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Endocrine Care |
Department of Pediatrics (K.O., D.D.), University of Cambridge, Addenbrookes Hospital, Cambridge CB2 2QQ, United Kingdom; Universitätskinderklinik und Poliklinik (J.K., W.K.), University of Leipzig, Leipzig, 04317 Germany; and Unit of Pediatric and Perinatal Epidemiology (ALSPAC Study Team), University of Bristol, Bristol BS8 1TQ, United Kingdom
Address all correspondence and requests for reprints to: Prof. David B Dunger, Department of Pediatrics, Level 8 Addenbrooke’s Hospital, Box 116, Cambridge CB2 2QQ, United Kingdom. E-mail: . dbd25{at}cam.ac.uk
Abstract
Rapid infancy growth predicts childhood obesity and earlier rate of maturation. We examined whether early growth rates might also influence levels of hormones relating to growth and weight gain by measuring IGF-I, IGF-II, and leptin levels in 497 normal 5-yr-old children who were followed closely from birth. IGF-I levels at 5 yr were unrelated to cord blood IGF-I levels at birth (r = 0.03; P = 0.7; n = 166) but were positively related to current weight (r = 0.32; P < 0.0005) and height (r = 0.30; P < 0.0005) and inversely related to birthweight (r = -0.21; P < 0.0005). By body composition, IGF-I levels correlated more closely with fat-free mass (r = 0.22; P < 0.0005) than with fat mass (r = 0.12; P < 0.05), whereas leptin (r = 0.57; P < 0.0005) and IGF-II levels (r = 0.15; P < 0.005) correlated more closely with fat mass. Independent of current body composition, IGF-I levels at 5 yr were significantly associated with rate of weight gain between 0–2 yr (ß = 0.19; P < 0.0005), and children who showed postnatal catch-up growth (i.e. those who showed gains in weight or length between 0–2 yr by >0.67 SD score) had higher IGF-I levels than other children (P = 0.02). IGF-II levels at 5 yr were positively related to IGF-II levels at birth (r = 0.17; P = 0.03; n = 166), and leptin levels at 5 yr were mainly related to current adiposity. Circulating IGF-I levels in childhood are influenced by infancy growth rates and possibly mediate the effects of early postnatal nutrition on later rates of growth and maturation.
WIDE VARIATION IN rates of growth of normal children is seen during the first 2 yr of life (1). More rapid or catch-up postnatal growth, as seen in approximately 25% of all children, follows intrauterine fetal growth restraint and in contemporary cohorts leads to increased adiposity and taller childhood stature than predicted from parental heights (2). Rapid early weight gain or large size in early childhood has also been linked to earlier sexual maturation (3, 4, 5, 6), adulthood obesity risk (7), and more recently to increased risks for adulthood type 2 diabetes and cardiovascular disease (8, 9, 10) as well as variable risks for cancer (11, 12). These associations could be underpinned by effects of early growth rates on circulating hormone levels or hormonal actions in later life.
Recent studies have demonstrated inverse relationships between circulating levels of IGF-I in childhood and birthweight (13, 14), and these suggest that IGF-I levels may be influenced by early life events (13). During infancy, IGF-I levels are largely nutritionally regulated (15), and a gradual transition toward GH regulation occurs as hepatic GH receptor numbers increase during the first 2 yr of life (16). Rapid weight gain during this period could possibly influence maturation of the GH/IGF-I axis. Catch-up growth has also been shown to result in elevated leptin levels in relation to body mass index in children born with intrauterine growth retardation (17). We hypothesized that variable early postnatal growth rates might program levels of IGF-I, IGF-II, and leptin in childhood, and we therefore measured these hormone levels in 497 normal 5-yr-old children followed closely from birth.
Subjects and Methods
Subjects and anthropometry
The large population-based Avon Longitudinal Study of Parents and Children (ALSPAC) Children in Focus birth cohort has been followed regularly from birth (18). Complete data on measurements of weight at birth, 2, 4, and 5 yr, and IGF-I levels at 5 yr were available in 497 children. Details of recruitment and anthropometry have been described previously (2). Briefly, birthweight was noted from hospital records, and supine length was measured by the ALSPAC study team using a Harpenden neonatometer (Holtain Ltd., Crosswell, Dyfed, UK). Weight (Seca 724 or 835 scales) and standing height (Leicester height measure, Child Growth Foundation, London, UK) were measured in the research clinic at 2, 4, and 5 yr. At 5 yr, sc skinfold measurements were made in duplicate at four sites (biceps, triceps, subscapular, and suprailiac) using a Harpenden Skinfold Caliper (Holtain Ltd.). Ethical approval was obtained from the ALSPAC ethical committee and the three local ethical committees.
Sample collection
Using a topical anesthetic, a nonfasting venous blood sample was collected from 497 children in the research clinic at the age of 61 months. Cord blood had also been collected at birth, and IGF-I, IGF-II, and leptin levels were measured in up to 166 of these children. Cord blood sample collection and associations between cord blood insulin, leptin, and size at birth have previously been reported (19, 20). All samples were centrifuged and stored at -70 C.
Assays
IGF-I levels were measured after acid ethanol extraction by a competitive solid phase immunoassay, modified from the method of Kratzsch et al. (21) by the use of biotin for labeling of IGF-I and streptavidin-Europium (Wallac, Inc., Turku, Finland) for the detection of labeled molecules by time-resolved fluorescence. The limit of sensitivity was below 15 ng/ml, and intra- and interassay coefficients of variation (CVs) were less than 10% in the range 100–500 ng/ml. We ruled out any effect of long-term blood sample storage on the IGF-I assay in a separate study comparing IGF-I levels in 19 sera first measured in 1996 and repeated in June 2001. The measurements showed close correlation (r = 0.82; P < 0.0001), the regression coefficient was approximately 1.0, and the intercept was negligible, confirming the stability of IGF-I in serum for at least 5 yr. We also validated our IGF-I extraction method for cord blood samples by comparison with an excess IGF-II method (Advantage-ILMA, Nichols Institute Diagnostics, San Juan Capistrano, CA), which is the most efficient inhibition step to suppress interference of IGF binding proteins (IGFBPs). We found a very close relationship (r = 0.84; P < 0.0001) between cord blood IGF-I levels measured by both assays, suggesting qualitatively comparable results of our extraction method and the Nichols assay.
IGF-II levels were measured by direct ELISA (DSL, Sinsheim, Germany) after dissociation of the IGF-II/IGFBP complexes. The lower limit of sensitivity was 40 ng/ml, and intra- and interassay CVs were less than 10% in the range 300-1200 ng/ml. Leptin assays were performed using a commercial leptin RIA (Linco, St. Charles, MO). Intra- and interassay CVs were 3.9 and 4.7% at 10.4 ng/ml and 8.3 and 6.2% at 4.9 ng/ml.
Calculations
Percentage body fat was derived from skinfold measurements using the equations of Brook (22) and Siri (23). Fat mass was calculated as the product of percentage fat mass and weight, and fat-free mass was calculated as weight minus fat mass.
SD scores were calculated [(measurement - mean)/SD] in each subject for weight and length or height at birth, 2, 4, and 5 yr. Changes in SD scores between birth-2 yr, 2–4 yr, and 4–5 yr were calculated. A gain in weight or length/height SD score 0–2 yr by more than 0.67 was taken to indicate clinically significant catch-up growth because 0.67 SD is equivalent to the width of each centile band on standard growth charts (i.e. 2nd centile to 9th, 9th to 25th, 25th to 50th, 50th to 75th, etc.) (24). Similarly, a decrease in SD score by more than 0.67 indicated catch-down growth.
Statistics
Natural logarithms of weight at 2, 4, and 5 yr, fat mass, fat-free mass, and IGF-I and leptin levels were normally distributed and allowed use of parametric tests. Geometric means for these variables are reported. Sex differences were tested using ANOVA. Multiple linear regression was used to examine the contribution of changes in SD scores to variance in hormone levels at 5 yr. In a separate multiple regression model, the relationship between birthweight and IGF-I levels at 5 yr was assessed by entering birthweight and current weight as continuous covariables and IGF-I at 5 yr as the dependent variable. Statistics were performed using SPSS v. 7.0 (SPSS, Inc., Chicago, IL).
Results
Females had higher levels of IGF-I, IGF-II, and leptin at 5 yr than males (Table 1
). These differences persisted after adjustment for current size and were taken into account before all subsequent analyses. IGF-I levels were positively related to levels of IGF-II (r = 0.44; P < 0.0005) and leptin (r = 0.21; P < 0.0005).
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Hormone levels at 5 yr were positively related to current size (Table 2). Leptin and IGF-II levels correlated most closely with fat mass, whereas IGF-I levels were more related to fat-free mass (r = 0.22; P < 0.0005) than to fat mass (r = 0.12; P < 0.05). Current fat mass and fat-free mass explained 46% of the variance in leptin levels, but only 12% of the variance in IGF-I and 5% of the variance in IGF-II levels.
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Cord blood levels of IGF-I (geometric mean, 83 ng/ml; range, 22–235), IGF-II (geometric mean, 266 ng/ml; range, 106–736), and leptin (geometric mean, 6.3 ng/ml; range, 1.1–42.1) have been described previously in this cohort (19, 20). A significant relationship between hormone levels at 5 yr and in cord blood at birth was seen for IGF-II (r = 0.17; P = 0.03; n = 166), but not for IGF-I (r = 0.03; P = 0.7; n = 166) or for leptin (r = 0.14; P = 0.2; n = 94). Birthweight was weakly inversely related to IGF-I levels at 5 yr (r = -0.09; P < 0.05), but not to IGF-II (r = -0.03; P = 0.7) or leptin levels (r = 0.03; P = 0.6). The inverse relationship between IGF-I at 5 yr and birthweight improved on allowing for current weight (r = -0.21; P < 0.0005). Thus, IGF-I levels at 5 yr were highest in children with low birthweight and large current size, indicating that degree of weight gain 0–5 yr was a major determinant of IGF-I levels at 5 yr (r = 0.35; P < 0.0005).
Hormone levels and weight gain
Changes in weight SD scores between birth-2 yr, 2–4 yr, and 4–5 yr were calculated for each subject as a measure of variation in growth rates during these age ranges. The contributions of these changes in SD scores to hormone levels at 5 yr were then examined using a separate multiple regression model for each hormone (Table 3). Independent of current body composition, IGF-I levels at 5 yr were significantly related to early changes in weight SD scores between birth-2 yr. In contrast, leptin levels at 5 yr were largely related to current degree of adiposity.
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), even allowing for current size (Table 4). IGF-II levels were also higher in these catch-up children, however leptin levels were similar in all early weight gain groups (Table 4). A similar effect of catch-up growth 0–2 yr on IGF-I levels at 5 yr was observed when changes in length or height SD scores were used instead of weight SD score (data not shown); this reflects the closer correlation between changes in weight and height or length from 0–2 yr (r = 0.7; P < 0.0005) compared with changes at later ages (2–4 yr, r = 0.4; P < 0.0005).
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In this large population-based birth cohort study, IGF-I levels at age 5 yr were completely unrelated to IGF-I levels at birth, and this finding was not explained by any bias in sample storage or assay. Rather, IGF-I levels at age 5 yr were highest in children with lower birthweight and more rapid early growth rates. Thus, children who showed more rapid weight gain or catch-up growth in the first 2 yr had higher IGF-I levels than other children at 5 yr, irrespective of their current size. Although such associations do not indicate causality, these data are consistent with previous reports linking childhood IGF-I levels to birthweight and childhood size (13, 14, 25). Those studies also demonstrated that circulating IGF-I levels were inversely related to birthweight and positively related to current size (13, 14) and urinary IGF-I levels were positively related to rate of growth between birth-9 yr (25). Our data further suggest that circulating levels of IGF-I in childhood are programmed by rates of weight gain, particularly in the first 1–2 yr of life.
Leptin levels at 5 yr were closely related to current adiposity as previously reported (26), but were not also related to early postnatal weight gain. It has been suggested that elevated leptin levels observed during infancy in subjects born after severe intrauterine growth retardation may reflect leptin resistance that promotes catch-up growth (17); however, in that study, the elevation in leptin levels did not persist to 2 yr. IGF-II was the only hormone for which levels at 5 yr were significantly related to levels at birth, suggesting that these levels may to some extent be determined by antenatal or genetic factors.
Rapid postnatal weight gain or catch up growth is particularly seen in infants who were small and thin at birth and probably represents an intrinsic compensatory mechanism that follows intrauterine growth restraint (2, 19). In addition to recently reported links with increased risks for cardiovascular disease and type 2 diabetes (8, 9, 10, 27), rapid early childhood growth predicts a faster tempo of growth during childhood and earlier onset of puberty (4, 5, 6). Conversely, poor weight gain in infancy may precede pubertal delay. IGF-I has a major role in the regulation of human growth (28), and circulating levels in childhood are predictive of height velocity during the following year (29). IGF-I has direct mitogenic effects on the growth plate/cartilage (30), promotes adrenal androgen production and gonadotropin activity (31, 32), and could therefore influence tempo of growth and timing of puberty (33). Programming of IGF-I levels could therefore explain links between postnatal rate of weight gain and rate of maturation in later childhood.
Observational studies have linked higher IGF-I levels to increased risks for sex hormone-dependent cancers, including prostate and breast cancer (34, 35), and IGF-I has been implicated in the pathogenesis of ovarian cancer (36). Further associations between childhood size or longer leg length in childhood and risk of breast and prostate cancer (37) have been interpreted as supporting links between IGF-I activity in childhood and later cancer risk (38). Our data could indicate that these cancer links with circulating IGF-I levels might also be secondary to effects of rapid infancy weight gain (12) and earlier onset of puberty, resulting in longer lifetime exposure to sex hormones (39). Cancer risk is also related to the ratio of IGF-I to its regulatory IGFBPs (38), and measurement of IGFBP levels during childhood may further help to clarify the effect of early postnatal growth rates on IGF-I activity in childhood and subsequent cancer risk (38).
In conclusion, we hypothesize that programming of circulating IGF-I levels by postnatal growth rates could link early growth patterns to rate of maturation in later childhood. High IGF-I levels after rapid early childhood weight gain may promote faster tempo of growth and earlier sexual maturation, whereas slower infancy weight gain may be related to lower IGF-I levels and delayed pubertal onset. We anticipate that further follow-up of this ALSPAC cohort will allow the confirmation of these early predictors of timing of puberty onset and other risk factors for disease in later life.
Acknowledgments
We are extremely grateful to all the children and parents who took part in this study and to the midwives for their cooperation and help in recruitment. The whole ALSPAC study team comprises interviewers, computer technicians, laboratory technicians, clerical workers, research scientists, volunteers, managers, and also the staff of the Children in Focus research clinics. ALSPAC is supported by the Medical Research Council (MRC), the Wellcome Trust, the Department of Health, the Department of the Environment and many others. W.K. and J.K. are supported by IZKF Leipzig, Germany (BMBF, Projects B11 and B15), and K.O. is a MRC Clinical Training Fellow.
Footnotes
Abbreviations: ALSPAC, Avon Longitudinal Study of Parents and Children; CV, coefficient of variation; IGFBP, IGF binding protein.
Received February 22, 2001.
Accepted December 11, 2001.
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