Growth Factor Binding Protein-1 Concentrations Research Articles

Biochemical evidence of impaired trophoblastic invasion of decidual stroma in women destined to have preeclampsia

OBJECTIVE: Reduced trophoblastic migration into the decidua during the first half of pregnancy is a fundamental abnormality in preeclampsia. CA 125 and insulin-like growth factor binding protein-1 are major endometrial proteins whose primary sources are decidual epithelial and stromal cells, respectively. We hypothesized that reduced trophoblastic invasion in pregnancies destined for preeclampsia would affect the maternal vascular deportation of these decidual proteins. STUDY DESIGN: CA 125 and insulin-like growth factor binding protein-1 concentrations were analyzed by radioimmunoassays of plasma from preeclamptic and matched control patients in a longitudinal, nested case-control study. RESULTS: CA 125 concentrations did not differ with respect to pregnancy outcome or trimester. Midtrimester plasma insulin-like growth factor binding protein-1 concentrations were significantly lower in women who later had preeclampsia compared with normal pregnant controls. CONCLUSION: These findings provide biochemical evidence that abnormalities of trophoblastic invasion affect the maternal vascular deportation of a decidual stromal protein. Lower circulating concentrations of insulin-like growth factor binding protein-1 in women destined to have preeclampsia were observed 12 to 26 weeks before the onset of clinical signs of this syndrome. (Am J Obstet Gynecol 1996;175:24-9.)

The Effects of Repeated Daily Recombinant Human Insulin‐like Growth Factor I Administration in Adolescents with Type 1 Diabetes

Reduced insulin-like growth factor bioactivity has been linked to poor metabolic control and growth hormone hypersecretion in adolescents with Type 1 diabetes. The safety and efficacy of recombinant human insulin-like growth factor I administered subcutaneously in a dose of 40 micrograms kg-1 for 28 days was studied in a group of 6 adolescent male subjects with Type 1 diabetes (aged 13.6-19.4 years, puberty stage 3-5). After a 4-week run-in period (week -4 day 0) recombinant human insulin-like growth factor I was administered for 4 weeks (day 0 to week +4) before a run-out of a further 4 weeks duration (week +4 to +8). HbA1c levels were measured throughout the study and overnight profiles were undertaken to study levels of insulin-like growth factor 1, insulin-like growth factor binding protein-3, and growth hormone concentrations (week -1, day 0, and week +4). The injections were well tolerated and hypoglycaemia was not problematic at any stage of the study. Recombinant insulin-like growth factor I administration appeared to lead to a sustained increase in insulin-like growth factor I levels (week -1; 198 +/- 16 ng ml-1, week +4; 422 +/- 18 ng ml-1, mean +/- SEM; p = 0.03). Insulin-like growth factor binding protein-3 concentrations (n = 6) increased in 5 subjects (week -1; 4.5 +/- 0.3 micrograms ml-1, week +4; 5.1 +/- 0.4 micrograms ml-1) and mean overnight growth hormone decreased (week -1; 14.0 +/- 3.1 mUI-1, week +4; 7.6 +/- 1.7 mUI-1) during the period of study but these differences were not statistically significant. HbA1c levels fell significantly at the time of rhIGF-I administration (day 0; 10.4 +/- 1.9% vs week +4; 9.4 +/- 1.9%; p = 0.03) despite a reduction in subcutaneous isophane insulin dose from 0.50 +/- 0.02 U kg-1 to 0.41 +/- 0.02 U kg-1 (p = 0.03). There was no significant change in biochemical and haematological indices, glomerular filtration rate or urinary albumin excretion. The restoration of IGF-I levels in adolescents with Type 1 diabetes may have a beneficial impact on glycaemic control.

Third trimester fetal growth and umbilical venous blood concentrations of IGF-1, IGFBP-1, and growth hormone at term.

Insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-1 (IGFBP-1) and growth hormone (GH) concentrations were measured in umbilical venous blood after delivery of 78 term newborn infants. Three groups of pregnancies were prospectively identified during the third trimester, according to fetal size and subsequent fetal growth, assessed by repeated ultrasound scans. Fetal size was considered either appropriate for gestational age (AGA) or small for gestational age (SGA), according to whether the first ultrasound measurement of abdominal circumference was equal to or above, or below the tenth centile for gestational age, respectively. Subsequent fetal growth was quantified by the change in the standard deviation score of abdominal circumference measurements between the first and last scans before delivery. Fetal growth retardation (FGR) was defined as a (negative) change in SD score of greater than -1.5. Eighteen SGA fetuses with evidence of FGR had significantly lower IGF-1 (median 0.05 (range 0.0-0.24) U/ml) at delivery than 35 SGA fetuses with normal growth (median 0.13 (range 0.0-0.94) U/ml; P < 0.05) and 25 AGA fetuses with normal growth (median 0.31 (range 0.0-0.84) U/ml; P < 0.05). The median concentration in the SGA group with normal growth was also significantly lower than that of the AGA group with normal growth. There were no significant differences in IGFBP-1 or GH concentrations between the three groups. These observations indicate that umbilical blood concentrations at birth of IGF-1, but not IGFBP-1 or GH, relate to both fetal size and fetal growth during the third trimester of pregnancies reaching term.

Fetal plasma insulin-like growth factor-binding protein-3 concentrations are elevated following bilateral nephrectomy in fetal sheep.

Insulin-like growth factors mediate many of the effects of growth hormone and are important in the regulation of growth, especially in the fetus where growth is less dependent on circulating growth hormone. In the ovine fetus, insulin-like growth factor-I (IGF-I) is bound mainly to the low molecular weight insulin-like growth factor-binding proteins (IGFBP), IGFBP-1 and IGFBP-2, with little binding to IGFBP-3 until near term at 147 days gestation. To determine if there was any difference in plasma IGF-I and IGFBP-3 concentrations in growth-retarded fetal sheep with altered renal status, concentrations were measured by specific radioimmunoassay from bilaterally nephrectomized fetal sheep between Days 113 and 135 gestation. Plasma IGFBP-3 concentrations were significantly (P < 0.001) increased in bilaterally nephrectomized fetuses (4.19 +/- 0.19 micrograms mL-1, n = 7) compared with control fetuses (2.33 +/- 0.10 micrograms mL-1, n = 7). There was no change in plasma IGFBP-3 concentration with gestational age in either experimental group. Maternal plasma IGFBP-3 concentrations did not differ between the bilateral nephrectomy group (3.11 +/- 0.09 micrograms mL-1, n = 7) and the control group (3.25 +/- 0.11 micrograms mL-1, n = 7) and showed no change within groups over the experimental period. Total plasma IGF-I concentrations in bilaterally nephrectomized fetuses and ewes were similar to those in control fetuses and ewes. The results indicate that the profile of IGF binding in fetal plasma is altered in the anephric fetal sheep. In nephrectomized fetal sheep, increased IGFBP-3 concentrations, and therefore increased IGF-binding capacity in fetal plasma, may have contributed to a decrease in free IGF in plasma and decreased IGF-I bioactivity. This would provide a possible mechanism for the growth retardation reported in bilaterally nephrectomized fetal sheep.

The influence of ovarian follicular activity on late proliferative phase serum IGFBP-1 in down-regulated assisted conception cycles.

Serum insulin-like growth factor binding protein-1 (IGFBP-1) concentrations were measured at the end of the proliferative phase in infertility patients undergoing normal menstrual cycle frozen embryo transfer, exogenous hormone-supported frozen embryo transfer and in-vitro fertilization (IVF) treatment cycles. These patients were divided into five groups according to their ovarian follicular activity. The exogenous hormone-supported frozen embryo transfer group, who had no ovarian follicles, and the IVF groups (number of follicles ranging from 4-38) showed statistically higher serum IGFBP-1 concentrations when compared to the normal menstrual cycle group (P < or = 0.01). There was no significant difference in the serum IGFBP-1 concentrations between the exogenous hormone support frozen embryo transfer group and the poor or normal response IVF groups (number of follicles ranging from 4 to 16). An IVF group that displayed an excessive response to our standard human menopausal gonadotrophin stimulation (> 20 mature follicles or oestradiol > 10,000 pmol/l) showed a significantly higher serum IGFBP-1 concentration when compared with the other groups (P = 0.001). This subgroup was subsequently given a modified (follicle-stimulating hormone) stimulation regime which resulted in a significant reduction in serum IGFBP-1 concentrations (P < 0.05). There was no correlation between serum oestradiol and IGFBP-1 overall or within the patient groups. We conclude that serum IGFBP-1 concentrations in our down-regulated assisted conception cycles did not increase in line with ovarian follicular activity, unless an excessive response was displayed.

Fetal membrane rupture is associated with the presence of insulin-like growth factor-binding protein-1 in vaginal secretions

Our purpose was to determine whether detection of insulin-like growth factor-binding protein-1 in vaginal secretions could be used in the diagnosis of fetal membrane rupture. Consenting patients (n = 105) with complaints suspicious of membrane rupture between 24 and 42 weeks of gestation who had no evidence of placenta previa were enrolled in the study. The diagnosis of membrane rupture required at least two of the following findings on vaginal examination: pooling of fluid, positive Nitrazine paper (Bristol-Myers Squibb, Cherry Hill, N.J.) test, or microscopic evidence of ferning. A swab of the posterior vaginal fornix was obtained, placed in sample buffer, and analyzed for insulin-like growth factor-binding protein-1 by immunoassay. Data analysis included chi 2 analysis, Student t test, or Mann-Whitney U test and linear regression and receiver operating characteristic curve analysis. A total of 78 (74.3%) patients met the criteria for membrane rupture. There was a highly significant difference in mean vaginal insulin-like growth factor-binding protein-1 concentrations between patients with and without clinical evidence of membrane rupture (553.6 +/- 731.4 micrograms/L vs 3.0 +/- 7.3 micrograms/L, p = 0.0002). Receiver operating characteristic curve analysis demonstrated that the optimal identification of patients with membrane rupture was achieved with an insulin-like growth factor-binding protein-1 value > 3 micrograms/L (sensitivity 74.4%, 95% confidence interval 64.7% to 84.0%; specificity 92.6%, 95% confidence interval 82.7% to 102.5%; positive predictive value 96.7%, 95% confidence interval 92.1% to 101.2%; negative predictive value 55.6%, 95% confidence interval 41.0% to 70.1%). The presence of vaginal insulin-like growth factor-binding protein-1 is highly predictive of membrane rupture, identifying 74.4% of affected patients with a very low false-positive rate.

Short-term effect of recombinant human growth hormone in patients with alcoholic cirrhosis

As growth hormone possesses anabolic properties that are active on protein metabolism, and thus of potential benefit to patients with chronic liver disease, we determined the metabolic effects of recombinant human growth hormone on insulin-like growth factor-I (IGF-I) its specific binding proteins, and liver function. Twenty consecutive patients with cirrhosis were randomized to recombinant human growth hormone (Norditropin, 4 I.U. twice daily) subcutaneously for 6 weeks (n = 10) or conventional medical treatment (n = 10). The serum concentrations of insulin-like growth factor-I in the recombinant human growth hormone group increased after 3 (p < 0.01) and 6 weeks (p < 0.02), whereas no significant changes were observed in the control group. The change in insulin-like growth factor-I during the treatment period was expressed as area under the curve (AUC). The AUCIGF-I was significantly larger in the recombinant human growth hormone group (median AUCIGF-I: 12.1, range: 0.0-54.7 weeks.nmol/l) than in the control group (median AUCIGF-I: 0.2, range: -10.6-9.9 weeks.nmol/l) (p < 0.007). Insulin-like growth factor binding protein-3 concentrations increased in the recombinant human growth hormone treated patients as well as in controls, whereas no change in insulin-like growth factor binding protein-1 concentrations was found. No significant changes were seen in the area under the curve for biochemical liver function tests. We conclude that administration of recombinant human growth hormone induces an increase in very low levels of insulin-like growth factor-I, even in patients with cirrhosis with advanced disease, but the clinical benefits remain to be demonstrated.

Glucagon stimulates insulin-like growth factor binding protein-1 secretion in healthy subjects, patients with pituitary insufficiency, and patients with insulin-dependent diabetes mellitus.

Glucagon (1-1.5 mg) was administrated iv as a bolus dose to healthy individuals (n = 7), patients with GH deficiency (n = 14), and patients with insulin-dependent diabetes mellitus (IDDM; n = 6). Thereafter, blood samples for determination of serum glucose, insulin, insulin-like growth factor-binding protein-1 (IGFBP-1), GH, and insulin-like growth factor-I (IGF-I) concentrations were collected for 180 min. IGFBP-1 concentrations increased significantly in response to glucagon, with maximal values observed at 90 min [in healthy subjects from 36 +/- 6 to 58 +/- 10 micrograms/L (P < 0.05), in GH-deficient patients from 36 +/- 4 to 54 +/- 6 micrograms/L (P < 0.001), and in IDDM patients from 115 +/- 18 to 167 +/- 27 micrograms/L (P < 0.05)]. The IGFBP-1 elevation was delayed in relation to the glucagon-induced increase in glucose and insulin concentrations. When the groups were combined, the individual IGFBP-1 peak value observed at 90 min was inversely correlated to the individual peak value of insulin observed at 15-30 min (r = -0.743; P < 0.001). In GH-deficient patients, serum GH concentrations remained undetectable (< 0.2 micrograms/L), and IGF-I concentrations were unchanged after the glucagon injection. In healthy subjects and IDDM patients, mean GH levels did not change significantly, whereas mean IGF-I concentrations decreased slightly at 30 min. In conclusion, glucagon increased serum IGFBP-1 concentrations in spite of increases in glucose and insulin. These results suggest that glucagon is a stimulator of IGFBP-1.

Aging is associated with decreased suppression of insulin-like growth factor binding protein-1 by insulin.

We determined whether aging influences circulating insulin-like growth factor-binding protein-1 (IGFBP-1) concentrations and, if so, whether this effect is explained by altered regulation of IGFBP-1 by insulin. Fasting levels of glucose, insulin, and IGFBP-1 were measured in 94 healthy volunteers, ages 24-93 yr. To determine the effect of aging on insulin-induced suppression of IGFBP-1, an oral glucose tolerance test (OGTT) was performed in 10 older (72-92 yr) and 10 younger (24-58 yr) nonobese subjects, matched for sex and body mass index. For all ages combined, the mean glucose level (+/- SE) averaged 4.9 +/- 0.1 mmol/L, and there was no significant change with aging. Fasting insulin and IGFBP-1 concentrations increased with advancing age (r = 0.37, P < 0.001 for age vs. insulin and r = 0.47, P < 0.001 for age vs. IGFBP-1). However, there was no correlation between insulin and IGFBP-1 concentrations. In multiple linear regression analysis, the age-related increase in IGFBP-1 was independent of body mass index. During the OGTT, the mean insulin concentration was significantly higher in the older group compared with the younger group (P < 0.001). Serum IGFBP-1 concentrations were higher in the fasting state as well as during the OGTT, and the mean percent decrease of IGFBP-1 below baseline was significantly smaller in the older compared to the younger subjects at 3 h (35 +/- 5% vs. 55 +/- 2%, P < 0.01). We conclude that aging is associated with decreased suppression of serum IGFBP-1 by insulin, as demonstrated by 1) lack of the inverse correlation between fasting insulin and IGFBP-1 seen in young adults; 2) concurrent elevation of fasting insulin and IGFBP-1 concentrations; and 3) a blunted decrease in serum IGFBP-1 during an OGTT.

Evaluation of plasma insulin-like growth factor-binding protein-3 as a potential predictor of preeclampsia

Elevated growth factor activity in women with preeclampsia is caused by an acid- and heat-labile protein complex with a native molecular mass of 150,000. The major plasma insulin-like growth factor-binding protein-3 has identical molecular characteristics. We hypothesized that increased endothelial cell release or decreased proteolytic degradation of insulin-like growth factor-binding protein-3 in preeclampsia would result in higher circulating levels of insulin-like growth factors and hence in increased mitogenic activity. Plasma insulin-like growth factor-binding protein-3 concentrations were determined by iodine-125 insulin-like growth factor-II radioligand blots of nonreducing gels in 16 normal and 16 preeclamptic patients collected from a prospective, case-control study. Enzyme-linked immunosorbent assays also were performed with a specific anti-insulin-like growth factor-binding protein-3 antiserum. Insulin-like growth factor-binding protein-3 concentrations were not different between women with normal versus preeclamptic pregnancies (p = 0.23). Enzyme-linked immunosorbent assays confirmed these results in a subset of patients. The findings indicate that insulin-like growth factor-binding protein-3 concentrations do not account for the elevated mitogenic activity observed in plasma from women with preeclampsia and are not a useful screening test for preeclampsia risk.

The effect of estrogen level on glucose-induced changes in serum insulin-like growth factor binding protein-1 concentration

The effect of estrogen level on glucose-induced changes in serum insulin-like growth factor binding protein-1 concentration

The effect of estrogen level on glucose-induced changes in serum insulin-like growth factor binding protein-1 concentration

To investigate the regulation of insulin-like growth factor binding protein-1 (IGFBP-1) concentration during ovarian stimulation. A prospective study of patients undergoing in vitro fertilization treatment. Infertility unit at the University Central Hospital of Oulu, a tertiary referral center. Sixteen healthy, regularly menstruating lean tubal infertility patients. Oral glucose tolerance test was performed first in a hypoestrogenic state after suppression by long-term gonadotropin-releasing hormone (GnRH) agonist and, second, in a hyperestrogenic state after stimulation by human menopausal gonadotropins. Serum concentrations of IGFBP-1, insulin-like growth factor I (IGF-I), insulin and sex hormone-binding globulin were measured before and 2 hours after glucose administration. Before and after glucose administration, the serum IGFBP-1 concentrations were significantly higher in the hyperestrogenic state (estradiol [E2] level 3.5 +/- 0.57 nmol/L) after ovarian stimulation than in the GnRH-analogue-induced hypoestrogenic state before the gonadotropin treatment (E2 level 0.10 +/- 0.02 nmol/L). On both occasions glucose-induced hyperinsulinemia caused a significant decrease in the circulating IGFBP-1 levels, whereas the IGF-I levels remained unchanged. There was a significant correlation between E2 and the insulin-suppressed IGFBP-1 level. The sum of follicular diameters correlated positively with the serum IGFBP-1 concentration. Gonadotropin-induced hyperestrogenism is related to elevated serum IGFBP-1 levels, either via estrogen-stimulated synthesis or via increased contribution from multiple follicles. Glucose-induced hyperinsulinemia suppresses serum IBFBP-1 concentration equally both in the hypoestrogenic and hyperestrogenic states. Because of similar IGF-I levels, it is likely that the biological activity of IGF-I is different before and after gonadotropin stimulations.

Oral contraceptives increase insulin-like growth factor binding protein-1 concentration in women with polycystic ovarian disease

Insulin-like growth factor-I (IGF-I) stimulates ovarian androgen production. Insulin-like growth factor binding protein-1 (IGFBP-1) inhibits IGF actions in vitro. To investigate the effect of oral contraceptive (OC) pills, given for 3 months, on serum gonadotropin, androgen, IGF-I, and IGFBP-1 concentrations, and glucose tolerance in seven women with polycystic ovarian disease (PCOD) and in five healthy control subjects. Seven women with PCOD and five healthy control subjects. An oral glucose tolerance test (OGTT) was performed before and after treatment with OC. After treatment with OC, serum luteinizing hormone, androstenedione, and free testosterone levels decreased, and sex hormone-binding globulin concentration increased in the women with PCOD as well as in the control subjects. The cumulative response of serum insulin to OGTT was larger in the women with PCOD than in the control subjects both before and after treatment. Serum IGF-I concentration, which was unchanged during OGTT, decreased from basal level of 326 ± 70 μ g/L to 199 ± 28 μ g/L, after treatment with OC in the women with PCOD, whereas no change was found in the control subjects (from 235 ± 11 μ g/L to 226 ± 11 μ g/L). Treatment with OC caused an increase of the mean basal IGFBP-1 concentration from 24 ± 7 μ g/L to 73 ± 14 μ g/L, in the women with PCOD. This increase was constant during the OGTT. In the control subjects, treatment with OC did not result in any significant change in IGFBP-1 concentrations (from 44 ± 11 μ g/L to 61 ± 9 μ g/L). The combination of decreased total IGF-I concentration and increased IGFBP-1 concentration induced by OC may decrease ovarian androgen production in PCOD.

Insulin-Dependent Regulation of Insulin-Like Growth Factor-Binding Protein-1*

In previous studies it has been determined that food ingestion or glucose infusion suppresses serum insulin-like growth factor-binding protein-1 (IGFBP-1) concentrations in normal subjects. It has not been determined, however, whether glucose-dependent suppression is due to enhancement of insulin-stimulated glucose transport, to some other insulin-mediated effect, or to a direct effect of glucose. These studies were undertaken to determine if infusion of other nutrients or energy sources that activate glycolysis, but not insulin secretion, could lead to suppression of the plasma concentrations of this protein. After infusion of 50 g glucose over 4 h, the mean plasma IGFBP-1 concentration fell from 44.3 +/- 13.8 to 17.4 +/- 8.1 micrograms/L (P less than 0.001). In contrast, when 50 g fructose were infused over 4 h, IGFBP-1 decreased from 44.6 +/- 7.4 to only 32.7 +/- 6.7 micrograms/L (P less than 0.01). Comparison of these changes showed that the mean decrease after glucose infusion was significantly greater than that after fructose (P less than 0.01). In contrast to these decreases, infusion of an isocaloric amount of triglycerides resulted in no significant change in IGFBP-1 concentrations (from 49.8 +/- 14.1 to 40.2 + 10.4 micrograms/L; P = NS). Concomitant measurements of immunoreactive C-peptide during the glucose and fructose infusions showed that plasma C-peptide levels rose from 1.6 +/- 0.2 to 3.9 +/- 0.7 nM (P less than 0.001) during the glucose infusion, whereas the maximum increase was from 1.7 +/- 0.4 to only 2.3 +/- 0.4 nM (P less than 0.05) during the fructose infusion. The difference between these mean changes was also significant. The change in C-peptide correlated inversely with the changes in IGFBP-1 during the glucose infusion (r = -0.68); P less than 0.001), but not during fructose infusion (r = -0.31). The results of this study suggest that insulin stimulation of cellular metabolic pathways is an important variable regulating the suppression of plasma IGFBP-1 concentrations. Activation of noninsulin-dependent glycolytic pathways appears to result in an equivalent degree of suppression, whereas provision of other energy substrates has no effect. We conclude that both insulin and glucose are important regulators of plasma concentrations of IGFBP-1 in vivo, and in this way they may significantly influence IGF action.