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Endocrine Care |
Research Institute of Child Nutrition Dortmund, D-44225 Dortmund, Germany
Address all correspondence and requests for reprints to: Thomas Remer, Ph.D., Research Institute of Child Nutrition, Forschungsinstitut fuer Kinderernaehrung, Heinstueck 11, D-44225 Dortmund, Germany. E-mail: remer{at}fke-do.de
Abstract
A small transient increase in growth, the midgrowth spurt, has been observed in several growth studies in healthy children around the age of 7 yr. During this time adrenarche (the physiological increase in adrenal androgen secretion) also occurs. Although it is now well established that estrogen, not androgen, has a critical role in the male (and female) pubertal growth spurt, a direct effect of androgens on growth cannot be excluded. In accordance with published observations that growth is frequently accelerated in infants and young children with late-diagnosed 21-hydroxylase deficiency (before adequate androgen suppression), it has been speculated that the adrenarchal increase in adrenal androgen secretion in healthy children could be responsible for the midgrowth spurt. To test this hypothesis we studied long-term serial changes in urinary 24-h excretion rates of dehydroepiandrosterone sulfate and total 17-ketosteroid sulfates in a group of healthy children (n = 12) in which yearly auxological measurements allowed the identification of a midgrowth spurt. Annual measurements of standing height were performed over periods of 6–9 yr before the onset of puberty. All children collected five to seven serial 24-h urine samples (1-yr intervals) each at the time of anthropometric examination. The peak of the midgrowth spurt was found to occur at a mean age of 6.8 ± 1.0 yr. The average height of the midgrowth peak, i.e. average maximum gain in height velocity, was 0.9 cm/yr. In a peak-centered examination of individual 24-h excretion rates of dehydroepiandrosterone sulfate and 17-ketosteroid sulfates, primarily weak 1-yr changes in adrenal androgens were observed until the peak was attained. Only after the peak did increments in urinary adrenal androgen output become more pronounced.
ANOVA performed on the peak-centered dehydroepiandrosterone sulfate and 17-ketosteroid sulfate excretion rates revealed a highly significant overall increase in adrenal androgen secretion from 2 yr before to 2 yr after the midgrowth spurt. After multiple testing, however, significant increments, when compared with the respective preceding androgen excretion levels, were for the first time seen 1 yr after the midgrowth spurt (dehydroepiandrosterone sulfate) or 2 yr later (17-ketosteroid sulfates). In conclusion, our longitudinal analysis of prepubertal growth and urinary adrenal androgen excretion in healthy children disproves the speculation that the midgrowth spurt is primarily caused by the adrenarchal increase in adrenal androgen secretion. However, the present results do not rule out a growth-accelerating effect of clearly higher androgen levels, as in premature adrenarche.
THE MIDGROWTH spurt, a small transient increase in growth rate occurring around the age of 7 yr, has been observed in individual velocity curves in a number of studies (1, 2, 3, 4, 5). During midchildhood adrenarche also occurs. Adrenarche is the physiological increase in adrenal androgen secretion several years before the onset of puberty. The chief hormonal product of adrenarche is the mild androgen dehydroepiandrosterone (DHEA) and its sulfated product (DHEAS) (6). As the midgrowth spurt and the adrenarchal androgen rise approximately coincide, and even modest hyperandrogenism may have a transient growth-accelerating effect (7), it has been speculated that adrenarche could be responsible for the midgrowth spurt (2, 8, 9). In accordance with this hypothesis, an accelerated growth has been reported in some children with premature adrenarche (8, 10). However, serial measurements of adrenal androgens together with longitudinal analyses of the midgrowth spurt have not been performed in healthy children to date. Therefore, we studied both adrenarche and growth rates of healthy children longitudinally to test the hypothesis that the midgrowth spurt could be the auxological manifestation of the adrenarchal rise in androgen secretion.
Subjects and Methods
Subjects
The study was performed in 19 healthy Caucasian children in whom long-term serial changes in urinary 24-h excretion rates of DHEAS had been determined to characterize the relationship between adrenarche and nutritional status (11). All children were participants in the DONALD (Dortmund Nutritional and Anthropometric Longitudinally Designed) Study. The study was approved by the institutional review board of the Research Institute of Child Nutrition Dortmund, and parental consent was obtained before entry into the study.
From the original cohort comprising 42 children (11) those 23 subjects older than 4 yr when providing their first anthropometric measurement were excluded. Anthropometric measurements were taken once a year. For weight measurements to the nearest 0.1 kg, an electronic scale was used. Height was measured to the nearest 0.1 cm, using a digital telescopic wall-mounted stadiometer. At each visit in the research institute the children were examined by a pediatrician. Serial collections of 24-h urine samples were performed as previously described (11). The day to day variability of DHEAS and total 17-ketosteroid sulfates (17-KSS) was tested in a separate group of 5 9- to 10-yr-old boys and 5 8- to11-yr-old girls (with 24-h urine samples collected on 3 consecutive days in each child), with coefficients of variation ranging from 13.8 ± 6.5% (17-KSS) to 18.8 ± 12.0% (DHEAS). For comparison, the intraindividual variability of daily urinary creatinine excretion in the same samples was 6.5 ± 2.9%.
Midgrowth spurt
Annual auxological measurements were available over periods of 6–9 yr before the onset of puberty. The midgrowth spurt was identified according to the procedure described by Molinari et al. (2). In 16 (84%) of the 19 children studied a midgrowth spurt could be clearly determined. However, 4 of these 16 children had their individual growth spurts before or at the time of their respective first available 24-h urine collection. For these 4 children it was not possible to compare the changes after 1 yr in urinary adrenal androgen excretion at the prepubertal growth spurt with the corresponding hormonal 1-yr changes before or after the peak. Thus, the study of hormonal and auxological changes was finally performed in 12 children (5 boys, 7 girls) with an identified midgrowth spurt and a 24-h urine collection series that started at least 1 yr before the spurt.
Hormone measurements
A commercial solid phase 125I RIA (Diagnostic Products, Los Angeles, CA) was used for the quantification of urinary DHEAS (11, 12). Intra- and interassay coefficients of variation were below 10%. Urinary total 17-KSS were measured without previous hydrolysis (as conjugated Zimmermann chromogens) after C18 reverse phase extraction and LH-20 chromatography (13). Intra- and interassay precisions for 17-KSS did not exceed 15% and 18%, respectively.
Statistical analysis
One-way ANOVA for repeated measurements and t test for paired observations were applied for statistical evaluation (P = 0.05). Significance was adjusted for multiple comparisons by the Bonferroni procedure (six two-way comparisons, adjusted significance level, P = 0.0083). Data are presented as the mean ± SD.
Results
The age at peak height velocity of the midgrowth spurt ranged
from 5.5–8.5 yr, with the exception of one boy with a peak at 4.5 yr.
His and two girls’ individual growth curves, with early increases in
height velocity, are shown in Fig. 1
. The
mean age at peak of the midgrowth spurt was 6.8 ± 1.0 yr in
all children, 6.5 ± 1.0 yr in girls, and 7.2 ± 1.0 yr in
boys. Figure 2 shows the mean
midgrowth spurt of all children after centering of the individual
growth velocities. The average height of the midgrowth peak,
i.e. average maximum gain in height velocity, was 0.9 cm/yr.
In a peak-centered examination of individual 24-h excretion rates of
DHEAS and 17-KSS, primarily weak 1-yr changes in adrenal androgens were
observed until the peak was attained (Fig. 3). Only after the peak did increments in
urinary adrenal androgen output become more pronounced.
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). After multiple testing,
however, significant increments, compared with the respective preceding
androgen excretion levels, were for the first time seen 1 yr after the
midgrowth spurt (DHEAS) or 2 yr later (17-KSS). In accordance with
this, the change after 1 yr in urinary 24-h DHEAS excretion was
significantly higher 1 yr after individual peak height velocity than
that at the time of peak height velocity (Fig. 4).
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This is the first longitudinal study examining the relationship between changes in urinary excretion of adrenal androgens and changes in growth during midchildhood using simultaneous hormone sampling and height measurements. As a physiological phenomenon, a transient increase in height velocity is present in a number of healthy children during midchildhood (1, 2, 3, 4, 5). In a detailed analysis of this growth spurt in 3- to 11-yr-old children of the First Zurich Longitudinal Study of Growth, a midgrowth spurt of standing height was observed at 6.5–7 yr of age in girls and 7.5–8 yr in boys (2). In accordance with these findings we observed an earlier peak in girls (6.5 ± 1 yr) than in boys (7.2 ± 1 yr). However, in our group of children with an identified midgrowth spurt, the average height of the peak was only 0.9 cm/yr compared with 1.4 cm/yr in the children of the First Zurich Longitudinal Study.
It is now well established that estrogens, not androgens, have a critical role in the male (and female) pubertal growth spurt (14). However, a certain direct effect of androgens on bone and growth cannot be excluded (14). Accordingly, in patients with 21-hydroxylase deficiency diagnosed later in childhood, a clear growth acceleration was observed during infancy and early childhood before adrenal androgen-suppressing glucocorticoid substitution (15). Based on such observations of apparent growth-stimulating effects of adrenal androgens, a number of researchrs have hypothesized (2, 8, 9) that the midgrowth spurt could be the auxological manifestation of the adrenarchal rise in adrenal androgen secretion.
Although our present knowledge of the timing of both adrenarche and the midgrowth spurt has come from separate studies with different subjects, the current longitudinal findings provide evidence that, in fact, around the time of the individual midgrowth spurt more pronounced increases in adrenal androgen output occur. However, if adrenarche is a primary cause of the midgrowth peak, one would expect particularly clear increases in adrenal androgens, either at the time of the peak or immediately before its occurrence. Our results show that this is not the case, as a statistically significant increase in the 24-h urinary output of the chief adrenal androgen, DHEAS, was only seen 1 yr after the midgrowth spurt. Thus, our data verify the hypothesis of Grumbach and Styne (16) that factors other than adrenal androgens primarily cause the midgrowth spurt. It needs to be further examined whether these factors are genetic or related to cyclic patterns of prepubertal growth.
In conclusion, our longitudinal analysis of prepubertal growth and urinary adrenal androgen excretion in healthy children disproves the speculation that the midgrowth spurt is primarily caused by the adrenarchal increase in adrenal androgen secretion. However, these results do not rule out a growth-accelerating effect of clearly higher androgen levels, as in premature adrenarche.
Acknowledgments
Footnotes
This work was supported by Ministerium für Schule und Weiterbildung, Wissenschaft und Forschung des Landes Nordrhein-Westfalen and Bundesministerium für Gesundheit.
Abbreviations: DHEA, Dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; 17-KSS, 17-ketosteroid sulfates.
Received February 27, 2001.
Accepted May 10, 2001.
References
This article has been cited by other articles:
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