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Original Studies |
Department of Pediatric Endocrinology (J.-C.C., J.-L.C.) and Laboratoire de Biochimie Hormonale (M.R., N.L.), and INSERM U-342 (J.-C.C., J.-L.C., M.R., N.L.), Hôpital Saint Vincent de Paul, 75014 Paris; and IPSEN-BIOTECH Laboratories (S.I., F.T., J.B.), 75014 Paris, France
Address all correspondence and requests for reprints to: Dr. Jean-Claude Carel, INSERM U-342, Hôpital Saint Vincent de Paul, 82 avenue Denfert Rochereau, 75014 Paris, France. E-mail: carel{at}cochin.inserm.fr
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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FH - height at the end of
treatment). The influence of the posttreatment growth spurt, itself
dependent on age and bone age at the interruption of treatment,
suggests that continuing treatment beyond the age of 11 yr in girls
does not improve and could actually decrease FH. This point should be
evaluated in a formal controlled trial. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Reported results of GnRH agonists on FH in CPP have been very variable, ranging from a complete restoration of growth prognosis to partial or absent benefit (6, 7, 8, 9, 10, 11, 12, 13, 14, 15). Several reasons might explain these discrepancies, in particular the heterogeneity of treated patients and the use of different GnRH agonists.
Although the criteria for the diagnosis of CPP and for the indication of treatment with GnRH agonists, have been widely discussed, the optimal age for interruption of these treatment has not been the focus of much attention. Recent textbooks recommend interrupting treatment "at an age acceptable for the onset of puberty" (16) or acknowledge that the "optimal time for discontinuation of therapy has yet to be determined" (17). This issue somewhat overlaps with the problem of the use of GnRH agonists in normal short children, as the decision to interrupt GnRH agonists in patients with CPP is made around the normal age of puberty. Although blocking puberty in short normal children transiently improves height prognosis, the results for FH are very disappointing (18), with the possible exception of patients treated for extended periods (19).
We report here FH results for 58 girls and 8 boys uniformly treated with triptorelin slow release formulation (Decapeptyl, triptorelin-SR) for CPP.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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All of the patients included in a French multicenter trial of triptorelin-SR in CPP that had been followed to FH (58 girls and 8 boys among 83 girls and 10 boys who participated in the study) were included in this study. Twenty-seven patients who participated in the French multicenter trial were not included in this analysis for the following reasons: onset of puberty after the age of 8 yr in girls or 10 yr in boys (n = 4), duration of treatment less than 2 yr (n = 4), and loss of follow-up (n = 17). Two girls with severe intrauterine growth retardation and FH of 148 and 142 cm were also excluded because their short stature was not due to CPP.
The principal characteristics of this trial were as follows.
Inclusion criteria. The inclusion criteria were onset of symptoms of precocious sexual development before the age of 8 yr in girls and 10 yr in boys, plasma testosterone levels greater than 0.5 ng/mL in boys, and pubertal response of LH to GnRH in both sexes (20).
Treatment. Triptorelin-SR (Decapeptyl, Ipsen-Biotech, Paris, France) was given im every 28 days at a dose of 3.75 mg in children weighing more than 20 kg and 1.87 mg in children weighing less than 20 kg as previously described (21). The efficacy of the treatment was assessed by the periodic evaluation of clinical pubertal development, measurement of plasma sex steroids, and LH response to GnRH. Treatment was given for at least 2 yr, and the decision to interrupt the treatment was left to the judgment of individual physicians following the patients and was mainly based on chronological age, bone age (BA), and height.
Follow-up. Patients were considered as having reached their FH if they had reached a BA of 15 yr in girls and 17 yr in boys (99% of FH by the Bayley-Pinneau method) or if their growth rate was inferior to 1 cm/yr, documented on at least two measurements 6 months apart. No correction was made to predict FH from BA at this stage.
Methods
BA was determined by the method of Greulich and Pyle (22). Height prognosis was calculated according to Bayley-Pinneau (23). French growth standards were used to calculate height SD score (24), and target height was calculated as the midparental height SD score. As hormonal measurements were not centralized and were performed at various centers with different methods, we cannot homogeneously present hormonal values, in particular gonadotropin levels (25). However, as each center had at each time point validated its method of gonadotropin measurement in prepubertal normal controls, every center could code the result of peak plasma LH response to GnRH test in one of three categories: type 1, peak LH value equal to or less than the median value observed in prepubertal children; type 2, peak LH value comprised between the median value of prepubertal children and the lower limit in pubertal children; and type 3, peak LH value superior to the lower limit in pubertal children.
Historical controls
Data on FH and age at onset of puberty of untreated children with CPP (58 girls and 25 boys) were collected from published reports of 24 girls and 13 boys (26), 8 girls and 4 boys (11), and 26 girls and 8 boys (27). Data from children treated with progestins for CPP at Hospital Saint Vincent de Paul were obtained (28 girls and 1 boy). Data from untreated and progestin-treated children were not statistically different and were combined. We also age-matched patients and controls on the basis of age at diagnosis of CPP. The pairs were selected to have an age difference of 0.5 yr or less, and when more than 1 patient was available for a pair, we randomly selected among them.
Statistical methods. Results are expressed as the mean
± SD. Analyses were performed with paired Student’s
t test (significance level, 
= 0.05, two-tailed),
Wilcoxon test, and Pearson correlation analysis. To determine the
determinants of FH, a stepwise multiple regression analysis was
performed. The predictors used in the final model were the parameters
showing a significant correlation with FH in the univariate analysis.
To evaluate the effect of qualitative predictors and to compare control
and treated patients, a variance analysis was also performed.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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)All patients had clinical criteria for true CPP, with an early onset of clinical symptoms of puberty, increased growth velocity, and advanced BA maturation. The peak LH value was coded as described in Subjects and Methods. In girls, 69% of the GnRH tests were considered indicative of an evolutive puberty, whereas 20% and 11% of the tests were intermediate or clearly prepubertal, indicating that some of the girls had been treated on the grounds of clinical symptoms rather than on the basis of GnRH test. In girls, there was a 1.2 ± 1-yr delay (range, 0–5) between the onset of clinical symptoms and the initiation of treatment. Fourteen girls and five boys had been treated with progestins before triptorelin-SR.
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and 3)As previously described (28), triptorelin-SR efficiently suppressed the gonadal axis, as illustrated by a suppressed LH response to GnRH. In girls, an average of 0.7 ± 0.3 GnRH test/yr was performed during treatment; 98% of these tests indicated gonadotropin suppression, whereas 1% were type 2 (intermediate) and 0.7% were type 3 (no suppression). In boys, an average of 0.6 ± 0.2 GnRH test/yr was performed during treatment; 95% of these tests indicated gonadotropin suppression, and 5% were type 2. Under further follow-up, GnRH tests indicated adequate suppression in these patients, suggesting that poor compliance was the explanation for incomplete suppression.
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). Treatment was interrupted at 11.2 ± 1.0 yr in girls with very wide variations, as no precise guidelines had been given to individual physicians participating in the study. After interruption of the treatment, clinical pubertal development resumed in all cases and was biologically confirmed by a GnRH test in most patients as previously described (29). Girls grew 11.1 ± 4.7 cm after interruption of the treatment, whereas boys grew 9.9 ± 3.3 cm, resulting in FH of 161.1 ± 5.9 and 172.8 ± 6.4 cm, respectively.
Improvement of FH after triptorelin-SR treatment (Table 3)
The FH of treated patients was similar to the midparental height SD score. In girls, FH exceeded height predicted before treatment by 4.8 ± 5.8 cm, with wide variations (-7.7 to +19.1 cm; P < 0.001). There was a small decrease in FH compared to predicted height at the end of treatment (-1.2 ± 3.8 cm; range, -12.5 to +6.0; P < 0.03). In contrast, in boys, predicted height before treatment was similar to target height and to the achieved FH.
As height benefit and more generally the use of GnRH agonists are
discussed in girls presenting with CPP after 6 or 7 yr of age, we
analyzed FH gain (i.e. the difference between predicted and
actual FH) in girls with first signs of puberty occurring before
(n = 16) or after (n = 42) 6 yr of age. FH gain was 5.3
± 7.2 cm in younger and 4.5 ± 5.3 cm in older girls
(P < 0.02 and P < 0.001,
respectively, predicted vs. FH, by Wilcoxon test;
P = NS, younger vs. older girls). No
correlation was found between FH gain and age at onset of puberty (Fig. 1) or age at initiation of treatment.
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).
At the time of diagnosis, patients in the treated group were older than
those in the control group. Variance analysis, after adjustment for the
age at diagnosis, indicated a positive effect of triptorelin-SR
treatment on FH. The FH difference between treated patients and
controls, after adjustment for age at diagnosis, was 8.3 cm in girls
and 13.7 cm in boys. To further ascertain that the difference in FH
between patients and controls was not due to the age difference between
the two groups, the comparison was made between age-matched pairs of
treated and untreated patients, as described in Subjects and
Methods. In the 39 pairs of girls (age difference, 0.02 ±
0.1 yr), the FH difference was 8.9 ± 8.7 cm (P <
0.0001, by Wilcoxon test). The FH difference between the treated and
control girl was 5 cm or more in 64% (25 of 39) of pairs. In the 7
pairs of boys, the FH difference was 12.9 ± 8.1 cm
(P < 0.02, by Wilcoxon test), with an age difference
of 0.2 ± 0.4 yr (P = NS). The FH difference
between the treated and control boys was 5 cm or more in 86% (6 of 7)
of pairs. Factors predicting FH in triptorelin-SR-treated girls
Factors affecting FH were analyzed in treated girls only, because
the small number of boys did not allow such an analysis. Predictors in
the univariate analysis (Table 4) were
used to construct a multivariate model (Table 5). Three explanatory variables were
found that could explain 66% of the variance of FH, one of them
descriptive of the initial characteristics of the patients and two
related to interruption of treatment. The BA/statural age ratio was a
negative predictor, indicating that severe initial characteristics had
a detrimental effect, not completely reversed by the treatment. The
height SD score at the end of treatment was positively
associated with outcome, whereas the effect of target height or height
before treatment disappeared in the multivariate analysis.
Unexpectedly, height gain after interruption of the treatment
(averaging 11 cm) was a predictor of FH with a slope of 0.54,
indicating that a 1-cm difference in posttreatment growth accounted for
a difference of 0.54 cm in FH when the other predictors were held
constant.
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). Age and BA at the end of treatment
were independently and negatively associated with height gain after
treatment.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The magnitude of height benefit induced by gonadotropin suppression in CPP has been widely discussed, mainly due to methodological problems. First, patients treated for CPP are heterogeneous in terms of age of onset, progression of pubertal development, and other factors influencing statural growth. Second, indirect methods are used, by us and others, to evaluate the height benefit: comparison with height predicted by the Bayley-Pinneau method or with historical patients. A few reports have evaluated the accuracy of prediction in untreated girls with CPP and indicate that the Bayley-Pinneau method overestimates FH by 4.2 cm (SD = 4.4 cm) (30), 3.7 cm (9), or 5.9 cm (14). Several studies have reported an increased FH in GnRH agonist-treated girls, measured as the difference between predicted and attained height (6, 7, 8, 9, 10, 11, 12, 13, 14, 15). However, the outcomes were variable, with results ranging from 1 cm (12) to 10 cm in younger children at diagnosis (11). Our results in a large group of children (+4.8 ± 5.8 cm) fall in the average of recently published series of patients (3–6 cm). Several factors can explain the discrepancies between these studies, including the use of daily forms of GnRH agonists in some reports, treatment of patients with long standing disease in older reports, and heterogeneity of treated patients. One important and unsolved question is whether treatment with GnRH agonists has beneficial effects on height in girls with pubertal onset after the age of 6 or 7 yr, the age of pubertal development in a significant proportion of girls of the general population (31). The analysis of the subgroup of 42 patients with onset of puberty between the ages of 6–8 yr shows a significant 4.5 ± 5.3 cm increase in FH over predicted height. In addition, no statistical association was found between age at onset of puberty or at initiation of treatment and FH gain or FH itself, suggesting that girls with late onset CPP benefited from GnRH agonist treatment similarly to girls with earlier pubertal onset.
The other method for estimating height benefit, i.e. the comparison with an historical control group, revealed an 8.3-cm increase in FH after adjustment for the age at diagnosis and a similar difference after age matching patients and controls. This result is consistent with those of Paul et al. (11), who found a difference between treated patients and historical controls of 14.1 and 4.2 cm in patients with onset of puberty before and after the age of 5 yr, respectively. Altogether, if we take into account the probable overestimation of height prognosis in the absence of treatment, the true benefit in a group of patients such as ours is probably in the range of 8–10 cm.
The availability of FH in a large group of treated girls allowed the analysis of factors associated with end results. We elected to use as the end point variable FH itself rather than the difference from predicted height because it avoids the error associated with prediction methods and because BA, a major determinant of height prognosis, could be analyzed as an independent variable. One variable descriptive of the patients at the onset of treatment and two variables relevant to the interruption of treatment explained 66% of the variance in FH. The negative association of BA/statural age at the onset of treatment emphasizes the fact that GnRH agonist treatment is not capable of restoring a full FH potential if started after an irreversible advancement of BA. Indeed, the slope of -16 indicated that a variation in this ratio of 0.1 altered FH by 1.6 cm. The second variable, height SD score at the end of treatment, is the most difficult to integrate, because it results from genetic height potential, the accelerating effect of CPP, and the decelerating effect of GnRH agonist treatment. Its slope (-1.82) indicates that a difference of 1 SD at interruption of treatment (roughly 5 cm) accounted for a 1.8-cm difference in FH. The last predictive variable, the amplitude of the growth spurt after the end of treatment, is of major interest because it is dependent on the time point selected for interrupting the treatment. This lead us to analyze separately the determinants of posttreatment growth; BA and age at interruption of treatment were negative independent predictors, indicating that discontinuing the treatment late had a negative effect directly and through BA advancement. This finding is reminiscent of the model proposed by Bourguignon in sex steroid-treated patients with hypopituitarism (32). Similarly, we found that interruption of puberty with GnRH agonists in girls with short stature and a normal timing of puberty has a limited effect, indicating that increasing prepubertal growth induces an equivalent decrease in pubertal growth (18). Although much emphasis has been put on the criteria for initiation of GnRH agonist treatment (3), determining the optimal time point for interruption of treatment has not received much attention. In a published series of patients, the mean age at interruption of treatment ranged from 10.6–11.3 yr (9, 10, 12, 13, 14, 15). In our patients, the age at interruption of treatment was similar (11.2 ± 1 yr), but the dispersion was somewhat wider. To put things into perspective, it can be derived from our data that an 11-yr-old girl, growing 4 cm and gaining 0.5 BA yr in a year, will lose 2.5 cm of FH if treatment is discontinued 1 yr later (combined effects of age, BA, and decreased height SD score). Therefore, until this point is evaluated through formal trials, we recommend stopping GnRH agonist treatment no later than 11 yr of age in girls.
The small number of boys did not allow a thorough analysis of the variables associated with the effect of treatment, as in other studies (7, 11, 13, 15). Initial height prognosis was not impaired compared with target height in our patients as well as in those reported by Oostdijk et al. (13) due to a moderate increment in BA. This should be regarded with caution due to the lack of data on the accuracy of height prediction in boys with CPP and to the markedly decreased FH in untreated boys. In consequence, only the comparison with historical controls indicated a FH benefit in boys.
In conclusion, our data confirm the restoration of genetic target height or a 5- to 10-cm increase in FH in girls treated with triptorelin-SR for CPP. We highlight a specific point of important practical and economical consequences, i.e. the optimal time for interrupting GnRH agonist treatments with respect to the improvement of FH. Although this point should certainly be better evaluated in a formal controlled trial, our results suggest that continuing GnRH agonists beyond the age of 11 yr in girls does not improve and could actually decrease FH by reducing the posttreatment growth spurt.
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Acknowledgments |
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Footnotes |
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Received September 1, 1998.
Revised January 8, 1999.
Accepted March 15, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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