IGFBP-3 Concentrations Research Articles

Pre- and Postoperative Circulating IGF-I, IGFBP-3, and IGFBP-7 Levels in Relation to Endocrine Treatment and Breast Cancer Recurrence: A Nested Case-Control Study

Insulin-like growth factor-I (IGF-I) and its binding proteins (BPs) have been associated with breast cancer risk, especially high IGF-I concentrations and the biologically active fraction estimated as the IGF-I/IGFBP-3 molar ratio. The relation of circulating IGF-I and IGFBP-3 concentrations with risk of breast cancer recurrence has been less documented. In addition a new member to a sub-group of the IGFBP-superfamily was recently identified, the low affinity IGFBP-7. To date, the role of systemic IGFBP-7 in breast cancer progression has not been investigated. Our purpose was to establish whether circulating IGF-I, IGFBP-3, and IGFBP-7 levels are related to recurrence-risk in breast cancer. A case-control study was nested within the population-based BCBlood cohort of 853 breast cancer patients diagnosed 2002–2010 in Sweden and followed through 2012. In total, 95 patients with recurrence and 170 controls were matched on age and tumor characteristics. Plasma IGF analytes and tumor membrane IGF-I receptor (IGF-IRm) positivity were analyzed and recurrence-risk was evaluated with conditional logistic regression. Preoperative tertiles of IGF-I and IGFBP-3 were both positively associated with recurrence-risk, but not IGFBP-7. The trend was of borderline significance for IGF-I, T1:REF, T2 OR:1.6, T3 OR: 2.2 adjusted P trend=0.057 and significant for IGFBP-3 T1:REF, T2 OR:1.2, T3 OR: 2.1 adjusted P trend=0.042. The models were adjusted for age, anthropometric factors, smoking, and treatments. There was a significant interaction between IGFBP-7 and IGF-IRm positivity on recurrence, where the highest IGFBP-7 highest IGFBP-7 tertile conferred increased recurrence-risk in patients with IGF-IRm positive tumors but not in those with IGF-IRm negative tumors (P interaction=0.024). By the 1-year visit, age-adjusted IGF-I levels were reduced by 17% while IGFBP-3 and IGFBP-7 were stable. IGF-I levels were significantly reduced by radiotherapy in all patients and by tamoxifen in patients with ER+ tumors. Postoperative changes >10% (n=208) in IGF-I, IGFBP-3, IGFBP-7, or the IGF-I/IGFBP-3 ratio did not predict recurrence after adjustment for preoperative levels, age, anthropometric factors, smoking, and treatments. In conclusion, this study suggests that preoperative IGF-I and IGFBP-3 levels, but not postoperative changes, might provide independent prognostic information and influence breast cancer recurrence. The role of IGFBP-7 in breast cancer merits further study.

The autocrine regulation of insulin-like growth factor-1 in human brain of Alzheimer’s disease

BackgroundInsulin-like growth factor (IGF) binding protein (IGFBP)−3 and cyclic Glycine-Proline (cGP) regulate circulating IGF-1 function that is associated with cognition. The association between IGF-1 function and Alzheimer’s disease (AD) remains inconclusive. This study evaluated the changes of IGFBPs and cGP, and their effects on the bioavailability and function of IGF-1 in human brain of AD cases. MethodsUsing biological and mathematic analysis we measured the concentrations of total, bound and unbound forms of IGF-1, IGFBPs and cGP in the inferior-frontal gyrus and middle-frontal gyrus of human AD (n = 15) and control cases (n = 15). The association between the changes of total concentration of these peptides and total protein concentration in brain tissues were also analyzed. ResultsThe unbound bioavailable IGF-1 was lower whereas the bound cGP and IGFBP-3 were higher in AD than the control cases. Total protein that was lower in AD than control cases, was negatively associated with cGP concentration of control cases and with IGFBP-3 concentration of AD cases. ConclusionsThe results provide direct evidence for IGF-1 deficiency in AD brain due to lower bioavailable IGF-1. The increase of bound IGFBP-3 impaired autocrine regulation. The increase of bound cGP is an autocrine response to improve the bioavailability and function of IGF-1 in AD brain. Availability of data and materialAll data generated or analysed during this study are included in this published article. Additional datasets analysed during the current study available from the corresponding author on reasonable request.

Investigating the Relationship Between IGF-I, IGF-II, and IGFBP-3 Concentrations and Later-Life Cognition and Brain Volume.

BackgroundThe insulin/insulin-like signaling (IIS) pathways, including insulin-like growth factors (IGFs), vary with age. However, their association with late-life cognition and neuroimaging parameters is not well characterized.MethodsUsing data from the British 1946 birth cohort, we investigated associations of IGF-I, IGF-II and IGF binding protein 3 (IGFBP-3; measured at 53 and 60-64 years of age) with cognitive performance [word-learning test (WLT) and visual letter search (VLS) at 60-64 years and 69 years of age] and cognitive state [Addenbrooke’s Cognitive Exam III (ACE-III) at 69-71 years of age], and in a proportion, quantified neuroimaging measures [whole brain volume (WBV), white matter hyperintensity volume (WMHV), hippocampal volume (HV)]. Regression models included adjustments for demographic, lifestyle, and health factors.ResultsHigher IGF-I and IGF-II at 53 years of age was associated with higher ACE-III scores [ß 0.07 95% confidence interval (CI) (0.02, 0.12); scoreACE-III 89.48 (88.86, 90.1), respectively). IGF-II at 53 years of age was additionally associated with higher WLT scores [scoreWLT 20 (19.35, 20.65)]. IGFBP-3 at 60 to 64 years of age was associated with favorable VLS score at 60 to 64 and 69 years of age [ß 0.07 (0.01, 0.12); ß 0.07 (0.02, 0.12), respectively], higher memory and cognitive state at 69 years of age [ß 0.07 (0.01, 0.12); ß 0.07 (0.01, 0.13), respectively], and reduced WMHV [ß −0.1 (−0.21, −0.00)]. IGF-I/IGFBP-3 at 60 to 64 years of was associated with lower VLS scores at 69 years of age [ß −0.08 (−0.15, −0.02)].ConclusionsIncreased measure in IIS parameters (IGF-I, IGF-II, and IGFBP-3) relate to better cognitive state in later life. There were apparent associations with specific cognitive domains (IGF-II relating to memory; IGFBP-3 relating to memory, processing speed, and WMHV; and IGF-I/IGFBP-3 molar ratio related to slower processing speed). IGFs and IGFBP-3 are associated with favorable cognitive function outcomes.

Sex Hormones, Insulin, and Insulin-like Growth Factors in Recurrence of High-Stage Endometrial Cancer.

The influence of sex hormone and insulin/insulin-like growth factor (IGF) axis signaling on endometrial cancer recurrence is unknown. We evaluated these pathways in a prospective cohort of Gynecologic Oncology Group (GOG)0210 trial endometrial adenocarcinoma patients. Stage II-IV patients (N = 816) were included in this study. Pretreatment specimens were tested for tumor mRNA and protein expression of IGF1, IGF2, IGF-binding proteins (IGFBP)-1 and -3, insulin (IR) and IGF-I receptors (IGF1R), phosphorylated IR/IGF1R (pIGF1R/pIR), and estrogen (ER) and progesterone receptors (PR) using qPCR and IHC. Serum concentrations of insulin, IGF-I, IGFBP-3, estradiol, estrone, and sex hormone binding globulin were measured. HRs and 95% confidence intervals (CI) for progression-free survival were calculated from Cox models adjusting for age, stage, and grade. Recurrence occurred in 280 (34%) cases during a median of 4.6 years of follow-up. ER positivity (HR, 0.67; 95% CI, 0.47-0.95), IR positivity (HR, 0.53; 95% CI, 0.29-0.98), and circulating IGF-I (highest vs. lowest quartile: HR, 0.66; 95% CI, 0.47-0.92) were inversely associated with recurrence risk. Circulating estradiol (highest vs. lowest tertile: HR, 1.55; 95% CI, 1.02-2.36) and pIGF1R/pIR positivity (HR, 1.40; 95% CI, 1.02-1.92) were associated with increased recurrence risk. Circulating estradiol and tumor tissue phosphorylated (activated) IGR1R/IR were independently associated with higher risk of recurrence in patients with endometrial cancer. This study may inform future clinical trials of endocrine-targeted adjuvant therapies in patients with endometrial cancer that could include baseline assessment of serum and tissue biomarkers of estradiol and insulin signaling pathways.

Reduced Fragmentation of IGFBP-2 and IGFBP-3 as a Potential Mechanism for Decreased Ratio of IGF-II to IGFBPs in Cerebrospinal Fluid in Response to Repeated Intrathecal Administration of Triamcinolone Acetonide in Patients With Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disease of the brain and spinal cord causing a wide range of symptoms such as impaired walking capability, spasticity, fatigue, and pain. The insulin-like growth factor (IGF) system has regulatory functions for the induction of inflammatory pathways in experimental encephalomyelitis. We have therefore assessed expression and regulation of the IGF system on the level of IGFs and IGFBPs in serum and cerebrospinal fluid (CSF) in the course of four repeated triamcinolone acetonide (TCA) administrations in two female and four male MS patients. Sample series of 20 treatment cycles were analyzed. IGF-I and IGF-II were quantified by ELISAs, and IGFBPs were analyzed by quantitative Western ligand (qWLB) and Western immunoblotting (WIB) in order to differentiate intact and fragmented IGFBPs. The ratios of fragmented to intact IGFBP-2 and -3 were calculated in serum and CSF. Finally, the ratios of IGF-I and IGF-II to the total IGF-binding activity, quantified by qWLB, were determined as an indicator of IGF-related bioactivity. After the fourth TCA administration, the average level of IGF-I was increased in serum (p < 0.001). The increase of IGF-I concentrations in serum resulted in an increased ratio of IGF-I to IGFBPs in the circulation. By contrast in CSF, fragmentation of IGFBP-2 and IGFBP-3 and the ratio of IGF-II to intact IGFBPs were decreased at the fourth TCA administration (p < 0.01). Furthermore, reduced fragmentation of IGFBP-3 in CSF was accompanied by increased concentrations of intact IGFBP-3 (p < 0.001). We conclude that reduced fragmentation of IGFBPs and concomitant reduction of IGF-II to IGFBP ratios indicate regulation of bioactivity of IGF-II in CSF during repeated intrathecal TCA administration in MS patients.

Kinetics of cytokines IL-6, IL-10 and TNF-α and their relationship with serum IGF-I and IGFBP-3 concentrations in adolescent swimmers throughout a training season

Aim: The objective of this study was to analyze the kinetics of the IL-6, IL-10, and TNF-α cytokines and their relationship with the serum IGF-I and IGFBP-3 levels of adolescent swimmers throughout a training season.

Is there a role for the IGF system and epidermal growth factor (EGF) in the pathogenesis of adrenocortical adenomas? A preliminary case-control study.

Adrenal incidentalomas (AI) are very common and mostly they are non-functioning adenomas (NFA). NFAs are often associated with insulin resistance and metabolic syndrome. Several biomarkers, including certain growth factors, may participatein the pathogenesis ofmetabolic changes in patients with adrenal adenomas.Patients with NFA and age-matched control subjects were enrolled in the study. Data on age, gender, presence of metabolic syndrome or its components were obtained for each subject. Blood samples were obtained and glycemia, insulinemia, lipid profile, and selected growth factor levels were measured. Forty-three patients with NFA and 40 controls were included in the study. Differences were not found in the metabolic syndrome and its components prevalence or in the biochemical profile between patients and the control group. Significant differences were noticed in the levels of IGF1, IGF2, and IGFBP3 (p=0.016, p=0.005, p=0.004, respectively), but there were no differences in VEGF or EGF concentrations. In NFA patients, an association between glycemia and EGF levels was present (p=0.026). No significant correlations between tumor size and insulin or growth factor concentrations were present in AI patients. Significantly higher serum IGF1, IGF2, and IGFBP3 concentrations in NFA patients may support the role of the IGF axis in the pathogenesis of adrenocortical lesions.No correlation between IGFs or IGFBP3 and parameters of glucose or lipid metabolism was found. Present results may support the role of the growth hormone axis rather than hyperinsulinemia and insulin resistance in the pathogenesis of adrenocortical adenomas.

Using β hCG, prolactin and IGFBP I single or in Pairs to diagnose PROM

Background: When diagnosing premature rupture membranes is query, choosing the appropriate management needsadditional confirmatory test. Based on their metabolomics, some biochemical markers have been proposed as diagnosticaids. A perfect test could be composed of combining more than one marker. Combining markers is not arbitrary as somecombinations could inversely impact the diagnostic accuracy of the test.Aim: Improving sensitivity and specificity of diagnosis of preterm premature rupture of membranes by combining quantitativeinsulin like growth factor binding protein 1 (IGFBP-1) with quantitative βHCG and/or quantitative prolactin in cervicovaginalfluid.Materials and Methods: It is a cross sectional study. IGFBP-1, prolactin and β-HCG concentrations in vaginal fluid wereexamined in 180 patients with sure membrane state and the diagnostic accuracy of each marker and each combination wasdetermined. The study was conducted between January 2018 and September 2018 in Ain-Shams University MaternityHospital after the approval of the institutional ethics committee. Informed consent has been obtained from the patientsbefore participation.Results: The sensitivity, specificity, PPV, and NPV of Prolactin with cutoff point 11 μIU/ml are 84.4, 73.2, 73.8,and 79.5, respectively, gives accuracy percentage 75.4%. The sensitivity, specificity, PPV, and NPV of ILGFBP-1 withcutoff point 102 μIU/ml are 88.3, 93.5, 100, and 69.4 respectively gives accuracy percentage 81.5%. The sensitivity,specificity, PPV, and NPV of Β-HCG with cutoff point 104 mIU/mL are 85.1, 83.9, 96.2, and 72.8 respectively givesaccuracy percentage 79.9%. The sensitivity, specificity, PPV, and NPV of the combination of IGFBP-1 and β-HCGare 78.4, 100, 100 and 64 respectively gives accuracy percentage 89.7. The sensitivity, specificity, PPV, and NPV of thecombination of IGFBP-1 and prolactin are 78.4, 100, 100 and 68.7, respectively, gives accuracy percentage 84.2. Thesensitivity, specificity, PPV, and NPV of the combination of β-HCG and prolactin are 79.8, 100, 100 and 63.6 respectivelygives accuracy percentage 77.2.Conclusion:Combining IGFBP-1 and β-HCG is the best diagnostic combination to detect amniotic fluid presence invaginal fluid. Combined IGFBP-1 and prolactin offered very little improvement compared to IGFBP-1 alone. Addingprolactin to β-HCG decreased accuracy than each of the other two markers alone.

The Influence of Gestational Diabetes Mellitus upon the Selected Parameters of the Maternal and Fetal System of Insulin-Like Growth Factors (IGF-1, IGF-2, IGFBP1-3)—A Review and a Clinical Study

Background: Gestational diabetes mellitus (GDM), defined as impaired glucose tolerance with onset or first recognition in pregnancy, increases the risk of not only maternal but also fetal and neonatal complications. Given the structural similarity of insulin-like growth factors with insulin and participation of components of the insulin-like growth factor system in glucose homeostasis, we hypothesized that the IGF axis is involved in the development of GDM complications or its pathogenesis. The aim of this study was to evaluate the effect of GDM on the selected parameters of the insulin-like growth factors (IGF-1, IGF-2, IGFBP1-3) in the maternal and fetal blood. Methods: The clinical material of this case-control study included 109 pregnant women and their offspring. The study group (n = 120) consisted of 60 patients with diagnosed gestational diabetes and their newborn babies. The control group (n = 98) comprised 49 healthy parturients and their offspring. We measured the concentrations of IGF-1, IGF-2, IGFBP-1, IGFBP-2, IGFBP-3, insulin and glucose made by the ELISA method in peripheral blood serum in patients suffering from GDM and pregnant women without GDM, and in the umbilical cord blood of newborn babies born to them. Results: The analysis of concentrations of IGF-1, -2 and IGFBP-3 in peripheral blood as well as umbilical cord blood did not demonstrate a statistically significant difference between the study group and the control group. Significantly lower concentration of IGFBP-1, IGFBP-2 in peripheral blood and in umbilical cord blood was detected in the study group in comparison to the control group. A statistically positive correlation between the concentration of IGF-1 in umbilical cord serum of newborn babies born to women with gestational diabetes and the length of a baby after its birth was observed. Conclusions: Gestational diabetes mellitus does not significantly affect the concentrations of IGF-1, -2, IGFBP-3 in the peripheral blood and umbilical cord blood, but has the greatest influence on maternal and fetal IGFBP-2 concentrations. A positive correlation between the concentration of IGF-1 in umbilical cord blood and the length of a newborn suggests an influence of IGF-1 on the process of fetal development.

Effects of a combined essential fatty acid and conjugated linoleic acid abomasal infusion on metabolic and endocrine traits, including the somatotropic axis, in dairy cows

The objective of this study was to test the effects of essential fatty acids (EFA), particularly α-linolenic acid (ALA), and conjugated linoleic acid (CLA) supplementation on metabolic and endocrine traits related to energy metabolism, including the somatotropic axis, in mid-lactation dairy cows. Four cows (126 ± 4 d in milk) were used in a dose-escalation study design and were abomasally infused with coconut oil (CTRL; 38.3 g/d; providing saturated fatty acids), linseed and safflower oils (EFA; 39.1 and 1.6 g/d; n-6:n-3 FA ratio = 1:3), Lutalin (CLA; cis-9,trans-11 and trans-10,cis-12 CLA, 4.6 g/d of each), or EFA and CLA (EFA+CLA) for 6 wk. The initial dosage was doubled twice after 2 wk, resulting in 3 dosages (dosages 1, 2, and 3). Each cow received each fat treatment at different times. Cows were fed with a corn silage-based total mixed ration providing a low-fat content and a high n-6:n-3 fatty acid ratio. Plasma concentrations of metabolites and hormones (insulin-like growth factor-binding proteins only on wk 0 and 6) were analyzed at wk 0, 2, 4, and 6 of each treatment period. Liver biopsies were taken before starting the trial and at wk 6 of each treatment period to measure hepatic mRNA abundance of genes linked to glucose, cholesterol and lipid metabolism, and the somatotropic axis. The changes in the milk and blood fatty acid patterns and lactation performance of these cows have already been published in a companion paper. The plasma concentration of total cholesterol increased with dosage in all groups, except CLA, reaching the highest levels in EFA+CLA and CTRL compared with CLA. The high-density lipoprotein cholesterol plasma concentration increased in CTRL and was higher than that in EFA and CLA, whereas the concentration of low-density lipoprotein cholesterol increased in a dose-dependent manner in EFA and EFA+CLA, and was higher than that in CLA. Hepatic mRNA expression of 3-hydroxy-3-methyl-glutaryl-CoA synthase 1 was upregulated in all groups but was highest in EFA+CLA. Expression of sterol regulatory element-binding factor 1 tended to be lowest due to EFA treatment, whereas expression of long chain acyl-CoA-synthetase was lower in EFA than in CTRL. Hepatic mRNA expression of GHR1A tended to be higher in EFA+CLA than in CTRL. The plasma concentration of insulin-like growth factor I increased in CLA, and the plasma IGFBP-2 concentration was lower in EFA+CLA than in CTRL at wk 6. The plasma concentration of adiponectin decreased in EFA+CLA up to dosage 2. Plasma concentrations of albumin and urea were lower in CLA than in CTRL throughout the experimental period. Supplementation with EFA and CLA affected cholesterol and lipid metabolism and their regulation differently, indicating distinct stimulation after the combined EFA and CLA treatment. The decreased IGFBP-2 plasma concentration and upregulated hepatic mRNA abundance of GHR1A in EFA+CLA-supplemented cows indicated the beneficial effect of the combined EFA and CLA treatment on the somatotropic axis in mid-lactation dairy cows. Moreover, supplementation with CLA might affect protein metabolism in dairy cows.

T regulatory cells and TGF-β1: Predictors of the host response in mesh complications

Polypropylene mesh is frequently used in urogynecology procedures; however, pain and mesh exposure into the vagina occur in ~10% of cases. Mesh-induced pain, which occurs with or without exposure, persists after removal in 50% of cases. Chronic pain history predicts poor response to mesh removal but only a fraction have this diagnosis. We hypothesize that mesh induced pain is correlated with fibrosis and failure to improve with a heightened inflammatory and fibrotic host response. Women undergoing mesh removal were offered participation in a mesh biorepository. Standardized questionnaires including visual analog scale (VAS) pelvic pain scores were completed at enrollment and 6 months after removal. Responders were considered those with ≥13 mm VAS improvement. 30 mesh-tissue explants were randomly selected for analysis. Samples were labeled for CD8, CD4 (Th) and FoxP3 (Tregs). Peri-fiber collagen deposition (fibrosis) was measured using a customized semi-quantitative assay. Concentrations of TGF-b1, bFGF, MCP-1, PDGF-BB, and IGFBP-1 in tissue were determined by immunoassay and compared to vaginal control biopsies with pathway analysis. VAS pain scores were correlated with degree of histologic fibrosis. Responders had more Tregs (7.8 vs 0.3 per mm2, p = 0.036) and patients were 1.6 times as likely to be a responder for every additional Treg/mm2 (p = 0.05). Pro-fibrotic TGF-β1 was doubled in nonresponders (p = 0.032). On pathway analysis, decreased bFGF and increased PDGF-BB provide a possible mechanism for upregulation of TGF-β1. In conclusion, fibrosis is a plausible mechanism of pain complications and the adaptive immune response likely contributes to mitigation/prevention of complications and recovery in affected patients. Statement of SignificancePolypropylene mesh improves anatomical outcomes in urogynecologic procedures, but is associated with complications, including pain and exposure through the vaginal epithelium. Mesh-induced pain is difficult to treat, and it is unclear why only half of women experience pain improvement after mesh removal. In this study, patient pain correlated with the presence of fibrosis and women with more T regulatory cells and lower TGF-β1 were more likely to have pain improvement following mesh removal. These findings implicate fibrosis as a mechanism of pain complications and suggest that the adaptive immune response may be responsible for prevention of complication and recovery. This improved understanding of how mesh can lead to pain moves us closer to the ultimate goal of preventing mesh complications.

Circulating IGFBP-2 levels reveal atherogenic metabolic risk in schizophrenic patients using atypical antipsychotics

Objectives Second generation antipsychotics (SGAs) induce weight gain and dyslipidemia, albeit with important intervariability. Insulin-like growth factor binding protein (IGFBP)-2 is proposed as a circulating biomarker negatively associated with waist circumference and hypertriglyceridemia. Thus, we tested whether metabolic alterations developed upon the use of SGAs are associated with plasma IGFBP-2 levels. Methods A cross-sectional study was performed in 87 men newly diagnosed with schizophrenia and administered for approximately 20 months with olanzapine or risperidone as their first antipsychotic treatment. Plasma IGFBP-2 concentration, anthropometric data, as well as glucose and lipid profiles were determined at the end of the treatments. Results IGFBP-2 levels were similar between patients using olanzapine or risperidone and were negatively correlated with waist circumference, insulin sensitivity, and plasma triglycerides (TG). A higher proportion of men with a hypertriglyceridemic (hyperTG) waist phenotype was found in patients with IGFBP-2 levels lower than 220 ng/mL (43% for olanzapine and 13% for risperidone) compared to those with IGFBP-2 above this threshold (10% and 0%, respectively). Conclusions IGFBP-2 may have a role in altering metabolic risk in schizophrenic patients using SGAs. Longitudinal studies are required to evaluate whether IGFBP-2 can predict the development of a hyperTG waist phenotype in this population.

SUN-060 Steroid Hormone Profile Differentiates Gynecomastia and Pseudo- Gynecomastia in Pubertal Boys

Background: Gynecomastia (defined by breast tissue) and pseudogynecomastia (defined by adipose tissue) is frequent in pubertal boys. However, the underlying pathomechanisms are not fully understood so far. An association to growth hormone axis- IGF-1 axis and sex hormones has been discussed. Methods: We analyzed serum steroid hormones (progesterone, estradiol [E2], estriol, estrone, cortisol, cortisone, testosterone [T], dihydrotestosterone [DHT]) by liquid chromatography-tandem mass spectrometry, as well as gonadotropins, prolactin, IGF-1 and IGFBP-3 in 124 pubertal boys with breast swelling (mean age 14 +/-2 years). The steroid hormones were compared to those of 84 healthy pubertal boys (mean age 14 +/-2 years) without breast swelling. The differential diagnosis of either gynecomastia or pseudogynecomastia was determined by ultrasound. Puberty was defined by testes volumes > 3ml on each side. Results: A total of 86 boys suffered from gynecomastia and 38 from pseudogynecomastia. In boys with gynecomastia the ratio E2/T (median 22, interquartile range [IQR] 8–75) was significantly (p<0.05) higher compared to boys with pseudogynecomastia (median 12 IQR 5–21) or healthy boys without breast swelling (median 18 IQR 6–44). DHT concentrations were significantly (p<0.001) lower in boys with gynecomastia (median 0.13 IQR 0.02–0.38 nM/L) or pseudogynecomastia (median 0.18 IQR 0.05–0.32 nM/L) compared to healthy boys (median 0.41 IQR 0.22–0.66 nM/L). T concentrations were significantly (p<0.05) lower in boys with gynecomastia (median 1.8 IQR 0.7–4.2 nM/L) compared to boys with pseudogynecomastia (median 4.3 IQR 1.4–6.9 nM/L) or healthy boys without breast swelling (median 3.1 IQR 0.6–7.6 nM/L). The ratio DHT/T was significantly (p<0.001) lower in boys with gynecomastia (median 0.09 IQR 0.02–0.17) or pseudogynecomastia (median 0.04 IQR 0.02–0.16) compared to healthy Boys without breast swelling (median 0.13 IQR 0.05–0.28). Boys with gynecomastia did not differ from boys with pseudogynecomastia according to the other steroid hormones, prolactin, IGF-1, or IGFBP-3 concentrations. Conclusions: Gynecomastia is characterized by a higher E2 to T ratio compared to healthy boys without breast swelling due to a relative T deficiency in the presence of similar E2 levels. The lower DHT/T ratio in gynecomastia and pseudogynecomastia compared to healthy boys without breast swelling points towards a functional 5 alpha reductase deficiency.

Differential production of insulin-like growth factor-binding proteins in liver fibrosis progression.

Noninvasive methods for liver disease diagnoses offer great advantages over biopsy, but they cannot be utilized in all cases. Therefore, specific indicators for chronic liver disease management are necessary. The aim was to assess the production of insulin-like growth factor-binding proteins (IGFBPs) 1-7 and their correlation with the different stages of fibrosis in chronic hepatitis C (CHC). A prospective, cross-sectional, multicenter study was conducted. CHC patients were categorized by FibroTest® and/or FibroScan®. Serum concentrations of IGFBPs 1-7 were determined through multiple suspension arrangement array technology. Significant differences were validated by the Kruskal-Wallis and Mann-Whitney U tests. Logistic regression models were performed to assess the association between the IGFBPs and fibrosis stages. The association was determined utilizing odds ratios (ORs), and receiver operating characteristic (ROC) curves were constructed to distinguish the IGFBPs in relation to the diagnosis of fibrosis. IGFBP-1 and IGFBP-7 concentrations were higher in CHC than in the healthy individuals, whereas IGFBP-3, IGFBP-5, and IGFBP-6 were downregulated in the patients. An apparent increase of all the IGFBPs was found at fibrosis stage F4, but with different regulations. IGFBP-2, -4, -6, and -7 had the best OR, showing the relation to fibrosis progression. The ROC curves showed that IGFBP-7 was the only protein that distinguished F1 from F3 and F2 from F3. IGFBPs participate in liver fibrosis progression and could be employed as circulating novel protein panels for diagnosis and as possible therapeutic targets in liver fibrosis progression.

Effects of a home-based exercise program on the insulin-like growth factor axis in patients operated for colorectal cancer in Sweden: Results from the randomised controlled trial PHYSSURG-C

We report results from a subgroup within the ongoing PHYSSURG-C trial with the aim to examine effects of exercise on IGF-1 and IGFBP-3 in patients undergoing colorectal cancer surgery. Randomised controlled trial. A Swedish university hospital. Between 2015 and 2016, 217 patients were enrolled (I=106, C=111), with 122 patients that had given blood samples at baseline and at least at one follow-up (I=51, C=71). Patients 20year or older with colorectal cancer were eligible. Exclusion criteria were emergency surgery, local surgery, language problems or inability to perform intervention. Patients were computer-randomised to either a daily home-based aerobic exercise intervention (I), or to usual care (C). The intervention lasted two weeks before surgery and four weeks after discharge from hospital and consisted of medium-intensity aerobic exercise and inspiratory muscle training. Circulating concentrations of IGF-1 and IGFBP-3 were determined by blinded personnel at baseline, time of surgery and 4-6weeks postoperatively. The outcome of this subpopulation report was change in IGF-1/IGFBP-3 ratio, IGF-1 and IGFBP-3 concentrations from baseline to surgery, and 4-6weeks postoperatively. The IGF-1/IGFBP-3 ratio increased from baseline to surgery by 11% in I and 8% in C with no difference between groups (I vs. C: 1.04, 95%CI: 0.97-1.11; p=1.000). Postoperative change was 5% in I and 3% in C with no difference between groups (I vs. C:1.03, 95%CI: 0.96-1.10; p=1.000). Results concerning IGF-1 and IGFBP-3 also showed statistically significant dynamics over time with no difference between groups. No adverse events were reported. The home-based exercise program in our trial did not have any effect on IGF-1, or IGFBP-3. The study was registered at ClinicalTrials.gov with identifier NCT02299596. This work was funded externally.

Production of insulin-like growth factor-binding proteins during the development of hepatic fibrosis due to chronic hepatitis C

Introduction and AimsInsulin-like growth factor 1 is modulated by the insulin-like growth factor-binding proteins (IGFBPs) that are synthesized in the liver. The aim of the present study was to evaluate the concentrations of IGFBPs 1–7 in patients with chronic hepatitis C and study their association with fibrosis stage. Patients and methodsA prospective, cross-sectional study was conducted that included patients with chronic hepatitis C. The stages of fibrosis were determined through FibroTest and FibroScan and the patients were compared with a control group. Serum levels of IGFBPs 1–7 were quantified through multiple suspension arrays. The Kruskal-Wallis test, Mann-Whitney U test, Spearman’s correlation, and ROC curves were used for the statistical analysis. ResultsUpon comparing the patients and controls, the highest concentrations were found in IGFBPs 1, 2, 4, and 7 (p=0.02, 0.002, 0.008, and <0.001, respectively). IGFBP-3 levels had a tendency to be lower in the patients (p=0.066), whereas values were similar between patients and controls for IGFBP-5 and 6 (p=0.786 and p=0.244, respectively). Of the seven IGFBPs, IGFBP-3 concentrations were the highest. There were significant differences between fibrosis stages for IGFBP-5 and IGFBP-7. ConclusionIGFBPs play a relevant role in the fibrotic process in liver damage. IGFBP-7, in particular, differentiates fibrosis stages, making it a potential serum biomarker.

Development of a novel assay for IGFBP-2 complexed with IGF-I and-II in human serum

BackgroundInsulin-like growth factor binding-protein 2 (IGFBP-2) was originally identified as an IGF-carrier, governing IGF half-life, tissue accessibility and biological effects. Later, IGFBP-2 was discovered to possess IGF-independent effects. IGFBP-2 circulates in several forms, as free protein, complexed with IGF-I or IGF-II, or as IGFBP-2 fragments. The various IGFBP-2 forms are all included when measuring serum IGFBP-2 concentrations by immunoassay (i.e., immunoreactive (ir-)IGFBP-2). In this study, we describe a novel method to measure the amount of IGF that circulates bound to IGFBP-2. MethodIGFBP-2 was immunoprecipitated from human serum using magnetic beads, which were subsequently eluted by acidification. After neutralization, eluates were assayed for ir-IGFBP-2, IGF-I and IGF-II and compared to serum concentrations. This allowed measurement of IGFBP-2-compexed IGF-I and IGF-II, respectively. To test the method clinically, serum from 146 patients with lung cancer, 151 patients with non-cancer pulmonary diseases and 28 healthy controls were analyzed. ResultsWe immuno-precipitated 97 ± 3.3% of serum IGFBP-2 and recovered > 75% of IGFBP-2-complexed IGFs, with intra- and inter-assay coefficient of variations (CVs) averaging < 5% and < 13%, respectively. No co-precipitation with IGFBP-1, −3 or − 4 was detected.Serum levels of ir-IGFBP-2 (median [25;75%]) differed between groups (cancer patients vs. non-cancer patients vs. healthy controls): 342 [260;480] vs. 262 [189;388] vs. 190 [141;269] μg/l (p < .0001). In parallel with this, concentrations of IGF-II carried by IGFBP-2 averaged: 45.0 [33.3;52.5] vs. 34.2 [25.4;46.1] vs. 19.8 [14.1;26.0] μg/l (p < .0001), and concentrations of IGF-I 8.0 [5.2;11.8] vs. 5.4 [3.6;7.3] vs. 7.0 [3.8;13.0] μg/l (p < .0001). Thus, IGFBP-2 carried more IGF-II than IGF-I in all groups (p < .0001). When expressed relative to IGF-concentrations, IGFBP-2 carried 9.0 [5.3;15.5] % of the IGF-I and 4.8 [2.9;5.8] % of the IGF-II in serum from healthy subjects. Notably, in patients, IGFBP-2 carried relatively less IGF-I, but more IGF-II (p < .0001). ConclusionUsing our novel assay, we demonstrate: that IGFBP-2 carries ≈10% of circulating IGF-I and ≈5% of circulating IGF-II in healthy subjects; that IGF-II is the primary ligand for IGFBP-2; and that IGFBP-2 carries even more IGF-II in patients than in healthy subjects. Thus, our assay may provide information on IGFBP-2 beyond what is achievable by simply measuring ir-IGFBP-2.

Wound Fluid Cytokine Profile Following Bone Regeneration Procedures.

Clinical parameters available to evaluate early healing phases of bone regeneration procedures are limited. This study explores wound fluid (WF) content for molecular markers to differentiate wound healing responses in the early postoperative period after bone graft placement. Fifteen patients (50 ± 5 years old; 8 men) scheduled to receive tooth extraction and bone graft placement at maxillary nonmolar single-tooth sites were recruited. Primary wound closure was not intended at time of surgery. Gingival crevicular fluid from adjacent teeth or WF from surgical wound edges were collected (30 seconds) at baseline, at 3, 6, and 9 days, and at 1 and 4 months. Multiplex protein assay was used to determine concentration of various wound healing mediators. Immediately after surgery, 87% of surgical sites exhibited open wound. At day 9, mean wound exposure was 4.8 ± 0.4 mm. At 1 month, all wounds were clinically closed. The WF tripled in volume at day 3 and day 6 (P ≤ .05), compared with baseline gingival crevicular fluid, and gradually decreased as wounds closed. The WF concentrations of interleukin (IL)-6, placental growth factor, plasminogen activator inhibitor 1, insulin-like growth factor binding protein 1, and soluble cluster determinant 40 ligand were increased during early healing days, generally with peak concentration at day 6 (P ≤ .004). Conversely, WF concentrations of IL-18 and epidermal growth factor were decreased after surgery, generally not reaching baseline values until wound closure (P ≤ .008). In general, WF cytokine expression kinetics were concordant with wound closure dynamics (P ≤ .04). These results suggest that WF molecular markers such as IL-6, and to a lesser extent placental growth factor and IL-18, might help differentiate wound healing responses after bone regeneration procedures.

Insulin-like growth factor I (IGF-I) and its present significance in digestive system diseases

Insulin-like growth factor I (IGF-I) is a main mediator of growth hormone’s (GH) action. Under physiological conditions, IGF-I is responsible for growth and development of organism through influence on proliferation and differentiation of cells. IGF-I is produced in almost all tissues of organism and its activity is determined by interaction with specific receptors (IGF-IR, IGF-IIR) and IGF-binding proteins (IGFBP-1 - IGFBP-6), and by proteases hydrolyzing IGFBPs as well. Currently, a surge of interest on insulin-like growth factor I as a potential factor contributing to the development of neoplasms, including neoplasms of digestive system, is observed. IGFBPs and IGF-IR may also be of importance in etiology and pathogenesis of cancer. It is assumed that high serum concentration of IGF-I may increase the risk of cancer development whereas high serum concentration of IGFBP-3 may inhibit the progression of the disease. Until recently, attempts of modulating the concentration of IGF-I with the use of pharmacological agents of diverse mechanisms of action under innovative anti-cancer therapies, have been made. Lately, it is pointed to the possibility of application of IGF-I in the management of certain diseases of digestive system. It was observed that IGF-I not only contributes to the maintenance of normal structure and function of epithelium in the gastrointestinal tract but also stimulates repair processes in damaged mucosa. Results of preliminary studies on the treatment of short bowel syndrome, gastric ulcer disease, enteritis induced by chemo- and radiotherapy, and inflammatory bowel disease with the use of exogenous IGF-I are encouraging.

IGF-1 and IGFBP-3 in cancer patients

Growth factors called somatomedins have been isolated from human plasma and described in the seventies of the last centry. Insulin-like growth factors and their binding proteins are synthesized mainly in the liver, this process is regulated by the growth hormone. Insulin-like effects of IGF-1 are primarily stimulating the uptake of glucose by adipocytes and muscle cells. Moreover, IGF-1 stimulates cell division, plays a significant role in the processes of differentiation, maturation, repair of damaged DNA and apoptosis. Insulin-like growth factor binding proteins by binding IGF-1 modulate its biological activity, counteract the potentially carcinogenic activity of unbound IGF-1. Furthermore, IGFBPs, especially IGFBP-3, have independent effects on cell growth, for example, IGFPB-3 has proapoptotic activities. Elevated level of IGF-1 with simultaneously reduced concentration of its binding protein are considered risk factors for the development of a number of diseases, including neoplastic diseases. High serum concentrations of IGF-1 and low levels of IGFBP-3 are associated with increased risks of lung, breast, prostate, and colorectal cancers.