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From the Clinical Research Centers |
Division of Endocrinology, Department of Medicine, Children’s Hospital (M.R.P., S.R.), Boston, Massachusetts 02115; the Clinical Investigator Training Program: Beth Israel Deaconess Medical Center-Harvard/Massachusetts Institute of Technology Division of Health Sciences and Technology, in collaboration with Pfizer, Inc. (M.R.P.), Boston, Massachusetts 02115; and the Pediatric and Reproductive Endocrine Units, Massachusetts General Hospital (P.A.B.), Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Paul A. Boepple, M.D., Reproductive Endocrine Unit, Bartlett Hall Extension 5, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114.
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Abstract |
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The mean SD scores of IPP and NPP girls were +0.4 ± 0.1 and +1.0 ± 0.5, respectively, compared with that of age-matched prepubertal girls and +0.7 ± 0.2 and +1.6 ± 0.6 compared with that of girls matched for pubertal stage. The CPP girls with lower BMIs contributed larger SD scores, such that the leptin SD score was negatively correlated with BMI. A similar, modest increase in leptin levels in the CPP girls was evident when additional normative data were considered. The mean leptin SD scores of IPP and NPP boys were -0.9 ± 0.5 and +0.7 ± 0.3, respectively, compared with that of normal boys at Tanner stage 3–4. Serum leptin levels in the boys with CPP were not different from those in healthy boys in any of the normative studies.
These data should be interpreted cautiously, but they suggest that girls with CPP have modestly elevated serum leptin concentrations compared with those in healthy children and adolescents. In addition, the negative correlation between the leptin SD score and BMI suggests that sufficient leptin levels may be associated with initiation of puberty in girls.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The idea that the function of the hypothalamic-pituitary-gonadal (HPG) axis is coordinated with the body’s fat stores is not new. In 1963, Kennedy and Mitra demonstrated that the initiation of puberty in the rat is influenced by body size and food intake (21). Subsequent data in humans revealed that mild obesity is associated with earlier menarche in American girls (22) and that a minimum weight for height is associated with the onset and maintenance of normal menstrual function in young women (23, 24). It is well established that highly trained athletes, ballet dancers, and women who diet excessively can develop primary or secondary amenorrhea (24). We now know that serum leptin concentrations are proportional to indexes of body fat (8, 9, 13, 25, 26, 27, 28, 29) and that the diurnal pattern of leptin levels is abnormal in women athletes with amenorrhea (30). These data along with the studies in mice indicate that leptin is likely to be the signal from adipose tissue that regulates the HPG axis in humans.
Data are just beginning to accumulate regarding leptin’s role in the regulation of puberty in humans. Several groups have performed cross-sectional evaluations of serum leptin concentrations in healthy children (31, 32, 33). Their data demonstrate that serum leptin levels increase with age in boys and girls until the onset of puberty. Another group has followed eight boys longitudinally through puberty and report that serum leptin levels rise 50% just before the onset of puberty and then decrease to approximately baseline concentrations as puberty progresses (34). A recent analysis in healthy girls has demonstrated an inverse correlation between rising serum leptin levels and the age of menarche (35). Taken together, these studies raise the possibility that the onset of puberty in humans is associated with sufficient, or threshold, serum leptin levels. Some researchers have even speculated that leptin is an important trigger for the initiation of puberty in boys and girls (33, 34, 36).
An extension of the hypothesis that leptin provides a trigger for the onset of puberty is that an alteration in leptin levels or leptin signal transduction could lead to precocious puberty in humans. In this study we report the comparison of serum leptin levels in 65 children with central precocious puberty (CPP) with those in healthy children.
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Subjects and Methods |
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The diagnosis of idiopathic central precocious puberty (IPP) was made based upon the onset of breast development and/or menses before 8 yr of age in girls or secondary sexual characteristics before 9 yr of age in boys associated with a pulsatile pattern of pituitary gonadotropin secretion and a pubertal response to exogenous GnRH in the absence of any identifiable adrenal, gonadal, or central nervous system pathology (37). Fifty girls and 3 boys who met these criteria were included in this study. The same criteria were used in the diagnosis of neurogenic central precocious puberty (NPP), except that these 5 girls and 7 boys had underlying neurological conditions that probably contributed to their pubertal dysregulation. NPP in the girls was associated with benign cysts and obstructive hydrocephalus (n = 2), William’s syndrome (n = 1), seizure disorder (n = 1), and history of neonatal hypoxia (n = 1). The underlying diagnoses in the boys with NPP were hypothalamic hamartoma (n = 4), neurofibromatosis type 1 (n = 1), seizure disorder (n = 1), and megencephaly (n = 1). Patients were excluded from analysis if they had additional conditions that might influence body composition and/or serum leptin concentrations. Leptin data from a subset of these patients have been reported previously (38).
Protocol
Informed consent was obtained from parents before the study. The protocol had been approved by the human research committee of each of the three participating institutions (Massachusetts General Hospital, Boston, MA; Children’s Hospital, Boston, MA; and Children’s Medical Center of the University of Virginia, Charlottesville, VA). Characterization of gonadotropin secretion was based upon LH and FSH serum levels during frequent blood sampling (every 10–20 min) during the night (2200–0200 h) and day (1000–1400 h) and after the iv administration of 2.5 µg/kg natural sequence GnRH. Standing height was measured in the morning at least 30 min after the patient’s rising using a wall-mounted stadiometer; the average of three replicates is reported. A left hand and wrist x-ray was obtained during the admission to monitor skeletal maturation. Leptin measurements in this report were performed in serum obtained during the children’s initial diagnostic evaluations before the initiation of therapy.
Methods
Serum leptin concentrations were measured by RIA using a commercially available kit (Linco Research, St. Charles, MO) with a sensitivity of 0.5 ng/mL, an intraassay coefficient of variation between 4.5–6.0%, and an interassay coefficient of variation between 6.1–8.5% in our laboratory. Serum leptin concentrations were measured in pools comprised of equal aliquots of every 20-min nighttime (2200–0200 h) and daytime (1000–1400 h) samples to permit investigation of the diurnal variation in leptin levels (30, 39, 40, 41) and to minimize the errors that arise when single measurements are employed to characterize a pulsatile pattern of secretion (41). LH, FSH, testosterone, and estradiol were measured using specific RIAs, as previously reported (42, 43). Bone age determinations were made using the Tanner-Whitehouse RUS (radius-ulnar-short) standards (44, 45, 46, 47).
In the only report to date that provides the basis for calculating
leptin SD scores for children and adolescents (32), serum
leptin levels were measured by a RIA that is now being used
commercially by Endocrine Sciences (Calabasas Hills, CA). To compare
accurately our leptin levels with those reported by Blum et
al. (32), we performed a cross-over study between the Linco and
Endocrine Sciences (ES) assays. Although the correlation between values
yielded by the two assays was extremely high, standards employed in the
Linco RIA (0.5–100 ng/mL) consistently read 25% lower when measured
in the ES system (linear regression equation: [leptin, ES] =
[leptin, Linco] x 0.76 - 0.6; r = 0.99;
P < 0.00001). A representative set of 31 patient
samples was also analyzed in both systems. After correcting for the
difference in the standards, the 2 assays generated very similar leptin
levels, with the slope of the line derived from the comparison among
the patient samples equaling 0.98 (r = 0.98;
P < 0.00001). Thus, when calculating the
SD scores used to compare our data with those of Blum
et al. (32), we adjusted the leptin concentrations assayed
in the Linco system accordingly. Sample volume did not permit the
measurement of leptin concentrations in each of our patients in both
systems. Comparison with other normative studies (31, 33, 35) that also
used the Linco assay system did not require adjustments of our data in
CPP patients (Table 2
).
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The Wilcoxon matched pairs (sign and rank) test for
nonparametric dependent variables was employed for the comparisons of
nighttime and daytime leptin concentrations. The generation of standard
curves for leptin vs. body mass index (BMI) at Tanner stages
3–4 (Fig. 1) and the calculation of
SD scores at Tanner stages 1–2 and 3–4 were based on the
equations provided by Blum et al. (32), who divided their
normative data into three groupings: Tanner stages 1–2, 3–4, and 5
for both boys and girls. We report SD scores for daytime
leptin values to permit comparison with most of the published data.
Statistical comparison of our leptin SD scores with the
normative data (32) was accomplished using the one sample t
test. Regression analyses and statistical tests were performed using
the Complete Statistical System: Statistica from StatSoft (Tulsa, OK).
All data are presented as the mean ± SEM; statistical
significance is attributed to P < 0.05.
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Results |
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The clinical characteristics of our patients with IPP and NPP are
summarized in Table 1. Leptin levels in
all patient groups correlated with BMI (girls: daytime values,
r = 0.78; nighttime values, r = 0.80;
P < 0.0001 for both; boys: daytime values,
r = 0.83; nighttime values, r = 0.86;
P < 0.01 for both). A slightly higher correlation
resulted from an exponential fit of the data (girls: daytime,
r = 0.81; boys: daytime, r = 0.90). The
diurnal pattern of leptin secretion (30, 39, 40, 41) was observed in our
patients, with nighttime serum leptin concentrations consistently
exceeding the daytime levels by 38% in the girls and by 22% in the
boys (P < 0.001 for the group overall).
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The IPP patients had lower daytime leptin levels than the girls
with NPP (mean, 10.6 ± 1.1 vs. 25.6 ± 7.1;
median, 7.8 vs. 14.8 ng/mL) at least in part because the NPP
cohort had greater BMIs. The combined data for our 55 girls with CPP
yielded a mean daytime serum leptin concentration of 11.9 ± 1.3
ng/mL and a median level of 8.5 ng/mL. To permit comparison of these
levels with normative data, the serum leptin concentration for each of
our female subjects is superimposed on standard curves generated per
Blum et al. for girls in Tanner stage 3–4 (32), after
correction for the difference between the assay systems (Fig. 1
; see
Materials and Methods). The mean SD scores for
serum leptin concentrations adjusting for BMI and pubertal stage were
+0.4 ± 0.1 (vs. Tanner stage 1–2) and +0.7 ±
0.2 (vs. Tanner stage 3–4) for the IPP patients and
+1.0 ± 0.5 (vs. Tanner stage 1–2) and +1.6 ±
0.6 (vs. Tanner stage 3–4) for the NPP patients (32). When
the data from the IPP and NPP girls were combined, the mean leptin
SD scores of the girls with CPP were +0.5 ± 0.1 and
+0.8 ± 0.2 compared to those of normal girls at Tanner stages
1–2 and 3–4, respectively (P < 0.002 for both). As
the mean BMI of our patient group was slightly higher than that of the
control population, we investigated whether our patients with higher
BMIs accounted for the increased mean SD score. The
opposite was true. The CPP girls with the lower BMIs contributed the
larger SD scores, such that the leptin SD score
was negatively correlated with BMI (Fig. 2; r = -0.33; P =
0.01).
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The normative data of Blum et al. (32) are the only values
that have been employed to date to generate leptin standards
conditional on sex, BMI, and pubertal stage, but several other large
cross-sectional studies have reported the serum leptin concentrations
in normal children and adolescents. Table 2 compares serum leptin levels in
patients with CPP with those from additional normative studies (31, 33, 35). The leptin levels in our girls with CPP modestly, but
consistently, exceeded these norms as well. The boys with CPP, on the
other hand, did not have elevated leptin levels compared with the other
normative datasets. The serum leptin concentrations reported in these
other studies (31, 33, 35) are often higher than those reported by Blum
et al. (32), probably in part because of the different
assays employed (see Materials and Methods).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The choice of an appropriate control group for children with CPP is a
difficult one. A comparison with mildly obese prepubertal children of
similar age and BMI is flawed because the majority of our patients are
not obese, although they are, on the average, taller and heavier than
age-matched peers. In addition, leptin levels have been shown to
increase as girls go through puberty but to decline as boys mature
(31, 32, 33). The significant reduction in leptin levels induced by
testosterone (38, 48); the small increase in leptin levels that has
been attributed to estrogen in some (49), but not other (38, 50)
studies; and hormonally induced changes in body composition all
probably play a role in this sexual dimorphism. These effects make the
comparison of leptin levels in our patients with prepubertal,
age-matched peers additionally problematic. The alternative control
group, older children who are at a similar stage of pubertal
development as our cohort, is problematic as well. Age has been
reported to be an independent variable that leads to increased leptin
levels in children (33), and young children with precocious puberty may
have different body composition and fat distribution than BMI-matched,
pubertal stage-matched young adolescents. Thus, we compared the serum
leptin levels in girls with CPP with previously reported levels in both
normal prepubertal and pubertal girls (31, 32, 33, 35). The normative data
presented by Blum et al. (32) permit the calculation of
SD scores for leptin conditional on pubertal stage and BMI.
The serum leptin concentrations in female subjects are elevated
compared with those in the Tanner stage 1–2 and 3–4 girls. While the
data from Blum et al. were derived from a large population
of 333 normal young girls and adolescents, we were concerned that
normative data in German subjects might not be applicable to children
from different cultures because population-specific differences in body
composition might be important. As shown in Table 2, the leptin levels
in our girls with CPP are also mildly elevated compared with those in
girls from England (31), Spain (33), and Columbus, OH (35), a total of
over 1000 healthy girls undergoing normal pubertal development.
In our analysis of male subjects, we compared results from our CPP boys to those from normal boys matched for pubertal stage but not to those from age-matched prepubertal boys because serum leptin levels have been shown to decrease sharply with the progression of puberty in boys. The serum leptin levels in the boys we studied are similar to the data reported by Blum et al. (32) and the levels published for English (31) and Spanish boys (33). Thus, our boys with CPP do not have elevated serum leptin levels compared with those in healthy boys undergoing normal pubertal develop-ment.
The dichotomy between the elevated serum leptin levels in the girls with CPP and the normal levels in the boys could have several explanations. CPP is more often idiopathic in girls, whereas an underlying central nervous system abnormality is the usual cause in boys. One could postulate that neurogenic NPP is less dependent on permissive leptin concentrations because the HPG axis may be activated independent of pathways modulated by leptin. This explanation does not seem applicable to our data. Our male and female patients with NPP have higher leptin levels than the patients with IPP. It is also possible that leptin plays a more pronounced role in modulating the HPG axis in girls than in boys. Teleologically, it makes sense that HPG axis function and reproductive competence might be more closely tied to indexes of fat and nutrition stores in females, who must bear children, than in males. Definitive testing of this hypothesis awaits further parallel studies in males and females. Many of the published studies have used only a single gender, as in the demonstration that leptin administration can accelerate puberty in female rodents (18, 19, 20) and the report that serum leptin concentrations do not seem to act as a trigger for the initiation of puberty in male monkeys (51).
We did not identify any patients with CPP who had such dramatically elevated serum leptin levels that a causal relationship between an elevated leptin level and CPP seemed likely. It remains possible, however, that rare patients with dramatic leptin abnormalities will be identified, as has occurred with obesity and congenital leptin deficiency (14). On the other hand, the negative correlation between the leptin SD score and BMI in girls with CPP is consistent with there being a relationship between a sufficient level of leptin and initiation of puberty in girls. The larger girls with CPP may be viewed as having achieved the threshold for puberty based upon leptin secretion appropriate for their body mass, whereas the attainment of the sufficient leptin levels in the smaller girls with CPP required higher than expected leptin secretion. This same conclusion is not as well supported for male puberty, as the inverse relationship between leptin SD score and BMI was not as robust in our boys with CPP.
Serum leptin levels in children with CPP represent important new information in a model that faithfully recapitulates normal sexual maturation. However, a more complete understanding of the role of leptin in the onset of puberty and the modulation of reproductive function in the human awaits further studies designed to probe the sexual dimorphism and developmental aspects of this physiology.
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Acknowledgments |
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Footnotes |
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Received December 15, 1997.
Revised March 24, 1998.
Accepted April 8, 1998.
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References |
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