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It is still unknown how insulin-like growth factor-I (IGF-I) regulates cancer cell growth in the condition of the limited availability of key nutrients, such as glutamine. We investigated the effects of IGF-I on cell growth and amino acid transport in a glutamine-deprived human neuroblastoma cell line, SK-N-SH. Cell growth was measured, and 3H-labeled amino acid transport was assayed after treatment with or without IGF-I (50 ng/ml) in 2 mM (control) and 100 microM glutamine concentrations. Cell growth rates were dependent on glutamine concentrations. IGF-I stimulated cell growth in both 2 mM and 100 microM glutamine. IGF-I stimulated glutamine transport in 100 microM glutamine with the mechanism of increasing carrier Vmax, but had no effect in 2 mM glutamine. IGF-I also stimulated leucine, glutamate and 2-(methylamino)isobutyric acid transport in 100 microM glutamine. There were significant increases in [3H]thymidine and [3H]leucine incorporation in IGF-I-treated cells in both 2 mM and 100 microM glutamine. These data suggest that IGF-I stimulates cell growth by increasing amino acid transport in the condition of low glutamine levels in a human neuroblastoma cell line. This mechanism may allow to maintain cell growth even in nutrient-deprived tumor tissues.

Co-culturing embryos on helper cells can mimic the in-vivo environment, thereby enhancing embryo development in vitro. Insulin-like growth factors (IGF) and their binding proteins (IGFBP) also enhance embryo development. To investigate the kinds of IGFBP produced by various cell monolayers and the effects of IGFBP-3 on mouse embryo co-culture systems, 2-cell ICR mouse embryos were cultured in either human tubal fluid medium alone or in the presence of Vero cells, human oviductal cells or endometrial cells. The helper cells were analysed immunohistochemically to investigate the types of IGFBP produced by various cell monolayers. The concentrations of IGF-I and IGFBP-3 in media obtained from the culture of embryos alone, cells alone or cells plus embryos were determined by radioimmunoassays. On day 7, more blastocysts hatched in the co-culture groups (73% in the Vero cell group, 76% in the endometrial cell group and 74% in the oviductal cell group) than in the control group (43%) (P < 0.0001). The results of immunohistochemistry revealed that (i) all three cell groups produced a lot of IGFBP-1, -2 and -3, but only a little of IGFBP-4 and -5; and (ii) IGFBP-1, -2, and -3 were present in 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 microg/l). The IGFBP-3 concentrations in media obtained from co-cultured embryos and cells were significantly higher than in media without embryos (median values in oviductal cell culture medium, 165 versus 127 microg/l, P = 0.04; median values in endometrial cell culture medium, 277.5 versus 183.5 microg/1, P = 0. 0002; median values in Vero cell culture medium, 219 versus 120 microg/l, P = 0.011). Although IGFBP-3 concentration in the medium that contained embryos alone was undetectable by radioimmunoassay (detection limit 1.1 microg/l), immunohistochemistry demonstrated the presence of IGFBP-3 in the embryos. Co-culture in systems in which there was an increased production of IGFBP-3 led to an improved development of mouse embryos. IGFBP can improve the binding of IGF to cell surface receptors of target tissue, and thus enhance the effect of limited IGF concentrations in promoting embryo development in a co-culture system. We conclude that Vero cells, human endometrial cells and oviductal cells produce IGFBP-1, -2, -3, -4 and -5. IGFBP-3 may play a role in embryotrophic potential by either regulating the action of IGF or directly enhancing embryo development.

Circulating levels of insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-1 (IGFBP-1) in Taiwanese women during normal pregnancy were investigated. Three hundred and eighty-five pregnant women at various gestational ages and 30 nonpregnant females were recruited into the study. Serum concentrations of IGF-I and IGFBP-1 were determined by immunoradiometric assay (IRMA) and radioimmunoassay (RIA). Maternal serum levels of IGF-I increased as pregnancy progressed. Circulating IGF-I levels in women during the first trimester of pregnancy were higher than those in nonpregnant females. Serum levels of IGFBP-1 rose rapidly before 12 weeks of gestation and remained high until term. Serum IGFBP-1 levels in pregnant women during the first trimester were significantly higher than those in nonpregnant females. However, there was no difference in maternal serum IGFBP-1 levels between the second and the third trimester of pregnancy. It is concluded that serum IGF-I levels during pregnancy may be regulated by various classes of IGF-binding proteins other than IGFBP-1.

Objective: To investigate the cyclic changes of serum insulin-like growth factor (IGF-I), IGF-binding protein-1 (IGFBP-1) and IGFBP-3 levels during ovulatory menstrual cycle., Design: A prospective study following a preset protocol., Setting: A tertiary-care academic medical center., Participants: Thirty young female adults with regular menstrual cycles were recruited (18 with normal luteal phase and 12 with inadequate luteal function confirmed by serum P levels)., Main Outcome Measures: Serum concentrations of IGF-I, IGFBP-1, and IGFBP-3 from women with regular menstrual cycles were assayed. Circulating E2 and P levels also were determined to certify the ovulatory cycles., Results: In women with normal luteal function, there was a peak of serum IGFBP-1 levels before ovulation concomitant with the preovulatory E2 peak. The nadir of serum IGFBP-1 levels was in the midluteal phase. Circulating IGFBP-1 elevated rapidly during late luteal phase and reached a peak on the 1st day of menstruation then declined slightly until a preovulatory IGFBP-1 peak occurred. In women with inadequate luteal function (midluteal serum levels of P < 10 ng/mL [conversion factor to SI unit, 3.180]), the preovulatory increase in serum IGFBP-1 was not significant and the circulating IGFBP-1 levels fluctuated throughout the menstrual cycle except for a unique peak of serum IGFBP-1 on the 1st day of menstruation. By contrast, there were no cyclic changes of serum IGF-I and IGFBP-3 levels in women with regular menstrual cycles, including both normal nad inadequate luteal functions., Conclusions: The preovulatory increase in serum IGFBP-1 levels may be of follicular origin and associated with the subsequent luteal function in females with ovulatory cycles. However, the involvement of IGFBP-1 in the process of follicular maturation and luteogenesis, as well as the regulation of luteal function, needs to be explored further.

Background: The purposes of this study were to explore whether serum levels of insulin, insulin-like growth factor-I (IGF-I), insulin-like growth factor-binding protein-1 (IGFBP-1) and IGFBP-3 in both maternal and fetal compartments were affected by the stress of labor, and to investigate the relationship between the fetal birthweight and serum levels of insulin, IGF-I and IGFBPs., Methods: Blood samples were collected at the time of delivery from 147 parturients with vaginal delivery and 128 cases of Cesarean section (112 cases without labor and 16 cases with arrest of cervical dilatation during the active phase of labor). Serum concentrations of insulin, IGF-I, IGFBP-1 and IGFBP-3 were determined by radioimmunoassays (insulin, IGFBP-1 and IGFBP-3) and immunoradiometric assay (IGF-I)., Results: Maternal circulating IGFBP-1 levels in parturients with normal spontaneous delivery (NSD) and in subjects receiving Cesarean section (CS) due to arrest of cervical dilatation during active phase of labor were higher than those undergoing scheduled CS without labor. By contrast, insulin levels in both maternal and umbilical cord serum were higher in parturients with CS without labor than those with NSD. No difference in maternal serum IGFBP-3 levels was observed between NSD and CS at the time of delivery. As for all measurements (insulin, IGF-I, IGFBP-1 and IGFBP-3), serum levels in pregnant women (from both NSD and CS) were strikingly higher than those in the fetus. Serum levels of IGFBP-1 in umbilical cords from both groups of NSD (p < 0.02) and scheduled CS (p < 0.01) were inversely correlated with birthweight (BW). By contrast, serum concentration of insulin and IGF-I in umbilical cords from NSD (p < 0.005 and p < 0.01; respectively) and scheduled CS (p < 0.01 and p < 0.05; respectively) were positively related to BW., Conclusions: From the present results, we conclude that insulin appears to be a regulator for circulating IGFBP-1 during pregnancy. The fetal growth may not be well reflected by maternal serum IGFBP-1 levels, nor by IGFBP-3. By contrast, cord serum IGFBP-1 from CS group without labor may preeminently reflect fetal weight. In additional, serum concentration of insulin and IGF-I in umbilical cord may also be good indicators to reflect the result of neonatal birthweight.

Objective: To evaluate interrelationships between levels of insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein (IGFBP-I), and ovarian steroids in late preovulatory follicular fluid (FF) after pituitary desensitization with GnRH agonist and controlled ovarian hyperstimulation., Design: Follicular fluid and matched serum were collected during the ovum pick-up. Insulin-like growth factor binding protein I, E2, P, and androstenedione (A) were measured by means of RIA, whereas T was measured by means of fluoroimmunoassay and IGF-I by means of immunoradiometric assay., Setting: University teaching hospital., Participants: Fifty-nine patients underwent 62 ovum pick-ups for IVF., Main Outcome Measures: Levels of IGF-I, IGFBP-I, E2, P4 (representative of follicular maturity), T, and A in FF and the volume of this fluid were determined. Levels of E2 to A (representative of aromatase activity) in FF were examined in relation to the volume of FF., Results: Levels of FF-IGF-I decreased with increasing volume of FF. This observation is unprecedented. In contrast, FF-P increased with increasing volume of FF. The reverse relationships with FF volume between FF-IGF-I and FF-P may not be causal because no correlation was found between concentrations of FF-IGF-I and FF-P. Our findings are consistent with and complementary to those in previous reports. The follicular fluid E2:A ratio, FF-E2, FF-A, FF-T, and FF-IGFBP-I were not found to be correlated with volume of FF., Conclusion: Decreased levels of FF-IGF-I with unaltered levels of FF-IGFBP-I in larger follicles may favor a shift toward diminished action of IGF-I at the time of immediate preovulation. The physiological significance of this shift remains uncertain as it is not reflected in the levels of steroids in FF.

Objective: To investigate the relationship between preterm delivery and maternal serum insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-1 (IGFBP-1) levels., Design: A study over a 12 month period in which all samples were collected according to a pre-set protocol., Setting: St. Bartholomew's Hospital, London., Subjects: Thirty-eight nonpregnant adult females, 456 pregnant women at various gestational ages, 84 women with average-for-gestational-age babies at term delivery, and 49 pregnant women with preterm delivery (44 with singleton pregnancy and five with twin pregnancy)., Main Outcome Measures: Serum IGF-I and IGFBP-1 levels were determined by radioimmunoassay., Results: Serum IGF-I concentrations increased as pregnancy progressed. In the third trimester, serum IGF-I levels in singleton preterm deliveries were lower than those in normal pregnancies, and IGFBP-1 concentrations were higher than those in normal pregnancies. This phenomenon was not obvious in the second trimester. Maternal circulating IGFBP-1 levels were correlated inversely with birthweight in women with singleton preterm delivery., Conclusions: Neither IGF-I nor IGFBP-1 appears to play a significant role in preterm delivery since maternal serum IGF-I and IGFBP-1 levels are similar in preterm and term deliveries.

Insulin-like growth factor-binding proteins (IGFBPs) in sera from non-pregnant and pregnant women, and from the umbilical cord at the time of delivery, were separated by gel filtration chromatography. The binding characteristics of the 150 and 40 kDa binding proteins were examined by Scatchard analysis. In serum from pregnant women, the affinity of the 150 kDa binding proteins (IGFBP-3) decreased as pregnancy progressed, with an apparent increase in the maximum binding capacity. In contrast, the affinity of the 40 kDa binding proteins showed a slight increase. In umbilical cord serum, the binding affinity of both the 150 and 40 kDa binding proteins was similar, whereas the binding capacity was two-fold higher in the 40 kDa than in the 150 kDa group. Both maternal and umbilical cord serum (artery and vein) contained unoccupied IGFBPs. Following acid treatment, there was an increase in binding of 125I-IGF-I to umbilical cord serum but a decrease in that to maternal serum. These changes in the characteristics of the binding proteins in the pregnancy sera are probably due to partial degradation of the 150 kDa binding proteins by proteases. The present data confirm that IGFBP-3 is the main binding protein for IGFs during pregnancy, although its affinity is decreased. In fetal circulation, the 40 kDa binding proteins appear to be the major IGFBP with a high affinity and high capacity.

Insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-1 (IGFBP-1) were measured in amniotic fluid, extraembryonic coelomic fluid and maternal serum from 23 women with apparently normal first trimester pregnancies prior to termination. The levels of IGF-1 and IGFBP-1 were significantly higher in coelomic fluid than amniotic fluid (IGF-1, P = 0.006; IGFBP-1, P = 0.0008 (paired t-test)). The levels of IGFBP-1 were lower in amniotic fluid than in maternal serum (P = 0.017), a finding in sharp contrast to the situation in the second and third trimesters of pregnancy. There was a significant relation between levels of IGF-1 and IGFBP-1 in amniotic fluid (r = 0.43; P = 0.04) and in coelomic fluid (r = 0.81; P less than 0.001) but not in maternal serum. The finding that both the absolute levels of IGFBP-1 and the ratio to IGF-1 were low in amniotic fluid implies that there is a very high level of unbound, biologically active IGF-1 in this compartment in the first trimester. Thus, the regulatory role of IGFBP-1 may change as pregnancy advances.

Serum levels of insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-1 (IGFBP-1) have been determined by radioimmunoassay in the maternal circulation (n = 91) and in the umbilical artery (n = 56) and vein (n = 90) of man. In both the umbilical artery and vein, the concentration of serum IGF-I showed an inverse correlation with birthweight (P less than 0.005 and P less than 0.001 respectively); the mean serum IGF-I levels in the small-for-gestational-age (SGA) group were significantly higher than those in average-for-gestational-age (AGA) neonates (P less than 0.01 and P less than 0.001 respectively). However, maternal serum IGF-I showed no association with birthweight and there was no significant difference between the SGA and AGA groups. These observations imply that the production of IGF-I in the maternal and fetal compartments is independent and that there is unlikely to be transfer of IGF-I across the placenta. Serum IGFBP-1 levels in both maternal and umbilical cord blood (artery and vein) showed an inverse relation to birthweight (P less than 0.001, P less than 0.005 and P less than 0.001 respectively). Increased IGFBP-1 levels in the umbilical artery and vein were observed in the SGA group. These findings suggest that IGFBP-1 might inhibit the action of IGF-I in both the maternal and the fetal compartments and that the rise in IGFBP-1 could be a primary factor in retardation of fetal growth. Alternatively, circulating IGF-I and IGFBP-1 levels may only be a secondary reflection of local tissue events involved in fetal growth.