Endocrine Journal 2010, 57 (3), 221-228

ORIGINAL

Reference Ranges for Serum IGF-1 and IGFBP-3 Levels in Chinese Children During Childhood and Adolescence
ShAnshAn XU1), XUEfAn GU1), HUi PAn2), HUiJUAn ZhU2), FEngYing GOng2), YUfEng Li3) AnD YAnMEi Xing4)
1)

Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China 2) Peking Union Medical College Hospital, Beijing 100730, China 3) Beijing Pinggu Hospital, Beijing 101200, China 4) Shunyi Maternal and Child Health Care Hospital, Beijing 101300, China

Abstract. Serum levels of insulin-like growth factor-1(IGF-1) and insulin-like growth factor binding protein-3(IGFBP-3) reflect endogenous growth hormone secretion, and serum IGF-1 and IGFBP-3 values should be ethnic-specific, thus we established the reference ranges for serum IGF-1 and IGFBP-3 in Chinese children aged 6-18 yr according to age, sex, puberty stage and BMI. The study was included 837 children (age 6-18 yr, 416 boys and 421 girls) from different schools in Daqing, Beijing and Shanghai. Serum IGF-1 and IGFBP-3 were determined by a chemiluminescent assay system (IMMULITE 1000). The results show that IGF1 reached peak levels at around 13 yr in boys and 11 yr in girls while IGFBP-3 peaked at 14 yr in boys, and 11 yr in girls. Both IGF-1 and IGFBP-3 were at platform or decreased slightly after these ages. At each corresponding age, IGF-1 levels tended to be higher in boys compared to girls, while girls had higher IGFBP-3 levels than boys. A model for calculation of standard deviation scores of IGF-1 and IGFBP3 according to age, sex and pubertal stage was established. These normative data should facilitate child care, growth monitoring, clinical diagnosis and to follow up on GH treatment. Key words: Insulin-like growth factor-1, Insulin-like growth factor binding protein-3, Reference values

GROWTH HORMONE (GH) release is pulsatile [1]. Serum levels of insulin-like growth factor-1(IGF-1) and insulin-like growth factor binding protein-3(IGFBP-3) reflect endogenous GH secretion in healthy children, and their serum levels are relatively stable with modest diurnal variation. Thus, serum IGF-1 and IGFBP-3 are widely accepted for diagnostic use and for monitoring of therapy in growth disorders. IGF-1 is a small peptide hormone, over 99% circulating IGF-1 are bound to serum proteins including IGFBP-3 and the acid labile subunit. However, both serum IGF-1 and IGFBP-3 levels are regulated by age, sex, pubertal stage, genetic factors, social factors, nutritional status and disease [2-3]. Numerous
Received Jul. 14, 2009; Accepted Dec. 1, 2009 as K09E-200 Released online in J-STAGE as advance publication Jan. 6, 2010

reports indicate that serum concentrations of IGF-1 and IGFBP-3 increase through childhood [3-7]. Also, puberty produces significant increases in IGF-1 and IGFBP-3, possibly as a result of increased GH secretion mediated by sex steroids. On the other hand, timing of pubertal onset can be influenced by ethnicity, therefore the reference values of serum IGF-1 and IGFBP-3 should preferably be ethnic-specific and may not be simply adopted from other population. In this study, we established the reference ranges for serum IGF-1 and IGFBP-3 in Chinese children aged 6-18 yr according to age, sex, puberty stage and BMI.

Materials and Methods
Subjects selection and measurements The study population was consisted of 837 children (age 6-18 yr, 416 boys and 421 girls) from different schools in difference provinces, including Daqing, Beijing and Shanghai. All subjects have had a routine

Correspondence to: Xuefan GU, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China. E-mail: guxuefan@online.sh.cn

0 (SPSS. IGFBP-3 levels seemed only correlated with age in boys and girls (Table 5. 1. and 11 yr in girls. and no transformation was required. p=0. 17. Effect of puberty on IGF-1 and IGFBP-3 Reference curves for serum IGF-1 and IGFBP-3 levels of each age. This study was approved by Ethical Committee of Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine. The serum IGF1 reached peak level around 13 yr in boys. coefficients α(intercept) and β(slope) were used to determine the age-. sex. Chicago. which were calculated for each variable. 2). p=0. and differences almost were statistically significant (p=0. just compatible to reported age of peak height velocity (table 1).. and height or weight greater than ±2SD from mean. Puberty staging was determined by endocrinologist according to Tanner stage criteria. p≤0. IGFBP-3 Removed the confounding effects of age and puberty stage. Results Age dependence of serum IGF-1 and IGFBP-3 levels Serum levels of IGF-1 and IGFBP-3 increased from early childhood into adolescence. Sera were separated after centrifugation of coagulated blood and stored at -20°C until analysis. sex. IGF-1 and IGFBP-3 levels exhibited Gaussian distribution. IGF-1 and IGFBP-3 assays were carried out using an automated chemiluminescent assay system (IMMULITE 1000. tumor.004 for age 6. 9. Multiple linear regression analysis was performed to evaluate the influence of age. IGFBP-3 levels in girls are higher than boys at the same ages. physical examination. 14. 10. 6).025 for age 10. ±1SD. IL) was used for the analysis. However. Body mass index (BMI) was calculated as weight (kg) divided by height (m) squared.002 for age 9. 13. p<0. USA). The SDS of IGF-1 and IGFBP-3 were calculated as follows: SDS(IGF-1)=(IGF-1 value-y)/SD. Informed consent was obtained from the parents of each child. IGFBP-3 according to age in certain puberty stage was proposed (table 3. IGF-1 and IGFBP-3 levels were maintained at platform or decreased slightly with increasing age. a weighted linear regression analysis was performed. Children with any of the following conditions will not be recruited into the study: chronic medical illnesses (e. According to sex and Tanner stage. The general pattern of IGFBP-3 changes was similar to IGF-1 and increased with age (table 2). IGF-1 and IGFBP-3 values above or below the detection limit were calculated as detection limit for the statistical analysis.001 for age 11.222 XU et al. 18.and puberty-corrected IGF-1 & IGFBP-3 levels based on the formula: y=β×age+α where y = IGF-1 or IGFBP-3 levels. CA. acute infection within two weeks of the study. BMI has no statistically significant effects on . hepatic. T test was used to compare levels in boys and girls of the same age group. p=0. puberty and BMI on serum IGF-1 and IGFBP-3 concentrations.05 was considered statistically significant. A prediction model for calculating the standard deviation scores of IGF-1. The statistical package SPSS 15. Diagnostic Products Corp. BMI and serum IGF-1.001 for age 7. precocious or delayed puberty. Due to the different variances within the Tanner groups. using weights equal to the reciprocal variance around regression lines for each combination of sex and Tanner stage of puberty. Los Angeles. sex and puberty stage all have significant influences on serum IGF-1 levels. Inc. Sexual differences in IGF-1 and IGFBP-3 IGF-1 levels tended to be higher in boys compared to girls at the corresponding ages except for 9-12 yr when lots of girls had gone into early puberty. But the differences were statistically significant only in some pubertal ages (p=0. Age-related regression lines and the corresponding 95% confidence intervals (equal to ±2SD) were constructed for each sex and puberty stage.. The blood was drawn from an antecubital vein in the morning with subjects fasting. 11. 4). 13. p≤0. All subjects had their heights and weight measured in schools. Statistical analysis Data were presented as mean. ±2SD. with focus on breast development in girls and testicular volume in boys. 16. In late puberty. 12. 8.045 for age 16).g. SDS(IGFBP3)=(IGFBP-3 value-y)/SD.003 for age 14). The relative importance of the variables was indicated by standardized coefficients β. renal and heart diseases). Multiple linear regression analysis demonstrated that age. and blood samples collected. 15. sex and puberty stage were determined and were constructed as 95% confidence intervals (fig.

27 765.23 223.00 6.26 Table 2.80 427. Age Boys Girls (yr) N -2SD -1SD Mean 1SD 2SD N -2SD 6 20 52.54 17 35 280.18 411.26 6.18 413.01 11 35 174.57 2SD 312.04 30 229.61 283. serum IGF-1 high values occurred around 13-15 yr in girls and 1416 yr in boys and IGFBP-3 peak level occurred from 13 yr to 15 yr in both sexes (Fig 3.25 501. and Japanese etc [4.62 8 35 108.74 32 258. Age Boys Girls (yr) N -2SD -1SD Mean 1SD 2SD N 6 20 2.28 9.84 335.39 3.99 30 -2SD 2.19 11. Such correlation between peak IGF-1 concentrations and peak height velocity has been reported [8].53 525.84 1SD 8.35 4.52 5.82 8.39 15 35 282.85 8.94 5. These peak serum IGF-1 levels correspond to peak height velocity.65 3.72 525.34 691.66 27 8 35 3.22 11.61 8.19 5.03 31 15 35 4.42 5.IGF-1 AND IGFBP-3 REFERENCE RANGES 223 Table 1.88 1SD 250.27 6.61 566.40 543.29 10.20 8. the reference values for serum IGF-1 and IGFBP-3 levels were established in a cohort of healthy Chinese children during childhood and adolescence aged 6-18 yr.32 447.24 7.54 550.59 5.96 9.67 4.90 11.83 606.14 33 341.09 5.88 Mean 6.66 7.76 serum IGF-1 and IGFBP-3 in both sexes (table 5.04 8.38 514.72 10. This trend has also been shown in some longitudinal studies [12-14].96 5.29 210.84 4.58 11.43 392.19 11.60 6.38 713.44 574.92 -1SD 4.59 4.12]. sex.59 18 16 224.93 9.27 8.43 34 11 35 2.63 4.87 13.55 869.39 4.06 3.70 9.38 696.05 9.98 36 245.46 276.29 337. Danes.18 236.71 30 64.67 725.22 850.86 444.54 360.96 11.40 7.67 16 36 334.32 12 35 204.68 11.36 868. reaching peak values during sexual maturation.29 6. our results also show that age.87 186.97 626.05 539.65 7. IGF-1 peaked at 13 yr and fell thereafter in boys.92 6.07 327.80 768.50 512.40 261.51 185.34 5. In our study.87 221.80 11.99 9.58 669.23 34 100.58 7.75 5.70 5.66 289.83 424.59 570.62 735.71 128.86 6.94 31 18 16 4.62 659.82 10.97 563.11 5.30 8.19 Mean 188. peaked at 14 yr in boys and 11 yr in girls then fluctuated around the peak level with increasing age [11].92 665.14 479.99 5.37 32 16 36 3.56 850.96 13.89 475.13 323.29 144.32 3.07 5.66 35 110.62 9.21 203. Agreeing with the data from previous studies for other populations including German.53 6. Discussion In this survey.58 10 35 122.60 8.15 448. Swedes.91 33 17 35 3.00 9.50 -1SD 126.34 4.07 7.08 1018. Serum levels of IGF-1 and IGFBP-3 were low during early childhood.08 5.14 770.71 279.55 7.33 6.15 8. while plateauing off after reaching peak at 11 yr in girls.30 139.93 359.64 625.38 9.67 11.77 5.85 27 68.57 7.96 35 83. 6).94 34 358.60 398.95 8.72 382.46 562. and puberty stage were important factors for determining serum levels of IGF-1 and IGFBP-3.73 8.27 352.40 721.83 8.67 10.89 33 284. The changes in IGFBP-3 were similar to IGF-1.80 10.55 5.25 5.46 395.37 9.41 6. Normal ranges for total IGF-1 serum levels (ng/mL) in 6 to 18 years children.49 4.89 30 7 30 3.03 8.18 359.77 676.31 8.58 7.11 8.84 152.36 681. Review the normative data published before. and increased with age.51 9.57 10.79 7.24 5. 4) [4-10.53 14 35 350.24 495.96 7.28 281. Normal ranges for IGFBP-3 serum levels (μg/mL) in 6 to 18 years children.78 600.15 35 9 34 2.54 5.64 916.52 247.40 35 10 35 2.13 7.97 553.31 7 30 52.63 6.25 13.32 6.48 427.93 34 14 35 4.54 692.45 392.54 834.40 13.16 715.76 716.48 33 12 35 3.82 7.47 36 13 35 3.50 6.74 8.27 12.12 806.71 854.54 408.87 6.78 537. Trukese.08 9 34 83.21 354. .45 31 221.83 12.96 419.75 6.59 447.77 930.63 904.40 13 35 343.98 8.50 6.90 290.39 9.58 444.48 9.80 2SD 11.17 857.07 609. 6-9]. implying that the significant increase in IGF-1 contribute to the accelerated bone growth in puberty.52 385.38 192.31 6.78 824.32 31 266.

15-16]. but decreased with increasing age of children from puberty stage III (in boys) or V (in girls). IGF-1 levels tended to be higher in boys compared to girls of the same ages. and hence have puberty growth spurt 1-2 yr earlier than boys. while IGFBP-3 levels in girls are higher than boys of the same ages as previously demonstrated in normal children [8.224 XU et al. puberty stage influenced serum levels of IGF-1 and IGFBP-3. It may be in line with that there are well known direct negative effects of estrogens on GH-regulated IGF-1 production with potentially di- vergent effects of androgens [17-19]. Apart from age and sex. Regression lines represent 95% confidence intervals. IGF-1 increased with increasing age in prepubertal children.2. Fig. IGF-1 and IGFBP-3 peak values in girls appear approximately 1-2 yr earlier than boys. It agreed with the observation that girls enter puberty earlier than boys. IGF-1 and IGFBP-3 varied with age within the same puberty stage. probably because of the sex steroids-induced increase in GH secretion in the pubertal years [12. 20]. Serum IGFBP-3 levels (μg/mL) in boys (upper panels) and girls (lower panels) according to the chronological age and pubertal stage. Serum IGF-1 levels (ng/mL) in boys (upper panels) and girls (lower panels) according to the chronological age and pubertal stage. Fig. It revealed that the older a child reached the final puberty stages.1. IGFBP-3 increased with in- . Regression lines represent 95% confidence intervals. the lower IGF-1 levels.

These results have a little difference from previous reports [21].17 0.084) -0.13(144.532(1.099) b (SE) SD 1.090(0.462 0.38 0. sex.523 2.54(16.51) 4. we have developed a model that can be used in Chinese children for relating serum IGF-1 and IGFBP-3 levels to age. β: slopes.598 p <0. sex and BMI as independent variables.353) 4.567 0.01(8. sex and BMI as independent variables.63) 74.241 0.416 0.015 Ⅲ 838.289.60 <0.167(4.95(202.006 40 0.026(0.75) 24.663 0.19) 133.035 0.284(0.838 0.44) 51.139(0.001 <0.27(3. in girls.197 0.001 170 0.386 1. It is possibly because of the judgment for puberty stage with different clinicians.1.11) 167. SD: standard deviations) Puberty stage α (SE) SD p n r b (SE) Boys -144. and age.553(0. In this study.758(0.150(0.078 0.126(0. Variables Age Puberty stage BMI Sex β 0.491 2.134) Table 5. IGFBP-3 parameters increased with age in all five stages.47 <0.78) 88. However. This .911 0.08) 47.244 0.131 p <0.141 82 0.018) -1.001 0.056 1.456 Ⅱ 638.129) -2.219(2.14) 146. p=0.30 0.676.019 0.65(15.000 (β: standardized coefficients β) R=0. y=β×age+α (SE: standard errors.140) 0.43(179.30(19.096 112 0.328 0.26(12.156) 0. y=β×age+α (SE: standard errors.249(0.706) 8.001 54 0.523) -0.541 0.603(1.22(135.45 0. puberty stage.001 n 170 54 49 82 60 112 14 40 190 65 r 0.0(45.228) 0. Using multiple regression analysis.94) 154.914(2.051(0. Multiple regression analysis with serum IGF-1 levels as dependent variables.074) 0. IGFBP-3 according to age in certain puberty stage. However.310 1. R2=0.15) 145.536 0.244 14 0.767) 4.353 Ⅴ Girls 148.36(58.144) 1. A similar model has been proposed in several studies such as for Trukese population. we can calculate the standard deviation scores of IGF-1.40) -42.47(9.263 0.027 Ⅳ 1252.543(2.18) 9.736 Ⅰ -192.072 Ⅳ 600. puberty stage.11(4.IGF-1 AND IGFBP-3 REFERENCE RANGES 225 Table 3. α: intercepts. Multiple regression analysis with serum IGFBP-3 levels as dependent variables.349) 4. puberty stage.439 0.048 0.376(2.123 0.532 1.244) 6.112(0.656) 5.70(5.316 0.170) 0. Linear regression data for the age distribution of IGF-1 levels in each puberty stage for both sexes. and sex si- multaneously.75) 137.920 49 0.072 0.365 Ⅱ -80.454 p <0.82) -1.000 Table 6.007 61 0. From this formula.001 <0.446 Ⅲ 464. Linear regression data for the age distribution of IGFBP-3 levels in each puberty stage for both sexes.305) 11. R2=0.022 Ⅴ Table 4.000 R=0. β: slopes.17 0.56) 50.873 65 0.026 0. SD: standard deviations) Puberty stage Boys Ⅰ Ⅱ Ⅲ Ⅳ Ⅴ Girls Ⅰ Ⅱ Ⅲ Ⅳ Ⅴ α (SE) 1.329 190 0.524(1.49) -13.072 0.596 0.73 0.570 2.030) 0.01) .436 1.15 0.458.731(1. we observed a strong relationship between IGF-1 and age. and ethnic disparity.000 (β: standardized coefficients β) creasing age till stage IV in boys. puberty stage. only age but not puberty stage has significant positive effect on IGFBP-3. and age. p=0.01(34.001 0.52(14. Variables Age Puberty stage BMI Sex β 0.538.013 0.077 0.344 2.61(244.160 Ⅰ 31.79) 118.73 0.001 0.81) 145.01(183. α: intercepts.51(140.

Compared to published reference data. We concluded that height or weight have strong positive linear association with age. chemiluminescnet assays). the reference values of serum IGF-1 and IGFBP-3 may be different from different laboratories [23]. (3) The impact of pubertal development is stronger on IGF-1 than on IGFBP-3. This time is about 1-2 yr earlier than previous studies. as well as differences between laboratories. and 11 yr in girls. we reached the following conclusions: (1) Serum IGF1 reached peak level around 13 yr in boys. or BMI would not increase the explanatory power of the models. comparing the boys (left panel) and girls (right panel) subjects.4. IGFBP-3 peaked at 14 yr in boys. (2) IGF-1 levels tended to be higher in boys compared to girls at the same ages. nutritional status. comparing the boys (left panel) and girls (right panel) subjects.8 12 and our study. 4. weight. Serum IGF-1 mean levels (ng/mL) in different population in Ref.and underweight patients. and 11 yr in girls. even the same commercial kits. Despite using the similar methodology (eg. And the impact of pubertal development is stronger on IGF-1 than on IGFBP-3. Fig. body composition influences IGF-1 secretion was found in these patients [22]. and when age variable is included in consideration. Fig. The multiple regression analysis showed that BMI has no statistically significant effects on serum IGF-1 and IGFBP-3 values in boys and girls. After peak. 6 and our study. Serum IGFBP-3 mean levels (μg/mL) in different population in Ref. might be explained that IGF-1 levels are more sensitive to GH regulation than IGFBP-3. In our opinion. In studies covering over. (4) Correcting for the confounding effects . and preanalytical influences like sample collection and storage. height. IGF-1 and IGFBP-3 decrease slightly or maintain the levels on peak with increasing age.226 XU et al. 3. 15]. This result is in line with previous studies in healthy children [12. differences come from genetic background. while IGFBP-3 levels in girls are higher than boys at the same ages.

and GeneScience Pharmaceuticals Co. Juul A.IGF-I. Jorgensen K. Juul A. sex. Ketelslegers JM. Chan MH. manage and study GH-IGF-axis-related metabolic disorders. Brabant G. J Clin Endocrinol Metab 84: 82-89. Dalgaard P.IGF-1 AND IGFBP-3 REFERENCE RANGES 227 of age. Ho CS. Tada C. 9. 8. Holm K. and puberty. Am J Dis Child 141: 562-564. Kong AP. Schemer R. Cara JF. Juul A. 5. testicular size and body mass index. BMI and IGF-1. Turan S. We thank Dr. sex and puberty stage. Rasmussen S. Wuster C. Frystyk J. Chan JC (2007) Reference values for serum levels of insulin-like growth factor(IGF-1) and IGF-binding protein 3(IGFBP-3) and their ratio in Chinese adolescents. 6.. Saller B. sex. Clayton PE. Dalqaard P. adolescents and adults. 08JC1416100). Lofqvist C. Hall CM (2004) Insulin-like growth factor 1 levels in healthy children. Albertsson Wikland K (2001) Reference values for IGF-1 throughout children and adolescence: a model that accounts simultaneously for the effect of gender. Tong PC. This study established age-. J Clin Endocrinol Metab 78: 744-752. Horm Res 65: 96-105. Skakkebaek NE (1994) Serum insulin-like growth factor I in 1030 healthy children. Acknowledgements This work has been supported by Hi-Tech Research and Development Program (2007AA02Z447). Lau JT. Hertel T. Skakkebaek NE (1996) Serum concentrations of free and total insulin-like growth factor-I. Muller J. Rosenfield RI. Muller J. also it could aid research worker and clini- cian to assess. Muller J. Bang P. Blum WF. 2. Horm Res 62: 2-7. Furlanetto R. 12. Pik-to Cheung for critical reading of the manuscript. Hertel HT. Ozen A. Takano-Watou S. References 1. Wilde J. and IGF-binding protein-3 concentrations in normal children and children with growth hormone deficiency. So WY. Skakkebaek NE (1995) Serum levels of insulin-like growth factor (IGF)binding protein-3 (IGFBP-3) in healthy infants. Akbenlioglu C. Endocr Rev 19: 717797. Bang P. Juul A. Skakkebaek NE (2000) Serum levels of growth hor- . Lam CW. Rosenfield RL. Kratzsch J. there is a lack of correlation between serum IGF-1 & IGFBP-3 and BMI in healthy children. Omer A. Shanghai government foundations (2008ZD001. Rosberg S. Scheike T. and pubertal maturation. 13.Ltd (Changchun. Clin Endocrinol 44: 515-523. 14. age. Pedersen SA . Kiess W. Kastrup KW. Wilhelmsen L. Michaelsen KF. German KIMS Board (2003) Serum insulinlike growth factor I reference values for an automated chemilumine scence immunoassay system: results from a multicenter study. 4. Furlanetto RW (1987) A longitudinal study of the relationship of plasma somatomedin-C concentration to the pubertal growth spurt. Bock D (1983) Relationship of somatomedin-C concentrations to pubertal changes. and its diagnostic value in patients suspected of growth hormone deficiency. Kann P. sex. Yamanaka Y. Juul A. Hulthen L. IGFBP-3 according to age in certain puberty stage. These normative data should facilitate child care and growth monitoring for healthy children. age. sex-. Giustina A. Ma RC. Scheike T. Haklar G. 3. IGFBP-3. China). pubertal stagespecific reference values for IGF-1 and IGFBP-3 in Chinese children. IGFBP-1. Kanzaki S. Andersson E. IGF binding proteins-1 and -3 and IGFBP-3 protease activity in boys with normal or precocious puberty. Mattsson A. Blum WF. Clemmons DR (2006) Clinical utility of measurements of insulin-like growth factor 1. Main K. and also constructed a model formula to calculate the standard deviation scores of IGF-1. Hall K. Miyata T. and adolescents: the relation to IGF-I. J Pediatr 103: 723-728. body mass index. Ranke MB. Fisker S. Flyvbjerg A. Ozaki R. Gelander L. children. Hall K. Clin Endocrinol Metab 80: 25342542. J Clin Endocrinol Metab 86: 58705876. Veldhuis JD (1998) Pathophysiology of neuroregulation of growth hormone secretion in experimental animals and the human. total IGF-I. Orskov H. (2006) Serum IGF-1 and IGFBP-3 levels of Turkish children during childhood and adolescence: establishment of reference ranges with emphasis on puberty. Muller J.IGFBP-2. Bereket A. Choi KC. 10. stage of puberty. pubertal. 7. 15. Horm Res 60: 53-60. 11. relation to age. Michaelsen KF. Wong GW. Oka M. Kawai N. Muller J. Nat Clin Pract Endocrinol Metab 2: 436-446. Clinical Biochemistry 40: 1093-1099. Skakkebaek NE (1997) Free insulin-like growth factor I serum levels in 1430 healthy children and adults. revealed the relationship between age. von zur Muhlen A. J Clin Endocrinol Metab 82: 2497-2502. Berber M. Takano-Watou S. Seino Y (1999) Serum free insulin-like growth factor I (IGF-I).

growth hormone. Horm Res 45: 74-80. body composition and gonadal steroids. 19. Kuhnel W. Weber MM. Attie KM. Johannsson G. 17. Gibney J. Brabant G. 22. Rosberg S. Ho KK. Elmlinger MW. Wallaschofski H (2007) Normal levels of serum IGF-1: determinants and validity of current reference ranges.228 XU et al. Carlsson LM. J Clin Endocrinol Metab 73: 428-435. Ranke MB (2004) Reference ranges for two automated chemiluminescent assays for serum insulin-like growth factor-I (IGF-I) and IGF-binding protein 3 (IGFBP-3). Merimee TJ (1994) Reduced concentration of serum growth hormone-binding protein in children with idiopathic short stature. J Clin Endocrinol Metab 78: 1325-1330. Pituitary 10: 129-133. insulin-like growth factor-1: neuroendocrine and metabolic regulation in puberty. 23. Uriarte MM. Clin Endocrinol 52: 165-172. Hulthen L. 16. Cassorla F. Cutler GBJr (1991) Spontaneous growth hormone secretion increases during puberty in normal girls and boys. 20. Ross JL. Meinhardt UJ. J Clin Endocrinol Metab 90: 1420-1427. Wikland KA (2005) Reference values for insulin-like growth factor-binding protein-3(IGFBP-3) and the ratio of insulin-like growth factor-I to IGFBP-3 throughout childhood and adolescence. Gelander L. Lofqvist C. Munichi G. Vitanqcol RV. gender. 18. Blum WF. Barnes KM. Veldhuis JD (1996) Sex steroids. Front Horm Res 35: 115-128. Kamp GA. Wolthers T (2006) Regulating of growth hormone sensitivity by sex steroids: implications for therapy. . Clin Chem Lab Med 42: 654-664. Roqol AD. Mauras N. National Cooperative Growth Study. Rose SR. mone binding protein in children with normal and precocious puberty: relation to age. Ho KK (2006) Modulation of growth hormone action by sex steroids. Compton PG. 21. Clin Endocrinol 65: 413-422. Andersson E. Haymond MW.