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From the Clinical Research Centers |
Divisions of Endocrinology (M.R.P., J.F.C.) and Adolescent Medicine (M.J.M.), Department of Medicine, Children’s Hospital, 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; the Reproductive Endocrine Unit (W.F.C., P.A.B.) and the Pediatric Endocrine Unit (J.D.C., P.A.B.), Massachusetts General Hospital, 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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Before the initiation of therapy (PRE), the girls with CPP had a mean BMI SD score for chronological age (CA) of 1.1 ± 0.1 and for bone age (BA) of 0.1 ± 0.1. By the end of the study, 12–24 months after the discontinuation of GnRHa, the mean BMI SD score was 0.9 ± 0.1 for CA and 0.6 ± 0.1 for BA. At the visit when GnRHa was discontinued, 41% and 22% of the girls had a BMI SD score for CA more than the 85th and 95th percentiles, respectively, indicating that obesity was present at a high rate among our subjects; the BMI SD score for CA at the PRE visit was its strongest predictor. Indeed, 86% of the girls with BMI SD score for CA above the 85th percentile when GnRHa was discontinued also had BMI SD score for CA above the 85th percentile at the PRE visit.
The proportion of boys with elevated BMI SD score for CA was also high. Fifty-four percent and 31% of the SD scores were greater than the 85th and 95th percentiles after 36 months of GnRHa therapy; the BMI SD score for CA PRE had been above the 85th percentile in 71% of these overweight subjects.
Obesity occurs at a high rate among children with CPP, but does not appear to be related to long term pituitary-gonadal suppression induced by GnRHa administration. Children with CPP should have a baseline BMI SD score calculated, and those at risk for obesity should be counseled appropriately.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The longitudinal analysis of body composition before, during, and after GnRHa administration provides a unique opportunity to dissect the physiological regulation of growth during the selective, reversible suppression of gonadal sex steroids (12, 16, 17, 18, 19, 20). The analysis also provides an opportunity to address the frequently raised clinical concern that children with CPP have a predilection for the development of obesity during GnRHa therapy (15). Here we report longitudinal height, weight, and BMI data from up to 16 yr of follow-up in 96 girls and 14 boys before, during, and after GnRHa administration. In subsets of these subjects, skinfold thickness and percent body fat by dual energy x-ray absorptiometry (DXA) were determined for more accurate assessment of body composition. Adrenarche and other clinical variables were assessed for their impact on growth and changes in body composition.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The diagnosis of CPP 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 or gonadal pathology (21). GnRHa administration was begun after an initial evaluation. Subjects were included in the study if 1) suppression of pituitary gonadotropin and gonadal sex steroid secretion had been uniform throughout the period of GnRHa administration, and 2) compliance with the GnRHa regimen was deemed adequate, as judged by parental report and record of medication administration. Pituitary-gonadal suppression during GnRHa administration was judged to be adequate if 1) peak LH and FSH levels after challenge with natural sequence GnRH were below 5 mIU/mL Second International Reference Preparation of human menopausal gonadotropin, and 2) either serum estradiol values were below RIA sensitivity (20 pg/mL) in girls or serum testosterone values were less than 50 ng/dL in boys. The hormonal characteristics of cohorts meeting these criteria have been published previously (4, 17, 19, 21, 22, 23). In this cohort, administration of exogenous GnRH to the girls with CPP resulted in mean peak LH and FSH values of 112.5 ± 9.4 and 31.8 ± 3.7 IU/L, respectively, before the initiation of GnRHa therapy (PRE) and values of 1.7 ± 0.1 and 2.9 ± 0.2 IU/L at the visit when GnRHa was discontinued (D/C). The boys had mean stimulated LH and FSH values of 81.5 ± 20.1 and 15.1 ± 5.1 IU/L, respectively, at the PRE visit and 1.6 ± 0.2 and 1.6 ± 0.2 IU/L at the D/C visit.
Ninety-six girls and 14 boys met the study criteria and are included in the present study. CPP was idiopathic in all of the girls and 5 of the boys. Eight of the boys had neurogenic CPP in association with hypothalamic hamartoma (n = 6), seizure disorder (n = 1), and megencephaly (n = 1); one of the boys had CPP that developed after treatment of a testicular tumor. Subjects were excluded from analysis if they had any additional conditions that might influence changes in body composition (e.g. GH deficiency, congenital adrenal hyperplasia, or primary hypothyroidism).
Protocol
The protocol was approved by the human research committee of each of the three participating institutions (Massachusetts General Hospital, Boston MA; Children’s Hospital, Boston MA; Children’s Medical Center of the University of Virginia, Charlottesville VA). Informed consent was obtained from parents before the enrollment of each subject in the study. Subjects were evaluated in their appropriate General Clinical Research Centers before, at 3- to 6-month intervals during, and at 6- to 12-month intervals after GnRHa administration. Each subject received daily sc injections of GnRHa, using either deslorelin ([D-Trp6,Pro9-ethylamide]GnRH; 4–8 mg/kg·day) or histrelin ([imBzl-D-His6,Pro9-ethylamide]GnRH; 10 mg/kg·day). During each inpatient evaluation, confirmation of either active, pubertal gonadotropin secretion (before and after discontinuation of GnRHa), or pituitary desensitization (during GnRHa administration) 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. Single serum samples were obtained for the measurement of estradiol, dehydroepiandrosterone sulfate (DHEAS), and testosterone. Standing height was measured in the morning at least 30 min after the subject’s rising using a wall-mounted stadiometer; the average of three replicates is reported. A left hand and wrist x-ray was obtained during each admission to monitor skeletal maturation. A subset of subjects underwent measurement of triceps skinfold thickness and/or DXA to assess body composition.
Methods
LH, FSH, estradiol, testosterone, and DHEAS were measured using
specific RIAs as previously reported (24, 25, 26). Bone age (BA)
determinations were made using the Tanner-Whitehouse radius-ulnar-short
standards (22, 27). Skinfold thickness was measured as described by
Tanner and Whitehouse (28). Total body DXA analysis (29) was performed
using a QDR-2000 instrument (Hologic, Inc., Waltham, MA).
The SD scores for height, weight, and BMI were calculated
using United States reference data from the second National Health and
Nutrition Examination Survey (30); skinfold standards were taken from
the same source. Because United States weight and BMI standard curves
display significant upward skewness (31, 32) and are non-Gaussian (see
Figs. 1–3
), the calculation of SD for weight and BMI was
performed using separate distributions for data above and below the
median. The method described by Dibley et al. (31) was used
for calculation of the SD score. The
SD used in the calculation of the
SD score for data above the median were derived
from smoothed, fourth order equations describing the 95th percentile
normative weight and BMI data, whereas the SD for
data below the median were based upon data from the 5th
percentiles.
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The paired comparison of data from the pretherapy visit (PRE)
with those from the visit after 36 months of therapy (36 ON) was chosen
to select a cohort who had all received GnRHa long enough so that its
effects on growth and body composition would be evident but who also
represented a spectrum of CA and BA at the PRE visit. A second
comparison was made among subjects for whom data were available from
the visit at which GnRHa administration was discontinued (D/C; after a
mean of 4.5 ± 0.2; range, 1.5–10.0 yr) and a follow-up visit 12
or 24 months later (OFF). The Wilcoxon matched pairs (sign and rank)
test for nonparametric dependent variables was employed for the paired
comparisons of weight, height, and BMI SD score.
Statistical comparison of SD score with the normative data
(30) was accomplished using one-sample nonparametric tests. Multiple
regression was performed in both standard and forward stepwise manners
with similar results. Four separate analyses were performed; the
dependent variables were BMI SD score for CA at the D/C and
OFF visits as well as BMI SD score for BA at the D/C visit
and OFF visits. CA and BA at initiation of therapy, age of thelarche,
duration of therapy, initial BMI SD score for CA and BA,
and serum DHEAS concentration before and at the discontinuation of
therapy were the independent variables. The above statistical tests and
linear regressions (skinfold thickness vs. BMI and percent
body fat vs. BMI) were performed using the Complete
Statistical System: Statistica from StatSoft, Inc. (Tulsa, OK). The
fourth order smoothed equations for the 95th and 5th percentile
normative data were generated using SigmaPlot from SPSS, Inc. (Chicago, IL). All data are presented as the mean ±
SEM, except in Fig. 6, where
SD are displayed for comparison with the
published normative data. Statistical significance was attributed to
P < 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. In some subjects,
rates of both linear growth and weight gain slowed when gonadal
steroids were suppressed, such that the indexes of body composition
remained well within the normal range for age during long term therapy
(Fig. 1, A–C). In other subjects, the decline in height velocity
associated with the initiation of GnRHa administration was accompanied
by continued exuberant weight gain, such that obesity became an
increasing concern (Fig. 1D). Of the girls with data available from
both PRE and D/C visits, the weight SD score for CA
declined in 41 and increased in 6 [absolute change (
), 
0.5]. Of
the 40 girls whose weight SD score changed little (absolute
, <0.5), 6 began therapy with a weight SD score of +2.0
or more. The weight gain required to maintain a weight SD
score of +2.0 or more during the course of therapy was substantial.
Group data presented in Figs. 2-4
and Table 1 reveal that the girls with
CPP are initially heavier and taller than CA-matched peers, although
their weights and, to a greater degree, their heights are below
BA-matched control values. Their BMI SD scores are
initially elevated for CA, but are appropriate for BA. After
suppression of gonadal sex steroids, the rates of linear growth and
skeletal maturation slowed, such that height SD score for
CA decreased, and height SD score for BA increased, both
moving toward the population mean. Rates of weight gain during and
after GnRHa administration were such that weight and BMI SD
score for CA decreased slightly and then plateaued, whereas weight and
BMI SD score for BA gradually increased. By the end of the
study, weight SD score for CA and BMI SD score
for both CA and BA were significantly elevated compared with those in
the reference population (30). Thus, the girls with CPP began and ended
the study with weight and BMI SD scores that were
significantly above the mean for CA-matched peers.
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and Table 1. Their height,
weight, and BMI SD scores for CA and BA displayed a similar
pattern as that in the girls at the initiation of therapy and after 36
months of GnRHa administration (36ON). Further conclusions about the
observed changes in weight and BMI SD scores are not
possible from our data because the heavier boys
disproportionally dropped out of the study as it progressed from 36ON
to D/C.
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for examples). One data
point from each subject on and/or off of GnRHa therapy was used to
determine the correlation between BMI and triceps skinfold thickness
within our population. This relationship was linear and highly
significant (P < 0.00001; r = 0.79). The serial
BMI and skinfold data were in good agreement, as shown in Fig. 1.
Moreover, the plot (Fig. 5) of the
skinfold thickness measurements in our subjects vs.
population norms (30) demonstrates a distribution of data points
similar to that seen in the BMI graphs (Fig. 3) and the
SD scores (Fig. 4 and Table 1).
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. The DXA analysis is in accord with the
skinfold data and provides further evidence that the BMI
SD score is a good measure of fatness in our
female subjects. Neither skinfold nor DXA data were available for the
boys with CPP.
Multiple regression analysis indicated that the BMI SD
score for CA at the PRE visit is the greatest predictor of BMI
SD score for CA at the D/C (Table 2) and OFF (data not shown) visits.
The duration of therapy also contributed modestly to the prediction of
BMI SD score at D/C, with shorter treatment periods being
associated with greater BMI SD scores. The relationship
between initial BMI SD score and duration of therapy is
revealed in the individual growth patterns depicted in Fig. 1. The
patient who began GnRHa therapy at less than 2 yr of age maintained
CA-appropriate values for BMI during and after more than 8 yr of
pituitary-gonadal suppression. In contrast, the girl who was already
obese at the initiation of therapy at age 7.9 yr (BA, 12.6 yr)
exhibited a dramatic increase in BMI during and after a much shorter
treatment period. The mean DHEAS levels (50.8 ± 4.9 and
129.3 ± 9.6 µg/dL at the PRE and D/C visits, respectively) were
appropriate for CA (40), but had no statistical correlation with the
BMI SD score for CA at D/C. The age of thelarche (4.2
± 0.3 yr) did not contribute significantly to the multiple regression
model.
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. Calculation of the percentage of girls
with CPP who have BMIs above the 85th and 95th percentiles for CA
provides an assessment of the rate of obesity among these subjects (41, 42). These data were compared among the girls with CPP at the PRE and
D/C visits and among the boys at the PRE and 36ON visits. The findings
indicate that a high proportion of the female and male subjects with
CPP is significantly overweight at each time point. Moreover, most of
the subjects with a BMI greater than the 85th percentile at the 36ON or
D/C visits had also been overweight at the PRE visit, and most of the
subjects with a BMI greater than the 85th percentile at the PRE visit
were overweight at the later time point. Fewer girls (n = 69) were
available for evaluation at the OFF visit, but an elevated BMI at the
PRE visit was similarly predictive of an elevated BMI at the last
visit.
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). The percentage of
girls with a BMI greater than the 85th and 95th percentiles for BA
increased from 14% and 5%, respectively, at the PRE visit to 22% and
9% at the D/C visit and 29% and 16% at the OFF visit (see Fig. 3).
In multiple regression analysis, the BMI SD score for CA at
the PRE visit was the strongest predictor of BMI SD score
for BA at the D/C visit. |
Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Although young children with CPP may not be viewed as obese at the initiation of GnRHa therapy, many of them have significantly elevated BMIs for CA. BMI is an index of body fatness that is relatively independent of height in children undergoing normal pubertal development (33). How much the early exposure to gonadal sex steroids that occurs in children with CPP changes the physiological meaning of a BMI for CA is unclear; certainly, these children are taller and heavier than their CA-matched peers, which may impact their BMI SD scores. The elevated BMI SD score for CA is not, however, the only data that suggest that these children have increased body fat. Measurement of skinfold thickness and percent body fat by DXA provided corroborative information, and the initial BMI SD score for CA was identified as the strongest predictor of BMI SD score for CA at subsequent visits. These data suggest that the initial BMI SD score for CA has clinical (and perhaps physiological) significance in children with CPP.
In children undergoing normal physical development, the BMI curve
increases in the first year of life, then decreases until about age 6
yr, when it rebounds and subsequently increases into adulthood. Because
of this pattern, a 6-yr-old child who has an elevated BMI
SD score may appear to be of normal weight or only slightly
overweight, and concerns about obesity are often not raised in this age
group (33). One should be concerned about the risk of obesity in this
age group, however, as it is known that an early adiposity rebound (or
earlier rise in BMI) is predictive of the development of obesity when
the child is older (33). Moreover, as the normative data for weight and
BMI exhibit a significant upward skew during late childhood and
adolescence (see
Figs. 1–3 for the normal curves), an individual can
track along the same percentile on the weight or BMI curve while
experiencing a continual increase in the absolute magnitude of the
difference between the population mean and the individual’s weight or
BMI. These factors make it important to identify those children with
elevated weight or BMI SD score early in childhood because
they are at risk of becoming markedly obese during later childhood and
adolescence (33, 38). This same tenet may well apply to children with
CPP.
Approximately 50% of our subjects met criteria for being significantly overweight at the beginning of GnRHa treatment (41, 42), and a similar percentage had BMIs that were greater than the 85th percentile at subsequent time points. Multiple regression analysis revealed that the PRE BMI SD score for CA was the most significant determinant of BMI SD score for CA at the D/C visit, and a BMI greater than the 85th percentile at the PRE visit was predictive of a BMI greater the 85th percentile at the D/C visit. Thus, the administration of GnRHa did not seem to influence the progression of these children toward obesity in the adolescent age range.
Other groups have also studied the changes in body composition during GnRHa administration, although with fewer subjects and without focusing on the development of obesity among children with CPP. The recent analysis by Feuillan et al. (15) reports data consistent with our findings. At the start of GnRHa therapy, patients with idiopathic precocious puberty and those with precocious puberty due to hypothalamic hamartoma had elevated mean BMI SD scores for CA (1.6 and 1.2, respectively). Subsequently, the BMI SD score did not change significantly through the course of GnRHa therapy or after its discontinuation, and several of their patients were noted to be obese. Oostidijk et al. (9) also reported elevated, but stable, BMI SD score for CA at the start of, end of, and after treatment with GnRHa. As was seen in our study, they report an increase in the BMI SD score for BA at the end of and after GnRHa administration in their 31 subjects with a mixture of idiopathic and neurogenic precocious puberty.
Boot et al. have recently published the results of a longitudinal study of body composition determined by DXA analysis before and during treatment with GnRHa (14). Their findings in girls with CPP and early puberty differ from other data, in that fat mass, percent body fat, and BMI SD score for CA all increased during the course of GnRHa administration. The subjects studied by this group also differ from the other studies in that 7 of the 32 girls had onset of puberty after age 8 yr. It would be interesting to know whether these older subjects experienced shorter treatment periods, because the duration of therapy is inversely related to the BMI SD score for CA in our data. In aggregate, however, the available data indicate that the mean BMI SD score for CA for a population of children with CPP does not change significantly during GnRHa administration, although some individuals may experience significant increases and decreases during the course of therapy.
The reason why so many of our subjects with CPP have BMI SD scores above the 85th percentile for CA is unclear. We do not have data regarding the parental weights of our subjects, but certainly the risk of being overweight is much increased in the children of obese adults (43). It will also be important to determine in future studies whether the subjects with CPP had elevated BMI SD scores before the onset of precocious pubertal development or only after exposure to a pubertal gonadal steroid milieu. This is an interesting consideration given data indicating that sufficient amounts of leptin are required for the initiation of puberty (reviewed in Ref. 44) and that mild obesity is associated with earlier menarche in American girls (45). Indeed, although elevated serum leptin concentrations have not been shown to cause precocious pubertal development in humans, we reported that CPP occurs in the setting of pubertal stage-appropriate (and hence sufficient) leptin levels (46).
In our cohort, the diminution of sex steroid and GH production that accompanies GnRHa administration (4, 47, 48, 49, 50) and the increased DHEAS levels seen with adrenarche did not have statistically evident impacts on mean BMI SD score for CA. However, more precise measures of lean and fat mass and an increased number of serial observations at shorter intervals are needed to assess fully the impact of alterations in gonadal and adrenal steroids on body composition (51, 52). Such analysis may be confounded by the diminished GH secretion that follows GnRHa administration, which may favor the maintenance of body fat and elevated BMI SD scores (53, 54).
Children with CPP develop obesity at a high rate. Practitioners caring for these children can be reassured that the obesity appears to be unrelated to GnRHa administration. However, many patients with CPP have elevated BMIs at the initiation of therapy, and tracking of BMI data has been shown to predict the subsequent risk of obesity (33, 38). Thus, we believe that children with CPP should have a baseline BMI SD score (or percentile) calculated for CA, and those at risk for obesity should be counseled accordingly to try to prevent the development of adolescent obesity and its attendant health risks (38, 55).
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Acknowledgments |
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Footnotes |
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Received June 25, 1999.
Revised September 17, 1999.
Accepted September 17, 1999.
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References |
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, midparental height (MPH).
