This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brito, V. N. Articles by Mendonca, B. B. Search for Related Content PubMed PubMed Citation Articles by Brito, V. N. Articles by Mendonca, B. B. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB LEUPROLIDE Related Collections Neuroendocrinology and Pituitary Pediatric Endocrinology Female Endocrinology

Factors Determining Normal Adult Height in Girls with Gonadotropin-Dependent Precocious Puberty Treated with Depot Gonadotropin-Releasing Hormone Analogs

Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo e Unidade de Endocrinologia do Desenvolvimento e Laboratório de Hormônios e Genética Molecular LIM/42 do Hospital das Clínicas, 05403 900, São Paulo, Brasil

Address all correspondence and requests for reprints to: Vinicius N. Brito, M.D., Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Disciplina de Endocrinologia e Metabologia. Av. Dr. Eneas de Carvalho Aguiar, 155 2°andar Bloco 6, 05403 900, São Paulo, SP, Brasil. E-mail: vinbrito{at}uol.com.br and beremen{at}usp.br.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: Several factors can affect adult height (AH) of patients with gonadotropin-dependent precocious puberty (GDPP) treated with depot GnRH analogs.

Objective: Our objective was to determine factors influencing AH in patients with GDPP treated with depot GnRH analogs.

Patients: A total of 54 patients (45 girls) with GDPP treated with depot GnRH analog who reached AH was included in the study.

Design: Univariate and multivariate analyses of the factors potentially associated with AH were performed in all girls with GDPP. In addition, clinical features of the girls who attained target height (TH) range were compared with those who did not. Predicted height using Bayley and Pinneau tables was compared with attained AH.

Results: In girls the mean AH was 155.3 ± 6.9 cm (–1.2 ± 1 SD) with TH range achieved by 81% of this group. Multiple regression analysis revealed that the interval between chronological age at onset of puberty and at the start of GnRH analog therapy, height SD scores (SDSs) at the start and end of therapy, and TH explained 74% of AH variance. The predicted height at interruption of GnRH therapy, obtained from Bayley and Pinneau tables for average bone age, was more accurate than for advanced bone age in both sexes. In boys the mean AH was 170.6 ± 9.2 cm (–1 ± 1.3 SDS), whereas TH was achieved by 89% of this group.

Conclusions: The major factors determining normal AH in girls with GDPP treated with depot GnRH analogs were shorter interval between the onset of puberty and start of therapy, higher height SDS at the start and end of therapy, and TH. Therefore, prompt depot GnRH analog therapy in properly selected patients with GDPP is critical to obtain normal AH.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
Gonadotropin-dependent precocious puberty (GDPP) results in the premature development of secondary sexual characteristics and accelerated bone maturation leading to premature fusion of the growth plates with consequent impairment of adult height (AH) (1, 2, 3). One of the goals of long-term treatment with depot GnRH analogs in patients affected by GDPP is to achieve normal AH.

Several factors can influence AH in patients with GDPP treated with GnRH analogs (2, 3, 4, 5, 6, 7). Advanced chronological and bone ages (CAs and BAs, respectively) at the start and end of GnRH analog therapy, delay in beginning treatment, lower height at the end of therapy, shorter statural growth after interruption of therapy, shorter GnRH analog treatment time, slow growth velocity during treatment, and low predicted height (PH) have all been pointed out as negative factors affecting attainment of AH. Besides these factors, target height (TH), which reflects the genetic influence on AH, represented a very well-known factor influencing AH in all cohorts (2, 3, 4, 5, 6, 7).

Predicted AH using the Bayley and Pinneau (BP) method is a frequent tool applied in the management of patients with GDPP (3). This method estimates AH as a percentage of current height, based on BA and its relationship to CA (8). However, the Bayley the Pinneau method was originally determined in normal children, and its accuracy in patients with GDPP, whose BAs are usually advanced, is debatable (8, 9, 10, 11).

In general, patients with GDPP treated with depot GnRH analogs reach their TH range, although a subset of patients fails to do so (3, 12). The aims of this study were to: 1) estimate the accuracy of PH of patients with GDPP using BP tables, 2) determine factors influencing AH, and 3) compare clinical features of girls with GDPP treated uniformly with GnRH analogs who reached their TH range against those who did not.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
This study was approved by the Ethics Committee of Hospital das Clinicas, Sao Paulo, Brazil, although formal submission was considered unnecessary in view of the methodology, i.e. a retrospective audit of clinical practice. From a total of 78 Brazilian patients with GDPP who were referred to the Developmental Endocrinology Unit of the Hospital das Clínicas at Sao Paulo University from 1991–2002, we selected the medical files of the 54 consecutive patients (45 girls and nine boys) who had reached AH after having been treated exclusively with depot GnRH analog. Among the 45 girls with GDPP, 41 were diagnosed as the idiopathic form, three had hypothalamic hamartomas, and one had a cerebellar glioma associated with neurofibromatosis. Among the nine boys with GDPP, six had hypothalamic hamartomas, one had the idiopathic form, one had a pilocytic glioma, and one developed GDPP as a consequence of previous exogenous androgen exposure. The remaining 24 of the 78 patients (31%) with the diagnosis of GDPP who fulfilled the same clinical and hormonal criteria for treatment were excluded from the analysis for different reasons: 14 did not finish the treatment; seven patients were lost in follow-up; and, finally, three (one boy and two girls) presented injection-site granuloma resulting in replacement of depot GnRH analog by cyproterone acetate or medroxyprogesterone.

The diagnosis of GDPP was based on the development of secondary sexual characteristics before the age of 8 yr in girls and 9 yr in boys (1). Pubertal stage for breast development in girls and testicular volume in boys were classified according to the Marshall and Tanner criteria (13, 14). Height was measured with a stadiometer and expressed as SD scores (SDSs) compared with British reference tables (15). We also assessed body mass index (BMI) and BMI SDSs before and after GnRH analog therapy (16). Girls with BMI above the 85th and 95th percentiles for their CAs were diagnosed as overweight or obese, respectively. Basal and GnRH-stimulated gonadotropin levels, basal testosterone or estradiol levels were measured by RIA up to 1991, or by immunofluorometric assay (IFMA) after this period. For RIA, LH peaks after GnRH (100 µg gonadorelin iv) more than 15 U/liter in girls and more than 25 U/liter in boys were considered pubertal responses (17, 18). For IFMA, basal LH more than 0.6 U/liter was considered a pubertal level in both sexes, and GnRH-stimulated LH peaks more than 6.9 U/liter in girls and more than 9.6 U/liter in boys were considered pubertal responses (18).

Serum testosterone and estradiol concentrations were measured by commercial solid-phase fluoroimmunoassay (AutoDELFIA Testosterone and AutoDELFIA Estradiol; PerkinElmer, Turku, Finland), using polyclonal antibodies and standards calibrated by gravimetric and spectrophotometric methods with sensitivities of 13.6 pg/ml and 14 ng/dl for estradiol and testosterone, respectively. Basal testosterone more than 30 ng/dl (RIA) or more than 19 ng/dl (fluorometric assay) was considered as the pubertal level (18). BA was carefully reevaluated by the same observer according to the Greulich and Pyle method (19). BA advancement was defined as BA minus CA. TH was calculated from parents’ height measurements, and determined by midparental height minus 6.5 cm for girls and plus 6.5 cm for boys. TH range was established as TH ± 8.5 cm (20).

The interval between CA at onset of puberty and at the start of GnRH analog therapy was calculated based on parents’ information in all patients.

PH of all patients was calculated using average and advanced BP tables at the start and end of GnRH analog therapy (8). Advanced BA was considered when it was advanced for CA by 1 yr or more.

All patients underwent the same treatment protocol with depot GnRH analogs provided by the Brazilian Public Health System. In 85% of the injections, they received 3.75 mg depot leuprolide acetate (Lupron; TAP Pharmaceuticals Products Inc., Lake Forest, IL) by the sc route every 28 d. However, when depot leuprolide acetate was not available, it was replaced by 3.6 mg goserelin (Zoladex; Zeneca, Cheshire, UK) or 3.6 mg triptorelin (Decapeptyl; Ipsen-Biotech, Paris, France) for short periods in all patients. The initial mean depot GnRH agonist dose corresponded to 133 ± 50 µg/kg (ranging from 77–350).

Clinical and hormonal evaluation was performed quarterly. Clinical parameters of adequate therapeutic response consisted of regression or stabilization of pubertal development [Marshall and Tanner criteria (13, 14)], deceleration of growth velocity, and adequate bone maturation. The rate of bone maturation (BA/CA ratio) was calculated considering the variation of BA and CA from the start to the end of GnRH therapy. LH levels during suppression of pituitary-gonadal function was monitored by the GnRH-stimulation test performed every 6 months throughout treatment, or alternatively, by a single LH determination 2 h after 3.75 mg depot leuprolide acetate (21). Adequate suppression was defined as an LH peak less than 2.3 U/liter on the GnRH stimulation test, or an LH level less than 6.6 U/liter if assessed 2 h after depot leuprolide acetate injection, in association with basal serum estradiol level less than 13 pg/ml in girls and serum testosterone level less than 14 ng/dl in boys (18, 21). BA was assessed annually by nondominant hand and wrist x-rays.

The decision to interrupt the depot GnRH analog treatment was based on individual patient features, mainly represented by CA (yr), BA (yr), PH, height (cm) itself, and psychological aspects. AH was defined as a growth rate less than 0.5 cm/yr during the preceding year in girls with BA 15 yr or more, and in boys with a BA 16 yr or more (5).

Statistical analysis

All data are presented as mean ± SD and range. PH obtained by both BP tables for average and advanced BAs were compared with AH and TH using ANOVA, followed by Bonferroni correction. The BMI SDS of girls at distinct points was compared by the Wilcoxon signed rank test. Correlations between two parameters were determined by Pearson’s correlation coefficient analysis. Stepwise multiple linear regression analysis was performed to determine the best predictors of each dependent variable: posttreatment linear growth and AH. In addition, the comparison of variables between the groups of girls who attained TH range and those who did not was performed by the Student’s t test. Statistical significance was set at P < 0.05. Statistical analysis was performed using SPSS software (version 15.0 for Windows; SPSS, Inc., Chicago, IL).

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Clinical and hormonal data at the start of GnRH analog therapy

The mean CA at the start of GnRH analog therapy of the 45 girls with GDPP was 7.3 ± 2 yr (ranging from 0.9–10.25), and the mean initial BA was 10.6 ± 2.16 yr (ranging from 2–13.5) (Table 1). Pubertal stage ranged from breast development (B2 to B4) and pubic hair (PH1 to PH4). Mean basal LH level, assessed by IFMA, was 1.8 ± 1.3 U/liter (range 0.6–7.4). Basal LH levels were at pubertal level (>0.6 U/liter) in 35 of 45 (77.8%) girls. Mean GnRH-stimulated LH peak, assessed by IFMA, was 19.5 ± 15 U/liter (ranging from 6–70). Only two of 45 girls (4.4%) had GnRH-stimulated LH peak below the pubertal cutoff level (<6.9 U/liter). In these two girls, GnRH-stimulated LH peaks were 6 and 6.3 U/liter, associated with pubertal development, advanced BA, and accelerated growth velocity. Mean basal estradiol (IFMA) was 24 ± 18 pg/ml (ranging from < 13.6 to 99) in 40 girls. In the remaining five girls, basal estradiol (RIA) was less than 10 pg/ml.

Clinical and hormonal data during and after therapy

All patients presented adequate clinical and hormonal control during GnRH analog therapy. We evaluated height, weight, growth velocity, pubertal stage, and injection site to exclude local reactions in all patients during their clinical visit. Clinical parameters of satisfactory therapeutic response consisted mainly of regression or stabilization of pubertal development, deceleration of growth velocity, and delay of bone maturation.

Adjustment in the depot leuprolide acetate dosage was necessary only in two of 45 girls (4.4%) who presented pubertal progression during treatment with 3.75 mg depot acetate leuprolide and LH 2 h after depot leuprolide acetate of above 6.6 U/liter. Depot leuprolide acetate dosage was increased to 7.5 mg/month, resulting in hormonal suppression and arrest of pubertal development.

During depot GnRH analog therapy, the basal LH measurement was less than 0.6 U/liter in all girls. The mean GnRH-stimulated LH peak was 1.25 ± 0.5 U/liter (range 0.6–2.3), indicating satisfactory hormonal control. More recently, single LH samples obtained 2 h after depot leuprolide 3.75 mg have been used as an alternative tool to assess hormonal suppression in these girls (21). The mean LH 2 h after leuprolide depot from 26 of 45 girls was 2.6 ± 1.5 U/liter (range 0.7–6.6), also indicating good hormonal control. In all girls, basal estradiol was suppressed (<13.6 pg/ml) as was basal testosterone (<14 ng/dl) in boys.

In girls, mean growth velocity during GnRH analog therapy was 4.8 ± 2.6 cm/yr (ranging from 2–8.2), and the mean duration of GnRH analog therapy was 3.2 ± 1.8 yr (ranging from 1–9).

In addition, in girls older than 2 yr, mean BMI SDS was 0.9 ± 0.7 (–0.7 to 2) before treatment, in which 18 of 43 (41.9%) were overweight. At withdrawal of GnRH analog therapy, mean BMI SDS was 1.0 ± 0.7 (–0.3 to 2.3), whereas 20 of 45 (46.6%) were overweight. Upon attaining AH, the mean BMI SDS was 0.8 ± 0.4 (–0.3 to 1.9), in which 18 of 45 girls (40%) were overweight. Mean BMI SDS in girls at these different points was not statistically different (P > 0.05).

Basal LH was suppressed (<0.6 U/liter) in all boys during therapy. Mean GnRH-stimulated LH peak was 1.4 ± 0.6 U/liter (range 0.7–2), and 2 h after depot leuprolide acetate was 2 ± 0.9 U/liter (range 0.7–2.7), indicating adequate hormonal control. The duration of GnRH analog therapy was 6.8 ± 3.4 yr (ranging from 2.25–11), and the mean growth velocity during GnRH analog therapy was 5.7 ± 0.9 cm/yr (ranging from 4.2–6.9).

PH at the start and end of GnRH analog therapy

All girls had accelerated BA at the start of GnRH analog therapy. The initial PHs, i.e. at the start of GnRH analog therapy, were 151.6 ± 9.7 cm and 147.3 ± 9 cm using BP tables for accelerated and average BA, respectively. In girls the achieved AH was significantly higher than the initial PH using both BP tables (P < 0.05). The mean BA at the end of GnRH analog therapy was 12.4 ± 0.9 yr (ranging from 11–14.6), whereas the mean adult PHs were 160.6 ± 6.5 cm and 158.1 ± 6.5 cm for advanced and average BA tables, respectively (Table 2). At the end of GnRH analog therapy, PH calculated by BP tables for average BA was closer to achieved AH (P > 0.05) (Table 2), whereas PH by BP tables for advanced BA was significantly higher than achieved AH (P < 0.05, ANOVA). The mean TH was 157.5 ± 4.5 cm (–0.8 ± 0.7 SD), whereas mean attained AH was 155.3 ± 6.9 cm, ranging from 141.3–168 (–1.2 ± 1 SD). In addition, the mean AH did not present a statistically significant difference when compared with mean TH in these girls (Table 2).

Factors influencing linear growth after depot GnRH analog therapy in girls (Tables 3 and 4)

Posttreatment linear growth was quite variable in the 45 girls with GDPP (Table 1). GnRH analog therapy was withdrawn for most of the girls (37 patients) at a BA of 12–13 yr. Linear growth gain ranged from 2.3–20.1 cm for a BA of 12 yr and 2.6–12.5 cm for a BA of 13 yr. In addition, the percentage of residual growth after GnRH therapy varied widely, ranging from 2.3–15.7% and 1.8–12% for a BA of 12 and 13 yr, respectively. These data support the evidence that BP tables are not reliable for height prediction in patients with GDPP.

Factors influencing AH (Tables 5 and 6)

The univariate analysis demonstrated that AH was negatively and significantly associated with CA at the start of therapy (r = –0.298; P = 0.023), with the interval between CA at onset of puberty and at the start of therapy (r = –0.419; P = 0.002), estradiol levels at the start of therapy (r = –0.299; P = 0.03), and CA at the end of therapy (r = –0.320; P = 0.016). In contrast, AH was positively and significantly associated with height SDS at the start and end of therapy (r = 0.616, P < 0.001; and r = 0.617, P < 0.001, respectively), duration of therapy (r = 0.305; P = 0.02), TH (r = 0.537; P < 0.001), and posttreatment statural growth (r = 0.338; P = 0.01). BA – CA at the end of therapy was weakly and positively correlated with AH (r = 0.327; P = 0.03) but significantly correlated with height SDS at the end of therapy (r = 0.6; P < 0.00001). Multiple regression analysis identified four major factors that explain 74% of AH variance: the interval between CA at onset of puberty and at the start of therapy (negatively), TH (positively) and height SDS at the start and end of therapy (positively) (Table 6).

We compared anthropometric and hormonal data before, during, and after GnRH analog therapy between these two groups that presented similar mean TH (Table 7). TH was available in 43 girls; 35 of them (81.4%) reached their TH range (group A), including 15 girls (44.1%) who exceeded their individual mean TH. Eight girls (19%) did not reach their TH range (group B) (Table 7). The mean growth velocity during GnRH therapy was similar in both groups (5.4 ± 2.5 cm/yr in group A vs. 4.6 ± 1.5 cm/yr in group B; P > 0.05). Group A presented significantly higher AH in comparison to group B (157.4 ± 6 cm vs. 147 ± 3.4 cm; P < 0.001). Three of the four factors influencing AH, previously determined by multiple regression analysis, were also significantly different between both groups: shorter interval between the onset of puberty and start of treatment, and greater height SDS at the start and end of GnRH analog therapy in group A (P < 0.05) (Table 7). The BA advancement (BA – CA) at the start of therapy was significantly greater than at the end of depot GnRH analog therapy in both groups (P < 0.001). In addition, basal estradiol levels at the start of GnRH analog therapy were significantly higher in group B (P = 0.04).

The small number of boys did not allow statistical analysis. Eight of nine boys (89%) reached their TH range, and three of them exceeded their individual TH. The patient who failed to achieve the TH range had been inadequately treated with androgen before starting GnRH analog therapy at a CA and BA of 8.5 and 13 yr, respectively.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
GnRH analogs have been used as the first-choice treatment for GDPP since the 1980s, and the final auxological outcome of patients with GDPP is now available (2, 3, 4, 5, 6, 7, 10, 12). In this study we analyzed the potential factors that could influence the AH of 45 Brazilian girls with GDPP who were exclusively treated with depot GnRH analogs. To address this question, we initially performed univariate analysis that allowed us to identify the following factors that were negatively associated with AH: CA at the start and end of therapy, the interval between onset of puberty and start of therapy, and basal estradiol levels before therapy. In contrast, the duration of therapy, BA advancement (BA – CA) at the end of therapy, posttreatment statural growth, and TH were positively associated with AH. Furthermore, multivariate analysis revealed that the interval between CA at onset of puberty and start of therapy, height SDS at the start and end of therapy, and TH explained 74% of AH variance.

To identify the factors that determined normal AH, we divided the 45 girls who reached AH into two groups: group A, girls who reached their TH range; and group B, girls who did not. Because TH was similar in both groups, the genetic influence was dismissed as a factor contributing to failure in achieving normal AH. Comparison between the two groups demonstrated that the interval between the onset of puberty and the start of treatment was shorter, estradiol levels were significantly lower, and height SDS at the start and end of therapy was significantly higher in group A. Among those factors that can compromise AH, only start of GnRH analog therapy can be optimized by the pediatric endocrinologist. Parents’ knowledge on precocious puberty and prompt medical diagnosis of GDPP are necessary for early therapy with depot GnRH analogs. However, proper patient selection (progressive GDPP) should be performed to avoid unnecessary treatment. Regarding the duration of GnRH analog therapy, earlier studies have demonstrated that prolonged GnRH analog therapy beyond 11 yr of age compromises AH (2, 3). In agreement with Carel et al. (2), we found that CA at the end of therapy was negatively associated with AH.

BA advancement is often used as one of the parameters in the decision process to treat, or not, GDPP to obtain normal height. In our study, pretreatment BA and BA advancement (BA – CA) were not a determinant of normal AH in multivariate analysis. Moreover, girls who achieved normal AH (group A) had higher pretreatment height SDSs for CA for similar BA advancement when compared with group B, suggesting that BA itself did not play a significant role in determining normal AH.

Recently, Lazar et al. (7) demonstrated that girls with GDPP diagnosed after the age of 6 yr had reduced posttreatment height gain and compromised AH, probably due to pretreatment intrinsic changes in the growth plate. In contrast, we found no significant association between CA at the start of therapy and posttreatment linear growth. Although CA at the start of therapy was significantly and negatively associated with AH, most of the girls who achieved normal AH (27 of 35) started GnRH analog therapy after the age of 6 yr, indicating that GnRH analog therapy is effective in preserving the potential genetic height in girls older than 6 yr. Similarly, Carel et al. (2), on studying a subgroup of 42 patients with onset of puberty between the ages of 6 and 8 yr, showed a significant increase in AH vs. PH. In contrast, several studies have demonstrated no effects of depot GnRH analog therapy on AH in girls with late onset of precocious puberty (3, 22, 23).

In our study overweight was similarly prevalent in the girls with GDPP at the start of therapy (42%), at the end of therapy (47%), and at AH attainment (40%). These findings confirm the previous evidence that GnRH analog therapy does not induce significant BMI increase and that a high percentage of girls with GDPP were overweight or obese before treatment (24, 25).

The optimal depot GnRH analog dosage to treat GDPP remains controversial (26). In the present study, the long-term outcome of patients treated with lower depot GnRH analog dosage showed adequate clinical and hormonal control and normal AH in the majority of patients, thus indicating the effectiveness of lower depot GnRH analog dosage in GDPP treatment. Therefore, we recommend starting the therapy with lower depot GnRH analog dosage and increasing dose if pubertal progression or inadequate hormonal control occurs.

One important practical aspect of the management of patients with GDPP is the possibility to predict AH. Although BP’s method is the most widely used, it overestimates AH in GDPP patients (9). In our study the mean AH of girls with GDPP was significantly higher than the initial height prediction using both BP’s tables for average and advanced BA, indicating a beneficial effect of GnRH analog therapy. In addition, PHs at the end of therapy calculated by tables for average BA were more reliable than those for advanced BA, as previously demonstrated by Kauli et al. (9).

Carel et al. (2) demonstrated that three variables were independently associated with AH in 58 girls and eight boys with GDPP: BA advance before treatment (negatively), height SDS at the end of treatment (positively), and height gain after interruption of treatment (positively). In our study no association between AH and posttreatment linear growth was demonstrated. However, the heterogeneity of posttreatment growth was remarkable, confirming previous findings (2, 7). In the present study, the major factors explaining 39% of posttreatment growth variance were CA and BA at the end of therapy.

In boys it has been demonstrated that GnRH analog therapy increased height gain above levels of historical untreated controls, suggesting efficacy and safety of the depot GnRH analog therapy (3, 27). In addition, other studies have demonstrated improvement of growth prognosis and restoration of genetic height potential in boys with progressive GDPP treated exclusively with GnRH analog (28, 29). In our study a small number of boys was analyzed, and eight of the nine boys (89%) reached their TH range. In addition, the prediction of AH at the end of GnRH analog therapy obtained by BP tables for average BA was more accurate than for advanced BA in boys.

We conclude that the major factors influencing normal AH attainment in girls with GDPP treated with depot GnRH analogs were shorter interval between the onset of pubertal signs and the start of therapy, higher height SDS at the start and end of therapy, and TH. Among these factors, the single one we are able to optimize is start of therapy. Therefore, we recommend prompt GnRH analog therapy in properly selected patients with GDPP to obtain normal AH.

	Acknowledgments

 
We thank Ms. Sonia Strong and Mr. Andy Davis for the English review, and Ms. Lourdes Conceição Martins from the Disciplina de Saude Coletiva da Faculdade de Medicina do ABC and Núcleo de Estudos em Epidemiologia Ambiental do LPAE-FMUSP, University of São Paulo for her assistance in the statistical analysis.

	Footnotes

 
This work was supported by grants from the Fundação Faculdade de Medicina do Hospital das Clínicas da Universidade de São Paulo (to V.N.B.), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (300469/2005–5 to A.C.L.; 300938/06–3 to I.J.P.A. and 300828/2005–5 to B.B.M.), and Fundação de Amparo à Pesquisa do Estado de São Paulo (05/04726–0 to A.C.L.).

Disclosure Statement: The authors have nothing to disclose.

First Published Online May 6, 2008

Abbreviations: AH, Adult height; BA, bone age; BMI, body mass index; BP, Bayley and Pinneau; CA, chronological age; GDPP, gonadotropin-dependent precocious puberty; IFMA, immunofluorometric assay; PH, predicted height; SDS, SD score; TH, target height.

Received September 28, 2007.

Accepted April 30, 2008.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

1. Partsch CJ, Heger S, Sippell WG 2002 Management and outcome of central precocious puberty. Clin Endocrinol (Oxf) 56:129–148[CrossRef][Medline]
2. Carel JC, Roger M, Ispas S, Tondu F, Lahlou N, Blumberg J, Chaussain JL 1999 Final height after long-term treatment with triptorelin slow release for central precocious puberty: importance of statural growth after interruption of treatment. J Clin Endocrinol Metab 84:1973–1978[Abstract/Free Full Text]
3. Carel JC, Lahlou N, Roger M, Chaussain JL 2004 Precocious puberty and statural growth. Hum Reprod Update 10:135–147[Abstract/Free Full Text]
4. Oostdijk W, Rikken B, Schreuder S, Otten B, Odink R, Rouwé C, Jansen M, Gerver WJ, Waelkens J, Drop S 1996 Final height in central precocious puberty after long term treatment with a slow release GnRH agonist. Arch Dis Child 75:292–297[Abstract/Free Full Text]
5. Klein KO, Barnes KM, Jones JV, Feuillan PP, Cutler GBJ 2001 Increased final height in precocious puberty after long-term treatment with LHRH agonists: the National Institutes of Health experience. J Clin Endocrinol Metab 86:4711–4716[Abstract/Free Full Text]
6. Arrigo T, Cisternino M, Galluzzi F, Bertelloni S, Pasquino AM, Antoniazzi F, Borrelli P, Crisafulli G, Wasniewska M, De Luca F 1999 Analysis of the factors affecting auxological response to GnRH agonist treatment and final height outcome in girls with idiopathic central precocious puberty. Eur J Endocrinol 141:140–144[Abstract]
7. Lazar L, Padoa A, Philip M 2007 Growth pattern and final height after cessation of gonadotropin-suppressive therapy in girls with central sexual precocity. J Clin Endocrinol Metab 92:3483–3489[Abstract/Free Full Text]
8. Bayley N, Pinneau S 1952 Tables for predicting adult height from skeletal age. J Pediatr 14:432–441
9. Kauli R, Galatzer A, Kornreich L, Lazar L, Pertzelan A, Laron Z 1997 Final height of girls with central precocious puberty, untreated versus treated with cyproterone acetate or GnRH analogue. A comparative study with re-evaluation of predictions by the Bayley-Pinneau method. Horm Res 47:54–61[Medline]
10. Antoniazzi F, Cisternino M, Nizzoli G, Bozzola M, Corrias A, De Luca F, De Sanctis C, Rigon F, Zamboni G, Bernasconi S 1994 Final height in girls with central precocious puberty: comparison of two different luteinizing hormone-releasing hormone agonist treatments. Acta Paediatr 83:1052–1056[Medline]
11. Bar A, Linder B, Sobel EH, Saenger P and DiMartino-Nardi J 1995 Bayley-Pinneau method of height prediction in girls with central precocious puberty: correlation with adult height. J Pediatr 126:955–958[CrossRef][Medline]
12. Heger S, Sippell WG, Partsch CJ 2005 Gonadotropin-releasing hormone analogue treatment for precocious puberty. Twenty years of experience. Endocr Dev 8:94–125[Medline]
13. Marshall WA, Tanner JM 1969 Variations in pattern of pubertal changes in girls. Arch Dis Child 44:291–303[Free Full Text]
14. Marshall WA, Tanner JM 1970 Variations in the pattern of pubertal changes in boys. Arch Dis Child 45:13–23[Abstract/Free Full Text]
15. Tanner JM, Whitehouse RH 1976 Clinical longitudinal standards for height, weight, height velocity, and weight velocity, and stages of puberty. Arch Dis Child 51:170–179[Abstract/Free Full Text]
16. Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, Flegal KM, Guo SS, Wei R 2000 CDC growth charts: United States. Adv Data 314:1–27[Medline]
17. Lee PA 1994 Laboratory monitoring of children with precocious puberty. Arch Pediatr Adolesc Med 148:369–376[Abstract/Free Full Text]
18. Brito VN, Batista MC, Borges MF, Latronico AC, Kohek MB, Thirone AC, Jorge BH, Arnhold IJ, Mendonca BB 1999 Diagnostic value of fluorometric assays in the evaluation of precocious puberty. J Clin Endocrinol Metab 84:3539–3544[Abstract/Free Full Text]
19. Greulich WW, Pyle SI 1959 Radiographic atlas of skeletal development of the hand and wrist. Stanford, CA: Stanford University Press
20. Tanner JM, Goldstein H, Whitehouse RH 1970 Standards for children’s height at ages 2–9 years allowing for height of parents. Arch Dis Child 45:755–762[Abstract/Free Full Text]
21. Brito VN, Latronico AC, Arnhold IJ, Mendonça BB 2004 A single luteinizing hormone determination 2 hours after depot leuprolide is useful for therapy monitoring of gonadotropin-dependent precocious puberty in girls. J Clin Endocrinol Metab 89:4338–4342[Abstract/Free Full Text]
22. Cassio A, Cacciari E, Balsamo A, Bal M, Tassinari D 1999 Randomized trial of LHRH analogue treatment on final height in girls with onset of puberty aged 7.5–8.5 years. Arch Dis Child 81:329–332[Abstract/Free Full Text]
23. Mul D, Oostdijk W, Otten BJ, Rouwe C, Jansen M, Delemarre-van de Waal HA, Waelkens JJ, Drop SL 2000 Final height after gonadotrophin releasing hormone agonist treatment for central precocious puberty: the Dutch experience. J Pediatr Endocrinol Metab 13(Suppl 1):765–772
24. Heger S, Partsch CJ, Sippell WG 1999 Long-term outcome after depot gonadotropin-releasing hormone agonist treatment of central precocious puberty: final height, body proportions, body composition, bone mineral density, and reproductive function. J Clin Endocrinol Metab [Erratum (2000) 85:657] 84:4583–4590[CrossRef]
25. Palmert MR, Mansfield J, Crowley Jr WF, Crigler JF, Crawford JD, Boepple PA 1999 Is obesity an outcome of gonadotropin-releasing hormone agonist administration? Analysis of growth and body composition in 110 patients with central precocious puberty. J Clin Endocrinol Metab 84:4480–4488[Abstract/Free Full Text]
26. Badaru A, Wilson DM, Bachrach LK, Fechner P, Gandrud LM, Durham E, Wintergerst K, Chi C, Klein KO, Neely EK 2006 Sequential comparisons of one-month and three-month depot leuprolide regimens in central precocious puberty. J Clin Endocrinol Metab 91:1862–1867[Abstract/Free Full Text]
27. Mul D, Bertelloni S, Carel JC, Saggese G, Chaussian JL, Oostdijk W 2002 Effect of gonadotropin-releasing hormone agonist treatment in boys with central precocious puberty: final height results. Horm Res 58:1–7[Medline]
28. Lazar L, Pertzelan A, Weintob N, Phillip M, Kauli R 2001 Sexual precocity in boys: accelerated versus slowly progressive puberty gonadotropin-suppressive therapy and final height. J Clin Endocrinol Metab 86:4127–4132[Abstract/Free Full Text]
29. Rizzo V, De Sanctis V, Corrias A, Fortini M, Galluzzi F, Bertelloni S, Guarnieri MP, Pozzan G, Cisternino M, Pasquino AM 2000 Factors influencing final/near-final height in 12 boys with central precocious puberty treated with gonadotrophin-releasing hormone agonists. Italian Study Group of Physiopathology of Puberty. J Pediatr Endocrinol Metab 13(Suppl 1):781–786

This article has been cited by other articles:

				D Mul and I A Hughes The use of GnRH agonists in precocious puberty Eur. J. Endocrinol., December 1, 2008; 159(suppl_1): S3 - S8. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brito, V. N. Articles by Mendonca, B. B. Search for Related Content PubMed PubMed Citation Articles by Brito, V. N. Articles by Mendonca, B. B. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB LEUPROLIDE Related Collections Neuroendocrinology and Pituitary Pediatric Endocrinology Female Endocrinology