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Original Studies |
A. I. duPont Hospital for Children, Wilmington, Delaware 19899; and Indiana University Medical School, Indianapolis, Indiana 46206
Address all correspondence and requests for reprints to: Dr. Karen Oerter Klein, Department of Clinical Science, A. I. duPont Hospital for Children, P.O. Box 269, 1600 Rockland Road, Wilmington, Delaware 19899.
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Abstract |
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Mean 24-h estradiol levels correlated significantly with chronological age and bone age as well as with insulin-like growth factor I, insulin-like growth factor-binding protein-3, dehydroepiandrosterone sulfate, mean 24-h GH, and lean body mass. Mean 24-h estradiol levels did not differ between obese and nonobese children [1.65 ± 1.47 vs. 2.75 ± 3.30 pmol/L (0.45 ± 0.40 vs. 0.75 ± 0.90 pg/mL), respectively]. Similar mean 24-h estradiol levels in obese and nonobese children are consistent with the increased bone maturation of the obese children. Estradiol did not correlate significantly with DEXA fat mass, body mass index, or arm fat measures of adiposity.
Obese children had higher 24-h mean leptin concentrations than nonobese children (28.6 ± 17.4 vs. 6.8 ± 7.1 ng/mL; P < 0.001). Leptin concentrations positively correlated with DEXA fat mass, body mass index, and arm fat measurement of adiposity. Girls had higher 24-h mean leptin levels than boys when controlling for adiposity.
Estradiol and leptin concentrations fluctuated over a 24-h period in both groups, with all children having higher leptin concentrations at night and higher estradiol concentrations in the morning. This diurnal rhythm was of a similar pattern, but at higher levels for leptin and lower levels for estradiol in the obese children compared to nonobese children. There was no significant correlation between estradiol and leptin levels.
Bone mineral density, as measured by DEXA, did not differ between obese and nonobese children. Similar bone mineral density values in obese and nonobese children are consistent with the increased bone maturation of the obese children. Bone mineral density was not correlated with estradiol or leptin level in these children.
In conclusion, obese children had similar estradiol levels and equivalent bone ages at a younger chronological age than nonobese children. Leptin was higher in these obese children, but did not correlate with estradiol level or bone age. These findings suggest that the role of leptin in both obesity and pubertal development is not directly correlated with the estradiol level.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Obesity in adult females has been associated with increased estradiol levels (2) and estradiol’s role in the physical changes in puberty in girls is well known. Estradiol also increases in boys as they approach and enter puberty (3). Estradiol levels have been unreliable in children as measured by RIA (4). This is the first study of the relationship between obesity and estradiol using an ultrasensitive recombinant cell bioassay for estradiol (4).
Leptin, a cytokine-like protein produced by the ob gene, is thought to be integral in the feedback loop from adipose stores to the satiety centers in the hypothalamus regulating appetite and energy expenditure (5, 6, 7). It is hypothesized that in human obesity, there is resistance to the action of leptin, which allows continued weight gain despite adequate energy stores (8, 9). We previously found a significant correlation between leptin concentrations and adiposity in children (9), consistent with similar reports in adults (10, 11, 12). In addition, leptin concentrations decreased with increasing pubertal stage when controlling for adiposity, suggesting a possible link between leptin concentrations and pubertal changes (9). These findings were consistent with the work of Chehab (13) and Barash (14) in the ob/ob mouse, which showed that leptin-deficient mice failed to achieve puberty, fertility, or pregnancy without the addition of leptin, and consistent with Ahima’s report of leptin accelerating puberty in normal mice (15). Obese children have elevated levels of leptin compared to normal weight children and achieve puberty earlier than normal weight children (16).
We studied estradiol and leptin levels over 24 h as well as bone mineral density (BMD) in obese and nonobese children to further understand their roles in obesity and puberty.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We studied 18 obese children (12 girls and 6 boys; average age,
8.9 ± 1.8 yr) and 30 nonobese children (11 girls and 19 boys;
average age, 10.0 ± 1.9 yr). Body mass index (BMI), defined as
weight in kilograms divided by height in meters squared, was more than
95% for age, race, and gender in the obese children and less than 85%
for age, race, and gender in the nonobese weight children (1). Arm fat
was calculated from the measured midarm circumference and triceps
skinfold according to the formulas provided by Must and colleagues
(17). The clinical characteristics of the 2 groups of children are
presented in Table 1
. Two of the obese
children were diagnosed as having attention deficit disorder and were
being treated with methylphenidate hydrochloride. Three children were
taking over-the-counter allergy medication, and 1 obese child was
taking an antibiotic. No other diseases or medications were present,
and all children had normal physical examinations, apart from increased
weight in the obese subjects.
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Protocol
Children were admitted to the hospital at 0700 h on day 1 of the study. An iv catheter was placed for blood withdrawal, and baseline blood samples were obtained in the fasting state at time zero. Baseline blood samples were analyzed for estradiol, leptin, GH, insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), dehydroepiandrosterone sulfate (DHEA-S), insulin, and glucose. After baseline studies, hourly blood samples were drawn for estradiol, leptin, GH, IGF-I, IGFBP-3, DHEA-S, insulin, and glucose determinations for 24 h.
Children ate breakfast after the first blood sample (
0800 h), ate
lunch at approximately 1200 h, and ate dinner at approximately
1800 h. Children ate snacks as desired between meals. Meals were
chosen from the hospital menu, and all intake was recorded. Calorie
consumption per day was obtained by recording all intake and converting
to calories consumed. Children went to sleep between 2200–2300 and
were awakened at 0700 h the following morning. At the end of the
24-h blood sampling, children underwent a radiograph of the left hand
for bone age determination and full body dual energy x-ray
absorptiometry (DEXA) to determine bone mineralization, total lean
mass, and total fat mass. DEXA analysis was performed on the QDR-200
(Hologic, Inc., Waltham, MA) with the DCA-1 module for
body composition analysis. A calibration standard, or phantom, for fat
and lean mass was scanned with each study to assure intramachine
accuracy. All bone age films were read by the same radiologist, who was
blinded as to subject classification, pubertal stage, and age.
Arm fat (F) was calculated by the formula (21): F = A - M,
where A is upper arm area in square millimeters, and M is upper arm
muscle area in square millimeters. Upper arm area is calculated by:
A = (
/4)(d) (2) (2), where d = C/, and C is upper arm
circumference, which was measured midway between the tip of the
acromion and the olecranon process. Upper arm muscle area is calculated
by the formula: M = [(C - T) (2) (2)]/4, where T is
the triceps skin fold measured to the nearest millimeter with a Lange
skin fold caliper over the triceps muscle in the same location as the
circumference was taken.
Informed consent was obtained from one parent and assent from each child before participation in the study. The clinical research review committee approved the protocol at duPont Hospital for Children.
Estradiol assay
The bioassay for estrogen was performed as described previously (4). Briefly, the assay uses a strain of Saccharomyces cerevisiae that was transformed with two plasmids, one containing the human estrogen receptor complementary DNA, and one containing an estrogen response element upstream from the structural gene for ß-galactosidase. After an 8-h incubation of yeast with ether extracts of 0.8 mL serum or estradiol standard, ß-galactosidase activity was measured using ortho-nitro-phenol-galactopyranoside as substrate. Estradiol equivalent units were calculated by linear interpolation from a standard curve. The sensitivity of the bioassay was 0.07 pmol/L. The intra- and interassay coefficients of variation at 7 pmol/L were approximately 15%.
Leptin assay
Serum leptin levels were determined using a well characterized (22), commercially available RIA kit (Linco, Inc., St. Charles, Mo) as previously described.
Human GH assay
Serum GH concentrations were determined by immunochemiluminescence assay (Nichols Laboratories, San Juan Capistrano, CA). Intra- and interassay coefficients of variation were 5.4% and 9.2% maximum, respectively. The lower limit of assay sensitivity was 0.02 µg/L.
Insulin and glucose
Insulin levels were measured by immunochemiluminescence assay at Endocrine Sciences, Inc. (Calabasas Hills, CA), with a sensitivity of 7.2 pmol/L. Intra- and interassay coefficients of variation were 5% and 15% maximum, respectively.
Plasma glucose levels were measured by a hexokinase method using ultraviolet detection with an assay sensitivity of 1 mg/dL. Intra- and interassay coefficients of variation were 1.1% and 3.0% maximum, respectively.
IGF-I assay
IGF-I was measured by a competitive binding RIA at Endocrine Sciences. Intra- and interassay coefficients of variation were 5.9% and 8.2% maximum, respectively.
IGFBP-3 assay
IGFBP-3 was measured by a competitive binding RIA at Endocrine Sciences. Intra- and interassay coefficients of variation were 13% and 18% maximum, respectively. The sensitivity was 0.3 mg/L.
DHEA-S assay
DHEA-S was measured by RIA after enzymolysis of the DHEA-S at Endocrine Sciences. Intra- and interassay coefficients of variation were 6.9% and 8.4% maximum, respectively. The sensitivity was 10 µg/dL.
Statistics
Comparisons between groups were made using the two-tailed Student’s t test and a paired t test when appropriate. A log (Ln) transformation of serum leptin levels was performed to normalize the distribution of values to meet the assumptions for subsequent analyses. Analyses were performed using the general factorial analyses of covariance model, controlling for the effects of both BMI and upper arm fat. Arm fat and BMI were selected as covariates because of their high correlations with serum leptin concentrations (8, 9). The 24-h time period was divided into six 4-h intervals for each child. Repeated measures multiple analysis of covariance with pairwise t tests were used to examine difference between the six time intervals and across all intervals. Post-hoc (Tukey) analyses were performed to determine differences between girls and boys, and between obese and nonobese children. Data are presented as the mean ± SD. Statistical significance was defined as P < 0.05. All analyses were two tailed and conducted with the SPSS software (version 7.5 for windows95 or NT, SPSS, Inc., Chicago, IL).
The nighttime rise in leptin was defined as (peak leptin - nadir leptin)/nadir leptin x 100, where peak leptin was the average of the three highest consecutive values, and nadir leptin was the average of the three lowest consecutive values for each child.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Obese children were significantly younger than nonobese children,
with no difference in pubertal stage, height, or bone age between the
two groups (Table 1
). As expected, obese children were heavier and had
greater BMI and arm fat measurements (Table 1). There was no difference
in racial distribution between the groups. Obese children had a
significantly greater bone age to chronological age ratio compared to
nonobese children (1.2 ± 0.3 vs. 0.99 ± 0.1 yr;
P < 0.001). Caloric intake and distribution of
calories did not differ between obese and nonobese children during the
study. The obese and nonobese groups consumed similar total calories
throughout the 24-h study period (2135 and 2180 Cal, respectively). The
distribution of calories among fat, carbohydrate, and protein was also
similar between the two groups (25% fat, 60% carbohydrate, and
11% protein).
Obese children had greater fat mass than nonobese children (DEXA z-scores, 6.36 ± 5.43 vs. -0.20 ± 0.87; P < 0.001), greater lean mass than nonobese children (DEXA z-scores, 1.77 ± 2.58 vs. -0.21 ± 0.98; P < 0.001), higher percent fat than nonobese children (DEXA, 44.77 ± 5.66 vs. 21.17 ± 9.01; P < 0.001), and lower percent lean body mass than nonobese children (DEXA, 53.04 ± 5.56 vs. 75.81 ± 8.89; P < 0.001). When combining obese and nonobese children into one group, girls had higher percent fat than boys (34.13 ± 12.44 vs. 26.24 ± 14.44; P < 0.05) and lower lean mass than boys (63.30 ± 12.08 vs. 70.93 ± 14.05; P < 0.05).
Estradiol levels
The mean estradiol level correlated significantly with chronological age (P < 0.02); bone age (P < 0.01); 24-h GH (P < 0.01), IGF-I (P < 0.01), IGFBP-3 (P < 0.05), and DHEA-S (P < 0.01); and lean body mass (P < 0.01), as measured by DEXA. Mean estradiol levels did not differ between obese and nonobese children [1.65 ± 1.47 vs. 2.75 ± 3.30 pmol/L, respectively (0.45 ± 0.40 vs. 0.75 ± 0.90 pg/mL)] and did not correlate with fat mass, BMI, or arm fat.
The obese children actually had similar estradiol levels for bone age compared to the nonobese children. The known difference in estradiol level between girls and boys (4) was confirmed by comparing the nonobese stage 1 girls to the nonobese stage 1 boys [2.90 ± 2.68 vs. 1.03 ± 0.62 pmol/L, respectively (0.79 ± 0.73 vs. 0.28 ± 0.17 pg/mL)]. Mean estradiol was significantly greater in nonobese boys stage 2 [5.03 ± 5.51 pmol/L (1.37 ± 1.5 pg/mL)] than in nonobese boys stage 1 [1.03 ± 0.62 pmol/L (0.28 ± 0.17 pg/mL)], as expected (3). There were not enough girls in stage 1 vs. 2 for adequate comparisons.
Concentrations of estradiol fluctuated over a 24-h period,
with both groups experiencing a significant morning rise. The peak
estradiol level, defined as the average of the three
highest consecutive values, was significantly higher than the nadir
estradiol level, defined as the average of the three
lowest consecutive values, in both obese and nonobese children. The
peak estradiol level in obese children was 4.59 ±
4.26 pmol/L (1.25 ± 1.16 pg/mL) at 0900 h, and the nadir
estradiol level was 0.55 ± 0.59 pmol/L (0.15 ±
0.16 pg/mL) at 2400 h. The peak estradiol
level for nonobese children was 6.72 ± 7.27 pmol/L (1.83 ±
1.98 pg/mL) at 0900 h, and the nadir estradiol level
was 1.14 ± 1.84 pmol/L (0.31 ± 0.50 pg/mL) at 1500 h.
The similarity in diurnal pattern between the obese and nonobese groups
is shown in Fig. 1.
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Obese children had higher 24-h mean leptin concentrations than nonobese children (28.6 ± 17.4 vs. 6.8 ± 7.1 ng/mL; P < 0.001) and had higher fasting leptin levels than nonobese children (26.3 ± 16.9 vs. 6.0 ± 6.5 ng/mL; P < 0.001). There was no difference in leptin concentrations between obese and nonobese children when controlling for adiposity. However, girls had higher 24-h mean leptin levels than boys only when controlling for adiposity, (12.8 ng/mL in girls vs. 8.62 ng/mL in boys; P < 0.008). Mean 24-h leptin correlated with total fat mass as well as with fat mass determined in the arms alone, legs alone, and trunk alone by DEXA. Leptin concentrations correlated with BMI (r = 0.84; P < 0.001), BMI SD score (r = 0.9; P < 0.01), and arm fat measurement of adiposity (r = 0.86; P < 0.001) in all children.
Obese children had higher 24-h mean insulin levels (430.5 ± 391.8 vs. 221.7 ± 104.8 pmol/L; P < 0.008) than nonobese children. There was a significant correlation between leptin and insulin (r = 0.56; P < 0.001). Twenty-four-hour mean glucose values were not different between obese and nonobese children. There were no significant correlations between leptin and glucose, IGF-I, IGFBP-3, or DHEA-S. There was no change in leptin concentration with meal timing or fasting.
Twenty-four-hour mean GH concentrations were lower in obese children compared to nonobese children (0.5 ± 0.5 vs. 1.4 ± 0.9 µg/L; P < 0.001). Twenty-four-hour mean leptin and 24-h mean GH levels were negatively correlated in the combined group of children (r = -0.59; P < 0.001). There was no correlation between the variability of leptin and the variability of GH where variability was calculated as a coefficient of variation (SD/mean).
Concentrations of leptin fluctuated over a 24-h period, with both
groups experiencing a significant nighttime rise. The peak leptin
(defined as for estradiol above) was significantly higher
than the nadir leptin in both the obese and nonobese children (Fig. 2). The mean nighttime rise was 100% for
obese and 123% for nonobese children. This difference did not achieve
statistical significance. There was also no significant difference in
the nighttime rise between stage 1 and stage 2 of puberty. The average
single peak leptin level for the obese children was significantly
greater than that for the nonobese children (39.7 ± 23.0 ng/mL at
an average time of 0100 h vs. 9.9 ± 10.1 ng/mL at
an average time of 0200 h; P < 0.001). The
average single nadir leptin level for the obese children was
significantly greater than that for the nonobese children (20.7 ±
13.1 ng/mL at an average time of 1200 h vs. 4.4 ±
4.5 ng/mL at an average time of 1100 h; P <
0.001). The similarity in diurnal pattern between the obese and
nonobese groups can be seen in Fig. 3.
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The nocturnal rise in leptin level coincided with the nocturnal rise in
GH and estradiol in the nonobese children, but not in the
obese children who had no nocturnal rise in GH (Fig. 4).
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BMD
BMD correlated with age and bone age, but was not significantly different between obese and nonobese children even when controlling for age or bone age (0.79 ± 0.06 vs. 0.82 ± 0.07 g/m2, respectively). Neither estradiol nor leptin correlated with total BMD as determined by DEXA, but estradiol did correlate with BMD as determined in the arms only in the combined group of children, in the boys alone, and in the normal group alone. Insulin did not correlate with BMD.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Mean 24-h leptin concentrations were increased in obese children compared to nonobese children at the same pubertal stage as reported by others (31). Girls had significantly higher 24-h mean leptin concentrations than boys when controlling for adiposity, as reported by others (32, 33), indicating that the difference in girls and boys is not secondary to adiposity. There was no difference in age, bone age, or pubertal stage between girls and boys to account for this difference in leptin levels. Argente et al. described fasting leptin levels in obese and nonobese children (34). In that study, fasting leptin levels correlated with BMI in obese and nonobese children throughout the pubertal stages. Fasting leptin increased with pubertal stage and was higher in obese compared to nonobese children at stage 1. Girls had higher leptin levels than boys throughout puberty, but this only achieved statistical significance at stage 5. The present study adds to these findings by studying 24-h profiles of leptin, estradiol, and the relationship among leptin, estradiol, and body composition.
Studies in children have shown that leptin concentrations are greater in early puberty than in late puberty or in adults independent of adiposity (8, 35). Leptin levels increase into stage 2 of puberty in girls and boys and then decrease quickly in boys and decrease more slowly by the end of puberty in girls (36, 37). Leptin increases before testosterone in prepubertal boys and then decreases during puberty (35). Leptin has been related to age at menarche (31) and to amenorrhea (38). In contrast, the onset of puberty in male rhesus monkeys was not related to circulating leptin levels (39). Apter in a commentary concludes that "leptin seems not to be a primary signal that initiates the onset of puberty: instead, it may act in a permissive way as one of several metabolic factors" (40).
Obese children were younger, taller, and had more advanced bone maturation than nonobese children of similar pubertal stage, confirming the accelerated bone maturation and relatively earlier puberty in the obese children. Both leptin and estradiol correlated with bone age. The link between body weight and timing of pubertal events has been documented by many observers (1, 18, 41, 42, 43, 44). Tanner (18) found that children with earlier puberty had more weight for height before and throughout the adolescent spurt than children with later puberty. Frisch and Revelle (1) showed that both the initiation of the adolescent growth spurt and the attainment of peak growth velocity were related to an unvarying mean weight independent of early or late attainment of puberty. In the present study, leptin levels correlated with all measures of adiposity, including fat mass by DEXA, whereas estradiol did not correlate with any measure of adiposity.
Leptin, estradiol, and GH were all secreted in a diurnal pattern. A diurnal pattern of estradiol has been described in nonobese children using a less sensitive assay and less frequent sampling (45). In the present study, both obese and nonobese children have a similar diurnal pattern of estradiol secretion. A diurnal pattern of leptin concentration was observed in all children, with a nighttime peak and midday nadir as previously described in adults (23, 24, 46, 47, 48) and children (24, 49). This pattern was similar between the obese and nonobese children despite higher absolute leptin concentrations in the obese group. The significance of a diurnal pattern of leptin secretion may be related to leptin’s interaction with the hypothalamus and its role in puberty.
BMD as measured by DEXA was similar in obese and nonobese children even when controlling for age or bone age and did not correlate with estradiol or leptin levels. BMD is spared in obese adults (50). There are not many reports of BMD in obese children. Manzoni et al. found greater bone mineral content in obese compared to nonobese children only when no correction was made for age and sex (51).
Twenty-four-hour mean GH was significantly decreased and insulin levels were significantly increased in obese children compared to nonobese children, as expected (52). Twenty-four-hour mean glucose levels did not differ between the two groups, confirming the preservation of normal glucose levels by increasing insulin levels in obese children. Leptin levels were negatively correlated and estradiol levels were positively correlated with 24-h mean GH when obese and nonobese children were combined into one group. Leptin concentrations were not related to the timing of meals, caloric intake, or the distribution of calories. Similar observations have been found in adults (8, 41, 53).
The mechanism behind the onset of puberty is still unknown, but may involve some effect of leptin on the hypothalamic-pituitary axis (46, 54). Increased leptin concentrations and earlier puberty in obese children compared to nonobese children are consistent with the hypothesis that leptin may play a role in the onset of pubertal changes in addition to its role in obesity. Alternatively, leptin may increase as a result of pubertal initiation by some other factor or combination of factors. Further studies are needed to define the relationship among puberty, estradiol, and leptin. The results of this study suggest that if leptin does play a role in the onset of puberty, it is doing so before changes in estradiol are appreciated. This is consistent with a previous report that leptin increases throughout puberty in boys and girls before estradiol, testosterone, LH, or FSH increases, which may indicate a role for leptin in pubertal initiation (55). Obese children have higher leptin levels and more advanced bone maturation before any appreciable difference in estradiol is observed. This hypothesis is consistent with a mechanism of action of leptin at the level of the hypothalamus. Leptin stimulated LH and FSH in adult male rat pituitaries in vitro and stimulated LH release in adult female rats in vivo (55). These findings are also consistent with the hypothesis that leptin may play a direct role in ovarian function at the level of the granulosa cell (56, 57).
In conclusion, estradiol levels are not directly correlated with leptin levels in obese and nonobese prepubertal and early pubertal children. However, obese children achieve similar estradiol levels and bone ages at significantly earlier chronological ages than nonobese children. The reasons for this remain unclear. A longitudinal study of children progressing from prepuberty into and through puberty is needed to further clarify the relationship between estradiol and leptin. Leptin may influence the onset of puberty independent of estradiol production by a direct effect on the hypothalamic-pituitary-gonadal axis or may influence the onset of puberty through an as yet undetermined intermediary factor.
Received April 28, 1998.
Revised June 22, 1998.
Accepted July 13, 1998.
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V. Simha, J. E. Zerwekh, K. Sakhaee, and A. Garg Effect of Subcutaneous Leptin Replacement Therapy on Bone Metabolism in Patients with Generalized Lipodystrophy J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 4942 - 4945. [Abstract] [Full Text] [PDF]
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 S E Moore, G Morgan, A C Collinson, J A Swain, M A O'Connell, and A M Prentice Leptin, malnutrition, and immune response in rural Gambian children Arch. Dis. Child., September 1, 2002; 87(3): 192 - 197. [Abstract] [Full Text] [PDF]
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 F. H. Bronson Puberty in Female Mice Is Not Associated with Increases in Either Body Fat or Leptin Endocrinology, November 1, 2001; 142(11): 4758 - 4761. [Abstract] [Full Text] [PDF]
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O. Ogueh, S. Sooranna, K. H. Nicolaides, and M. R. Johnson The Relationship between Leptin Concentration and Bone |
