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Original Studies |
Research Institute of Child Nutrition, 44225 Dortmund, Germany
Address all correspondence and requests for reprints to: Dr. Thomas Remer, Forschungsinstitut fuer Kinderernaehrung (Research Institute of Child Nutrition), Heinstueck 11, 44225 Dortmund, Germany. E-mail: remer{at}fke.uni-dortmund.de
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Abstract |
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5
consecutive 24-h urine collections). For 4-yr intervals highly
significant tracking coefficients (P < 0.001) of
0.73 (PreC) and 0.93 (PubC) were observed for DHEAS, emphasizing the
importance of individual (and genetic) influences on adrenal androgen
excretion. In both cohorts almost 3-fold higher median increases in
urinary DHEAS excretion rates (P < 0.05) were
observed during the 1-yr period of the individually highest rises in
BMI compared with the 1-yr period of significantly lower rises in BMI
(P < 0.01) in the same children after the factor
age was controlled for. However, no consistently significant
associations were found between urinary DHEAS output and BMI from
simple cross-sectional correlations at defined age points. These
findings provide the first in vivo evidence that a
change in the nutritional status, measurable in the form of 
-BMI
(but not BMI alone), is an important physiological regulator of
adrenarche regardless of individual adrenal androgen excretion level,
age, and developmental stage. |
Introduction |
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Subjects and Methods |
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Inclusion criteria
Prepuberty. Specific inclusion criteria for the PreC were a
minimum age of 3 yr on entry, no signs of puberty during the period
between the first and fourth individual urine collections, and a still
prepubertal or at most an early pubertal stage at the time of the last
individual (i.e. the fifth, sixth, or seventh) 24-h urine
collection. Boys were classified as prepubertal or early pubertal
according to testicular volume (
5 mL) or Tanner stage (2) for pubic
hair and genital development, and girls were classified according to
Tanner stages (2) for pubic hair and breast development.
Puberty. For the PubC the minimum age at the time of the
first urine collection (allowed for in this longitudinal analysis) was
8 yr (girls) or 9 yr (boys). All children were prepubertal or at most
early pubertal (according to the above classification) at the time of
entry into this cohort. The follow-up age criteria were as follows: the
minimum age at the time of the last individual (fifth, sixth, or
seventh) urine collection had to be 13 yr for girls and 14 yr for boys,
and clear signs of puberty (testicular volumes >10 mL and/or Tanner
stages 4 for at least one of the above criteria) had to be present.
Based on these criteria, the youngest individual examined in the PubC
was a girl with an age range of 8–13 yr, and the oldest was a boy with
an age range of 13–18 yr.
Additional grouping criteria
For the PreC serial urine collections were grouped according to five equal age segments, 5–7, 6–8, 7–9, 8–10, and 9–11 yr (U1–U5), to make allowance for the fact that the age of the children’s first urine collection varied considerably within the cohort. U1 was defined as the first urine collection of each child within the age segment 5–7 yr. Correspondingly, U2 was the subsequent 24-h urine sample collected 1 yr later within the age segment 6–8 yr. With this approach a prepubertal 4-yr interval from 5.2–9.2 yr of age for girls and from 6.2–10.2 yr for boys was covered.
To relate the urinary DHEAS output of the PubC with a biological age scale, AA excretion data were synchronized with time of occurrence of individual peak height velocity (PHV). Serial measurements in one girl and five boys ended before the biological age 2 yr after PHV was attained. These data were not included in the specific PHV-centered analyses starting 2 yr before and ending 2 yr after PHV.
Anthropometry, 24-h urine collection, and hormone measurements
Body weight (BW), body height, and skinfold thickness (triceps, biceps, and subscapular and suprailiac sites) were measured each time with the same devices (electronic scale, electronic stadiometer, and precision caliper) under comparable conditions by the same observer team at the Research Institute of Child Nutrition. The estimations of body fat (BF) and fat-free mass (FFM) from skinfold measurements and the procedure for the 24-h urine collection have been described previously (16).
Before analyzing urinary DHEAS output, urinary 24-h creatinine excretion (16) was determined to test for possible inaccuracies with the repeated home urine collections. After relating urinary 24-h creatinine excretion (Cr) to individual body weight (Cr/BW), a check for extreme values was performed on the Cr/BW ratios (one per child), which differed noticeably from the other values in the same child. If a suspected value was found that lay outside the range defined by each subject’s long term mean ± 3 SD (excluding the suspect value), a correction factor for the respective urinary DHEAS output was calculated to reduce potential sampling-related errors. For this, the two immediately neighboring Cr/BW ratios of the identified extreme value were averaged and divided by the extreme value. Urinary DHEAS excretion at the time of the identified extreme was multiplied by the resulting factor. This correction procedure was applied to eight samples each in the PreC and PubC groups. Urinary DHEAS was quantified using a commercial solid phase RIA (Diagnostic Products, Los Angeles, CA) (17, 19). Intra- and interassay coefficients of variation for urine samples were both below 10%.
Statistical analysis
Wilcoxon signed rank test, two-way ANOVA for repeated measurements, and paired t test were applied for statistical analysis (significance level, P = 0.05). Significance was adjusted for multiple comparisons using the Bonferroni procedure. Tracking was evaluated using Spearman rank correlations between pairs of repeated hormone measurements separated by a fixed (4-yr) time interval. Pearson’s correlation coefficients were calculated to examine the cross-sectional associations between DHEAS and anthropometric variables. Data are presented as either the mean ± SD, the geometric mean with 95% confidence limits, or the median with its 25th and 75th percentiles. All analyses were performed using SPSS statistical software (SPSS, Inc., Chicago, IL).
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Results |
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and 2. According to the BMI reference data
for obesity presented by Must et al. (20) and the guidelines
for overweight reported by Himes and Dietz (21), two prepubertal
children were overweight on entry, and another one became overweight
during the course of the follow-up period. In the PubC group one child
was overweight when the study began, and one developed obesity after a
few years. None of the children was underweight.
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). Urinary DHEAS
excretion was related to individual body surface area (BS; standardized
to the adult BS of 1.73 m2 by multiplying each
individual DHEAS/BS ratio by 1.73) to control for DHEAS excretion
changes caused by BS-related growth of the adrenal gland (19). AA
secretion, reflected by urinary DHEAS output, continued to increase in
both sexes during puberty (Fig. 1B). The DHEAS excretion of one boy in
the PreC group was clearly in the pubertal range (his DHEAS exceeded 10
µmol/day·1.73 m2 at age 10 yr). However, no
physical signs of pubarche and no acne were seen in this normal weight
subject (BMI, 14.0–17.4 kg/m2). His testicular
volume was 3 mL (each testis) at age 10 and 11 yr and then doubled to 6
mL in the following year, clearly indicating the onset of puberty
around 12 yr (which was an exclusion criterion for further inclusion in
the PreC).
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). Although mean DHEAS excretion rates
were slightly higher in boys at all ages (Fig. 2A), this was not a
significant gender effect. The combined DHEAS excretion data of both
sexes displayed a virtually linear 4-yr increase on a logarithmic scale
(Fig. 2B). To examine the pubertal AA excretion pattern, mean DHEAS
values were plotted against a biological age scale. DHEAS excretion
data were synchronized with time of occurrence of individual PHV (Fig. 2C). The overall change in DHEAS excretion of both sexes during puberty
showed an almost monotonic linear increase and not the almost
exponential increase (linear only after logarithmic transformation)
seen in the PreC (Fig. 2A). The DHEAS increase over the whole 4-yr
interval was highly significant (P < 0.001; see Fig. 2C). To assess the stability and predictability of urinary DHEAS output
over time, tracking correlations were calculated for the 4-yr intervals
depicted in Fig. 2, B and C. Highly significant tracking coefficients
of 0.73 and 0.93 were found for DHEAS excretion in the PreC and PubC,
respectively (Fig. 3).
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depicts this association using the example of two prepubertal boys. One
(boy 1) had a relatively high urinary DHEAS output and BMIs mostly
between the 50th and 85th percentiles according to reference data (20).
The other (boy 2), who had low to normal DHEAS excretion, was at risk
of overweight (21). His BMI varied consistently between the 85th and
95th percentiles of BMI (20). It is discernible that the individually
largest (or second largest) DHEAS increase can occur along with the
individually highest BMI increase (Fig. 4, shaded
areas) even in individuals with either high BMIs and low to normal
DHEAS excretion rates or normal BMIs and high DHEAS values (Fig. 4).
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the average change after 1 yr in
urinary 24-h DHEAS excretion (-DHEAS), that occurred with the
individually highest increase in BMI (-BMI) was compared
to the average -DHEAS with the individually lowest
-BMI in the PreC. A significantly elevated -DHEAS was found with
the highest -BMI. However, this association was confounded by age,
in that the high increases in DHEAS (together with the highest -BMI)
occurred at a significantly older age than the respective -DHEAS
with the individually lowest -BMI (Fig. 5A).
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-DHEAS at the time
of the individually highest -BMI and -DHEAS 1 yr later
(i.e. at the time of a lower -BMI), a nearly 3-fold
higher median -DHEAS (P < 0.05) was observed with
the higher -BMI (P < 0.01) at the younger age
(P < 0.01; Fig. 5B
). Similar findings were obtained in
the PubC, but the difference in -DHEAS between the individually
highest -BMI and the lower -BMI 1 yr later just failed to reach
statistical significance (P = 0.058; Fig. 5C). Due to
an individually specific type of BMI increase over the respective
observation periods the data from four children in the PreC and two
children in the PubC had to be excluded from the statistical comparison
depicted in Fig. 5, B and C. All of these six excluded children showed
steadily increasing BMI values, with the second highest -BMI
followed by the highest -BMI at the end of the respective
observation period.
For the PubC an additional approach to test the statistical
significance of the relationship between -DHEAS and -BMI was
tried. The average -DHEAS at the time of the two individually
highest -BMI (-BMI
) was compared with the average -DHEAS at
the time of the two individually lowest -BMI (-BMI
). With this
approach the statistical significance (P < 0.05) of
the elevated DHEAS increases could also be confirmed at the time of the
individually highest BMI gains in the PubC [median -DHEAS at
-BMI, 0.58 (interquartile range, 0.11–1.1) µmol/day·1.73
m2; median -DHEAS at -BMI, 0.21
(interquartile range, 0.03–0.61) µmol/day·1.73
m2]. No age confounding was present for the
latter comparison (average ages at -BMI, 13.2 ± 1.3 yr;
-BMI, 13.2 ± 1.6 yr).
After analyzing both groups (PreC and PubC) together for -DHEAS at
the time of the individually highest -BMI and -DHEAS 1 yr later,
a highly significantly (P < 0.005) elevated median
-DHEAS [0.39 (interquartile range, 0.07–0.74) vs. 0.13
(interquartile range, -0.11 to 0.34) µmol/day·1.73
m2] was found for the greatest BMI increments in
both groups combined. When instead of -BMI the changes in the two
major components of body composition, BF and FFM, were analyzed with
regard to their relation to -DHEAS, only nonsignificantly
(P > 0.05) elevated DHEAS changes were noted at the
times of the individually largest increases in BF or FFM. This was true
for both cohorts.
On the other hand, the changes in body composition occurring at the
same time as the individually largest BMI increments were significantly
higher (for BF and FFM in the PreC and for BF in the PubC) than the
subsequent body composition changes 1 yr later (Table 3).
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Discussion |
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An important goal of longitudinal studies, apart from their potential to prove causal relationships between biological variables, is the assessment of tracking. The highly significant tracking coefficients found for DHEAS excretion in the PreC and PubC demonstrate for the first time that during human adrenarche there is a marked between-subject stability in individual DHEAS secretion levels. This confirms the effectiveness of the individual specificity (22) or the genetic component (23, 24) on the adrenarchal variation in DHEAS. The numerous developmental and environmental influences that occur during childhood and adolescence are obviously not great enough to obscure the important individual (genetic) influence (23, 24) on AA secretion. This individual influence is also reflected in the consistently high urinary DHEAS excretion of one deviant subject (followed from age 7–11 yr) in the PreC. Previous findings of Tanner and Gupta (25) had already revealed that some healthy children can be high excretors of urinary DHEA(S) before clear signs of puberty occur.
The fact that the individually highest DHEAS increases were found to occur mainly at the same time as the individually highest increases in BMI does not definitely prove a causal relationship, because age markedly confounded the results. As a consequence it could not be excluded that AA secretion could be stimulated with advancing age by a hitherto unidentified factor that is independent of the nutritional status but rises in parallel with age or developmental status.
The observed age confounding is primarily due to the fact that in
childhood during normal growth the BMI curves decrease until an average
age of 6 yr and increase thereafter (2). This increase is termed
adiposity rebound (2) and can also be seen (from age 6 yr onward) in
the mean BMI pattern of the PreC shown in Table 1. BMI values continue
to increase in pubertal children (2, 20) (Table 2). Thus, during
adrenarche both parameters, BMI and DHEAS, on the average, start off
low and then increase steadily. Accordingly, the comparison of changes
in DHEAS with high vs. low BMI increases is unavoidably
confounded by age.
When age was controlled for, a clearly elevated median -DHEAS
(P < 0.05) was noted at the time of the individually
largest BMI increases in both cohorts. Thus, individual -BMI is
probably a causal factor that, independent of age and individually
(genetically) (23, 24) determined AA level, markedly affects the
adrenarchal rise in AA. However, we cannot fully rule out the existence
of an as yet undetermined factor causing increases in both BMI and
DHEAS.
The fact that no significant relationship could be demonstrated between
-DHEAS and individually varying increases in BF or FFM suggests that
neither the gain in fat nor the gain in FFM alone is specifically
responsible for the overall impact of nutritional status on changes in
AA secretion. Contrary to the long term changes in body composition
during aging, which are commonly associated with a reduction in FFM,
each change in BMI in the PreC and almost every change in BMI in the
PubC corresponded to an increase in FFM, thus clearly reflecting
anabolism. It is discernible from Table 3 that even if BF decreased all
corresponding FFM changes were positive (except for one specified child
in the PubC). Consequently, our study strongly suggests that a clear
anabolic change in the nutritional status (i.e. an
individually high -BMI) is an important determinant of
adrenarche.
On the other hand, it might also be argued that increasing DHEAS may
induce weight gain and anabolism. However, according to experimental
diet and DHEA(S) replacement studies, the direction of
causality of the relationship between -BMI and -DHEAS appears to
be well established. Experimentally induced weight gain in adults
(associated with an increase in FFM) has been shown to result in an
elevated urinary AA excretion (6), whereas experimental weight loss
drastically reduced AA excretion and secretion (26). Also,
DHEA(S) replacement therapy in humans caused no change in
body weight (27, 28, 29). Furthermore, the fact that the association
between individually highest -BMI and individual highest -DHEAS
was also seen in individuals with an overall low urinary DHEAS output
(and thus with low DHEAS increases despite normal BMI increments)
strongly suggests that it is not the increasing amount of DHEAS that
induces weight gain. Similarly, the significant cross-sectional
correlation between urinary DHEAS and FFM (r = 0.56) observed in
the present study for the 8-yr-old prepubertal children does not
necessarily reflect an anabolic effect of higher AA levels on FFM. The
greater correlation between DHEAS and height (r = 0.62) occurring
at the same time in these children suggests that the association
between DHEAS and FFM could simply be a consequence of an individually
varying maturational status. In children of the same chronological age
a relatively greater height is often an index of individually advanced
maturation (30).
Anabolic changes have been repeatedly shown to be biochemically reflected in increases in the bioactivity of insulin and/or IGF-I (Ins/IGF) (5, 6, 7, 8, 9). As the adrenal cortex expresses Ins/IGF receptors (12), and both mitogenic peptides enhance AA secretion in human adrenocortical cells in vitro (10, 11, 12), it appears reasonable to assume that Ins/IGF play a pivotal role as nutritional signals in the modulation of AA production in vivo.
There is increasing evidence that obesity, increased insulin secretion, insulin resistance, and adrenal and ovarian hyperandrogenism are common features in a large subset of women with polycystic ovarian syndrome (PCOS) (31). Recent studies indicate that a number of girls with premature adrenarche are at risk of developing ovarian hyperandrogenism, PCOS, and hyperinsulinism (32). On the basis of our data it could now be speculated that marked weight gain and obesity (associated with strong insulin increases) might be causally involved in the development of premature adrenarche and the subsequent manifestation of PCOS, at least in such predisposed girls with a high responsiveness of adrenal and ovarian steroidogenesis to Ins/IGF stimulation.
Our findings that strong anabolic changes in the nutritional status obviously augment AA secretion explain why under a number of physiological and pathological situations, such as aging (33), fasting (33), anorexia nervosa (33), critical illnesses (34), and severe stress (34), pronounced decreases in DHEAS secretion occur. All of the above conditions are characterized by catabolism, clear decreases in IGF-I bioactivity, and losses in FFM. The fact that the secretion of ACTH, which is an essential stimulator of AA production, is markedly increased in most of these situations clearly demonstrates that sustained in vivo stimulation of AA requires more than the increased activity of only one tropic compound.
The observation that cortisol synthesis is down-regulated in the AA-secreting adrenal zona reticularis (10, 35) suggests that in addition to ACTH and Ins/IGF at least a third category of factors (with cortisol-suppressing properties) is involved in AA regulation. As has been recently speculated (36), suppressed cortisol production may stimulate ACTH secretion to correct the circulating cortisol level, which would result in increased AA production. Several factors with the potential to inhibit production of cortisol relative to that of AA have been identified in vitro, e.g. leptin (37, 38), ß-endorphin (36), and joining peptide (36). Considering these in vitro findings and the fact that leptin is closely related to nutritional status (39), it would be tempting to hypothesize that (in addition to ACTH) two important nutritional signals, leptin and Ins/IGF, are involved in the regulation of AA. A leptin-mediated reduction in cortisol production would not only raise POMC-derived ACTH, but also POMC-derived ß-endorphin and joining peptide, which together with nutritionally stimulated Ins/IGF levels would augment AA secretion relative to that of cortisol.
Theleologically, what could be the evolutionary advantage of increased AA secretion in response to increments in BMI? Based on the results of DHEA replacement experiments in humans and studies on human osteoblastic cells in vitro, DHEA appears to exert physiological effects that have relevant genetic advantages: increase in the bioavailability of IGF-I (28, 29), enhancement of immune functions (28, 40), and stimulation of bone formation (41, 42). These effects (attributable at least in part to the intracrine conversion of DHEA to potent sex steroids) imply that an improved immunological protection against infection and an enhanced bone mineral accretion during prepuberty could be functional consequences of increased AA production triggered by increased body mass. The observations that anabolic changes, i.e. increases in BMI and IGF-I (in vitro results) (10, 11, 12) enhance AA production and that AA themselves increase bioactive IGF-I levels (28, 29) and stabilize anabolic changes (28, 40, 41, 42) indicate that the adrenarchal increase in AA is part of a complex interacting self-stabilizing homeostatic system that has evolutionarily developed in higher primates.
In conclusion, our findings provide the first in vivo
evidence that a change in the nutritional status, measurable in the
form of -BMI, is an important physiological regulator of adrenarche
regardless of individual AA excretion level, age, and developmental
stage. -BMI may integrate the combined long term action of insulin
and IGF-I, which have been shown to augment AA production and
expression of steroidogenic enzymes in human adrenocortical cells
(10, 11, 12). Whether additional metabolic signals to the adrenal gland,
such as leptin (37, 38), are also involved in the complex regulation of
AA secretion has to be determined in further studies.
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Acknowledgments |
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Footnotes |
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Received February 17, 1999.
Revised June 7, 1999.
Accepted July 7, 1999.
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