Genes or placenta as modulator of fetal growth: evidence from the insulin-like growth factor axis in twins with discordant growth

To determine whether fetal growth is regulated by placental and/or fetal factors, we measured maternal and fetal concentrations of insulin-like growth factor-I (IGF-I), IGF-II and insulin-like growth factor binding protein-1 (IGFBP-1) (total and non-phosphorylated) in dichorionic (DC) and monochorionic (MC) twins with (DC, n = 13; MC, n = 12) or without (DC, n = 13; MC, n = 12) discordant birth weight. In the discordant MC pregnancy, growth-restricted (IUGR) twins had lower IGF-II concentrations (P < 0.001) but similar IGF-I concentrations compared to the appropriate for gestational age(AGA) co-twin. The differences in IGF-II concentrations showed a positive association with percentage birth weight discordance (r = 0.60; P < 0.05) in MC twins. In contrast, IUGR DC twins had lower IGF-I concentrations (P < 0.05) but similar IGF-II concentrations compared to the AGA co-twins. There was a positive correlation between IGF-I concentrations and birth weight (r = 0.47; P < 0.05) in DC twins. Total IGFBP-1 concentrations were higher in both MC and DC IUGR twins (P < 0.05) compared to AGA twins. A negative association was found between total IGFBP-1 concentrations and birthweight of both MC (r = 0.47; P < 0.05) and DC (r = 0.58; P < 0.01) twins. No such differences in IGF concentrations were found between concordant MC and DC twin pairs. The maternal IGF concentrations were comparable between the MC and DC groups. These data suggest that growth discordances of twins exposed to the same maternal environment may be due to variations in either IGF-I or IGF-II/IGFBP-1, depending upon the functioning of the placenta.     

The role of insulin-like growth factor binding protein-1 phosphoisoforms in pregnancies with impaired placental function identified by doppler ultrasound.

This study was performed to investigate the hypothesis that insulin-like growth factor binding protein-1 (IGFBP-1) is involved in the pathogenesis of trophoblast invasion and impaired placentation in human pregnancy. The role of total and non-phosphorylated IGFBP-1 in women with fetal growth restriction and in high risk pregnancies identified by uterine artery Doppler ultrasound screening was examined. This was a prospective study of women booked for antenatal care having second trimester anomaly scans and Doppler screening between 22-26 weeks gestation. Women were divided into three groups and compared: normal uterine artery Doppler and normal fetal growth (control group, n = 10); abnormal Doppler and normal fetal growth [bilateral uterine artery notches (BN; n = 16); abnormal Doppler and intrauterine growth restriction (IUGR; n = 8)]. Maternal serum was collected, stored and assayed simultaneously for total and non-phosphorylated IGFBP-1. There was elevated total and non-phosphorylated IGFBP-1 (mean 44.99 +/- 12.19 and 29.61 +/- 10.38 microg/l respectively) in the IUGR group compared with controls (mean 17.96 +/- 3.24 and 12.18 +/- 1.55 microg/l, P < 0.05). This finding suggests that the various IGFBP-1 isoforms, the degree of phosphorylation and the ratios of these different forms locally may be important during trophoblast invasion and may be implicated in clinical manifestations of impaired placentation later in the second trimester.     

Prenatal exposure to excess testosterone modifies the developmental trajectory of the insulin-like growth factor system in female sheep

Experimental elevation of maternal testosterone (T) from 30 to 90 days of gestation leads to intrauterine growth retardation (IUGR) and increased prepubertal growth rate in female lambs. This study tested the hypothesis that prenatal T treatment during mid-gestation alters the trajectory of the fetal insulin-like growth factor (IGF)–insulin-like growth factor binding protein (IGFBP) system to promote IUGR and subsequent postnatal catch-up growth in female lambs. Plasma IGF-I and IGFBPs were measured by radioimmunoassay and Western ligand blot, respectively, on 65, 90 and 140 days (d) of gestation, at birth, ∼5 months (prepubertal, the catch-up growth period), and ∼9.5 months (postpubertal). Northern blot analysis was used to measure hepatic mRNA content of IGF system components during fetal stages. At fetal 65 d, plasma protein and hepatic mRNA content of IGFBP-1, an inhibitor of IGF bioactivity, was elevated in prenatal T-treated fetuses although body weight did not differ. There was a transient increase in plasma IGF-I and IGFBP-3 concentrations at fetal 90 d in prenatal T-treated fetuses. Hepatic IGF-I mRNA and plasma IGFBP-3 content were reduced by 140 d when body weight was reduced in prenatal T-treated fetuses. Plasma IGFBP-2 content was significantly reduced in prenatal T-treated newborns, but by 4 months these females had significantly higher circulating IGF-I and IGFBP-3 concentrations and faster growth rates than control females. After puberty, plasma IGF-I remained elevated in prenatal T-treated females. These findings provide evidence that prenatal T excess programmes the developmental trajectory of the IGF/IGFBP system in female sheep to reduce IGF bioavailability during IUGR and increase IGF bioavailability during prepubertal catch-up growth.     

宫内生长迟缓胎儿脐血IGF-Ⅰ及IGFBP-3水平观察

目的：探讨新生儿脐血中胰岛素样生长因子-I（IGF-I）和胰岛素样生长因子结合蛋白-3（IGFBP-3）水平与胎儿宫内生长发育的关系。方法：采用放射免疫分析,分别对出生时体重正常新生儿与宫内生长迟缓的低体重新生儿脐血的IGF-I及IGFBP-3水平进行检测。结果：宫内发育迟缓组新生儿脐血的IGF-I及IGFBP-3的含量明显低于正常对照组（P〈0.01）,有显著差异性。结论：：IGF-I和IGFBP-3与胎儿宫内生长发育密切相关,对胎儿的宫内生长发育起着重要的调节作用。     

Insulin-like growth factor (IGF)-I and IGF binding protein-3 concentrations in fluid from human stimulated follicles

Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP- 3) play an important role in regulating follicle growth and maturation. We have evaluated whether responsiveness to gonadotrophins during an in- vitro fertilization (IVF) treatment is related to follicular fluid IGF- I and IGFBP-3 concentrations. We also investigated if a difference is present in IGF-I and IGFBP-3 concentrations between patients treated with human menopausal gonadotrophin (HMG) and patients treated with highly purified follicle stimulating hormone (FSH). We have measured IGF-I and IGFBP-3 in follicular fluid from pre-ovulatory follicles in an IVF programme. All 70 patients were stimulated after being down- regulated with a gonadotrophin-releasing hormone (GnRH) analogue. IGF-I concentrations in follicular fluid were significantly inversely correlated with the number of ampoules FSH administered and number of days of FSH administration, and significantly correlated with the number of follicles aspirated. IGFBP-3 concentrations were not correlated with any other parameter measured nor were IGF-I and IGFBP-3 concentrations correlated. IGFBP-3 concentrations were significantly higher in patients receiving highly purified FSH compared with patients receiving HMG (P < 0.005). These results are new evidence that IGF-I concentration in follicular fluid is higher in women who respond better to follicular stimulation, i.e. women who grow many follicles, women who need a shorter duration of stimulation and women who need fewer ampoules FSH before oocyte retrieval.      

Insulin-like growth factors and their binding proteins in the venous effluents of ovary and adrenal gland in severely hyperandrogenic women

Insulin and insulin-like growth factors (IGF) are thought to play an important role in the pathogenesis of excessive androgen production. To explore this question further we measured the concentrations of IGF-I and -II and their binding proteins (IGFBP-1 and-3) in adrenal and ovarian vein samples of severely hyperandrogenic women (serum testosterone > 5 nmol/l) collected as part of their diagnostic work-up. The concentration of IGF-II was slightly but not significantly higher in the ovarian vein than in the adrenal and peripheral veins. The concentrations of IGF-I and IGFBP were identical in both the adrenal and ovarian veins and did not differ from those in the peripheral circulation. The concentration of IGFBP-1 was negatively correlated (r = -0.60, P > 0.05) with insulin and IGFBP-3 showed a strong positive correlation with IGF-1 (r = 0.90, P > 0.01). These results indicate that neither the ovary nor the adrenal gland contributes significantly to the circulating pool of IGF or their binding proteins in severely hyperandrogenic subjects. Hyperinsulinaemia is associated with low circulating IGFBP-1 concentrations and IGFBP-3 seems to be an excellent indicator of the peripheral IGF-I concentration. The concentrations of IGF-I suggested decreased somatotrophic activity in these obese, hyperinsulinaemic subjects.      

Hepatocyte growth factor concentration in the early second-trimester amniotic fluid does not predict fetal growth at birth.

The purpose of this study was to evaluate whether hepatocyte growth factor (HGF) concentrations in the early second-trimester amniotic fluid predict fetal growth at birth. HGF and insulin-like growth factor-I (IGF-I) concentrations in the early second-trimester amniotic fluid were measured in 12 pregnancies with small for gestational age (SGA) infants, 84 pregnancies with appropriate for gestational age (AGA) infants, and eight pregnancies with large for gestational age (LGA) infants. HGF concentrations were measured from the early second-trimester amniotic fluid samples using an enzyme-linked immunosorbent assay. IGF-I concentrations were measured from the early second-trimester amniotic fluid samples using an immunoradiometric assay. Maternal age in AGA group (34.2 +/- 5.5 years) was significantly lower than in SGA (37.9 +/- 3.0 years) and LGA (37.6 +/- 3.3 years) groups (P < 0.05). There were no significant differences for parity or gestational age at amniocentesis among the groups. There were significant differences for birth age, birth weight, neonatal height, and placental weight among the groups (P < 0.05). HGF concentrations in SGA, AGA and LGA groups were 16.9 +/- 6.6, 16.7 +/- 9.0 and 20.2 +/- 14.8 ng/ml respectively (not significant). There was no correlation between amniotic fluid HGF concentrations and birth weight, height or placental weight. There were also no significant differences for amniotic fluid IGF-I concentrations among the three groups. These results suggest that differences in HGF concentrations in the early second-trimester amniotic fluid do not predict fetal growth at birth. Further study is needed to clarify the role of high HGF concentrations in early second-trimester amniotic fluid during pregnancy.     

Changes in serum concentrations of growth hormone, insulin, insulin- like growth factor and insulin-like growth factor-binding proteins 1 and 3 and urinary growth hormone excretion during the menstrual cycle

Few studies exist on the physiological changes in the concentrations of growth hormone (GH), insulin-like growth factors (IGF) and IGF-binding proteins (IGFBP) within the menstrual cycle, and some controversy remains. We therefore decided to study the impact of endogenous sex steroids on the GH-IGF-IGFBP axis during the ovulatory menstrual cycle in 10 healthy women (aged 18-40 years). Blood sampling and urinary collection was performed every morning at 0800 h for 32 consecutive days. Every second day the subjects were fasted overnight before blood sampling. Follicle stimulating hormone, luteinizing hormone (LH), oestradiol, progesterone, IGF-I, IGFBP-3, sex hormone-binding globulin, dihydroepiandrosterone sulphate and GH were determined in all samples, whereas insulin and IGFBP-1 were determined in fasted samples only. Serum IGF-I concentrations showed some fluctuation during the menstrual cycle, with significantly higher values in the luteal phase compared to the proliferative phase (P < 0.001). Mean individual variation in IGF-I concentrations throughout the menstrual cycle was 13.2% (SD 4.3; range 0.1-18.3%). There were no cyclic changes in IGFBP-3 serum concentrations and no differences in IGFBP-3 concentrations between the luteal and the proliferative phases. Mean individual variation in IGFBP- 3 concentrations throughout the menstrual cycle was 8.8% (SD 2.7; range 3.2-14.1). IGFBP-1 concentrations were inversely associated with insulin concentrations, and showed a significant pre-ovulatory increase that returned to baseline at the day of the LH surge. Fasting insulin concentrations showed large fluctuations throughout the menstrual cycle without any distinct cyclic pattern. No cyclic changes in urinary GH excretion during menstrual cycle were detected. We conclude that, although IGF-I concentrations are dependent on the phase of the menstrual cycle, the variation in IGF-I concentrations throughout the menstrual cycle is relatively small. Therefore, the menstrual cycle does not need to be considered when evaluating IGF-I or IGFBP-3 serum values in women suspected to have GH deficiency.      

Clomiphene citrate increases insulin-like growth factor binding protein-1 and reduces insulin-like growth factor-I without correcting insulin resistance associated with polycystic ovarian syndrome

The induction of ovulation by clomiphene could be the result of interaction of the drug at various levels: hypothalamus, pituitary and ovary. It was demonstrated that administration of clomiphene to women with polycystic ovarian syndrome (PCOS) is accompanied by a reduction in plasma concentrations of insulin-like growth factor-I (IGF-I). IGF-I seems to have an overall negative effect on normal folliculogenesis and ovulation. The aim of the present study was to evaluate the effect of clomiphene on plasma concentrations of IGF-I and IGF binding protein (IGFBP)-1 and on insulin resistance associated with PCOS. Fifteen patients diagnosed with PCOS were recruited. Clinical diagnosis was based on chronic oligomenorrhoea or amenorrhoea and hyperandrogenaemia. Clomiphene citrate was administered at a dose of 100mg/day to all women from day 5 to day 9 of the spontaneous or medroxyprogesterone acetate (MAP)-induced menstrual cycle. Blood sampling and a 2 h oral glucose loading test (75 g) were performed the day before and after the course of clomiphene. Ovulation was confirmed in 13/15 PCOS patients. Plasma concentrations of IGF-I decreased by 31.5% (434 +/- 84 versus 297 +/- 71 ng/ml; P: < 0.05) after 5 days of clomiphene therapy, whereas plasma concentrations of IGFBP-1 increased by approximately 28.1% (26.3 +/- 4 versus 36.6 +/- 7 ng/ml; P: < 0.05). This gave a 56.5% reduction in the IGF-I:IGFBP-1 ratio (21.9 versus 9.53). No significant changes in basal plasma concentrations of fasting insulin or area under the insulin curve were observed in response to oral loading. The present results show that clomiphene does not cause changes in insulin resistance associated with PCOS but reduces plasma concentrations of IGF-I and increases those of IGFBP-1, with a consequent marked reduction in the IGF-I:IGFBP-1 ratio.     

IGF-I与宫内发育迟缓及其结合蛋白的关系

目的：检测宫内发育迟缓（IUGR）儿脐血胰岛素样生长因子-I（IGF-I）、胰岛素样生长因子结合蛋白-3（IGFBP-3）水平,分析这些指标的变化程度与胎儿期生长的关系。方法：将86例脐血标本分为IUGR（即小于胎龄儿）组和适于胎龄儿（AGA）组。采用放射免疫分析（RIA）测定IGF-I水平,免疫放射分析（IR-MA）测定IGFBP-3水平。两组间比较用t检验,两变量之间的关系采用相关回归分析。结果：与AGA组相比,IUGR组脐血IGF-I和IGFBP-3水平显著降低（P均〈0.01）;IGF-I、IGFBP-3均随胎龄及出生体重增加而增加（P均〈0.01）;IGFBP-3与IGF-I呈正相关（P〈0.01）。结论：脐血IGF-I和IGFBP-3的含量可作为判断新生儿生长发育程度的一项客观指标。     

Insulin sensitivity and insulin secretion at birth in intrauterine growth retarded infants

AIM: To study insulin sensitivity, secretion and relation of insulin levels with birth weight and ponderal index in intrauterine growth retarded (IUGR) infants at birth. METHODS: We studied 30 IUGR and 30 healthy newborns born at term by vaginal delivery in Jipmer, Pondicherry, India. Cord blood was collected at the time of delivery for measurement of plasma glucose and insulin. RESULTS: When compared with healthy newborns, IUGR newborns had lower plasma glucose levels (mean 2.3+/-0.98 versus 4.1+/-0.51 mmol/L, p<0.001); lower plasma insulin levels (mean 4.5+/-2.64 versus 11.03+/-1.68 microU/L, p<0.001); higher insulin sensitivity calculated using G/I ratio (mean 11.6+/-5.1 versus 6.7+/-0.31, p<0.001), HOMA IS (mean 5.5+/-6.0 versus 0.53+/-0.15, p<0.001), and QUICKI (mean 0.47+/-0.12 versus 0.34+/-0.02, p<0.001); and decreased pancreatic beta-cell function test measured as I/G (mean 0.10+/-0.037 versus 0.15+/-0.006, p<0.001). A positive correlation was identified between insulin levels and birth weight in both the healthy control group (r2 = 0.17, p = 0.024) and IUGR group (r2 = 0.13, p = 0.048). However correlation of insulin levels with ponderal index was much more confident in both healthy control (r2 = 0.90, p<0.001) and IUGR groups (r2 = 0.28, p = 0.003). Insulin status correlated both with birth weight and ponderal index more confidently in control group than in IUGR group. CONCLUSION: At birth, IUGR infants are hypoglycaemic, hypoinsulinaemic and display increased insulin sensitivity and decreased pancreatic beta-cell function. Insulin levels correlate with ponderal index much more confidently than with birth weight.     

Relationships between the uterine environment and maternal plasma concentrations of insulin-like growth factor binding protein-1 and placental protein 14 inearly pregnancy

Blood was obtained from 218 women between 6 and 13 weeks ofgestation. Measurements of serum insulin-like growth factorbinding protein-1 (IGFBP-1) and placental protein 14 (PP14)concentrations were compared withmaternal weight and height,maternal smoking habit, indices of maternal haematological statusand two placental hormones [human chorionic gonadotrophin (HCG)and human placental lactogen (HPL)]. IGFBP-1 concentration wasnegatively correlated with maternal weight (P < 0.001) andbody mass index (P <0.001); PP14 concentration was not correlatedwith these measurements. PP14 concentration was negatively correlatedwith maternal haemoglobin concentration (P equals; 0.010), meancorpuscular volume (P equals; 0.003) and serum ferritin concentration(P equals; 0.016). The concentrations of PP14 were significantlyless among smokers (P < 0.001); IGFBP-1 concentrations wereuninfluenced by smoking. IGFBP-1 concentration was positivelycorrelated with maternal serum HCG (P equals; 0.003) and maternalserum HPL (P equals; 0.002). PP14 concentration was positivelycorrelated with maternal serum HCG (P < 0.0001) but not withHPL. These findings demonstrate that the maternal environmenthas an early influence on both endometrial and placental function.     

Association of serum insulin-like growth factor-I and erythropoiesis in relation to body iron status

This study investigated the associations between serum insulin-like growth factor-I (IGF-I) concentrations and erythropoietic activities in relation to body iron status. Serum IGF-I concentrations, free erythrocyte protoporphyrin (FEP), hemograms, and serum iron markers were measured in 71 female adolescents, age 14 to 17 yr. No significant differences were observed in hemograms, iron parameters, or FEP between the subjects with IGF-I <681.2 ng/ml and IGF-I 681.2 ng/ml. However, blood hemoglobin and serum iron concentrations averaged 13.4 +/- 0.8 g/dl and 93.7 +/- 41.2 microg/dl in the subjects with IGF-I >809 ng/ml, which were above the values in those with IGF-I <523 ng/ml (12.3 +/- 0.9 g/dl and 50.5 +/- 30.8 microg/dl, p < 0.05, respectively). On the other hand, FEP was significantly lower in the adolescents with IGF-I >809 ng/ml than in those with IGF-I <523 ng/ml (38.9 +/- 16.2 microg/dl vs 63.4 +/- 23.1 microg/dl, p <0.05). Prevalences of iron deficiency or iron deficiency anemia were 3- or 5-fold higher in the subjects with IGF-I <523 ng/ml, compared to those with IGF-I >809 ng/ml. Serum IGF-I correlated significantly with FEP (r = -0.45, p <0.05) and serum iron concentrations (r = 0.40, p <0.05) in iron deficient subjects. In summary, IGF-I seems to have an important relationship to iron metabolism and protoporphyrin synthesis in adolescents.     

Antenatal dexamethasone therapy does not affect circulating concentrations of insulin-like growth factor binding protein-1

In animals, dexamethasone administration during pregnancy leads to fetal growth restriction due to enhanced expression of insulin-like growth factor binding protein-1 (IGFBP-1). In humans, there is also a significant inverse correlation between maternal and fetal concentrations of IGFBP-1 and birth weight. During pregnancy, maternal IGFBP-1 is derived from the decidualized endometrium. We have studied the effect of dexamethasone on circulating concentrations of IGFBP-1 in 12 pregnant women who received dexamethasone therapy for fetal lung maturation in anticipation of premature delivery before 34 completed weeks of gestation. Blood samples were collected before dexamethasone administration, at 24 h and 48 h after the course of dexamethasone, and within 24 h of delivery, for the measurement of IGFBP-1. There was no significant change in plasma IGFBP-1 concentrations at 24 and 48 h following dexamethasone therapy, and at delivery (P = 0.666, 0.307 and 0.398, respectively). Therefore, antenatal dexamethasone therapy does not influence decidual synthesis of IGFBP-1.      

脐血中胰岛素、胰岛素样生长因子-I及胰岛素样生长因子结合蛋白-2与胎儿生长受限的关系

目的探讨脐血中胰岛素、胰岛素样生长因子-I及胰岛素样生长因子结合蛋白-2的水平与胎儿生长受限的关系及意义。方法收集2011年7月～2013年5月在本院分娩的单胎足月正常妊娠（无产科并发症）孕妇及其新生儿各120例,根据出生体重将新生儿分为小于胎龄儿（SGA）组、适于胎龄儿（AGA）2组。胎儿娩出后即抽脐静脉血5ml,标本收集后用高效液相色谱法测定脐血中胰岛素、胰岛素样生长因子-I及胰岛素样生长因子结合蛋白-2的水平。结果SGA组脐带血清胰岛素、胰岛素样生长因子-I水平明显低于AGA组,差异均有统计学意义（P〈0.01）;SGA组脐血胰岛素样生长因子结合蛋白-2水平明显高于AGA、组,差异有统计学意义（P〈0.01）;脐血中胰岛素样生长因子-I与胰岛素水平呈正相关关系,而与胰岛素样生长因子结合蛋白-2呈负相关关系;脐血胰岛素、胰岛素样生长因子-I水平与新生儿出生体重呈正相关关系,而胰岛素样生长因子结合蛋白2与之呈负相关关系。结论脐血胰岛素、胰岛素样生长因子-I、胰岛素样生长因子结合蛋白2与胎儿生长受限的发生密切相关。     

Somatotropic axis and body weight in pre-menopausal and post-menopausal women: evidence for a neuroendocrine derangement, in absence of changes of insulin-like growth factor binding protein concentrations

The altered function of the somatotropic axis observed in perimenopause may underlie the changes in body weight and fat distribution. The aim of the present study was to evaluate, in pre-menopausal and post- menopausal women with body mass index (BMI) > or = or <25, the basal plasma levels of growth hormone (GH), insulin-like growth factor (IGF)- I and -II, IGF binding protein (IGFBP)-1 and -3, and the response of GH and IGFBP-1 and -3 to GH releasing hormone (GHRH) and GHRH plus arginine tests. GH and IGF-I basal concentrations were significantly higher in pre-menopausal than in post-menopausal women, while IGF-II, IGFBP-1 and IGFBP-3 concentrations did not vary significantly. IGFBP-1, but not IGFBP-3, concentrations were higher in lean than in obese patients. Insulin concentrations were significantly higher in obese patients, while no differences were observed between pre-menopausal and post-menopausal women. In all subjects, GH concentrations increased significantly during GHRH test; pre-menopausal and lean women showed a higher response compared to post-menopausal and obese women. The GHRH plus arginine test stimulated GH response in all women, irrespective of age and BMI. IGFBP-1 and -3 concentrations did not vary in response to GHRH or GHRH plus arginine tests. The somatotropic axis undergoes modifications in post-menopausal women, apparently not involving IGFBP- 1 and -3. Arginine infusion restores the response of GH to GHRH, in both post-menopausal and obese subjects. A somatostatinergic hyperactivity at the climateric period may underlie the changes both in body weight and somatotropic axis.      

Biochemical profile of fetal blood sampled by cordocentesis in 35 pregnancies complicated by growth retardation

AIM OF THE STUDY: Intra-uterine growth retardation (IUGR) is a frequent pathology in obstetrics characterized by high heterogeneity. Fetal smallness is sometimes constitutional, but can also be accompanied by fetal distress and vital risks for the infant. In 35 pregnancies complicated by IUGR of different etiologies, we measured on fetal blood obtained by cordocentesis, biochemical variables characteristic of the fetuses' respiratory and metabolic status. The aim of the study was to identify the discriminative biological alterations, related to growth retardation and fetal distress. PATIENTS AND METHODS: The studied population includes 27 cases of severe IUGR, of gestational age 30,2+/-4,6 weeks of gestation (WG) (divided into 20 cases of isolated IUGR and 7 cases of IUGR associated with malformative syndrome), as well as 8 cases of moderate IUGR, of gestational age 26+/-4,5 WG; all fetuses had normal karyotypes. A group of 73 normal fetuses, of gestational age 26,3+/-5,7 WG, constituted a reference population. PH, pCO(2), bicarbonate concentration, pO(2) and SaO(2), as well as glucose, pyruvate, lactate, free fatty acids, aceto-acetate, beta-hydroxybutyrate and cholesterol concentrations were measured on umbilical venous blood (UVB). RESULTS: In case of severe but isolated growth retardation, UVB analysis showed the frequency of acid-base and gasometric disturbances: acidemia and hypoxemia (65% of cases), hypercapnia (60% of cases). Metabolic abnormalities were shown: decrease in glycemia (35% of cases), increase in pyruvatemia and lactatemia (40% of cases), increased free fatty acids serum concentration; a diminution of umbilical venous cholesterol level, the most frequent abnormality, can be seen in 70% of fetuses. In case of severe IUGR associated with malformative syndrome, UVB acid-base and metabolic changes were rarely seen; however, UVB cholesterol level is low in some cases. In case of growth retardation classified as moderate, modifications are relatively not frequent and essentially gasometric. CONCLUSION: In about 60% of cases of severe and isolated IUGR, there is a risk of fetal distress, related to an alteration of the transplacental transfer of respiratory gases and nutritional substrates; chronic fetal malnutrition can be involved, with an impact on the growth of the fetus. In case of IUGR associated with malformative syndrome, fetal smallness is probably a result of intrinsic fetal damage, without nutritional origin.     

Insulin-like growth factor system in patients with HIV infection: effect of exogenous growth hormone administration.

The purpose of this study was to characterize changes in the levels of insulin-like growth factor-I (IGF-I) and IGF binding proteins (BP) 1, 2, and 3 in HIV-infected adults throughout the course of their disease, and to assess the responsiveness of the IGF system components to growth hormone (GH) administration (6 mg/day) for 2 weeks. Healthy control study subjects (n = 10) were compared with patients who were either HIV-positive (n = 9), had AIDS without weight loss (n = 13), or had AIDS with >10% weight loss (n = 6), all of whom had been free of acute illness for at least 3 months. Under basal conditions, fasting serum concentrations of epinephrine, norepinephrine, cortisol, glucagon, insulin, IGF-I, and IGFBP-3 were not significantly different among the four groups. The serum concentrations of IGFBP-1 and IGFBP-2 were significantly higher in AIDS patients with wasting than in the other three groups (p < .05). In addition, there was a statistically significant positive correlation between the levels of IGFBP- 1 (p = .004) and IGFBP-2 (p = .03) and the stage of disease. Following GH administration, the serum concentrations of insulin and IGF-I were increased in all groups (p < .05). In addition, the increases in insulin levels correlated with stage of disease (p = .004). The responses of the IGFBPs were more variable. GH administration significantly increased the levels of IGFBP-3 in all groups except the patients with AIDS wasting, whereas the levels of IGFBP-1 were significantly decreased in controls and AIDS patients. These results demonstrate that there is a continuum of both elevations in the IGFBPs and altered metabolic responsiveness in patients infected with HIV that increases with the severity of the disease. These data also demonstrate that AIDS patients, who are free from secondary infection, respond to administration of GH by significantly increasing hepatic IGF-I production.     

Insulin-like growth factor-binding proteins produced by Vero cells, human oviductal cells and human endometrial cells, and the role of insulin-like growth factor-binding protein-3 in mouse embryo co-culture systems

Co-culturing embryos on helper cells can mimic the in-vivo environment,thereby enhancing embryo development in vitro. Insulin-likegrowth factors (IGF) and their binding proteins (IGFBP) alsoenhance embryo development To investigate the kinds of IGFBPproduced by various cell monolayers and the effects of IGFBP-3on mouse embryo co-culture systems, 2-cell ICR mouse embryoswere cultured in either human tubal fluid medium alone or inthe presence of Vero cells, human oviductal cells or endometrialcells. The helper cells were analysed immunohisto-chemicallyto investigate the types of IGFBP produced by various cell monolayers.The concentrations of IGF-I and IGFBP-3 in media obtained fromthe culture of embryos alone, cells alone or cells plus embryoswere determined by radioimmunoassays. On day 7, more blastocystshatched in the co-culture groups (73% in the Vero cell group,76% in the endometrial cell group and 74% in the oviductal cellgroup) than in the control group (43%) (P < 0.0001). Theresults of immunohistochemistry revealed that (i) all threecell groups produced a lot of IGFBP-1, -2 and -3, but only alittle of IGFBP-4 and -5; and (ii) IGFBP-1, -2 and -3 were presentin blastocysts in either the presence or absence of helper cells.The IGF-I secreted by cell monolayers or embryos was undetectable(detection limit 0.83 ug/1). The IGFBP-3 concentrations in mediaobtained from co-cultured embryos and cells were significantlyhigher than in media without embryos (median values in oviductalcell culture medium, 165 versus 127 µg/1, P = 0.04; medianvalues in endometrial cell culture medium, 277.5 versus 183.5µg/1, P = 0.0002; median values in Vero cell culture medium,219 versus 120 µg/1, P = 0.011). Although IGFBP-3 concentrationin the medium that contained embryos alone was undetectableby radioimmuno-assay (detection limit 1.1 µg/1), immunohistochemistrydemonstrated the presence of IGFBP-3 in the embryos. Co-culturein systems in which there was an increased production of IGFBP-3led to an improved development of mouse embryos. IGFBP can improvethe binding of IGF to cell surface receptors of target tissue,and thus enhance the effect of limited IGF concentrations inpromoting embryo development in a co-culture system. We concludethat Vero cells, human endometrial cells and oviductal cellsproduce IGFBP-1, -2, -3, -4 and -5. IGFBP-3 may play a rolein embryotrophic potential by either regulating the action ofIGF or directly enhancing embryo development