nonpregnant adults.     

Progesterone, 20 alpha-dihydroprogesterone and 20 beta-dihydroprogesterone in mother and child at birth.

In 14 healthy pregnant women at term progesterone (P) and 20 alpha-dihydroprogesterone (20 alpha-DHP) were determined by radioimmunoassay both in the maternal and foetal compartments. The average concentrations were as follows (ng/ml blood or ng/g wet weight tissue): peripheral maternal blood P 56 +/- 26, 20 alpha-DHP 16 +/- 8; placental tissue P 2514 +/- 1516, 20 alpha-DHP 429 +/- 412; placental blood P 365 +/- 160, 20 alpha-DHP 35 +/- 18; blood of the umbilical vein P 388 +/- 121, 20 alpha-DHP 33 +/- 15; blood of the umbilical arteries P 162 +/- 62, 20 alpha-DHP 28 +/- 10. In 5 healthy pregnant women at term progesterone (P), 20 alpha-dihydroprogesterone (20 alpha-DHP) and 20 beta-dihydroprogesterone (20 beta-DHP) were also determined by gas-liquid chromatography both in the maternal and foetal compartments. The average concentrations were as follows (ng/ml plasma or ng/g wet weight tissue): peripheral maternal plasma P 129 +/- 49, 20 alpha-DHP 15 +/- 15, 20 beta-DHP 1.7 +/- 0.9; placental tissue P 5060 +/- 1435, 20 alpha-DHP 230 +/- 158, 20 beta-DHP 38 +/- 30; placental plasma P 723 +/- 245, 20 alpha-DHP 24 +/- 13, 20 beta-DHP 1.0 +/- 0.1; plasma of the umbilical vein P 740 +/- 227, 20 alpha-DHP 17 +/- 3, 20 beta-DHP 1.2 +/- 0.3; plasma of the umbilical arteries P 324 +/- 94, 20 alpha-DHP 17 +/- 5, 20 beta-DHP 2.6 +/- 2.1. These results show that, contrary to the progesterone concentrations, no significant difference exists in the concentrations of 20 alpha-DHP and 20 beta-DHP between the blood from the umbilical vein and arteries. Furthermore, no significant difference could be found in the concentrations of P and 20 alpha-DHP between the sexes in either the blood from the umbilical vein or from the umbilical arteries.     

Immunoreactive corticotropin-releasing hormone in human plasma during pregnancy, labor, and delivery

We previously reported that immunoreactive corticotropin-releasing hormone (CRH) is present in human placenta and third trimester maternal plasma, and that such material is very similar to rat CRH and the predicted structure of human CRH. We suggested that maternal plasma immunoreactive CRH may be of placental origin. To further investigate this possibility, we measured plasma immunoreactive CRH in women during pregnancy, labor, and delivery and 1 and 2 h postpartum, and in nonpregnant women. Umbilical cord plasma and placental CRH concentrations were also measured. In the first trimester of pregnancy, the mean maternal plasma level was 5.9 +/- 1.0 pg (+/- SEM)/ml (n = 24), not significantly different from that in 10 nonpregnant women (5.8 +/- 0.8 pg/ml). Plasma CRH concentrations progressively increased during pregnancy (second trimester, 35.4 +/- 5.9 pg/ml (n = 39); early third trimester (28-34 weeks), 263 +/- 41 pg/ml (n = 14); late third trimester (35-40 weeks), 800 +/- 163 pg/ml (n = 20)]. There was a significant correlation between maternal plasma CRH levels and weeks of pregnancy. Plasma CRH concentrations were further elevated (2215 +/- 329 pg/ml; n = 9). During early labor, peaked at delivery (4409 +/- 591 pg/ml; n = 28), and declined rapidly after delivery [1 h postpartum, 1042 +/- (353 pg/ml (n = 13); 2 h postpartum, 346 +/- 91 pg/ml (n = 13)]. There was a significant correlation (r = 0.562; P less than 0.01) between matched maternal plasma and placental CRH concentrations. The mean umbilical cord plasma CRH level (50.6 +/- 6.1 pg/ml; n = 28) was much lower than that in the mother at the time of delivery. Umbilical venous plasma CRH levels were significantly greater than those in simultaneously obtained umbilical arterial plasma (70.8 +/- 11.3 and 41.8 +/- 4.9 pg/ml, respectively; n = 11). There was a significant correlation (r = 0.384; P less than 0.05) between maternal and fetal CRH concentrations. Gel filtration of plasma obtained from women during the third trimester, at delivery, and early postpartum and placental extracts revealed two major peaks of immunoreactive CRH: a high mol wt peak and one at the elution position of rat CRH. In contrast, only rat CRH-sized material was detected in plasma from nonpregnant women and umbilical cord plasma. Maternal plasma immunoreactive CRH-sized material stimulated ACTH release from anterior pituitary tissue in a dose-dependent manner and was equipotent with rat CRH.(ABSTRACT TRUNCATED AT 400 WORDS)     

Maternal and foetal resistin and adiponectin concentrations in normal and complicated pregnancies

OBJECTIVE: The aim of this study was to evaluate how resistin and adiponectin (ApN) are involved in maternal energy metabolism and foetal growth. DESIGN: A cross-sectional study. PATIENTS AND MEASUREMENTS: Resistin and ApN were measured in 30 healthy nonpregnant women, 73 pregnant women [10-41 weeks of gestation; 18 with gestational diabetes mellitus (GDM), five with pregnancy-induce hypertension (PIH), nine with pre-eclampsia (PE), eight with chronic hypertension (CH) and 33 normal] and 40 foetal samples (20-41 weeks of gestation; 18 from GDM mothers and 22 from normal mothers). RESULTS: Resistin levels were significantly higher in normal pregnant women than in nonpregnant controls (13.7 +/- 2.1 vs. 6.3 +/- 1.6 ng/ml; P < 0.005) and showed a negative correlation with gestational age (P < 0.0001, r = -0.7). Only women with PE presented resistin levels significantly lower than normotensive women of the same gestational age (8.2 +/- 1.2 vs. 17.9 +/- 4.3 ng/ml; P < 0.005). ApN levels, although similar in normal pregnant women to those in nonpregnant controls, were significantly lower in women with GDM (37-41 weeks; 5.2 +/- 0.5 vs. 8.2 +/- 0.8 mg/l; P < 0.0001) and PE (20-37 weeks; 5.0 +/- 0.7 vs. 9.5 +/- 0.7 mg/l; P = 0.008) than those found in normal women matched for gestational age. Resistin was detected in the umbilical venous blood in foetuses from 20 to 41 weeks of gestation. In all newborns, both resistin and ApN levels were significantly higher than those recorded in adult life and did not correlate with maternal levels (P = ns, r = 0.03 for resistin and P = ns, r = -0.3 for ApN). Foetuses from diabetic mothers had ApN significantly lower than normal foetuses (26.8 +/- 2.6 vs. 37.5 +/- 3.5 mg/l; P = 0.02), while resistin levels were similar (17.3 +/- 3.7 vs. 18.2 +/- 1.5 ng/ml; P = ns). CONCLUSION: The secretion pattern of ApN in normal and complicated pregnancies strongly suggests an involvement of ApN in insulin resistance during gestation, while resistin seems to have a minor role. Moreover, the detection of high levels of resistin and ApN in cord blood during gestation is consistent with a regulatory action of these adipokines on tissue differentiation and foetal growth.     

Diurnal rhythms in plasma melatonin concentrations in the fetal sheep and pregnant ewe during late gestation

We have measured plasma melatonin (MT) concentrations in the pregnant ewe and fetal sheep during 24-h periods between 114 and 142 days gestation. There was a clear diurnal rhythm in the plasma MT concentrations in both the ewe and fetus from 114 days gestation. Blood samples were also collected from the pregnant ewe and fetus during the day every 2-3 days from 112 days gestation to term. There was no gestational age trend in maternal or fetal day time plasma MT concentrations during late pregnancy. To establish whether there was transplacental transfer of MT, pregnant ewes were injected with [3H]MT, and total radioactivity (disintegrations per min) was measured in maternal and fetal arterial plasma and in amniotic fluid collected before and for 1 h after the [3H]MT injection. Two minutes after [3H]MT injection, radioactivity was detected in both maternal and fetal sheep plasma. Extraction of fetal plasma with chloroform indicated that [3H]MT accounted for 48.0 +/- 7.2 (SE) % of total radioactivity at 2 min after the injection. In one pregnant ewe infused with unlabeled MT (0.3 microgram/ml saline.min for 20 min) maternal and fetal plasma MT concentrations increased within 6 min after the start of the MT infusion. We conclude that there is a diurnal rhythm in the plasma concentrations of MT in the fetal lamb and pregnant ewe between 114 and 142 days gestation, and that MT crosses the ovine placenta from the maternal to the fetal circulation. Therefore, the MT present in the fetal sheep circulation may be solely of maternal origin or it may be derived from both fetal and maternal sources.     

Parathyroid hormone-related protein(1-34) in gestational fluids and release from human gestational tissues

Parathyroid hormone-related protein (PTHrP) is present in fetal and gestational tissues, in which its proposed roles include stimulation of epithelial growth and differentiation, vasodilatation of the uteroplacental vasculature, relaxation of uterine muscle and stimulation of placental calcium transport. The aim of this study was to determine whether the release of PTHrP from gestational tissue explants was tissue specific. In addition, PTHrP concentrations were measured in maternal plasma, umbilical artery and vein plasma, and amniotic fluid from term, uncomplicated pregnancies before the onset of labour. PTHrP was detected in low concentrations in the mother, fetus and placental tissue. Amniotic fluid had ten times the PTHrP concentration compared with that in the maternal or fetal circulations. Using late pregnant human gestational tissues in an in vitro explant system, we found that amnion over placenta, choriodecidua, reflected amnion, and placenta released PTHrP into culture medium in progressively greater amounts over 24 h (P<0.05). This release was not associated with a loss of cell membrane integrity, as indicated by measurement of the intracellular enzyme, lactate dehydrogenase, in the incubation media. After 24 h incubation, the fetal membranes released significantly (P<0.05) greater amounts of PTHrP than did the placenta (placenta 3. 7+/-0.5 pmol PTHrP/g protein). Amnion over placenta released significantly more PTHrP (139.3+/- 43.1 pmol PTHrP/g protein) than did reflected amnion (29.0+/-8.3 pmol PTHrP/g protein) (P<0.05). This study unequivocally demonstrated that human gestational tissues release PTHrP and it was concluded that the main contributors to PTHrP in amniotic fluid were the human fetal membranes, particularly amnion over placenta. Fetal membrane-derived and amniotic fluid PTHrP are proposed to have stimulatory effects on epithelial growth and differentiation in fetal lung, gut, skin and hair follicles and paracrine effects on placental vascular tone and calcium transport.     

Amniotic fluid prolactin in the third trimester of pregnancies complicated by gestational or pregestational diabetes mellitus

Amniotic fluid concentrations of immunoreactive prolactin were measured during the third trimester in 184 diabetic gravidas and correlated with concurrent levels of prolactin in maternal plasma. Prolactin measurements concorded with previously published estimates in normal gravid women and averaged 825 +/- 32 ng/mL (mean +/- SEM) in amniotic fluid and 168 +/- 6.5 ng/mL in simultaneously sampled plasma. Cross-sectional and longitudinal analyses indicated that the prolactin levels in amniotic fluid of pregnant diabetics declined significantly between weeks 32 and 40 of gestation, whereas plasma levels did not change consistently during the same interval. Mean values for amniotic fluid prolactin did not correlate with simultaneous prolactin concentrations in plasma, nor with maternal age, clinical estimates of polyhydramnios, amniotic fluid creatinine content, or lecithin/sphingomyelin (L/S) ratios or subsequent birth weight of the offspring. Clear-cut correlations with overall maternal glucose regulation could not be demonstrated. However, subtle effects may be operative since amniotic fluid prolactin displayed weak but significant correlations with concurrent levels of maternal plasma glucose, and mean values for hemoglobin A1c (HbA1c) but not with mean values for fasting plasma glucose (FPG). Amniotic fluid prolactin concentrations were significantly greater in patients with pregestational diabetes (White classes C, D, and F) than in women with gestational diabetes mellitus (GDM) (our classes A1, A2, and B1). The differences could not be accounted for by differences in metabolic regulation, maternal age, or weights of these two populations.(ABSTRACT TRUNCATED AT 250 WORDS)     

High concentrations of plasma immunoreactive inhibin during normal pregnancy in women

The plasma inhibin concentrations in 190 normal pregnant women at 5-40 weeks gestation and in 4 puerperal women were measured by a specific RIA for human inhibin. The average plasma inhibin concentrations in pregnant women throughout pregnancy (minimum, 2.25 +/- 0.48 IU/mL at 17 weeks gestation; maximum, 24.15 +/- 6.99 IU/mL at 39 weeks gestation) were much higher than those in nonpregnant women with a normal menstrual cycle (0.46 +/- 0.04 IU/mL in the midfollicular phase and 2.02 +/- 0.47 IU/mL in the midluteal phase). The inhibin concentrations were already high at 5 weeks gestation (7.54 +/- 1.10 IU/mL) and rose to peak at 8-10 weeks gestation. The concentrations then decreased and remained relatively low during 14-30 weeks gestation, but rose again during the third trimester. The inhibin concentrations decreased to undetectable levels after delivery. Immunoreactive inhibin was demonstrated in the corpus luteum and term placental extracts, and the dose-response curves were parallel to an inhibin preparation from human follicular fluid. Immunoreactive inhibin concentrations were also high in both the umbilical vein and artery (7.77 +/- 0.80 and 7.84 +/- 0.78 IU/mL, respectively). These observations suggest that both the corpus luteum and placenta are likely sources of inhibin.     

Plasma adrenomedullin, a new independent predictor of prognosis in patients with chronic heart failure.

BACKGROUND: Adrenomedullin, a potent endogenous vasodilating and natriuretic peptide, may play an important role in the pathophysiology of chronic heart failure. Plasma levels of immunoreactive adrenomedullin were examined for prediction of prognosis in chronic heart failure. METHODS AND RESULTS: Plasma levels of immunoreactive-ADM (ir-ADM) were measured by radioimmunoassay in 117 chronic heart failure patients with idiopathic or ischaemic cardiomyopathy (mean ejection fraction: 28 +/- 10%, in the NYHA functional class I/II/III/IV:8/73/29/7, and treated with ACE inhibitors and diuretics. Plasma levels of immunoreactive adrenomedullin were significantly increased in chronic heart failure patients by comparison to controls (618 +/- 293 pg x ml(-1) vs 480 +/- 135 pg x ml(-1), P=0.01). During the follow-up period (237 +/- 137 days) 14 cardiovascular deaths and four urgent cardiac transplantations occurred. In the univariate Cox model, immunoreactive adrenomedullin plasma levels were related to prognosis (P=0.004). A multivariate analysis including heart rate, systolic blood pressure, NYHA class, left ventricular ejection fraction, left ventricular echocardiographic end-diastolic diameter, plasma levels of immunoreactive adrenomedullin, endothelin-1, norepinephrine and atrial natriuretic peptide was performed: plasma levels of immunoreactive adrenomedullin (P=0.03), of endothelin-1 (P=0.0001), and systolic blood pressure (P=0.003) were significantly associated with outcome. CONCLUSION: Our results suggest that elevated plasma levels of immunoreactive adrenomedullin are an independent predictor of prognosis in predominantly mild to moderate chronic heart failure treated by conventional therapy and provide additional prognostic information.     

Relationships between glucose and mannose during late gestation in normal pregnancy and pregnancy complicated by diabetes mellitus: concurrent concentrations in maternal plasma and amniotic fluid

Enzymatic assays were modified to permit sensitive and highly reproducible simultaneous measurements of D-mannose and D-glucose in biological fluids during weeks 34-40 of human pregnancy. Plasma mannose and glucose averaged 9.8 +/- 0.4 (+/- SEM) and 790 +/- 16 micrograms/ml, respectively, after an overnight fast in pregnant women (n = 22) with normal carbohydrate metabolism. Significantly higher plasma mannose levels were found, despite only minor increases in plasma glucose, in pregnant women with relatively well controlled diabetes mellitus after an overnight fast (16.9 +/- 0.6 micrograms/ml mannose; 883 +/- 29 micrograms/ml glucose; n = 31) or 3-4 h after breakfast (15.7 +/- 1.2 micrograms/ml mannose; 1159 +/- 101 micrograms/ml glucose; n = 19). Plasma mannose correlated significantly with plasma glucose in the women with diabetes mellitus, particularly after an overnight fast. Samples of amniotic fluid were also obtained from the gravida with diabetes mellitus to provide some index of simultaneous relationships in utero. Amniotic fluid mannose and glucose averaged 5.9 +/- 0.4 and 302 +/- 24 micrograms/ml, respectively, after an overnight fast and 6.7 +/- 1.3 and 459 +/- 84 micrograms/ml 3-4 h after breakfast. In amniotic fluid, as in plasma, the concurrent levels of mannose and glucose conformed to relatively fixed relationships. Thus, both fetus and mother appear to be exposed to readily demonstrable amounts of mannose during late gestation and the absolute as well as relative abundance of mannose may be increased coincident with faulty maternal glucoregulation. However, since mannose did not exceed 3% of the concurrent concentration of glucose in any instance, it does not seem likely that endogenous levels of circulating mannose can modify glucose utilization appreciably by competing with glucose for phosphorylation via hexokinase and subsequent intracellular processing.     

The role of parathyroid hormone-related protein in intra-tracheal fluid

Parathyroid hormone-related protein (PTHrP), a multi-functional protein, is produced by many tissues in fetus. PTHrP concentration in amniotic fluid is reported to be significantly higher than in either fetal or maternal plasma. Other investigators have reported that PTHrP in amniotic fluid is derived mainly from amnion. The aim of this study was to investigate the contribution of fetus to PTHrP in amniotic fluid and the role of PTHrP in human fetal lung tissue. Samples of amniotic fluid, neonatal intra-tracheal fluid, gastric fluid, and the first urine of neonates were obtained at the time of elective cesarean section (n=11), and the concentrations of PTHrP were measured. The PTHrP level in intra-tracheal fluid (41.0+/-19.6 pmol/l, mean+/-SD) was significantly higher than the levels in amniotic fluid (22.1+/-0.8), neonatal gastric fluid (13.5+/-2.5), first urine (0.95+/-0.6), umbilical cord venous and arterial plasma (1.35+/-0.2, 1.63+/-0.3) and maternal plasma (1.05+/-0.1). PTHrP and PTH/PTHrP receptor mRNA were detected in human lung tissue obtained from a fetus stillborn at 36 weeks of gestation. The effects of PTHrP on fetal lung maturation were studied in H441 cells from a human lung epithelial cell line. PTHrP (10(-7)M) significantly suppressed cell proliferation (p<0.05) to approximately 80% of the control level, while administration of PTHrP significantly increased surfactant protein A production (p<0.01). We first demonstrated the high concentration of PTHrP in intra-tracheal fluid that may suggest the positive production of this protein from the fetal lung. The results obtained by in vitro study using a human lung epithelial cell line suggest that PTHrP derived from the fetal lung might modulate its own maturation.     

Acute effect of caffeine on arterial stiffness and aortic pressure waveform

Adrenomedullin is a potent vasodilatory peptide with plasma levels that increase during pregnancy. Although fetoplacental adrenomedullin levels are reported to increase in preeclampsia, maternal plasma levels may be elevated or decreased, or they may resemble those in normal pregnancy. In other hypertensive conditions, adrenomedullin increases. Therefore, we hypothesized that maternal plasma adrenomedullin levels would be higher in hypertensive pregnancies than in normotensive pregnancies and that the higher placental resistance found in preeclamptic pregnancies results from blunted activity of adrenomedullin on the vasculature. Adrenomedullin concentrations in plasma from women with normotensive pregnancies, gestational hypertension, and preeclampsia were determined by radioimmunoassay. Stem villous arteries from normotensive and preeclamptic pregnancies were dissected and mounted on a wire myograph system. Arteries were first preconstricted to 80% of their maximum constriction with U46619, a thromboxane A(2) mimetic, and exposed to cumulative doses of adrenomedullin (1x10(-)(9) to 3x10(-)(7) mol/L). Contrary to our hypothesis, there were no significant differences in maternal plasma adrenomedullin levels among patients with normal pregnancies, gestational hypertension, and preeclampsia. Adrenomedullin significantly relaxed arteries from both normal and preeclamptic placentas, but there was no significant difference between the 2 groups. During normal pregnancy, adrenomedullin may contribute to the low placental vascular resistance. This pathway appears to be intact in preeclampsia. We conclude that the increased placental vascular resistance observed in preeclampsia is due neither to reduced adrenomedullin secretion nor to an attenuated vascular responsiveness. Moreover, unlike other hypertensive disorders, there is no compensatory rise in circulating adrenomedullin levels.     

Response to corticotropin-releasing hormone during pregnancy in the baboon

CRH is secreted by the placenta into human maternal and fetal plasma during gestation. In the present study plasma CRH was measured in the plasma of five pregnant baboons and their fetuses to ascertain whether the baboon is a suitable model for study of placental CRH. Studies were performed in chronically catheterized animals that exhibited no behavioral or endocrinological signs of stress; maternal animals moved freely about the cage. Mean maternal plasma CRH was 620 +/- 110 pmol/L (2970 pg/mL) at 146 +/- 11 days gestation, and mean fetal plasma CRH was 133 +/- 29 pmol/L (640 pg/mL) at delivery in four animals. Plasma CRH was undetectable (less than 8.5 pmol/L; less than 41 pg/mL) in nonpregnant animals and in animals 8 h after delivery. Maternal and fetal plasma CRH levels in the chronically catheterized baboon were very similar to human maternal and umbilical cord CRH levels at comparable gestational ages. In addition, the majority of maternal plasma CRH eluted in the same position as synthetic human CRH by gel filtration. CRH stimulation tests were performed in the chronically catheterized maternal baboon to investigate whether pituitary-adrenal function during pregnancy is similar to that observed after chronic CRH infusion; blunted ACTH and cortisol responses to acute injections of CRH are observed after chronic CRH infusion. The administration of 0.5 micrograms/kg ovine CRH (oCRH) failed to result in an ACTH or cortisol rise in four pregnant baboons. Baseline ACTH levels were 5.2 +/- 0.4 pmol/L (23.5 pg/mL), and baseline cortisol levels were 800 +/- 55 nmol/L (29.1 micrograms/dL); neither rose after CRH administration. In contrast, 0.5 micrograms/kg oCRH did result in significant ACTH and cortisol elevations in five nonpregnant baboons [ACTH: baseline, 5.9 +/- 1.4; peak, 16 +/- 4.8 pmol/L (P less than 0.05); cortisol: baseline, 430 +/- 55 nmol/L; peak, 960 +/- 200 nmol/L (P less than 0.05)]. In contrast, the administration of a larger dose of oCRH (5.0 micrograms/kg) led to stimulation of ACTH release in five pregnant baboons (baseline, 6.6 +/- 1.3 pmol/L; peak, 34.1 +/- 6.4; P less than 0.001). After this dose cortisol levels also rose in the pregnant animals (baseline = 1040 +/- 30 nmol/L; peak, 1620 +/- 130); however, this response was blunted compared to that in the nonpregnant animals (P less than 0.05). CRH (5.0 micrograms/kg) significantly stimulated both ACTH and cortisol in the nonpregnant animals.(ABSTRACT TRUNCATED AT 400 WORDS)