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Original Studies |
Department of Pediatrics, John Radcliffe Hospital (M.L.A., K.K.L.O., N.D., D.B.D.), Oxford, United Kingdom OX3 9DU; Reproductive Medicine Laboratory, University of Edinburgh Center for Reproductive Biology (D.J.M.), Edinburgh EH11 9EW, Scotland; the Biochemistry, Endocrinology, and Metabolism Unit, Institute of Child Health (L.C., M.A.P.), London, United Kingdom WC1N 1AH; and the Department of Clinical Biochemistry, St. Bartholomew’s Hospital (L.P.), London, United Kingdom EC1A 7BE
Address all correspondence and requests for reprints to: Dr. David B. Dunger, Department of Pediatrics, John Radcliffe Hospital, Oxford, United Kingdom OX3 9DU. E-mail: david.dunger{at}paediatrics.ox.ac.uk
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Animal studies also indicate that leptin signaling results in interaction with neurotransmitters in the hypothalamus, principally neuropeptide Y (3, 11), and may influence gonadotropin secretion. Thus, leptin could have a role in pubertal development (12, 13, 14). Mutation of human genes encoding leptin and its receptor result in a failure of initiation of puberty and the establishment of secondary sexual characteristics (6, 7). There is debate as to whether the accumulation of fat mass, leading to a permissive leptin signal, is required for the initiation of puberty or whether dynamic short term changes in leptin levels result in pubertal development (15). The only previous longitudinal study suggested that there might be a brief pulse of leptin preceding the onset of puberty in males (16). Other studies of leptin levels during puberty have been cross-sectional and have identified a sexual dimorphism in leptin levels, with an increase in girls and a decrease in boys (17, 18, 19, 20). These differences have been partly explained by differences in body mass index or hormone levels (17, 21), but estimates of fat mass were only available in a minority of the subjects studied, and the cross-sectional design could distort the association with pubertal stage and pubertal hormone levels.
We present data from a longitudinal study of normal children between the ages of 8.6–16.6 yr, in which we have investigated the relationships between leptin levels and the onset of puberty, progression through puberty, and gains in fat mass and fat-free mass.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The study group comprised 40 children (20 boys and 20 girls) selected on the basis of the availability of blood samples from the beginning to the end of puberty, as defined by Tanner staging G1–G5 in boys and B1–B5 in girls (22), from a total cohort of 126 normal children whose growth and endocrine changes were studied during puberty (the Chard study group, Somerset, UK). These children were 8–9 yr old at entry into the study and 16–17 yr old at its conclusion. They were all healthy children recruited through their school. The study was approved by the ethical committee of the Hospital for Sick Children (London, United Kingdom), and parental consent and children’s assents were obtained before the study began.
Study design
The children were seen every 6 months between the ages of 8.6–16.6 yr. At each visit, height, weight, skinfold thicknesses, and pubertal stage were assessed. A nonfasting blood sample was obtained between 0800–1400 h on the day of measurement.
Anthropometry
A Harpenden stadiometer (Holtain Ltd., Crymych, Wales) was used to measure height. The child was positioned with his head in the Frankfurt plane, and gentle pressure was applied to the mastoid processes. Electronic scales were used to measure weight. Subcutaneous skinfold measurements were made at four sites: biceps, triceps, subscapular, and suprailiac on the left side of the body using a Harpenden skinfold caliper. Standard techniques were used for all measurements following the guidelines described by Cameron (23).
Laboratory assays
Serum samples were separated, stored at -20 C, and subsequently used for the measurement of testosterone, estradiol, dihydrotestosterone, sex hormone-binding globulin, dehydroepiandrosterone sulfate, androstenedione, insulin-like growth factor I and thyroid hormones.
Serum insulin-like growth factor I concentrations were determined by RIA after acid-ethanol extraction (24). The intraassay imprecisions were 5.2% and 4.8% at 27.5 and 220 ng/mL, respectively. The interassay imprecisions were 12.7% and 10.6% at 77 and 242 ng/mL, respectively. Free T4 was measured by a two-step, back-titration method previously validated against an equilibrium dialysis method (25). Total T4 was measured by an in-house RIA using barbitone buffer, pH 8.6, and 8-anilino-1-naphthalene sulfonic acid as a blocker, with a second antibody separation step (25). The interassay imprecisions were 8.6% and 6.7% for free and total T4, respectively. Serum estradiol was determined using the double antibody Diagnostics Products Corp. kit (Llanberis, Wales). The interassay imprecision was less than 10% at the three concentrations tested (approximately 150, 500, and 1000 pmol/L). Serum testosterone and androstenedione were measured using an in-house RIA after ether extraction. The assays use an iodinated tracer and a dextran-coated charcoal separation step. The between-assay imprecision was less than 10% for both assays (26). Endogenous testosterone was removed using a potassium permanganate oxidation step, and dihydrotestosterone was determined using RIA after ether extraction. The assay used an 3H tracer, and correction was made for procedural losses. The interassay imprecision was less than 12% at 0.5 nmol/L and less than 10% at 2 nmol/L. Sex hormone-binding globulin was measured using an 3H saturation assay (27). Interassay variation was less than 8% at the concentrations (20, 40, and 70 nmol/L) tested. Dehydroepiandrosterone sulfate was determined with in-house reagents. The assay required predilution of the sample (20-fold) with assay buffer followed by RIA with an 125I tracer. Interassay imprecision was less than 10% at the concentrations (2, 10, and 20 µmol/L) tested (26). Serum leptin was measured by RIA (Linco Co., St. Charles, MO). All samples from a given individual were included in the same assay. The detection limit of the assay was 0.5 ng/mL (manufacturer’s data). None of the sample values was less than 1.0 ng/mL; therefore, there were no undetectable values. Intraassay imprecisions were 5.7% and 6.7% at 2.5 and 12.5 ng/mL, respectively. Interassay imprecisions were 6.6% and 6.8% at 2.5 and 12.5 ng/mL, respectively.
Calculations of body composition
Two equations were used to estimate body density from skinfold measurements to accommodate the effect of maturation on the skinfold-density relationship. The equations of Brook (28) (for prepubertal children up to the age of 11 yr) and of Durnin and Rahaman (29) for pubertal children were used. Reilly et al. (30) recently carried out a validity exercise on these methods. The percent body fat was then derived using the equation of Siri (31), and fat mass (kilograms) was calculated as the percent body fat x body weight. Fat-free mass was calculated as body weight (kilograms) - fat mass (kilograms).
Statistical analysis
Data are presented as the mean [95% confidence interval (CI)] unless otherwise stated. Leptin concentrations were log transformed, fat-free mass and other hormone levels were also transformed to normal distributions by taking logarithms or square roots as appropriate, and parametric tests were used. Analysis of covariance was used to analyze the data longitudinally, by entering the subject identifier as a fixed factor. This analysis assumes that variables are similarly related by slope in each subject, but allows for intersubject differences in constants and thus is equivalent on a scattergraph to drawing parallel lines through the points for each subject (32). Associations between variables are presented as B (regression coefficient) ± SE. In the scattergraphs, the drawn lines, therefore, represent the line through the median subject. To examine sex differences by puberty stage where any subject was measured more than once in a puberty stage the mean in each stage was calculated, and differences were examined using Student’s t test. All analyses were performed using SPSS for Windows (SPSS Inc., Chicago, Illinois) version 7.5.1. P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Age-related changes in leptin levels were observed. In all girls,
leptin levels increased with age (B, 0.143 ± 0.012;
P < 0.0005), whereas in boys leptin levels decreased
(B, -0.063 ± 0.010; P < 0.0005; Fig. 1A
). The sexual dimorphism in leptin
levels was strongly related to puberty stage.
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With the onset of puberty in girls, leptin levels increased from B2 to
B5, whereas in boys, leptin levels decreased from G2 to G5, so a
significant sex difference in leptin was apparent by Tanner stage 3
(Fig. 1B
). Analyzed longitudinally, these changes by pubertal stage
were significant in girls (P < 0.0005) and in boys
(P < 0.0005). In girls, the change in leptin levels
appeared to be particularly marked between B4 [3.15 (2.77–3.59)] and
B5 [4.99 (4.45–5.60); P = 0.0005]; however, this
largely related to marked continuing increases in leptin after reaching
stage 5. The girls were observed for a median of 2.5 yr (range,
1.0–4.0 yr) and the boys for 1.5 yr (1.0–4.0 yr) in stages B5 and G5,
respectively. During this period there was a more rapid rise in leptin
levels with age in girls (B, 0.220 ± 0.044; P <
0.0005) but not in boys (B, -0.010 ± 0.031; P =
0.75).
Leptin levels and body composition
The association between leptin and fat mass in girls was positive
and significant (B, 0.048 ± 0.010; P < 0.005),
but this was not seen in boys (B, 0.021 ± 0.013;
P = 0.12; Fig. 2A).
Between leptin and fat-free mass there was again a positive and
significant relationship in girls (B, 0.523 ± 0.193;
P = 0.008) but a negative nonsignificant one in boys
(r = -0.225 ± 0.143; P = 0.12; Fig. 2B).
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). Furthermore, the relationship
between leptin and fat-free mass, when allowing for the effects of fat
mass, was negative and similar in boys (B, -1.288 ± 0.217;
P < 0.0005) and in girls (B, -1.104 ± 0.381;
P < 0.005; Fig. 3B). There were no significant
differences in the regression coefficients between the sexes for leptin
and fat mass, allowing for fat-free mass (P = 0.21) or
for leptin and fat-free mass allowing for fat mass (P =
0.33).
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, A and B). Fat mass and fat-free
mass contributed 27% and 27%, respectively, to changes in leptin in
boys; in girls, these variables contributed 22% and 9.3%,
respectively, to variances in leptin.
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Correlations between leptin levels and levels of a large number of
other hormones were observed (Table 1);
however, these associations reflected the individual changes in these
hormone levels with age during puberty and the corresponding changes in
leptin levels. No independent relationships between leptin and other
hormone levels were detected when fat mass and fat-free mass were
included in the covariance model.
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Before the onset of puberty, leptin levels were closely related to
fat mass in all children (B, 0.097 ± 0.034; P =
0.007). In girls, data concerning leptin levels at the last visit in B1
before the onset of B2 were available for 12 of the 20 subjects. These
levels were clearly related to subsequent change in percent body fat
(B1 to B5); a lower leptin level was associated with a greater gain in
percent body fat (B, -12.28 ± 3.46; P = 0.005;
Fig. 5). However, in boys, leptin levels
before the onset of puberty did not predict a subsequent change in
percent body fat (B, -1.04 ± 4.11; P =
0.81).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Only one other longitudinal study of leptin levels in relation to normal puberty has been reported (16). That study of eight boys indicated that there might be a brief pulse in leptin levels preceding the onset of puberty. We were unable to detect such a pulse in any of the subjects that we studied despite having data relating to a median of 1.5 yr of observation in G1 or B1. The pulse in leptin levels detected by Mantzoros et al. (16) was in most cases only observed at one time point, and our failure to detect it could reflect the longer sample interval in our study (every 6 months) compared with theirs (4 months). Correct identification of the exact time of transition from G1 to G2 or from B1 to B2 could also be of importance, as, given the profound effects of puberty on leptin levels, incorrect assignment of a patient as G1 when they were in fact already in puberty may suggest an erroneous late prepubertal change in leptin levels. However, the subjects reported by Mantzoros et al. (16) were all males, and the decline in leptin levels with the onset of puberty would not have been a confounding factor. Thus, we cannot provide any support for their observations and the hypothesis that short term changes in leptin levels initiate pubertal devel-opment.
Leptin levels before the onset of puberty were similar in both sexes and were within relatively narrow ranges (2.17–3.2 ng/mL in boys, 2.08–2.94 ng/mL in girls). We observed a negative relationship between age at menarche and percent body fat at menarche (r = -0.45; P = 0.08). Matkovic et al. (34) reported negative correlations between leptin levels and age at menarche, but we were unable to confirm this in our study. It has often been reported that early age at menarche is associated with greater gains in weight during childhood (35). These observations of leptin levels in relation to the onset of puberty provide some support for the proposal of Frisch (36) that a critical amount of body fat is needed for the initiation of puberty. The leptin level may be the permissive signal, as recently demonstrated in studies of leptin replacement for congenital leptin deficiency (7) and in several animal models (13). However, although obese children tend to have an earlier puberty, extremely obese children do not invariably have precocious puberty, so the permissive effect of leptin must also be linked to other maturational events in the hypothalamus.
Pubertal development in the subjects that we studied was associated with the characteristic sex-specific changes in body composition (33); gains in fat mass were greater in girls, and gains in fat-free mass were greater in boys. These differences in the acquisition of adult body composition largely account for the pubertal divergence in leptin levels between boys and girls, which has previously been described but not fully explained (17, 18, 19, 20). We observed similar relations between leptin and body composition in each sex; allowing for fat-free mass, fat mass was positively related to leptin, and allowing for fat mass, fat-free mass was negatively related to leptin levels. Together, fat mass and fat-free mass accounted for 54% of the variance in leptin levels in boys and for 31% of the variance in girls. Fat mass is a major source of circulating leptin, and thus, a close relationship with leptin levels is expected. However, the negative relationship with fat-free mass is unexplained and may relate to the parallel effects of other hormones on both leptin production and the acquisition of fat-free mass.
Similar to previous studies (17), we identified significant relationships between leptin and a large number of other hormone levels during puberty. However, these could largely be predicted by the relative changes in leptin and in each hormone with age during puberty. For some of these hormones, such as testosterone, direct effects on adipocyte leptin production have been reported (21, 37, 38, 39, 40). However, in observational studies it is difficult to determine the effects of each hormone independent from their relation to other hormones or from their effects on body composition. Jockenhovel et al. demonstrated that testosterone replacement reduces leptin levels in hypogonadal males (37). In that study, the strongest determinant of leptin levels was the androgen/estrogen ratio, which could not be assessed in our subjects because of the lack of estradiol data in the boys. Overall, although these data suggest that a large number of other hormones may influence leptin production during puberty, these associations largely parallel the gains in fat mass and fat-free mass.
We report the first data in support of the hypothesis that leptin levels may predict subsequent gains in fat during puberty. Lower leptin levels in prepuberty were highly predictive of subsequent gains in percent body fat in girls. This association was not independent of prepubertal fat mass, suggesting that gains in fat mass during earlier childhood may not only determine the age at onset of puberty, but may also influence subsequent gains in fat mass, and these effects could be signaled through leptin. Interestingly, we did not observe an association between prepubertal leptin levels and gain in absolute fat mass, perhaps indicating that leptin levels determine relative gains in fat mass and fat-free mass during puberty rather than fat mass alone. As a result of this inverse relationship between leptin levels and gain in percent body fat, the variance in percent body fat was lower at B5 (mean ± SD, 19.5 ± 6.4%) than at B1 (27.6 ± 3.1%), but overall there was still a positive correlation between the percent body fat at B1 and B5 (r = 0.8; P < 0.0005). These observations are similar to those reported in a study of Pima Indians (10) where an association was detected between larger gains in body fat and lower leptin levels. In contrast, in a study of Japanese Americans, higher leptin levels predicted subsequent weight gain (9), suggesting that weight gain in those subjects may be related to leptin resistance. Our data, therefore, suggest that normal adolescent children are still sensitive to the weight-regulating effects of leptin.
In our study, lower leptin levels at prepuberty also predicted lower gains in the percent fat-free mass. However, this was related to the method of derivation of the percent fat-free mass and the percent body fat. Our observation of a link between leptin and gains in percent body fat in girls was not seen in boys. One might speculate that the regulation of fat mass may be more important in girls, in anticipation of pregnancy, than in boys and may indicate a sex difference at the hypothalamic receptor or in postreceptor events.
From our data, we conclude that a permissive level, rather than a transient elevation, in leptin levels signals the initiation of puberty. Similar relationships with leptin levels were seen in boys and girls; these were positive with fat mass and negative with fat-free mass. The sexual dimorphism in leptin levels after the onset of puberty largely relates to the characteristic sex-specific gains in fat mass and fat-free mass. The marked continuing increase in leptin levels in the girls after attainment of stage 5 is an interesting observation that we are pursuing. The importance of pubertal changes in other hormones in regulating leptin levels is difficult to dissect from each other and from their effects on fat mass and fat-free mass. Finally, and perhaps most importantly, we observed that in girls, low prepubertal leptin levels predict subsequent changes in body composition and greater gains in percent body fat. Thus, an earlier age at onset of puberty may be linked to a greater prepubertal fat mass, but later onset of puberty could predispose to larger pubertal gains in percent body fat.
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Acknowledgments |
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Footnotes |
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Received July 21, 1998.
Revised December 3, 1998.
Accepted December 11, 1998.
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References |
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and - - -; B, -0.063 ± 0.010; P <
0.0005) and girls (• and —-; B, 0.143 ± 0.012;
P < 0.0005). B, Mean leptin ± 95% CI (log
scale) by puberty stage in boys (
