IGF Binding Protein-3 Molar Ratio Research Articles

Relationship between Serum Sirtuin 1 and Growth Hormone/Insulin-like Growth Factor 1 Concentrations in Children with Growth Hormone Deficiency and Idiopathic Short Stature.

Sirtuin 1 (SIRT1) inhibits growth hormone (GH) intracellular signaling for the insulin-like growth factor 1 (IGF-1) synthesis via the janus kinase (JAK)/signal transducer and activator of transcription proteins (STATs) pathway. The aim of this study was to compare SIRT1 concentrations in children with GH deficiency (GHD) and so-called idiopathic short stature (ISS, non-GH deficient), in order to determine the possible impact of changes in serum SIRT1 concentrations on the GH-IGF-1 axis. The study group included 100 short-stature children: 38 with GHD and 62 with ISS (maxGH in two stimulation tests <10 and ≥10 ng/mL, respectively). The control group consisted of 47 healthy, normal-height children. For each child, the concentrations of SIRT1, IGF-1 and insulin-like growth factor-binding protein 3 (IGFBP-3) were determined and the IGF-1/IGFBP-3 molar ratio was calculated. The level of SIRT1 was significantly higher in both groups of short children than in the controls (p < 0.0001), but there were no differences between GHD and ISS (mean ± SD: 0.89 ± 0.45 for ISS; 1.24 ± 0, 86 for GHD; and 0.29 ± 0.21 for controls). A significant negative correlation was found between SIRT1 and height standard deviation score (SDS), IGF-1 and IGF-1/IGFBP-3, but not between SIRT1 and maxGH. Elevated SIRT1 levels may serve as one of the mechanisms through which the secretion of IGF-1 is reduced in children with short stature; however, further research is required to confirm this issue.

Effects of lifestyle intervention on IGF-1, IGFBP-3, and insulin resistance in children with obesity with or without metabolic-associated fatty liver disease.

Obesity is a strong predictor for metabolic associated fatty liver disease (MAFLD), which has been associated with decreased insulin like growth factor 1 (IGF-1). In obesity, weight loss increases growth hormone secretion, but this is not unequivocally associated with increases in serum IGF-1 and IGF binding protein-3 (IGFBP-3). We studied the changes in the IGF axis in relation to weight loss and improvement in insulin resistance in children with or without MALFD after 10weeks of lifestyle intervention at a weight loss camp (WLC). We investigated 113 (66 females) Caucasian children with obesity, median age 12.4 (range 7.3-14.6) years, before and after 10weeks of lifestyle intervention at a WLC. We investigated children who was either MAFLD positive (n = 54) or negative (n = 59) before and after WLC. Children with MAFLD had lower baseline IGF-1 (249 ± 112 vs 278 ± 107µg/l, P = 0.048), whereas the IGF-1/IGFBP-3 molar ratio was similar to children without MAFLD (19.4 ± 6.6 vs. 21.8 ± 6.6%, P = 0.108). When all children were considered as one group, WLC decreased SDS-BMI and HOMA-IR (P < 0.001, both) and increased IGF-1 (264 ± 110 vs 285 ± 108µg/l, P < 0.001) and the IGF/IGFBP-3 molar ratio (20.7 ± 6.7 vs 22.4 ± 6.1%, P < 0.001). When categorized according to liver status, IGF-1 increased significantly in children with MAFLD (P = 0.008) and tended to increase in children without MAFLD (P = 0.052). Conclusions: Ten weeks of lifestyle intervention decreased insulin resistance and improved the IGF axis. We observed slight differences in the IGF axis in relation to MAFLD status. This suggests that the IGF axis is primarily influenced by insulin resistance rather than MAFLD status. What is New: •Weight loss decreases insulin resistance and subsequently increases the IGF axis in children with obesity. •Children with MAFLD had an aberration in the IGF axis compared to their MAFLD negative counter parts and the IGF axis was primarily influenced by the decreased BMI-SDS and insulin resistance, rather than MAFLD status. What is Known: • NAFLD has previously been associated with reduced serum IGF-1 concentrations. • Data on the impact of MAFLD and aberrations in the growth hormone and IGF axis and the effects of lifestyle interventions in children are limited.

Circulating IGF-1 Independently Predicts Blood Pressure in Children With Higher Calcium-Phosphorus Product Levels.

To study the association between insulin-like growth factor 1 (IGF-1) and blood pressure in children, in particular, the potential interaction with the serum calcium-phosphorus product (Ca*P). A longitudinal study included 521 children (age 8.8 ± 0.1) from northeastern Spain, of whom 158 were followed-up after 5 years. IGF-1, insulin-like growth factor-binding protein 3 (IGFBP-3), and serum calcium and phosphorus were measured at baseline. Anthropometric (body-mass index [BMI] and waist) and cardiometabolic variables (systolic [SBP] and diastolic blood pressure), pulse pressure, insulin, homeostatic model assessment of insulin resistance [HOMA-IR], high-density lipoprotein [HDL]-cholesterol, and triglycerides) were assessed at baseline and at the end of follow-up. Statistical analysis included Pearson correlations followed by multivariable linear regression analyses. Baseline IGF-1 and IGF-1/IGFBP-3 molar ratio positively correlated with baseline and follow-up BMI, waist, SBP, pulse pressure, insulin, HOMA-IR and triglycerides (r 0.138-0.603; all P < 0.05). The associations with SBP were stronger with increasing Ca*P (r 0.261-0.625 for IGF-1; and r 0.174-0.583 for IGF-1/IGFBP-3). After adjusting for confounding variables, baseline IGF-1 and IGF-1/IGFBP-3 remained independently associated with both baseline and follow-up SBP in children in the highest Ca*P tertile (β = 0.245-0.381; P < 0.01; model R2 = 0.246-0.566). Our results suggest that IGF-1 in childhood is an independent predictor of SBP in apparently healthy children, especially in those with high Ca*P levels.

Association of insulin-like growth factor-1 and IGF binding protein-3 with 25-hydroxy vitamin D in pre-pubertal and adolescent Indian girls.

There is a high prevalence of vitamin D deficiency (VDD) in India. Molecular mechanisms suggest a strong relationship between vitamin D and growth factors. However, there is a paucity of literature with regard to a relationship between insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3) and vitamin D particularly in subjects with VDD. The objective of the study was to assess the relationship between growth factors and serum vitamin D-parathormone (PTH) status in school girls and study the impact of vitamin D supplementation on growth factors in pre-pubertal girls with VDD. Our study subjects were apparently healthy school girls aged 6-18 years. The baseline height, weight, body mass index (BMI), pubertal status, serum 25-hydroxy vitamin D (25OHD), PTH, IGF-1 and IGFBP-3 were assessed in 847 girls aged 6-18 years and in 190 pre-pubertal girls with VDD following supplementation. The mean age, BMI and serum 25OHD of girls were 11.5±3.2 years, 18.7±4.8 kg/m2 and 9.9±5.6 ng/mL, respectively. VDD was observed in 94.6% of girls. Unadjusted serum IGF-1 levels and IGF-1/IGFBP-3 molar ratio were significantly higher in girls with severe VDD as compared to girls with mild-to-moderate VDD. However, these differences disappeared when adjusted for age, height or sexual maturation. The serum IGF-1 and IGFBP-3 levels increased significantly post supplementation with vitamin D. There were no differences in serum IGF-1 levels and the IGF-1/IGFBP-3 molar ratio among VDD categories when adjusted for age, height and sexual maturation in girls. Vitamin D supplementation resulted in a significant increase in serum IGF-1 levels in VDD pre-pubertal girls.

Circulating insulin-like growth factor-related biomarkers: Correlates and responses to calcium supplementation in colorectal adenoma patients.

Circulating insulin-like growth factor 1 (IGF-1) may be directly associated with colorectal cancer risk, and IGF binding protein 3 (IGFBP-3) is one of the most abundantly expressed binding proteins in various cancers. Calcium intakes, primarily from food, have been directly associated with circulating IGF-1, but whether supplemental calcium affects IGF-1 and IGFBP-3 is unknown. We tested the effects of 1.0 and 2.0 g of supplemental elemental calcium daily on circulating IGF-1 and IGFBP-3 concentrations in colorectal adenoma patients in a randomized, double-blinded, placebo-controlled clinical trial (n = 193). IGF-1 and IGFBP-3 were quantified using enzyme-linked immunoassay and quantitative Western ligand blot, respectively. We also assessed cross-sectional associations of these biomarkers with participants' baseline characteristics. We found no appreciable effect of calcium relative to placebo on circulating IGF-1, IGFBP-3, or the IGF-1:IGFBP-3 molar ratio. Mean IGF-1 concentrations were 11.1% higher in those with greater milk intakes (P = 0.05). Mean IGF-1 and IGFBP-3 concentrations were, respectively, 18.0% (P = 0.003) and 16.5% (P = 0.01) higher in men and were monotonically lower with increasing age (both P = 0.01). IGFBP-3 was 17.7% higher among those with higher relative to no alcohol consumption (P = 0.04). While these results support previous findings that IGF-1 concentrations are higher with greater milk intakes, and IGF-1 and IGFBP-3 concentrations differ according to sex and age, they provide no evidence to suggest that supplemental calcium appreciably affects circulating IGF-1, IGFBP-3, or the IGF-1:IGFBP-3 molar ratio in sporadic colorectal adenoma patients.

Influence of The -202 A/C insulin-like growth factor-binding protein-3 promoter polymorphism on individual variation in height in Korean girls.

PurposeThe most common single nucleotide polymorphism in the IGFBP3 promoter region occurs at position -202. This polymorphic variation occurs frequently and may influence growth hormone responsiveness and somatic growth. However, the effects of IGFBP3 promoter polymorphism on growth in children are unknown.MethodsRestriction fragment length polymorphism-based genotyping of the -202 single nucleotide polymorphism was performed in 146 Korean girls aged between 15 and 16 years, who were selected randomly from the Seoul School Health Promotion Center. The participants were divided into 3 groups (tall, medium, and short) according to the height percentile established from normal reference values for Korean children. The serum levels of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were then compared according to genotype.ResultsThe genotype distribution in the participants was 79 AA (54.1%), 60 AC (41.1%), and 7 CC (4.8%). The C allele frequency at the -202 IGFBP3 position was 25.4% in this group. The mean serum IGFBP-3 concentration in girls with the AA genotype was higher than that in girls with the AC genotype in the medium (P=0.047) and short (P=0.035) groups, respectively. There was no difference in the IGF-I to IGFBP-3 molar ratio between the AA and AC genotype groups (P=0.161).ConclusionIn conclusion, the -202 polymorphism in the IGFBP3 promoter region is assumed to affect the serum concentration of IGFBP-3 in children as well as in adults. However, it is unclear whether this affects physical development according to the concentration of IGFBP-3.

Abstract 1758: Circulating insulin-like growth factors: Correlates and responses to calcium supplementation in colorectal adenoma patients

Abstract Insulin-like growth factor 1 (IGF-1) and its binding proteins are an important part of the IGF/growth hormone axis needed for normal growth and organ function. IGF-1 signaling has also been implicated in tumorigenesis with higher circulating levels of IGF-1 and the molar ratio of IGF-1 to IGF binding protein 3 (IGFBP-3) being directly associated with colorectal, breast, and prostate cancers, as well as with colorectal adenomas. IGF binding protein 2 (IGFBP-2) also appears to be overexpressed in colorectal and lung cancers and leukemias. Limited evidence suggests that various dietary and lifestyle factors may influence circulating levels of IGF-1, IGFBP-2, and IGFBP-3. Among these factors, calcium has been statistically significantly associated with IGF-1, IGFBP-2, and IGFBP-3, but its effects on them have not been tested in a clinical trial. To investigate the effects of supplemental calcium (1.0 or 2.0 g/day) on serum levels of IGF-1, IGFBP-2, and IGFBP-3, we analyzed samples from a randomized, double-blinded, placebo-controlled, dose-response clinical trial of patients with previous sporadic, colorectal adenoma. We also investigated associations of various risk factors with the growth factors at baseline. IGF-1 was measured using an enzyme-linked immunosorbent assay, and IGFBP-2 and IGFBP-3 were measured using quantitative Western ligand blot assays. We found no appreciable effects of calcium over the 4-month treatment period on IGF-1, IGFBP-2, and IGFBP-3. At baseline, lower levels of IGF-1 and IGFBP-3 were associated with being female (P = 0.02 and 0.01, respectively) or older (P = 0.02 and 0.02, respectively); the IGF-1/IGFBP-3 molar ratio was inversely associated with body mass index (BMI) (P = 0.04); and IGFBP-2 was directly associated with age (P = 0.002) but inversely associated with BMI (P &amp;lt; 0.0001). We calculated residuals of non-fat milk intake as a novel method of examining the non-calcium, non-fat component of milk, modeled after the energy adjustment residual method. These residuals were inversely associated with IGFBP-2 (P = 0.05) and directly associated with the IGF-1/IGFBP-3 molar ratio (P = 0.11). Overall, our results do not support that calcium supplementation can modulate circulating levels of IGF-1, IGFBP-2, or IGFBP-3 among patients with previous colorectal adenoma. However, our findings do suggest potential associations of these growth factors with established risk factors for colorectal cancer (age [inversely associated with IGF-1 and IGFBP-3, directly associated with IGFBP-2] and adiposity [inversely associated with IGFBP-2 and the IGF-1/IGFBP-3 molar ratio]). Finally, our results provide new evidence of potential associations of IGF-1, IGFBP-2, and IGFBP-3 with milk intake independent of its calcium and fat content. Citation Format: Caroline Um, Veronika Fedirko, Christine Höflich, W Dana Flanders, Roberd M. Bostick. Circulating insulin-like growth factors: Correlates and responses to calcium supplementation in colorectal adenoma patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1758.

Metformin may protect nondiabetic breast cancer women from metastasis.

Metformin, a widely prescribed oral hypoglycemic agent, has recently received a big interest because of its potential antitumorigenic effects in different cancer types. The present study investigated the impact of adding metformin to breast cancer adjuvant therapy in nondiabetic women on, insulin like growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3), insulin, fasting blood glucose (FBG), the molar ratio of IGF-1 to IGFBP-3, homeostatic model assessment of insulin resistance (HOMA-IR) and metastasis. 102 women with newly diagnosed breast cancer were divided into 2 main groups, a control group and a metformin group. All women were treated with adjuvant therapy, according to the protocols of Ministry of Health and Population and National Cancer Institute, Egypt. Moreover, the women in the metformin group received 850mg of metformin twice daily. Blood samples were collected at baseline, after chemotherapy (CT), after 6 months of hormonal therapy (6-HT) and 12months of hormonal therapy (12-HT) for analysis of serum IGF-1, IGFBP-3, insulin, FBG and cancer antigen 15-3 (CA15-3). Metformin resulted in a significant reduction of IGF-1, IGF-1: IGFBP-3 molar ratio, insulin, FBG and HOMA-IR. On the other hand, metformin caused a significant increase of IGFBP-3. Moreover, metformin significantly decreased the numbers of metastatic cases after 6-HT. Metformin may have potential antitumor and antimetastatic effects that need further clinical investigations. This may be attributed to either the significant increase of the apoptotic inducer IGFBP-3 or/and the significant reduction of mitogenic insulin, IGF-1, free bioactive IGF-1, FBG and HOMA-IR.

Circulating levels of IGF-1, IGFBP-3, and IGF-1/IGFBP-3 molar ratio and colorectal adenomas: A meta-analysis

BackgroundsInsulin-like growth factor-1(IGF-1) promotes cell proliferation and inhibits apoptosis, and is thereby implicated in carcinogenesis. Insulin-like growth factor binding protein-3 (IGFBP-3) may antagonize IGF-1 action, leading to inhibition of the potential tumorigenicity of IGF-1. We conducted this meta-analysis to estimate the association between IGF-1, IGFBP-3 and IGF-1/IGFBP-3 ratio and the risk of colorectal adenomas (CRAs). Further, we investigated whether this association was different between occurrent and recurrent CRA, by adjustment for obesity, and by advanced CRA. Materials and methodsPubmed and Embase were searched up to April, 2015 to identify relevant observational studies and summary odds ratio (OR) and the corresponding 95% confidence interval (95% CI) was estimated using a random-effects model. ResultsA total of 12 studies (11 studies including 3038 cases for IGF-1, 12 studies including 3208 cases for IGFBP-3, and 7 studies including 1867 cases for IGF-1/IGFBP-3 ratio) were included in this meta-analysis. The summary ORs of occurrent CRA for the highest versus lowest category of IGF-1, IGFBP-3 and IGF-1/IGFBP-3 ratio were 1.13 (95% CI: 0.95–1.34), 0.99 (0.84–1.16), and 1.05 (0.86–1.29), respectively. Higher IGF-1 and IGF-1/IGFBP-3 ratio were significantly associated with decreased risk of recurrent CRA (OR for IGF-1=0.60 [95% CI: 0.42–0.85]; IGF-1/IGFBP-3 ratio=0.65 [0.44–0.96]). A stratified analysis by advancement of occurrent CRA produced a significant summary OR of IGF-1 for advanced CRA (OR=2.21 [1.08–4.52]) but not for non-advanced CRA (OR=0.89 [0.55–1.45]). We did not find significant publication bias or heterogeneity. ConclusionCirculating levels of IGF-1, IGFBP-3 and their molar ratio were not associated with the risk of occurrence of CRA, but IGF-1 was associated with the increased risk for occurrence of advanced CRA.

A prospective study of insulin-like growth factor 1, its binding protein 3, and risk of endometriosis.

Several retrospective case-control studies suggested that insulin-like growth factor 1 (IGF-1) or insulin-like growth factor binding protein 3 (IGFBP-3) was associated with endometriosis. However, results are inconsistent and no prospective study exists. We prospectively evaluated associations between plasma levels of IGF-1 and IGFBP-3 and laparoscopically confirmed endometriosis in a case-control study nested within the Nurses' Health Study II. Between blood collections in 1996-1999 and 2007, we ascertained 310 premenopausal women with incident endometriosis and 615 matched controls. We estimated incidence rate ratios and 95% confidence intervals using multivariable conditional logistic regression. We observed no statistically significant associations between endometriosis and IGF-1 (incidence rate ratio (IRR) = 0.88, 95% confidence interval (CI): 0.61, 1.27; Ptrend = 0.48), IGFBP-3 (IRR = 1.12, 95% CI: 0.80, 1.57; Ptrend = 0.51), and the IGF-1:IGFBP-3 molar ratio (IRR = 0.94, 95% CI: 0.66, 1.34; Ptrend = 0.64), comparing the top with the bottom tertile. IGF-1, IGFBP-3, and the molar ratio appeared to be positively associated with endometriosis risk among women aged <40 years at blood draw (IGF-1: IRR = 1.60, 95% CI: 0.86, 2.98; IGFBP-3: IRR = 1.85, 95% CI: 1.08, 3.16; IGF-1:IGFBP-3: IRR = 1.57, 95% CI: 0.85, 2.88) but not among women aged ≥40 years at blood draw (all Pheterogeneity ≤ 0.05). Overall, these data suggest that, if IGF-1 or IGFBP-3 plays a role in the etiology of endometriosis, it is minimal and perhaps only among younger women.

Insulin-Like Growth Factor-I, Insulin-Like Growth factor Binding Protein-3 and Blood Hemoglobin Concentration in an Elderly Population

Insulin-like growth factor-I (IGF-I) serum level decreases with age, and this decrease may underlie hemoglobin (Hb) decrease. The objective of the study was to assess the relationship between IGF-I and insulin-like growth factor binding protein-3 (IGFBP-3) serum levels and Hb, after adjustment especially for major nutritional factors in an elderly population because IGF-I system depends on nutritional state, often impaired in the elderly. Hemoglobin concentration was tested for 672 participants evaluated during an outpatient geriatric assessment. IGF-I and IGFBP-3 serum levels were assessed by Enzyme Linked Immunosorbent Assay. The molar ratio of IGF-I/IGFBP-3 that reflects the bioavailable IGF-I was calculated. Levels of IGF-I and IGFBP-3 were plotted against quartiles of Hb. Final linear models for IGF-I, IGFBP-3 and ratio molar included factors that could modify the Hb level. Mean age (SD) of the sample was 78.0 (8.5) years old and 32% were men. After adjustment for age and sex, IGF-I serum level, IGFBP-3 serum level and molar ratio significantly increased with increasing quartiles of Hb. After adjustment for age, gender, diabetes, albumin, pre-albumin, renal function, total cholesterol, angiotensin converting enzyme inhibitors and angiotensin II receptor blockers consumption, C-Reactive Protein, Hb was significantly associated and with IGF-I level (p = .002) and molar ratio (p = .02). IGF-I serum level and IGF-I/IGFBP-3 molar ratio were associated with Hb in an elderly population, independently of nutritional biological parameters. Thus, the association between the IGF-I system and Hb merits further investigation to determine whether interventions that modulate circulating IGF-I or IGF-I/BP3 ratio might preserve Hb in the elderly.

Bone mineral density and hormonal status in adolescent athletic girls

The aim of this study was to determine the relationships of bone mineral density (BMD) and content (BMC) with selected fasting hormones in adolescents with different exercise training patterns. The participants were female athletes of weight-loaded (n=23) and weight-supported (n=24) sports, and 33 non-athletic girls aged 13–15 years. BMD (g/cm2) and BMC (g) at the femoral neck (FN) and lumbar spine (LS) were measured. Venous blood samples were drawn to determine the concentration of insulin-like growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3), estradiol, visfatin, adiponectin, leptin, insulin, and glucose. After adjusting for age, height, and body mass, the relationships of BMD variables with IGF-1, IGF-1/IGFBP-3 molar ratio, estradiol, and leptin levels remained significant only in the weight-loaded sport group (r=0.41–0.60; p&lt;0.05). Adiponectin was inversely correlated to FN and LS BMD and BMC (r=–0.47–0.62; p&lt;0.05) in weight-supported sport group only, but after adjustments for age, height, and body mass, these associations disappeared. In this study, concentrations of visfatin, a fairly new adipocytokine, were not related to bone parameters in adolescent girls with different training patterns.

Increase in circulating levels of IGF-1 and IGF-1/IGFBP-3 molar ratio over a decade is associated with colorectal adenomatous polyps

High levels of circulating insulin-like growth factor-1 (IGF-1) have been associated with increased risk of several cancers. Regarding colorectal cancer, these associations are generally weak. We hypothesized that an increase in IGF-1 over time would be a stronger risk factor for cancer-related outcomes than the actual levels. In this analysis we utilized existing data from the Insulin Resistance and Atherosclerosis Study (IRAS). Circulating IGF-1 levels and molar ratios of IGF-1 to IGF binding protein 3 (IGFBP-3) were measured at three time points, within a 10-year follow-up period. We examined the associations of increase of the two variables with the presence of colorectal adenoma at the end of follow-up among participants with normal glucose tolerance at baseline. This included 143 individuals, from which 24 were diagnosed with adenomatous polyps. Although the mean levels of IGF-1 and IGF-1/IGFBP-3 decline with age, ~ 30% of the participants showed an increase of at least fifteen percent ("ever increase") in one or both of these variables, compared to baseline. We found a positive association between "ever increase" in IGF-1 or IGF-1/IGFBP-3 and the presence of colorectal adenoma: ORs were 3.81 (95% CI: 1.30-10.8) and 2.83 (95% CI: 1.00-8.22), respectively. No association was found when analyzing the actual levels of both variables at any time point. Our data suggest that an increase in circulating IGF-1 or IGF-1/IGFBP-3 may represent a disturbed GH/IGF1 homeostasis, which could favor the development of precancerous lesions such as colorectal adenoma.

The vitamin D pathway and mammographic breast density among postmenopausal women

Laboratory studies have demonstrated that vitamin D has a number of chemopreventive properties, and that these properties may be mediated or modified by other molecules in the vitamin D pathway, such as parathyroid hormone (PTH) or calcium. However, there is little epidemiologic data exploring the effects of vitamin D on breast cancer risk in the context of these other molecules. We examined a panel of molecules in the vitamin D pathway in relation to mammographic breast density, a marker of breast cancer risk, in the Wisconsin Breast Density Study. A total of 238 postmenopausal women (ages 55-70, with no history of postmenopausal hormone use) were enrolled from mammography clinics in Madison, Wisconsin. Subjects provided blood samples that were analyzed for levels of 25-hydroxy vitamin D [25(OH)D], PTH, insulin-like growth factor-1 (IGF-1), IGF-binding protein 3 (IGFBP-3), retinol, and calcium. Percent breast density was measured using Cumulus software. In age-adjusted analyses there was a positive association between 25(OH)D and percent breast density (P = 0.05; mean percent density = 11.3% vs. 15.6% for 1st vs. 4th quartile of 25(OH)D). Breast density was inversely associated with PTH (P = 0.05; 16.0% vs. 11.4% for Q1 vs. Q4) and positively associated with the IGF-1:IGFBP-3 molar ratio (P = 0.02; 11.9% vs. 15.6% for Q1 vs. Q4). However, these associations were all null after further adjustment for body mass index (BMI; P > 0.25). The independent relation between 25(OH)D and breast density remained null among subgroups defined by BMI and serum levels of retinol, calcium, and estradiol. These results suggest no strong independent associations between the circulating molecules of the vitamin D pathway and mammographic breast density in postmenopausal women. While it remains possible that vitamin D could influence breast cancer risk, our results suggest that such an effect would be mediated through pathways other than breast density.

Serum insulin-like growth factor-I and insulin-like growth factor binding protein-3 levels with risk of malignant melanoma

We examined the relationship of insulin-like growth factor-I (IGF-I) and its primary growth factor, IGF binding protein-3 (IGFBP-3) with malignant melanoma using interview data and sera from cases (n = 286) and controls (n = 289) in a population-based case-control study conducted in 1986-1992 on Oahu, Hawaii. Serum IGF-I and IGFBP-3 concentrations were measured by ELISA. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression and adjusting for age, sex, education, number of blistering sunburns, ability to tan, hair color, energy intake, BMI, height, smoking status, and drinking status. An inverse relationship was found between IGF-I concentration and melanoma (OR for upper vs. lower tertile: 0.44, 95% CI: 0.25-0.79), but clear associations were not observed between malignant melanoma and upper tertiles of IGFBP-3 and the IGF-1/IGFBP-3 molar ratio. The inverse association with IGF-I was strongest among subjects who did not report a history of non-melanoma skin cancer (NMSC) (OR for ≥ vs. < median: 0.39, 95% CI: 0.24-0.65), and a positive association was found among those with such a history (OR: 3.6, 95% CI: 1.0-13; p (interaction) = 0.0035). Our findings observed here between serum IGF-I and malignant melanoma warrants replication in studies with a larger sample size and a prospective design.

Elevated Insulin-Like Growth Factor-I Values in Children with Prader-Willi Syndrome Compared with Growth Hormone (GH) Deficiency Children over Two Years of GH Treatment

Children with Prader-Willi syndrome (PWS) are routinely treated with GH and have a response comparable with that observed in children with GH deficiency (GHD). The objective of the study was to compare changes in serum IGF-I, IGF binding protein 3 (IGFBP-3), IGF-I to IGFBP-3 molar ratio, and growth velocity during the first 2 yr of GH therapy in PWS and GHD children. Thirty-three children with PWS (14 boys, 4.9 ± 3.8 yr) and 591 with GHD (351 boys, 9.6 ± 3.6 yr), all naive to GH treatment, were included in this study. Serum IGF-I and IGFBP-3 were measured at 0, 6, 12, and 24 months of GH therapy. The mean initial dose of GH was 0.9 and 1 mg/m(2) · d in the PWS and GHD groups, respectively. Mean ± SD IGF-I sdscore (SDS) and IGFBP-3 SDS were significantly higher in PWS compared with GHD. The IGF-I to IGFBP-3 molar ratio was significantly lower at baseline and subsequently not different. Despite significantly lower GH doses in PWS children at 6, 12, and 24 months (P = 0.021, P = 0.021, P = 0.001), IGF-I reached 2.8 ± 1.2 SDS at 24 months (72% of values > 2 SDS), and remained at 0.7 ± 1.6 SDS in GHD children (17% of values > 2 SDS). IGFBP-3 did not exceed 2 SDS in either group. There was no significant change in the IGF-I to IGFBP-3 molar ratio. IGF-I SDS increases to a greater extent in PWS than GHD. Bioavailable IGF-I is apparently not different, suggesting that any possible safety issues related to elevated IGF-I are similar in both groups.

Dietary predictors of the insulin-like growth factor system in adolescent females: results from the Dietary Intervention Study in Children (DISC)

The insulin-like growth factor (IGF) system is associated with the adult diet and chronic disease. Childhood diet may influence chronic disease through its effect on the IGF system; however, there is limited information describing the dietary predictors of the IGF system in adolescents. We examined associations between dietary food intake [fat, protein (animal and vegetable), carbohydrate, lactose, dietary fiber, calcium, zinc, and sodium] and serum IGF-I, IGF binding protein 1 (IGFBP-1), IGF binding protein 3 (IGFBP-3), and the IGF-I:IGFBP-3 molar ratio in adolescent females. One hundred fifty-nine adolescent females in the Dietary Intervention Study in Children (age range: 14-18 y; 0.2-6.3 y postmenarche) were included. The dietary intake was assessed via three 24-h dietary recalls. IGF-related biomarkers were determined by using radioimmunoassays. Associations between dietary intakes and biomarkers were assessed with Pearson's correlations and multivariable linear regression. Dietary intakes and biomarkers were logarithmically transformed; thus, beta coefficients represented percentages. In analyses adjusted for energy, age, and time since menarche, significant correlations (P < 0.05) were as follows: IGF-I with total protein, lactose, calcium, and sodium; IGFBP-3 with total fat (inverse), lactose, fiber, and calcium; IGF-I/IGFBP-3 with lactose and calcium; and IGFBP-1 with vegetable protein. In multivariable analyses, significant predictors of IGF-I were energy (beta = 0.14, P < 0.05) and calcium (beta = 0.14, P < 0.01), the significant predictor of IGFBP-3 was calcium (beta = 0.07, P < 0.05), and significant predictors of IGFBP-1 were vegetable protein (beta = 0.49, P < 0.05) and body mass index-for-age percentile (beta = -0.01, P < 0.001). This study provides evidence that dietary intake affects IGF-related biomarkers-particularly elevated calcium with IGF-I and IGFBP-3 and elevated vegetable protein with IGFBP-1-and, to our knowledge, is novel in reporting these associations in adolescent females. The Dietary Intervention Study in Children was registered at clinicaltrials.gov as NCT00000459.

Plasma levels of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 in women with cervical neoplasia

The goal of this study was to investigate the relationship between plasma levels of insulin-like growth factors-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) and the risk for cervical intraepithelial neoplasia (CIN) and cervical cancer. Plasma levels of IGF-1 and IGFBP-3 of 44 cervical cancer patients, 82 CIN patients and 40 neoplasm-free patients were investigated. Then the associations of the plasma levels of IGF-1 and IGFBP-3 with cervical neoplasm or its clinicopathologic parameters were analyzed. The mean IGF-1 concentrations were significantly different among the control, CIN, and cervical cancer groups; the levels were higher in the CIN group compared to the controls. According to the quartile category, the plasma IGF-1 level was significantly higher (p=0.0015) in the CIN group than in the controls. The IGFBP-3 level showed no association between the controls and CIN groups (p=0.842). Although the mean IGF-1/IGFBP-3 molar ratio had borderline significance (p=0.08) among the study population, the quartile comparison showed a significantly higher IGF-1/IGFBP-3 molar ratio in the CIN group compared to the control group (p=0.041). Plasma levels of IGF-1 and the IGF-1/IGFBP-3 molar ratio might be useful for the development early detection of cervical lesions and used as an adjuvant diagnostic tool for cervical neoplasia after more larger scale research.

Anthropometric Correlates of Insulin-Like Growth Factor 1 (IGF-1) and IGF Binding Protein-3 (IGFBP-3) Levels by Race/Ethnicity and Gender

Insulin-like growth factor 1 (IGF-1) levels are positively related to some cancers and negatively related to cardiovascular disease. These conditions are also related to insulin resistance and high body weight, leading to the hypothesis that IGF-1 levels may, in part, mediate the association of high body weight with these health outcomes. Using the National Health and Nutrition Examination Survey (NHANES) III population, we examined the associations between IGF-1, IGF binding protein-3 (IGFBP-3), and the IGF-1/IGFBP-3 molar ratio with anthropometric measures in a large, U.S. population-based study where these associations could also be stratified by race/ethnicity and gender. The study population consisted of 3,168 women and 2,635 men (44% non-Hispanic white, 28.2% non-Hispanic black, and 27.7% Mexican-American). Anthropometric measures were obtained by trained personnel in the NHANES mobile examination centers. IGF-1 and IGFBP-3 were measured using immunoassays by staff at Diagnostic System Laboratories (DSL) Inc. (Webster, TX). Associations of IGF-1, IGFBP-3, and IGF-1/IGFBP-3 molar ratio with anthropometric variables across race/ethnicity and gender were evaluated by using linear regression modeling. Body mass index (BMI) was inversely associated with IGF-1 levels across all of the race/ethnicity and gender subgroups. In contrast, BMI, waist to hip ratio (WHR), and waist circumference were positively associated with IGFBP-3 levels only in non-Hispanic black men and non-Hispanic white women. The IGF-1/IGFBP-3 molar ratio was inversely associated with all anthropometric measures, except height, in all subgroups of the population. The significant inverse associations of BMI with IGF-1 levels and of all anthropometric variables, except height, with the IGF-1:IGFBP-3 molar ratio in all subgroups do not support existing hypotheses that associations of excess weight with negative health outcomes, such as specific cancer diagnoses, are mediated through high IGF-1 levels.

The relationships among bone health, insulin-like growth factor-1 and sex hormones in adolescent female athletes

The aim of this study was to determine the relationships of bone mineral density (BMD) and content (BMC) with insulin-like growth factor-1 (IGF-1), IGF-binding protein-3 (IGFBP-3) and estradiol in pubertal female athletes. The participants were 170 healthy adolescent girls (13-15 years) who participated in competitive extramural athletic programs, i.e., sports games (n = 49), track sprinting (n = 24), rhythmic gymnastics (n = 23), swimming (n = 24) and cross-country skiing (n = 17). The control group (n = 33) consisted of girls who took part only in compulsory physical education classes at school. The whole-body BMD and femoral neck and lumbar spine BMD and BMC were measured using DXA, and the volumetric BMD was calculated. Venous blood samples to determine the concentration of IGF-1, IGFBP-3 and estradiol were drawn after an overnight fasting. After adjusting for age, body height and body mass, the relationships among BMD variables, IGF-1 and the IGF-1/IGFBP-3 molar ratio remained significant only in the rhythmic gymnast group. BMDs at the femoral neck and lumbar spine were also related to estradiol levels (r = 0.45-0.60; p < 0.05) only in the rhythmic gymnast group. No relationships were found among the measured BMD, IGF axis and estradiol in other athletic groups. Only BMC at the femoral neck remained associated with the IGF-1/IGFBP-3 molar ratio in the rhythmic gymnast group after adjusting for age, body height and body mass. Stepwise multiple regression analysis indicated that IGF-1 and estradiol together explained 42.6% (R(2) x 100) of total variance in the femoral neck BMD and IGF-1 alone 35.4% (R(2) x 100) of the total variance in the femoral neck BMC only in the rhythmic gymnast group. We conclude that femoral neck and lumbar spine BMD correlated with IGF-1, IGF-1/IGFBP-3 molar ratio and estradiol in rhythmic gymnasts. No relationships were found between bone parameters and the hormones used in other athletic groups.