Growth Factor Binding Protein-1 Concentrations Research Articles

SUN-267 Relationship between Height Velocity and Change of Serum Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor Binding Protein-3 Concentrations during Gonadotropin-Releasing Hormone Agonist Treatment in Korean Girls with Idiopathic Central Precocious Puberty

Purpose : This study aims to investigate the effect of gonadotropin-releasing hormone agonist (GnRHa) on the growth velocity during treatment in Korean girls with idiopathic central precocious puberty (ICPP). Methods : Data was collected from 97 girls, diagnosed under 9 year of age and treated by GnRHa for at least 1 year between 2014 and 2015. Their body height, weight, ∆ Height standard deviation score (SDS), serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) concentrations and bone age were measured at the start and after a year of GnRHa treatment. Possible correlations between the variables were calculated. Results : During the treatment, height SDS, IGF-1 SDS, IGFBP-3 SDS and IGF-1/IGFBP-3 ratio significantly decreased. There were significant correlations between serum IGF-1 level and ∆ Height SDS (r=0.405, p=0.000), and between serum IGFBP-3 level and ∆ Height SDS (r=0.228, p=0.025). C allele had significant correlation with IGFBP-3 level (p=0.004) but had no significant correlation with ∆ Height SDS (p=0.947). Conclusions : The results suggest that the height velocity during GnRHa treatment may be related to serum IGF-1 and IGFBP-3 concentration thus GnRHa may affect GH-IGF-1 axis.

The Relevance of Insulin-Like Growth Factor-1 and Insulin-Like Growth FactorBinding Protein-3 Concentrations as a Screening Test for Diagnosis of Growth Hormone Deficiency

Background and objective: Growth hormone deficiency (GHD) is one of the most important endocrine and treatable causes of short stature. Reports regarding the sensitivity and specificity of insulin-like growth factor-1 (IGF-1) and IGF binding protein-1 (IGFBP-3) are not consistent. The aim of our study was to analyze the relevance of IGF-1 and IGFBP-3 concentrations as a screening test for diagnosis of GHD. Design: We retrospectively studied 40 patients whom were evaluated for short stature at the Endocrinology Department of King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia between January 2015 to December 2018. For IGF-1 and IGFBP-3 concentrations, laboratory reference ranges were based on age and sex. For all eligible patients, IGF-1 and IGFBP-3 concentrations were determined and an insulin tolerance test (ITT) was performed. Patients with a peak GH of ≤5.0 ng/ml were considered to be GHD. Results: We retrospectively included 40 patients evaluated for SS for analysis. Mean age was 14.7 ±1.7 years. There were 38 males (80.9%) and 9 females (19.1%) and mean IGF-1 concentration was 146.4 ±69.4 ng/dl. The observed male to female ratio was 4.2:1. Results from the ITT indicated that 27 (57.4%) had GHD. Age was not statistically significant different between GHD (14.7 ±1.8 years) and non-GHD (14.8 ±1.6 years), p=0.9. Moreover, there was non statistical significant more males (59%) than females (50%) in the GHD patients, P=0.7. In addition, there were not statistically significantly different between GHD and non-GHD patients in mean IGF-1 concentration (156.0 ±71.1 ng/dl vs. 140.8 ±68.1 ng/dl, p=0.5) and IGFBP-3 concentration (3752.9 ±1295.9mcg/L vs. 3816.8 ±867.0mcg/L, p=0.9). The mean peak for GH concentration was significantly lower in patients with GHD than without GHD (2.2 ±1.3 ng/ml vs. 9.9 ±5.6 ng/ml, p<0.0001). Peak GH concentration was not significantly positively correlated with IGF-1 concentration (r=0.181, P=0.3) and IGFBP-3 concentration (r=0.103, P=0.5). With a threshold of IGF-1 concentration, sensitivity was 48% (95% confidence interval (95%CI); 26%, 70%), specificity was 37% (95%CI; 16%, 62%) and the negative predictive value for the diagnosis of GHD was 39% (95% CI; 24%, 57%). With a threshold of IGF-1+IGFBP-3 concentration, the sensitivity was 19% (95% CI; 5%, 42%) and the specificity was 89% (95%CI; 67%, 99%). A positive predictive value of 67% (95% CI; 29%, 91%) but a negative predictive value of 50% (95%CI; 44%, 56%). 17 of the patients with IGF-1+IGFBP-3 concentration above the threshold (N = 34) were normal and 17 had GH deficiency. These 17 GHD patients had IGF-1+IGFBP-3 concentration below the reference range for age and sex that did not differ significantly from those of their GH-sufficient counterparts (66.7% vs 50% , P=0.7) respectively. If IGF1+IGFBP-3 concentration was used as a screening test (with a concentration threshold below the reference range for age and sex) and ITT as a confirmatory test, 34 (85%) out of 40 ITT would not have been performed, leading to the misdiagnosis of 17 GH-deficient adults. Thus, in our study population, such a procedure would misdiagnose 17 out of 21 GHD patients (81%) and yield a sensitivity of 19%. Conclusion: Our study demonstrated the good negative predictive value of IGF-1+IGFBP-3 concentration for the diagnosis of GHD, making it possible to minimize the use of the “reference test” method ITT. This observation remains to be validated by population-based studies.

Markers of Systemic Inflammation and Environmental Enteric Dysfunction Are Not Reduced by Zinc or Multivitamins in Tanzanian Infants: A Randomized, Placebo-Controlled Trial

ObjectiveTo examine whether daily zinc and/or multivitamin supplementation reduce biomarkers of environmental enteric dysfunction (EED), systemic inflammation, or markers of growth in a sample of infants from Dar es Salaam, Tanzania.Study designSubgroup analysis of infants participating in a randomized, double-blind, placebo-controlled trial received daily oral supplementation of zinc, multivitamins, zinc + multivitamins, or placebo for 18 months starting at 6 weeks of age. EED (anti-flagellin and anti-lipopolysaccharide immunoglobulins), systemic inflammation (C-reactive protein and alpha-1-acid glycoprotein), and growth biomarkers (insulin-like growth factor-1 and insulin-like growth factor binding protein-3) were measured via enzyme-linked immunosorbent assay in a subsample of 590 infants at 6 weeks and 6 months of age. EED biomarkers also were measured in 162 infants at 12 months of age.ResultsWith the exception of anti-lipopolysaccharide IgG concentrations, which were significantly greater in infants who received multivitamins compared with those who did not (1.41 ± 0.61 vs 1.26 ± 0.65, P = .006), and insulin-like growth factor binding protein-3 concentrations, which were significantly lower in children who received zinc compared with those who did not (981.13 ± 297.59 vs 1019.10 ± 333.01, P = .03), at 6 months of age, we did not observe any significant treatment effects of zinc or multivitamins on EED, systemic inflammation, or growth biomarkers.ConclusionsNeither zinc nor multivitamin supplementation ameliorated markers of EED or systemic inflammation during infancy. Other interventions should be prioritized for future trials.Trial registrationClinicaltrials.gov: NCT00421668.

Current practice in diagnosis and treatment of growth hormone deficiency in childhood: a survey from Turkey.

Objective:Approaches to diagnosis and treatment of growth hormone deficiency (GHD) in children vary among countries and even among centers in the same country. This survey, aiming to facilitate the process of preparing the new consensus on GHD by the Turkish Pediatric Endocrinology and Diabetes Society, was designed to evaluate the current practices in diagnosis and treatment of GHD in different centers in Turkey. Methods:A questionnaire covering relevant items for diagnosis and treatment of GHD was sent out to all pediatric endocrinology centers.Results:Twenty-four centers returned the questionnaire. The most frequently used GH stimulation test was L-dopa, followed by clonidine. Eighteen centers used a GH cut-off value of 10 ng/mL for the diagnosis of GHD; this value was 7 ng/mL in 4 centers and 5 ng/mL in 2 centers. The most frequently used assay was immunochemiluminescence for determination of GH, insulin-like growth factor-1 and insulin-like growth factor binding protein-3 concentrations. Sex steroid priming in both sexes was used by 19 centers. The most frequently used starting dose of recombinant human GH (rhGH) in prepubertal children was 0.025-0.030 mg/kg/day and 0.030-0.035 mg/kg/day in pubertal children. Growth velocity was used in the evaluation for growth response to rhGH therapy in all centers. Anthropometric measurements of patients every 3-6 months, fasting blood glucose, bone age and thyroid panel evaluation were used by all centers at follow-up. Main indications for cessation of therapy were decreased height velocity and advanced bone age. Fourteen centers used combined treatment (rhGH and gonadotropin-releasing analogues) to increase final height.Conclusion: Although conformity was found among centers in Turkey in current practice, it is very important to update guideline statements and to modify, if needed, the approach to GHD over time in accordance with new evidence-based clinical studies.

Final height and insulin-like growth factor-1 in children with medulloblastoma treated with growth hormone

Medulloblastoma is a highly malignant childhood brain tumor. Survival from medulloblastoma is increasing. This study was performed to examine growth outcomes, insulin-like growth factor-1(IGF-1), and response to growth hormone (GH) treatment in children with medulloblastoma. Retrospective analysis of 34 children treated with GH for medulloblastoma was performed. We evaluated serum IGF-1 and insulin-like growth factor binding protein-3 concentrations. Further, we examined growth status and changes with GH treatment according to treatment modality. GH deficiency was observed in 28 patients (82 %). The initial height at the start of GH treatment was -2.35 ± -1.53 standard deviation score (SDS) and increased to -1.85 ± -1.28 SDS by 1 year, -1.64 ± -1.46 SDS by 2 years, and -1.42 ± -1.49 SDS by 3 years after GH treatment. The final height was -1.54 ± -1.06 SDS. Gender, surgical method, tumor location, tumor size, and type of radiation did not correlate with height gain. A younger age at the initiation of GH treatment correlated with height gain. The initial serum IGF-1 concentration was -1.73 ± -0.42 and increased significantly to -0.74 ± -0.21 SDS by 1 year after GH treatment. The serum IGF-1 SDS increment correlated significantly with height gain. Beginning GH treatment at a younger age was an important prognostic factor for growth outcome. Serum IGF-1 increment correlated with height gain during GH treatment. Thus, early GH treatment and analysis of serum IGF-1 might be helpful for improving final height or growth outcome.

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To examine whether daily zinc and/or multivitamin supplementation reduce biomarkers of environmental enteric dysfunction (EED), systemic inflammation, or markers of growth in a sample of infants from Dar es Salaam, Tanzania.Subgroup analysis of infants participating in a randomized, double-blind, placebo-controlled trial received daily oral supplementation of zinc, multivitamins, zinc + multivitamins, or placebo for 18 months starting at 6 weeks of age. EED (anti-flagellin and anti-lipopolysaccharide immunoglobulins), systemic inflammation (C-reactive protein and alpha-1-acid glycoprotein), and growth biomarkers (insulin-like growth factor-1 and insulin-like growth factor binding protein-3) were measured via enzyme-linked immunosorbent assay in a subsample of 590 infants at 6 weeks and 6 months of age. EED biomarkers also were measured in 162 infants at 12 months of age.With the exception of anti-lipopolysaccharide IgG concentrations, which were significantly greater in infants who received multivitamins compared with those who did not (1.41 ± 0.61 vs 1.26 ± 0.65, P = .006), and insulin-like growth factor binding protein-3 concentrations, which were significantly lower in children who received zinc compared with those who did not (981.13 ± 297.59 vs 1019.10 ± 333.01, P = .03), at 6 months of age, we did not observe any significant treatment effects of zinc or multivitamins on EED, systemic inflammation, or growth biomarkers.Neither zinc nor multivitamin supplementation ameliorated markers of EED or systemic inflammation during infancy. Other interventions should be prioritized for future trials.Clinicaltrials.gov: NCT00421668.

Elevated C-peptide and insulin predict increased risk of colorectal adenomas in normal mucosa

BackgroundLower concentrations of the insulin–like growth factor binding protein-1 (IGFBP-1) and elevated concentrations of insulin or C-peptide have been associated with an increase in colorectal cancer risk (CRC). However few studies have evaluated IGFBP-1 and C-peptide in relation to adenomatous polyps, the only known precursor for CRC.MethodsBetween November 2001 and December 2002, we examined associations between circulating concentrations of insulin, C-peptide, IGFBP-1 and apoptosis among 190 individuals with one or more adenomatous polyps and 488 with no adenomatous polyps using logistic regression models.ResultsIndividuals with the highest concentrations of C-peptide were more likely to have adenomas (OR = 2.2, 95% CI 1.4-4.0) than those with the lowest concentrations; associations that appeared to be stronger in men (OR = 4.4, 95% CI 1.7-10.9) than women. Individuals with high insulin concentrations also had a higher risk of adenomas (OR = 3.5, 95% CI 1.7-7.4), whereas higher levels of IGFBP-1 were associated with a reduced risk of adenomas in men only (OR = 0.3, 95% CI 0.1-0.7). Overweight and obese individuals with higher C-peptide levels (>1st Q) were at increased risk for lower apoptosis index (OR = 2.5, 95% CI 0.9-7.1), an association that remained strong in overweight and obese men (OR = 6.3, 95% CI 1.0-36.7). Higher levels of IGFBP-1 in overweight and obese individuals were associated with a reduced risk of low apoptosis (OR = 0.3, 95% CI 0.1-1.0).ConclusionsAssociations between these peptides and the apoptosis index in overweight and obese individuals, suggest that the mechanism by which C-peptide could induce adenomas may include its anti-apoptotic properties. This study suggests that hyperinsulinemia and IGF hormones predict adenoma risk, and that outcomes associated with colorectal carcinogenesis maybe modified by gender.

Loss of the pregnancy-induced rise in cortisol concentrations in the ewe impairs the fetal insulin-like growth factor axis

Maternal cortisol levels increase during pregnancy. Although this change is important for optimal fetal growth, the mechanisms of the changes in growth remain unclear. The hypothesis examined was that alterations in maternal plasma cortisol concentrations are associated with changes in the fetal insulin-like growth factor (IGF) axis. Pregnant ewes in late gestation (115 ± 0.4 days) were studied: six control animals, five ewes given 1 mg kg(-1) day(-1) cortisol (high cortisol) and five adrenalectomised ewes given 0.5-0.6 mg kg(-1) day(-1) cortisol (low cortisol). Blood samples were taken throughout the experiment and at necropsy (130 ± 0.2 days) and fetal liver was frozen for mRNA analysis. Fetal IGF-I and insulin plasma concentrations were lower and insulin-like growth factor-binding protein-1 (IGFBP-1) concentrations were higher in the low cortisol group compared with those in the control group (P < 0.05). Fetal liver IGF-II and IGFBP-3 mRNA were decreased in low cortisol animals compared with controls (P < 0.05). There were no significant changes in these parameters in the high cortisol group, and there were no changes in fetal liver IGF-I, growth hormone receptor, IGF-I receptor, IGF-II receptor, IGFBP-1 or IGFBP-2 mRNA levels between the groups. These data suggest that reduced fetal IGF availability contributes to reduced fetal growth when maternal cortisol secretion is impaired, but not during exposure to moderate increases in cortisol.

Proteomic profiling of amniotic fluid in preterm labor using two-dimensional liquid separation and mass spectrometry

Objective. Simultaneous analysis of the protein composition of biological fluids is now possible. Such an approach can be used to identify biological markers of disease and to understand the pathophysiology of disorders that have eluded classification, diagnosis, and treatment. The purpose of this study was to analyze the differences in protein composition of the amniotic fluid of patients in preterm labor.Study design. Amniotic fluid was obtained by amniocentesis from three groups of women with preterm labor and intact membranes: (1) women without intra-amniotic infection/inflammation (IAI) who delivered at term, (2) women without IAI who delivered a preterm neonate, and (3) women with IAI. Intra-amniotic infection was defined as a positive amniotic fluid culture for microorganisms. Intra-amniotic inflammation was defined as an elevated amniotic fluid interleukin (IL)-6 (≥2.3 ng/mL). Two-dimensional (2D) chromatography was used for analysis. The first dimension separated proteins by isoelectric point, while the second, by the degree of hydrophobicity. 2D protein maps were generated using different experimental conditions (reducing agents as well as protein concentration). The maps were used to discern subsets of isoelectric point/hydrophobicity containing differentially expressed proteins. Protein identification of differentially expressed fractions was conducted with mass spectrometry. Enzyme-linked immunosorbent assays (ELISA) as well as surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS)-based on-chip antibody capture immunoassays were also used for confirmation of a specific protein that was differentially expressed.Results. (1) Amniotic fluid protein composition can be analyzed using a combination of 2D liquid chromatography and mass spectrometry for the identification of proteins differentially expressed in patients in preterm labor. (2) While total insulin-like growth factor-binding protein-1 (IGFBP-1) concentration did not change, IGFBP-1 fragments at about 13.5 kDa were present in patients with IAI. (3) Proteins that were over-expressed in group 1 included von Ebner gland protein precursor, IL-7 precursor, apolipoprotein A1, tropomyosin sk1 (TPMsk1) fragment, ribosomal protein S6 kinase alpha-3, and alpha-1-microglobulin/bikunin precursor (AMBP). (4) Proteins that were over-expressed in group 3 included fibrinopeptide B, transferrin, major histocompatibility complex (MHC) class 1 chain-related A antigen fragment, transcription elongation factor A, sex-determining region Y (SRY) box 5 protein, Down syndrome critical region 2 protein (DSCR2), and human peptide 8 (HP8). (5) One protein, retinol-binding protein, was over-expressed in women who delivered preterm, regardless of the presence of IAI.Conclusions. A combination of techniques involving 2D chromatography, mass spectrometry, and immunoassays allows identification of proteins that are differentially regulated in the amniotic fluid of patients with preterm labor. Specifically, the amount of the IGFBP-1 fragments at approximately 13.5 kDa was found to be increased in patients with IAI, while the amount of the intact form of IGFBP-1 was decreased.

Racial Differences in Prognostic Value of Adult Height for Biochemical Progression Following Radical Prostatectomy

Adult height, as a surrogate of childhood and adolescent hormone activity and diet, has been associated with the risk for development and death from prostate cancer in predominantly White populations. However, hormonal activity and diets vary between races. We examined whether height was significantly associated with biochemical progression following radical prostatectomy and whether there was an interaction between height and race. Multivariate Cox proportional hazards analysis was used to determine if height significantly predicted biochemical progression among 1,503 men (450 Black and 1,053 White) treated with radical prostatectomy between 1988 and 2003. We examined for possible interactions between height and race. Taller men (>175.3 cm) were significantly younger (P = 0.001), treated in more recent years (P = 0.02), had more clinical stage T(1) disease (P = 0.001), and were less likely to have extraprostatic extension (P = 0.02) than shorter men (< or =175.3 cm). Height was not significantly related to race, preoperative serum prostate-specific antigen concentrations, biopsy or pathologic Gleason sum, positive surgical margins, seminal vesicle invasion, or lymph node metastasis. Height was significantly associated with progression among Black men [relative risk (RR), 1.67; 95% confidence interval (95% CI), 1.00-2.79] but not among White men (RR, 1.03; 95% CI, 0.77-1.38). The interaction between race and height for predicting biochemical progression was statistically significant (P(interaction) = 0.05). There was an interaction between height and race in that height predicted progression for Black men but not for White men. The explanation for these findings is unclear, although lower insulin-like growth factor-binding protein-3 concentrations among Black men may be involved.

Infliximab reverses growth hormone resistance associated with inflammatory bowel disease

Increasing evidence shows that inflammation plays a major role in the aetiology of catabolism and wasting observed in inflammatory bowel disease via growth hormone resistance. To evaluate the effect of infliximab treatment on the growth hormone/insulin-like growth factor-1 axis. Fourteen adults with active Crohn's disease or ulcerative colitis underwent three infliximab infusions at a dose of 5 mg/kg for induction of remission, plus two maintenance infusions 8 weeks apart. Blood samples were collected for the analysis of serum growth hormone, insulin-like growth factor-1, insulin-like growth factor-binding protein-3 and acid labile subunit. Serum insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 concentrations, which were significantly lower in inflammatory bowel disease patients before treatment compared with controls (P < 0.01), significantly increased during the induction phase (+58% and +29%, respectively, after the second infusion, P < 0.01), and dropped to baseline levels during maintenance therapy. Both insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 showed significant negative correlations with C-reactive protein (rho = -0.37, P = 0.002; rho = -0.35, P = 0.01, respectively). Growth hormone and acid labile subunit levels were not statistically different between controls and inflammatory bowel disease patients either at baseline or during treatment. Infliximab induction treatment reverses growth hormone resistance observed in active inflammatory bowel disease through the suppression of systemic inflammation. The restored growth hormone/insulin-like growth factor-1 axis is impaired again following the prolonged interval between maintenance infusions, possibly because of the subclinical reactivation of the inflammatory process.

Maternal plasma concentrations of insulinlike growth factor-1 and insulinlike growth factor-binding protein-1 in early pregnancy and subsequent risk of preeclampsia

Abstract Objectives: We investigated the relationship between maternal plasma free insulinlike growth factor-1 (IGF-1) and insulinlike growth factor-binding protein-1 (IGFBP-1) concentrations and risk of preeclampsia. Design and methods: Maternal blood samples were collected at 13 weeks' gestation on average. From the cohort, we selected 53 women who developed preeclampsia and 477 who remained normotensive. Free IGF-1 and IGFBP-1 concentrations were measured using immunoassays. Logistic regression procedures were used to calculate odds ratios (OR) and 95% confidence intervals (95% CI). Results: Women who developed preeclampsia had 18% and 27% lower concentrations of free IGF-1 and IGFBP-1, respectively, than controls ( P < 0.05). There was a 57% reduced risk of preeclampsia among women with free IGF-1 concentrations of ≥ 0.81 ng/mL (OR = 0.43, 95% CI 0.23–0.83) and a 43% reduced risk among women with IGFBP-1 concentrations of ≥ 72.36 ng/mL (OR = 0.53, 95% CI 0.23–1.21). Conclusions: Alterations of free IGF-1 and IGFBP-1 concentrations in maternal plasma during early pregnancy are associated with risk of preeclampsia. These associations may help to further elucidate the pathologic processes of preeclampsia.

Longitudinal analysis of serum insulin-like growth factor-I and insulin-like growth factor binding protein-1 in antiphospholipid syndrome and in healthy pregnancy

Objective: The purpose of this study was to determine the concentrations of serum insulin-like growth factor-I and insulin-like growth factor binding protein-1 in pregnancies that are complicated with primary antiphospholipid syndrome. Study Design: Longitudinal blood samples were collected from 8 weeks of gestation in 28 women with treated primary antiphospholipid syndrome and 19 control women. Serum insulin-like growth factor-I and insulin-like growth factor binding protein-1 were measured by immunoradiometric assay. Results: Three antiphospholipid syndrome pregnancies miscarried, four pregnancies had intrauterine growth restriction and preeclampsia, six pregnancies had a thrombotic event, and one pregnancy had abruptio placentae. Mean (±SD) birth weight in antiphospholipid syndrome group was 2867 ± 914 g (control, 3492 ± 527 g; P =.02), and the mean gestation at delivery was 36.5 ± 5.2 weeks (control, 40.3 ± 0.7 weeks; P =.002). Insulin-like growth factor binding protein-1 and insulin-like growth factor-I concentrations increased with gestational age in both groups (2.8% and 2.4% per week), but insulin-like growth factor binding protein-1 was 61% higher in the antiphospholipid syndrome group (95% CI, 16%-122%; P =.004). Insulin-like growth factor-I was not significantly different (8% higher in antiphospholipid syndrome; 95% CI, −10% to 30%; P =.41). Conclusion: Serum concentrations of insulin-like growth factor binding protein-1 are abnormal in the antiphospholipid syndrome group and may reflect abnormalities in trophoblast invasion. (Am J Obstet Gynecol 2003;189:274-9.)

Regulation of insulin-like growth factor-I and insulin-like growth factor binding protein-1 concentrations in preterm fetuses

Objective: Our purpose was to evaluate which factors regulate insulin-like growth factor-I and insulin-like growth factor binding protein-1 concentrations in preterm fetuses. Study design: We studied 76 singleton births between 25 and 36 weeks of gestation. Forty-nine pregnancies were complicated by hypertensive disease; 24 pregnancies were complicated by preterm labor or preterm rupture of membranes; and antenatal glucocorticoids were given in 49 pregnancies. Pathology reports showed infarct(s) or hematoma(s) in 31 of 69 placentas. We recorded blood gas values in umbilical artery and vein and measured glucose, C-peptide, and insulin-like growth factor-I and insulin-like growth factor binding protein-1 concentrations in umbilical vein. Results: Birth weight correlated with umbilical vein insulin-like growth factor-I (r = 0.68, P < .0001) and inversely with insulin-like growth factor binding protein-1 (r = −0.26, P = .02). Babies with birth weight of ≤25th percentile had lower insulin-like growth factor-I but higher insulin-like growth factor binding protein-1 levels than babies at >25th percentile. Two-factor analysis of variance showed that umbilical vein insulin-like growth factor-I was determined by gestational age (P = .0004) and birth weight percentile (P < .0001), whereas insulin-like growth factor binding protein-1 was not affected by gestational age. Umbilical vein C-peptide was highly correlated with insulin-like growth factor binding protein-1 (r = −0.55, P < .0001), but not insulin-like growth factor-I, levels. Blood gas values in umbilical artery and vein, particularly umbilical artery PO2, were correlated with umbilical vein insulin-like growth factor-I and insulin-like growth factor binding protein-1 (r = 0.51 and −0.48, respectively; P < .0001); changes in insulin-like growth factor-I and insulin-like growth factor binding protein-1 occurred at umbilical artery PO2 <14.8 mm Hg. Multiple regression analysis showed that umbilical vein insulin-like growth factor-I was predicted by umbilical artery PO2, gestational age, and the presence of placental infarcts/hematomas (R2 of model = 0.58, P < .0001), and umbilical vein insulin-like growth factor binding protein-1 by umbilical vein C-peptide, umbilical artery PO2, and placental infarcts/hematomas (R2 = 0.49, P < .0001). Conclusion: In the preterm fetus, circulating insulin-like growth factor-I is related to gestational age and the in utero growth potential, whereas insulin-like growth factor binding protein-1 is related only to the in utero growth potential. The PO2 is a robust determinant of both insulin-like growth factor-I and insulin-like growth factor binding protein-1 levels; hypoxia may restrain fetal growth through its effects on the insulin-like growth factor/insulin-like growth factor binding protein axis. Insulin is a powerful determinant of insulin-like growth factor binding protein-1, but not insulin-like growth factor-I, concentrations in the preterm fetus. (Am J Obstet Gynecol 2003;188:485-91.)

A longitudinal study of maternal plasma insulin-like growth factor binding protein-1 concentrations during normal pregnancy and pregnancies complicated by pre-eclampsia

Insulin-like growth factor binding protein-1 (IGFBP-1) is synthesized by the decidual stroma, and is thought to act locally to inhibit IGF activity and so limit trophoblast invasion. Cross-sectional studies have reported conflicting data on maternal circulating concentrations of IGFBP-1 in early pregnancy before the development of pre-eclampsia. A longitudinal study was performed in 10 women who went on to develop pre-eclampsia and a group of 12 normal pregnant controls, chosen to be similar for maternal age, booking body mass index (BMI) and gestational age. Maternal IGFBP-1 concentrations were measured in plasma obtained at 16, 20, 24, 28, 32 and 36 weeks. Plasma IGFBP-1 concentrations were unchanged over this period in normal pregnancy. In contrast, the concentrations in women who developed pre-eclampsia increased progressively. At 16, 20, and 24 weeks the concentrations were significantly lower compared to normal pregnancy, at 28 and 32 weeks, similar, but by 36 weeks the concentrations were significantly greater than the normal controls. The data show that circulating IGFBP-1 concentrations are lower in early pregnancy before the development of pre-eclampsia. Thus, it is suggested that IGFBP-1-induced inhibition of IGF activity is unlikely to be responsible for the impaired trophoblast invasion observed in pre-eclampsia.

The effect of intrauterine and oral levonorgestrel administration on serum concentrations of sex hormone‐binding globulin, insulin and insulin‐like growth factor binding protein‐1

The concentrations of sex hormone-binding globulin (SHBG) have been shown to decrease during the use of levonorgestrel (LNG)-containing contraception. This decrease has been thought to be due to the androgenic action of LNG. In endogenously hyperandrogenic women, particularly in those with increased body weight, serum SHBG correlates with circulating insulin-like growth factor binding protein-1 (IGFBP-1) concentration, and both are inversely related to insulin. LNG-containing combined contraceptives have also been reported to increase the pancreatic insulin secretion. To examine whether serum insulin and IGFBP-1 levels are related to SHBG during the use of intrauterine or oral levonorgestrel contraception. Thirty-one fertile women were divided into three study groups: A copper-releasing intrauterine device (IUD) was inserted in control group (n= 10), and the LNG-releasing intrauterine contraceptive system (LNG-IUS) in group II (n= 10), and 30 mirog LNG-containing contraceptive minipills were given in group III (n=11). Twenty-nine women completed the study and one woman was excluded because of a high body mass index. Fasting concentrations of blood glucose, insulin, SHBG, IGFBP-1, testosterone and LNG before and after three-months-use of contraception were measured. SHBG concentrations decreased slightly during oral LNG contraception, but not during the use of the LNG-IUS. No change was found in blood glucose, serum insulin, serum IGFBP-1 and serum total testosterone concentrations in either group. In our study group, including women with normal body weight, no correlation was detected between insulin and SHBG concentrations before or after LNG contraception, whereas an inverse correlation was found between insulin and IGFBP-1 levels at the baseline as well as after LNG-IUS use (R2= 0.578; p=0.001). Multiple regression analysis showed no significant association between the levels of SHBG and IGFBP-1 as dependent factors, and glucose, insulin, LNG, age, waist-hip ratio and body mass index as dependent factors. Our data imply that the effect of levonorgestrel on variables associated with endogenous hyperandrogenism remains borderline in women with normal body mass index.

Valproate-induced hyperandrogenism during pubertal maturation in girls with epilepsy.

Valproate is effective for treatment of a variety of seizure types both in adults and in children with epilepsy, but it induces obesity and polycystic ovaries in a considerable proportion of adult women, particularly when the medication is started before the age of 20. In the present study we evaluated reproductive endocrine function in 41 girls, 8 to 18 years old, taking valproate for epilepsy and in 54 healthy control girls. Among the girls taking valproate, 16 were prepubertal, 11 were pubertal, and 14 were postpubertal, and the corresponding numbers were 20, 13, and 21 in the control group. The mean serum testosterone concentrations of prepubertal, pubertal, and postpubertal girls taking valproate were significantly higher than those of the control girls at the same pubertal stage. Hyperandrogenism, defined as serum testosterone levels higher than the mean + 2SD in the control girls at the same pubertal stage, was seen in 38% of prepubertal, 36% of pubertal, and 57% of postpubertal girls taking valproate. In addition, postpubertal girls taking valproate were more obese than the controls and the mean serum insulin-like growth factor binding protein-1 concentration of pubertal and postpubertal hyperandrogenic girls taking valproate was lower than in valproate-treated girls without hyperandrogenism. Valproate may induce hyperandrogenism in girls with epilepsy during the sensitive period of pubertal maturation, and the frequency of hyperandrogenism increases with pubertal development. This emphasizes the importance of careful endocrine observation of girls taking valproate for epilepsy.

Influence of circulating epinephrine and norepinephrine on insulin-like growth factor binding protein-1 in humans.

The aim of the present study was to investigate the influence of circulating epinephrine (Epi) and norepinephrine (Norepi) on serum insulin-like growth factor binding protein-1 (IGFBP-1) concentrations. Healthy men received 0.3 nmol.kg.min Epi iv (n = 6), 0.5 nmol.kg.min Norepi iv (n = 7), or saline (n = 5) during 30 min. Arterial blood samples were obtained before, during, and 120 min after infusion. During the catecholamine infusion arterial Epi and Norepi plasma concentrations reached 6.35 +/- 0.53 and 15.65 +/- 2.71 nmol/L, respectively, which resulted in significant increases in glucose concentrations. When Epi was infused, IGFBP-1 increased from 45 +/- 6 micrograms/L to 76 +/- 10 micrograms/L (P < 0.05) 60 min after the infusion. Epi was also followed by increases in insulin, C-peptide, and glucagon. Norepi resulted in a slight increase in circulating IGFBP-1 (43 +/- 6 to 54 +/- 8 nmol/L, NS). The findings suggest that Epi, at plasma concentrations similar to those reached during physical stress, stimulates the production of IGFBP-1 in humans.

Influence of Circulating Epinephrine and Norepinephrine on Insulin-Like Growth Factor Binding Protein-1 in Humans

The aim of the present study was to investigate the influence of circulating epinephrine (Epi) and norepinephrine (Norepi) on serum insulin-like growth factor binding protein-1 (IGFBP-1) concentrations. Healthy men received 0.3 nmol·kg·min Epi iv (n = 6), 0.5 nmol·kg·min Norepi iv (n = 7), or saline (n= 5) during 30 min. Arterial blood samples were obtained before, during, and 120 min after infusion. During the catecholamine infusion arterial Epi and Norepi plasma concentrations reached 6.35 ± 0.53 and 15.65 ± 2.71 nmol/L, respectively, which resulted in significant increases in glucose concentrations. When Epi was infused, IGFBP-1 increased from 45 ± 6 μg/L to 76 ± 10 μg/L (P < 0.05) 60 min after the infusion. Epi was also followed by increases in insulin, C-peptide, and glucagon. Norepi resulted in a slight increase in circulating IGFBP-1 (43 ± 6 to 54 ± 8 nmol/L, NS). The findings suggest that Epi, at plasma concentrations similar to those reached during physical stress, stimulates the production of IGFBP-1 in humans.

C-peptide, insulin-like growth factors I and II, and insulin-like growth factor binding protein-1 in cord serum of twins: Genetic versus environmental regulation

OBJECTIVE: Our purpose was to examine the regulation of fetal serum concentrations of insulin (C-peptide), insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding protein-1, which are growth-regulating factors in the fetus, in monozygotic and dizygotic twin pairs. STUDY DESIGN: Cord serum samples were collected from 110 twin pairs and compared with 178 nonsibling singleton pairs with the same gestational age. Five twin pairs were excluded from the statistical analyses because of severe intrauterine growth restriction and placental abnormalities in one. Zygosity was assigned by histologic examination of the placenta and by a questionnaire sent to the mother when the twins were ≥6 months old. Analyses included the calculation of correlation coefficients, between-pair variation, and univariate genetic analysis. RESULTS: Cord serum C-peptide concentrations were highly correlated in monozygotic ( r = 0.94) and dizygotic twins ( r = 0.79) but not in singleton pairs ( r = -0.05); the between-pair variation was also smaller in twins than in singletons. Genetic analysis demonstrated a large contribution of the common environment to the variance in C-peptide concentrations (80%) and a smaller genetic contribution (12%). Insulin-like growth factor-I concentrations were better correlated in monozygotic ( r = 0.82) than in dizygotic twins ( r = 0.42), with a smaller between-pair variation in the former group (22% ± 4% vs 51% ± 5%). Univariate genetic analysis indicated that insulin-like growth factor-I levels were regulated predominantly by genetic mechanisms (93% in boys and 77% in girls). The regulation of insulin-like growth factor-II was more complex, with a gender-specific genetic contribution (50% for both sexes combined, 63% for girls but only 5% for boys). Insulin-like growth factor binding protein-1 was regulated by genetic mechanisms (41%) and the common environment (32%) but also by the specific or unique environment of each fetus (27%). In all five twins with intrauterine growth restriction of one member, insulin-like growth factor binding protein-1 concentrations were markedly higher in the growth-restricted fetus. CONCLUSIONS: Insulin secretion in twin fetuses is determined primarily by their common, probably maternal, environment, whereas insulin-like growth factor-I production is predominantly genetically regulated. Insulin-like growth factor-II and insulin-like growth factor binding protein-1 are regulated by both genetic and environmental factors. Of these growth-regulating factors, insulin-like growth factor binding protein-1 appears to be the best marker of intrauterine growth restriction in the individual case. (Am J Obstet Gynecol 1996;175:1180-8.)