Reference Intervals for Insulin-like Growth Factor-1 (IGF-I) From Birth to Senescence: Results From a Multicenter Study Using a New Automated Chemiluminescence IGF-I Immunoassay Conforming to Recent International Recommendations (original) (raw)

Age- and Sex-Specific Reference Intervals Across Life Span for Insulin-Like Growth Factor Binding Protein 3 (IGFBP-3) and the IGF-I to IGFBP-3 Ratio Measured by New Automated Chemiluminescence Assays

The Journal of Clinical Endocrinology & Metabolism, 2014

Context: Measurement of IGF-binding protein-3 (IGFBP-3) can aid the diagnosis of GH-related diseases. Furthermore, epidemiological studies suggest that IGFBP-3 and the molar IGF-I to IGFBP-3 ratio are associated with clinical end points like cancer or cardiovascular disease. However, their clinical use is limited by the lack of validated reference intervals. Objective: The objective of the study was the establishment of age-and sex-specific reference intervals for IGFBP-3 and the molar IGF-I to IGFBP-3 ratio by newly developed automated immunoassays. Setting: This was a multicenter study with samples from 11 cohorts from the United States, Canada, and Europe. Participants: A total of 14 970 healthy subjects covering all ages from birth to senescence participated in the study. Main Outcome Measures: Concentrations of IGFBP-3 and the IGF-I to IGFBP-3 ratio as determined by the IDS iSYS IGF-I and IGFBP-3 assays were measured. Results: Both the concentration of IGFBP-3 and the IGF-I to IGFBP-3 ratio are mainly determined by age. IGFBP-3 concentrations increase until the age of 22 years, with a plateau being visible between 15 and 25 years. Determined by the high peripubertal peak in IGF-I, the peak in the IGF-I to IGFBP-3 ratio occurs already around the age of 15 years, with a slightly earlier and higher peak in females. Beyond the age of 60 years, IGFBP-3 concentrations remain higher in females, whereas IGF-I as well as the IGF-I to IGFBP-3 ratio remains significantly higher in males. Conclusions: We present an extensive set of assay-specific age-and sex-adjusted normative data for concentrations of IGFBP-3 and the molar IGF-I to IGFBP-3 ratio and demonstrate distinct sex specific differences across the life span.

Timing of Puberty Determines Serum Insulin-Like Growth Factor-I in Late Adulthood

The Journal of Clinical Endocrinology & Metabolism, 2006

Context: IGFs may play an important role in disease etiology, especially cancer. Changes in diet can alter acute levels, but little is known about life course influences on IGF levels. Objective: The objective of the study was to examine the association between timing of puberty and adulthood serum IGFs (IGF-I and IGF binding protein-3). Design: This was a retrospective cohort study. Setting: Male pupils who attended a single school in Southern England were part of the study. Participants: Participants in the study were a cohort of 1028 men born between 1927 and 1956 with anthropometric measures between 9 and 18 yr and adulthood serum IGF levels. Main Outcome Measure: The study measured serum IGF-I and IGF binding protein-3 at mean age 63 yr. Results: Age at peak height velocity (APHV) was inversely associated with adult IGF-I levels. IGF-I decreased by 3.7 ng/ml (95% confidence interval 1.0-6.4, P ϭ 0.007) for each SD increase in APHV. Prepubertal childhood height and body mass index were both inversely associated with APHV (P trend Ͻ 0.001). APHV was positively associated with adult height and inversely associated with adult body mass index. Adjustment for childhood, adult anthropometry, and other lifestyle factors did not substantially alter the association between APHV and adult IGF-I. Conclusions: This is the first study to document an association between timing of puberty and adult IGF-I levels. A better understanding of life course determinants of the IGF system may provide new insights into disease etiology and primary prevention.

Genetic and environmental components of interindividual variation in circulating levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3

Journal of Clinical Investigation, 1996

We assessed the magnitude of the genetic component in the variation of circulating levels of insulin-like growth factors I and II (IGF-I and IGF-II), and their binding proteins IG-FBP-1 and IGFBP-3 by measuring their serum concentrations in 32 monozygotic and 47 dizygotic adult twin pairs of the same sex. The intrapair correlation for the IGF-I levels was r ϭ 0.41 ( P Ͻ 0.009) for monozygotic twins and r ϭ 0.12 ( P Ͻ 0.22) for dizygotic twins. For the IGF-II concentration the intrapair correlations were r ϭ 0.66 ( P Ͻ 0.0001) for the monozygotic and r ϭ 0.34 ( P Ͻ 0.01) for the dizygotic twins. No significant intrapair correlation was found for IGFBP-1 levels in either group. The correlations for IGFBP-3 concentration were r ϭ 0.65 ( P Ͻ 0.0001) and r ϭ 0.23 ( P Ͻ 0.06) for monozygotic and dizygotic twins, respectively. Women had higher IGF-II levels than men (635 Ϯ 175 vs. 522 Ϯ 144 g/liter; P Ͻ 0.0001) and IGFBP-3 levels were also higher in women compared with men (5441 Ϯ 1018 vs. 4496 Ϯ 1084 g/ liter; P Ͻ 0.001). The proportion of variance attributable to genetic effects was 38% for the IGF-I concentration, 66% for the IGF-II concentration, and 60% for the IGFBP-3 concentration. No significant heritability was found for the IGFBP-1 concentrations. Our results show that, in adults, there is a substantial genetic contribution responsible for interindividual variation of the circulating levels of IGF-I, IGF-II, and IGFBP-3, but not for the IGFBP-1 levels. ( J. Clin. Invest. 1996Invest. . 98:2612Invest. -2615

Reference Values for IGF-I throughout Childhood and Adolescence: A Model that Accounts Simultaneously for the Effect of Gender, Age, and Puberty

The Journal of Clinical Endocrinology & Metabolism, 2001

We have constructed a reference model to facilitate comparison of serum IGF-I values among children, and thereby to improve the value of IGF-I measurements for diagnosis. The data set consists of serum values measured in 969 samples from 468 healthy children and adolescents (232 males, 236 females; ages, 1.1-18.3 yr). One sample per child was used for the model, each being selected so as to provide sufficient observations for each stage of puberty. The samples not selected were used to validate the reference data. The IGF-I values were log transformed, and multiple regression analysis was used in the model-building process. The best linear model, which converts serum IGF-I concentrations into SD scores and explains 66% of the variation in logIGF-I values, includes the variables of age, gender, and puberty, and takes the interactions among these variables into account. In prepubertal and early pubertal children, the relationship between age and logIGF-I was positive, with greater effect in girls older than 8 yr. In mid-puberty, logIGF-I values were higher in girls than in boys of the same age, up to 16 yr of age. Among boys, the most pronounced positive relationship between age and logIGF-I occurred in mid-puberty, whereas the relationship between age and logIGF-I among girls in mid-puberty is fairly constant. In late puberty, logIGF-I values were higher than earlier in puberty, and there was a negative relationship with age in both boys and girls. Instead of separate models for each combination of puberty and gender, estimating a single regression model permits simultaneous estimation of all explanatory variables and uses all observations in the data set, thereby making it easier to select those variables that have a significant effect on logIGF-I. Our model shows that IGF-I levels are related to age during each stage of puberty. The model also accounts for the fact that serum IGF-I concentrations during puberty are different for boys and girls. (J Clin Endocrinol Metab 86: 5870 -5876, 2001)

Early programming of the IGF-I axis: Negative association between IGF-I in infancy and late adolescence in a 17-year longitudinal follow-up study of healthy subjects

Growth Hormone & IGF Research, 2009

Background: IGF-I is a major regulator of growth, influenced primarily by diet in infancy and primarily by GH in childhood. Breastfed infants have lower IGF-I levels compared to formula fed and tend to be shorter. The higher protein content of infant formula has a stimulatory effect on IGF-I production. Conversely, studies suggest that later in childhood, those breastfed are taller and have higher IGF-I levels. Therefore, it has been suggested that the IGF-I axis may be programmed by diet during infancy. The association between IGF-I in infancy and later life is not known. Objective: To examine the association between IGF-I in infancy and adolescence. Design: Infants (109) from the observational Copenhagen cohort study. Methods: Serum-IGF-I was measured during infancy (2, 6, and 9 months) and at follow-up at 17 years. Associations were examined by correlation tests and linear regression controlling for gender, breastfeeding, and other covariates. Likelihood ratio test based on residual log likelihood was applied for analysis including all measurements during infancy.

Assessment of age-related changes in heritability and IGF-1 gene effect on circulating IGF-1 levels

AGE, 2014

It is well established that insulin-like growth factor 1 (IGF-1) circulating levels correlate with age and that heritability and influence of IGF-1 gene variation on IGF-1 levels also well-known. However, the influence of age on the genetic factors determining IGF-1 levels is not clear. In this study, we compared heritability estimates between younger (<52 years) and older (>52 years) twins and tested: (a) whether single nucleotide polymorphisms (SNPs) lying within 100 kbp of the IGF-1 gene are also associated with IGF-1 variation and (b) whether associated SNPs show interaction with age on IGF-1 levels. To achieve these aims, we measured plasma levels of IGF-1 and genotyped 18 SNPs with minor allele frequency >0.1 in a large sample, 4,471 UK female twins. Heritability explained 42 % of IGF-1 variation adjusted for age and in unadjusted sample was independent of age. Ten SNPs in four haploblocks showed significant association with IGF-1 levels, with p=0.01-0.0005. The most distal SNP was located up to 90 kbp from the IGF-1 gene. When their age-dependent effects were examined, one SNP, rs855203, showed significant (p = 0.0009) agedependent interaction effect on IGF-1 levels variation. This is the first study to test the age×genotype interaction in IGF-1 levels. The genomic region marked by rs855203 may consequently be of significance for further molecular and pharmacogenetic research, in particular in advanced age.