Seasonal variations in vitamin D in relation to growth in short prepubertal children before and during first year growth hormone treatment.

PURPOSE: This study investigated the relationship between seasonal variations in 25-hydroxyvitamin D (25(OH)D) levels and growth in prepubertal children during both the pretreatment year and the first year of GH treatment. METHODS: The study included 249 short prepubertal children with a broad range of GH secretion, GH(max) during a 24 h profile median 23; range 1-127 mU/L, 191 boys (mean age ± SD, 8.6 ± 2.6 years), 58 girls (7.5 ± 1.9 years) receiving GH treatment (mean 43 µg/kg/day; range 17-99 µg/kg/day). Serum 25(OH)D was measured using an automated IDS-iSYS immunoassay. RESULTS: 25(OH)D levels showed seasonal variation, and decreased significantly during GH treatment. 25(OH)D levels at start and first year reduction in 25(OH)D, correlated (-) with the first year growth response during treatment. The degree of GH secretion capacity within our study population of mainly non-GH deficient children and 25(OH)D sufficient (67 ± 29 nmol/L) had no influence on 25(OH)D levels. Growth during GH treatment were independent of seasonal variations in 25(OH)D. Multiple regression analysis showed that 25(OH)D levels at treatment start, together with auxological data and IGF-binding protein-(3)SDS, explained 61 % of the variation in first year gain in heightSDS. CONCLUSION: 25(OH)D levels were associated with first year growth response to GH and may be a useful contribution to future growth prediction models.

Body composition, as assessed by bioelectrical impedance spectroscopy and dual-energy X-ray absorptiometry, in a healthy paediatric population.

UNLABELLED: The aim of this study was to determine the level of agreement between body composition measurements by dual-energy X-ray absorptiometry (DXA), single-frequency bioelectrical impedance analysis (BIA) and multifrequency bioelectrical impedance spectroscopy (BIS). Fat-free mass (FFM), body fat mass and body fatness (percentage fat) were measured by DXA, BIA and BIS in 61 healthy children (37M, 24F, aged 10.9-13.9 y). Estimates of FFM, body fat mass and body fatness were highly correlated (r = 0.73-0.96, p < 0.0001) between the different methods. However, a Bland-Altman comparison showed wide limits of agreement between the methods. The mean differences between methods for FFM ranged from -2.31 +/- 7.76 kg to 0.48 +/- 7.58 kg. Mean differences for body fat mass ranged from 0.16 +/- 5.06 kg to 2.95 +/- 5.65 kg and for body fatness from -2.3 +/- 7.8% to 0.8 +/- 9.3%. Calculations of body composition with BIS were not superior to BIA. However, BIA overestimated fat mass in lean, subjects and underestimated fat mass in overweight subjects more than BIS, compared with DXA. CONCLUSION: The methods used provided estimates of FFM, body fat mass and body fatness that were highly correlated in a population of healthy children. However, the large limits of agreement derived from the Bland-Altman procedure suggest that the methods should not be used interchangeably.

Reference values for IGF-I throughout childhood and adolescence: a model that accounts simultaneously for the effect of gender, age, and puberty.

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.

Monthly measurements of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 in healthy prepubertal children: characterization and relationship with growth: the 1-year growth study.

The usefulness of measurements of IGF-I or IGF-binding protein-3 (IGFBP-3) in the clinical management of growth disorders is dependent on the extent of physiologic variation in their concentrations. Our purpose was therefore to investigate the longitudinal intraindividual variation in serum concentration of IGF-I and IGFBP-3 in healthy prepubertal children. Monthly serum samples and auxologic measurements were taken over a period of 1 y from 65 prepubertal children (38 boys, 27 girls; mean age 9.1 y, range 7.8-10.8). Concentrations of IGF-I and IGFBP-3 were measured by RIA. The mean (+/-SD) serum concentration of IGF-I in the children was 165 +/- 42.0 microg/L, with a mean coefficient of variation (CV) of 13.9% around the annual mean serum concentration for each child. The corresponding mean concentration of IGFBP-3 was 3273 +/- 604.5 microg/L, and the mean CV for each child was 9.7%. These monthly longitudinal variations in IGF-I and IGFBP-3 were parallel to changes in longitudinal growth. Short-term changes (1 mo) in IGF-I were positively correlated with changes in weight (r(s) = 0.42, p < 0.0005) and body mass index (r(s) = 0.45, p < 0.0005), and negatively correlated with minor intercurrent illnesses (-0.32; p < 0.05). Seasonal fluctuations also occurred, with short term changes in IGF-I (1 mo) and IGFBP-3 (3 mo), increasing with increasing outdoor temperatures (r(s) = 0.30, p < 0.05 and r(s) = 0.39, p < 0.005, respectively). We conclude, that there are significant changes in both IGF-I and IGFBP-3 that occur in association with growth, and that IGF-I is more sensitive than IGFBP-3 to short-term changes in weight, body mass index, and intercurrent illnesses. Physiologic short-term changes must therefore be taken into consideration when using serum levels of IGF-I or IGFBP-3 in the evaluation of the short or slowly growing child.

Growth hormone-binding protein levels over one year in healthy prepubertal children: intraindividual variation and correlation with height velocity.

The role of GH-binding protein (GHBP) in growth regulation is still under debate. We investigated 29 prepubertal healthy children (13 girls/16 boys; mean age 9.3 y to study intraindividual variation in serum GHBP and to explore whether any such variation was related to changes in IGF-I, IGF-binding protein-3 (IGFBP-3) or urinary excretion of GH. The relationship between changes in GHBP concentrations, short-term height velocity, and changes in body composition was also studied. Blood samples were taken every month for 1 y, for measurements of GHBP, IGF-I, and IGFBP-3. The mean coefficient of variation in monthly GHBP concentrations in individual children was 18% (range, 6.7-33.0%). The values for each child were normalized by expressing the concentration as a ratio to the mean GHBP concentration. GHBP values were highest in January and lowest in August (22% difference). Maximal monthly changes in GHBP correlated with simultaneous changes in weight (rs = 0.38, p < 0.05) and IGF-I (rs = 0.38, p < 0.05). The mean GHBP concentration during the year correlated with height velocity (rs = 0.37, p < 0.05) and the mean serum concentration of IGF-I (rs = 0.42, p < 0.05) and IGFBP-3 (rs = 0.60, p < 0.001). We conclude that there is a significant monthly variation in GHBP concentrations in healthy prepubertal boys and girls, which is correlated to changes in weight and IGF-I. The mean GHBP concentration during the year is correlated with the mean serum concentrations of IGF-I, IGFBP-3, and with height velocity. Thus, the variation in GHBP concentrations appears to mirror GH sensitivity, because no parallel changes in urinary GH excretion were observed.

Overnight urinary growth hormone in normally growing prepubertal children: effect of urine volume. The one-year growth study.

Growth hormone excretion can easily be measured in the urine using ultrasensitive methods. The large day-to-day variation has, however, restricted its diagnostic usefulness. The present study aimed to evaluate the individual variation of GH in the urine (uGH) during normal prepubertal growth. Eighty-four prepubertal normally growing children were followed monthly for 13 months. During this period, 3,207 overnight urine samples were collected. The urine collection time was unrelated to the uGH concentration (p > 0.05), while there was a significant negative correlation between the uGH concentration and urine volume (the Spearman correlation coefficient of -0.33, p < 0.0001), while the calculated excretion of GH in the urine showed a positive correlation with the urine volume (r = 0.35; p < 0.0001). A reference chart, based on SD scores, was developed in order to avoid this volume dependency and to optimally normalize the skewed distribution of the uGH concentrations. The use of this model reduced the individual day-to-day variation of uGH from a coefficient of variation of 43 to 21%. Differences in mean cross-sectional urinary GH concentration was found between different months exceeding the expected methodological variation. This variation showed no seasonal pattern. Only 0.2% of triplicate values (three consecutive overnight uGH values) were all below -2 SD scores and 0.1% were above +2 SD scores. The mean uGH SD score for the boys was 0.01 (SD = 0.98), which was similar to that for the girls (-0.04; SD = 1.06). We found that uGH excretion can be estimated in a more robust way, using a SD score based reference chart that handles both the positive correlation between urinary GH and urine volume and the skewed distribution of urinary GH. This model reduced the day-to-day variability of uGH by half. Overestimation of GH in large urine volumes may be due to increased gradient between GH in urine and serum following increased urine volumes.

Leptin levels are strongly correlated with those of GH-binding protein in prepubertal children.

OBJECTIVE: Nutritional status is an important determinant of growth, and previous studies have indicated that this is due, at least in part, to an increased target-tissue sensitivity to GH. An attractive candidate for mediating this effect is leptin, a hormone secreted by the adipose tissue. The aim of this study was to investigate if there was a connection between GH-binding protein (GHBP) and leptin. DESIGN AND METHODS: We investigated the relationship between serum levels of leptin and those of GHBP in 229 prepubertal children. These included 107 healthy children with normal GH secretion, 55 GH-deficient (GHD) children and 55 children born small for gestational age (SGA) sampled on one occasion for GHBP and leptin, and 12 healthy children followed longitudinally at monthly interval for 1 year. RESULTS: In the healthy children and in those born SGA, the serum concentration of GHBP was positively correlated with that of leptin (r = 0.65, P < 0.001; r = 0.74, P < 0.001 respectively). There was no correlation between GHBP and leptin in the group of children with GHD (r = 0.27, not significant). This means that leptin alone explained 42% of the variation of GHBP in the healthy group and 55% in the SGA group. The correlation remained after adjustment for body mass index and age in the healthy children (r = 0.57, P < 0.0001, r2 = 0.33) and for children born SGA (r = 0.74, P < 0.0001, r2 = 0.55). There was a positive correlation between the intra-individual monthly changes in GHBP and changes in leptin respectively, in the 12 healthy children followed longitudinally, the mean of the correlation coefficients was 0.38 (median = 0.29; range 0.03 to 0.86; P < 0.05). CONCLUSIONS: There was a highly significant correlation between serum levels of leptin and those of GHBP, except in children with GHD. The possibility that leptin could mediate the effects of body fat mass on GH sensitivity, therefore, merits further investigation.

Seasonality in lower leg length velocity in prepubertal children.

Despite low measuring error, annual growth is poorly predicted by short-term measurements of the lower leg. In order to study if this low correlation can be explained by seasonal changes in lower leg length (LLL) velocity, we followed short-term growth longitudinally in 50 prepubertal children with normal height and growth velocities. Height measurements were performed at 4-week intervals and LLL measurements at 1-2 week intervals. Analysis of annual growth showed seasonality in the monthly mean height velocity values: 5.06 (SD 5.02) cm/year during the autumn and 8.15 (SD 5.22) cm/year in the spring. Similarly, the monthly mean LLL velocity values changed from 1.80 (SD 1.07) cm/year in the autumn to 2.63 (SD 0.92) cm/year in the spring. The correlation between monthly LLL and annual height velocity was low (r = 0.27). The technical error of the LLL measurement was 7-8% of the mean monthly LLL velocity, while the mean values changed by 31% over the seasons. The annual height velocity was virtually independent of the variation in growth rate over the seasons. It is concluded that there is significant seasonality both in height and LLL velocity and that it takes place at the same time for both measures. Seasonality in LLL has not been reported previously and must be considered when studying short-term growth, for example when LLL is used for prediction of annual height velocity or when a short-term treatment effect is examined using LLL.

Distinctions between short- and long-term human growth studies.

It is known what the aim is in a complete long-term growth study; the final height is the outcome measure, although the annual height velocity values provide additional information. Strictly, short-term growth studies are also defined in terms of minimum length of observation, i.e. one month, as well as the type of measurement errors to be considered. The poor correlation between short- and long-term growth velocity values has led to the conclusion that the short-term study cannot be interpreted in long-term perspectives, and vice versa. There is a need to debate the way in which results of short-term studies should be interpreted. This is especially important when short-term growth is taken as the outcome measure in a controlled study. Our proposal is that such studies must include information about the growth achieved for a period after the treatment has ended in order to describe possible compensatory growth. Without weighing in some long-term consequences, we may incorrectly document short-term growth as a positive or negative effect of a certain treatment.

Growth hormone (GH) release after administration of GH-releasing hormone in relation to endogenous 24-h GH secretion in short children.

Endogenous GH secretion was measured every 20 min for 24 h in 36 short children. This was immediately followed by an i.v. injection of GH-releasing hormone (GHRH)(1-29)-NH2 (1 microgram/kg), and GH was estimated every 15 min for the following 2 h. The aim was to determine whether endogenous pulsatile GH secretion had any relation to, or influence on, the GH release induced by GHRH. A high variability was found both in the 24-h GH secretion expressed as area under the curve above the baseline (0-1588 mU/l x 24 h) and the maximal GH response to GHRH (5-296 mU/l), as well as after an arginine-insulin tolerance test (4-59 mU/l). We found a positive correlation (correlation coefficient of Spearman (rs) = 0.49; P less than 0.01) between the GH response to GHRH and the spontaneous GH secretion over a 24-h period, in spite of a negative correlation (rs = -0.80; P less than 0.01) with the GH secretion during the preceding 3 h. We conclude that the GH response to a GHRH test correlates with endogenous GH secretion in short children, and may be helpful in estimating the ability to release GH. It is important, however, to be aware of the influence of the spontaneous GH secretion during the 3 h immediately preceding administration of GHRH.

Effects of acute intravenous injection of two growth hormone-releasing hormones (GHRH 1-40 and 1-29) on serum growth hormone and other pituitary hormones in short children with pulsatile growth hormone secretion.

We administered two different growth hormone-releasing hormones (GHRH) to 20 short, prepubertal children who had spontaneous secretion of growth hormone (GH), assessed from 24-hour GH secretion profiles (72 sampling periods of 20 min). We compared one i.v. injection of 1 microgram/kg of GHRH 1-40 with that of GHRH 1-29 regarding serum concentrations of GH, prolactin, luteinizing hormone, follicle-stimulating hormone and IGF-I. The children were allocated to two groups without statistical randomization. Both groups were given both peptides, with at least 1 week in between. The first group started with GHRH 1-40, the other with GHRH 1-29. The peptides both induced an increased serum concentration of GH of the same magnitude: mean maximal peak of 89 +/- 12 mU/l after GHRH 1-40 and 94 +/- 10 mU/l after GHRH 1-29 (n.s.). The mean difference in maximum serum GH concentration in each child after injection was 52 +/- 9 mU/l, range 1-153 mU/l. GHRH 1-29 also induced a short-term, small increase in the concentrations of prolactin (p less than 0.05), luteinizing hormone (p less than 0.01) and follicle-stimulating hormone (p less than 0.05). We conclude that the shorter sequence GHRH 1-29, when given in a dose of 1 microgram/kg, gives a rise in serum concentration of GH similar to that after the native form GHRH 1-40.