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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 10 3575-3578
Copyright © 1999 by The Endocrine Society

Original Studies

Lack of Effect of GnRH Agonists on Final Height in Girls with Advanced Puberty: A Randomized Long-Term Pilot Study

C. Bouvattier, J. Coste, D. Rodrigue, C. Teinturier, J. C. Carel, J. L. Chaussain and P. F. Bougnères

Pediatric Endocrinology (C.B., D.R.R., C.T., J.C.C., J.L.C., P.F.B.) and Biostatistics (J.C.), Hôpital Cochin-Saint Vincent de Paul, Paris, France 75014

Address correspondence and requests for reprints to: Pierre Bougnères, Endocrinologie, Hôpital St Vincent de Paul, 82 avenue Denfert Rochereau, Paris, France 75014; E-mail: bougneres{at}cochin.inserm.fr


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
GnRH agonists improve final height in girls with "true" precocious puberty. To test if a comparable effect can be obtained in older girls, we performed a long-term controlled study in 30 caucasian girls whose puberty started between 8.4 and 10 yr (9.4 ± 0.1 yr), a variant of normal called "advanced" puberty. At entry into trial, these girls had clinical, biological, and sonographic manifestations of puberty and a bone age greater than 10.9 yr. They were randomized 2:1 to receive 3.75 mg triptorelin im every 4 weeks for 2 yr (n = 20, group I) or no treatment (n = 10, group II). Mean height at inclusion was 135.2 ± 4.3 cm (+0.6 SDS) in group I, 136.1 ± 4.2 cm (+0.8 SDS ) in group II, with target height 157.6 ± 4.3 cm (group I) and 157.8 ± 4.7 cm (group II), and predicted height (Bayley-Pinneau) 154.1 ± 3.9 cm and 155.2 ± 3.7 cm. Although GnRH agonists transiently delayed sexual maturation as well as bone age and growth rate, they had no clear-cut long-standing effect, and final height was comparable in treated (157.6 ± 4.0 cm) and untreated girls (156.1 ± 5.3 cm) (NS).


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PUBERTY increases growth velocity and bone maturation, leading to epiphyseal fusion and achievement of final height. "True" precocious puberty is defined as the development of secondary sex manifestations within a variable time course in caucasian girls before 8 yr of age (1). Thirty years ago, untreated girls with precocious puberty were found to reach a mean adult height of 155.5 cm (2). Later reports included either small cohorts of untreated girls with good height prognosis (3, 4, 5) or patients studied retrospectively after attainment of final height (6, 7). Adult heights varied in these studies between 156 and 156.5 cm. The effect of GnRH agonists on adult height in girls with "true" precocious puberty has been documented only in long-term uncontrolled trials (8) and remains a hotly debated topic. Because of the limited amount of data and increasing clinical interest in using GnRH agonists, a collaborative study of the Lawson Wilkins and European Society for Pediatric Endocrinology collected final height data in a large cohort of girls treated with GnRH analogs and compared them with a historical untreated control group. Data were obtained retrospectively from 131 treated girls, 49 of whom had a diagnosis of precocious puberty after 8 yr of age (7). Conclusions were that "treatment with GnRH agonists does not significantly alter the final adult height of girls with idiopathic central precocious puberty whose age at diagnosis is greater than 6 yr". Average final height was nevertheless greater by 1.3 cm than in the historical group (2, 3, 9).

In contrast with idiopathic central precocious puberty stricto sensu, "advanced" puberty can be defined by the onset and rapid progression of pubertal signs between 8 and 10 yr of age in caucasian girls, earlier than the average age in the general population, 10 yr (10). Although this situation is a simple variant of normal, it carries a risk of short final height when it happens in girls born to relatively short parents. It is therefore a common cause of referral in pediatric endocrinology. Because the long-term statural or pubertal blockade with GnRH agonists has not been evaluated in such subjects, we performed a controlled trial to evaluate the effects of these agents on adult stature in girls with advanced puberty and short predicted height.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients and treatment

Thirty caucasian girls, ages 8.4–10.0 yr, were included in the trial during the year 1992 according to the following criteria: manifestations of advanced puberty: recent and progressive pubertal onset, defined by breast development (B2-B3) with or without pubic hair (P1-P3) since 3–6 months, uterine length greater than 35 mm at ultrasonography, peak plasma LH response to GnRH greater than 5 UI/L (9), recent acceleration of growth rate, bone age greater than 10.5 yr; predicted adult height between -1 and -3 SD.

At time of entry into the trial, children heights were between -1 and +1.5 SD. Mean maternal and paternal heights were 157.3 ± 5.4 cm and 170.9 ± 5.7 cm, respectively, leading to a mean target height of 157.7 ± 4.3 cm. Bone age was 10.9 ± 0.2 yr. Mean height prognosis, calculated at time of entry using the Bayley-Pinneau method (11), was 154.5 ± 3.8 cm.

We performed a 2:1 randomization. Twenty girls (group I) were allocated to receive depot triptorelin (Decapeptyl, Ipsen-Biotech, Paris, France) at a dose of 3.75 mg im every 28 days as described (10). Ten girls were left untreated (group II). Adequate inhibition of the gonadotrophs was assessed clinically by the blockade of pubertal development and biologically by the suppression of estradiol and of the LH response to GnRH. Duration of trial was 2 yr. During and after treatment, growth and bone age were assessed biyearly. Plasma gonadotropins, estradiol, and sonographic uterine length were measured every 2 yr in treated patients. Patients in both groups were followed until final height was considered attained, i.e. after bone age had reached 16 yr, or when growth rate was less than 0.5 cm the preceding year. No patient was lost for follow-up.

Informed consent regarding the experimental nature of the study was obtained from the patients and parents after the protocol had been approved by the ethical committee of our institution.

Measurements

Bone age was evaluated by two of us (C.B and D.R) according to Greulich and Pyle (12). Height prognosis was defined by the predicted height using the method of Bayley-Pinneau (11). Target height was calculated using Tanner’s formula (the sum of parental heights -13)/2. Plasma LH and FSH were measured with an immunoradiometric assay (Coatria, Biomerieux, Macy l’Etoile, France) at baseline, and at 20, 40, 60, and 90 min after iv injection of GnRH (100 µg/m2). Estradiol was measured by RIA with a limit of detection of 8 pg/mL.

Statistics analysis

Data are reported as mean ± 1 SD. Due to a reasonably normal distribution of the main variables of interest (initial and final heights, biological variables), parametric methods were used–t-test (2-sample test) and Pearson correlation test–to examine relationships between variables. Multiple regression models of final height prediction were constructed to study factors simultaneously, to adjust for the potential confounding effect of baseline characteristics, and to account for the effect of regression toward the mean (13). A forward stepwise procedure was used (enter P value = 0.05, remove P value = 0.10).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The initial characteristics of the studied patients, including chronological age, bone age, height, predicted, and target heights were comparable in the two groups, as well as hormone values and sonographic measurements of uterus and ovaries (Table 1Go).


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  		Table 1. Clinical and biological characteristics of the patients at entry

 
In girls receiving GnRH agonists, growth velocity decreased from 8.3 ± 1.8 cm/yr before treatment to 6.4 ± 1.3 cm/yr during the first year, and 4.3 ± 0.3 cm/yr the second year of treatment, with individual rates as low as 2.5 cm/yr. Untreated girls had a growth velocity of 8.3 ± 0.4 cm/yr before study, 8.0 ± 1.8 cm/yr the first year, 6.1 ± 1.4 cm/yr the second year. Height was lower at 2 yr in the treated group, with a catch-up curve after the cessation of GnRH agonists, whereas growth rate was decreasing in untreated girls (Fig. 1Go). These kinetics are explained by the evolution of bone age in the two groups (Fig. 1Go), the decreased maturation leading to a full-year delay in treated girls at 2 yr. One year after cessation of GnRH agonists, bone age was still only 12.7 ± 0.2 yr in group I (vs. 14.4 ± 0.3 yr in group II, P = 0.04) and took two more years to reach 15.5 yr (Fig. 1Go). The total height gain averaged 22.4 ± 0.9 cm (range 15.5–31.5 cm) in treated girls and 20.1 ± 1.4 cm in untreated girls (range 15–29.6 cm, NS). Beyond 2 yr of trial, treated girls had a further height gain of 6 ± 1 cm, vs. 11.7 ± 0.8 cm in the untreated girls.



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  		Figure 1. Evolution of height and age in the untreated ({circ}) and treated ({square}) girls vs. years of study.

 
As expected, GnRH agonists blocked sexual maturation. During treatment, peak plasma LH and FSH responses to GnRH were all at 0.5 UI/L and 0.5–1.2 UI/L, respectively, and estradiol was undetectable in all samples. At 2 years, treated girls had a pubertal stage similar to or reduced compared with the onset of treatment. Menarche occurred at 11.2 ± 0.5 yr in untreated and 12.8 ± 0.6 yr in treated girls, i.e. an average of 1.5 yr after discontinuation of therapy. Since then, all girls have had normal menstrual cycles.

Mean final height of the treated girls at 6 yr of follow-up was 157.6 ± 3.9 cm, higher but not significantly different from the 156.1 ± 5.3 cm observed in the untreated. In the overall cohort, a weak positive correlation was found between final height and height at onset of study (r = 0.48, P = 0.007), as well as with predicted height (r = 0.50, P = 0.004) and target height (r = 0.44, P = 0.015). A weak negative correlation was observed in all girls between final height and LH peak at GnRH test (r = -0.36, P = 0.046). There was no correlation between final height and chronological age, bone age at onset, or birth length. The difference between final height and height predicted before treatment averaged 3.4 ± 0.9 cm and 0.9 ± 1.1 cm, respectively, in the treated and untreated groups The final difference of adult height between the two groups was 1.44 cm (-2.08 to +4.97 cm).

Multiple regression analysis revealed that adult height was only independently influenced by height at the start of treatment (P = 0.04).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
GnRH agonist therapy appears to improve final height in girls with onset of puberty before 6 yr of age (8), an observation based both on the improvement of predicted height in treated patients and on a retrospective comparison with untreated historical controls (8). This suggests that agonist administration can reduce the untoward effect of very early puberty on final height. When precocious puberty occurs later, between 6 and 8 yr of age, the magnitude of the height benefit due to GnRH agonists remains debatable. Thirty-four girls who started deslorelin at 7.2 yr of age and 11.6 yr of bone age reached 157 ± 5.9 cm, an average of 6.4 cm below their target height (14). In another GnRH agonist study, average adult stature was 154.7 cm in patients whose mean predicted height was 151.7 cm and whose target height was 159.9 cm (15). A retrospective review used historical (and possibly heterogeneous) controls collected in various centers with no guarantee of exhaustivity (7). The degree of sexual maturation of the skeleton at initiation and after GnRH therapy is likely to play an important role in the reported results. Bone age at start of therapy was more than 3 yr in advance of chronological age in three studies (7, 16, 14), vs. only 1.5 yr in the present trial.

Onset of breast development occurred at 10 yr in caucasian girls recently studied in the United States (10), an age close to that indicated in textbooks (1).

Our study deliberately selected girls with their first signs of puberty occurring after 8 yr, the commonly used threshold for defining precocious puberty (1), and whose bone age advance was only 1.5 yr. Our results were comparable with those obtained in a nonrandomized subset of girls with advanced puberty diagnosed after 8 yr (5). Those patients, treated for 2.4 yr with triptorelin at a dose similar to ours, reached a mean final stature of 157.4 ± 1.2 cm, 99% of their target height. The results of the few studies performed in girls of this age group are summarized in Table 2Go. Despite variations in treatment duration and regimens and the relative heterogeneity of treated cohorts, the overall results did not support a clear effect of GnRH on the final stature of girls with advanced puberty. In the absence of control groups, however, this conclusion has remained in question by many endocrinologists, who are still inclined to use GnRH agonists to maintain the height prognosis.


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  		Table 2. Results of several trials of GnRH analogs in 8–10-yr-old girls with advanced puberty

 
The current data establish that triptorelin administration for 2 yr does not increase final height significantly (1.44 cm) in a subset of caucasian girls with advanced puberty. Additional studies are required to test if, in some situations of combination of height SDS (extremely short girls) and skeletal age, such therapy may nevertheless be useful.


   Acknowledgments
 
We thank Dr. N. Lahlou and the biochemistry lab for routine hormone measurements.

Received March 15, 1999.

Revised June 2, 1999.

Accepted June 21, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Grumbach MM, Styne DM. 1998 Puberty: ontogeny, neuroendocrinology, physiology, and disorders. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds. Williams Textbook of Endocrinology, 9th ed. W.B. Saunders; 1512–1584.
  2. Sigurjonsdottir TJ, Hayles AB. 1968 Precocious puberty. A report of 96 cases. Am J Dis Child. 115:309–321.[Medline]
  3. Murram D, Dewhurst J, Grant DB. 1984 Precocious puberty: a follow-up study. Arch Dis Child. 64:1170–1176.[Abstract]
  4. Kreiter M, Burstein S, Rosenfield RL, et al. 1990 Preserving adult height potential in girls with idiopathic true precocious puberty. J Pediatr. 117:364–370.[CrossRef][Medline]
  5. Brauner R, Adan L, Malandry F, Zantleifer D. 1994 Adult height in girls with idiopathic true precocious puberty. J Clin Endocrinol Metab. 79:415–420.[Abstract]
  6. Schoevaart CE, Drop SLS, Otten BJ, et al. 1990 Growth analysis up to final height and psychosocial adjustment of treated and untreated patients with precocious puberty. Horm Res. 34:197–203.[CrossRef][Medline]
  7. Kletter GM, Kelch RP. 1994 Clinical review 60:effects of gonadotropin-releasing hormone analog therapy on adult stature in precocious puberty. J Clin Endocrinol Metab. 79:331–334.[CrossRef][Medline]
  8. Paul D, Conte F, Grumbach MM, Kaplan SL. 1995 Long-term effect of gonadotropin-releasing hormone agonist therapy on final and near final height in 26 children with true precocious puberty treated at a median age of less than 5 years. J Clin Endocrinol Metab. 80:546–551.[Abstract]
  9. Thamdrup E. 1961 Precocious sexual development: a clinical study of 100 children. Springfield: Thomas; 44–63.
  10. Herman-Giddens ME, Slora EJ, Wasserman RC, Bourdony CJ, Bhapkar MV, Koch GG, Hasemeir CM. 1997 Secondary sexual characteristics and menses in young girls seen in office practice: a study from the pediatric research in office setting network. Pediatrics. 99:505–512.[Abstract/Free Full Text]
  11. Bayley N, Pinneau S. 1952 Tables for predicting adult height from skeletal age. J Pediatr. 14: 432–441.
  12. Greulich WW, Pyle SI. 1959 Radiographic atlas of skeletal development of the hand and wrist. Stanford: Stanford University Press.
  13. Coste J, Letrait M, Carel JC, et al. 1997 Long term results of growth hormone treatment in France in children of short stature: population, register based study. BMJ. 315: 708–713.
  14. Oerter KE, Manasco PK, Barnes KM, Jones J, Hill S, Cutler Jr GB. 1991 Adult height in precocious puberty after long-term treatment with deslorelin. J Clin Endocrinol Metab. 73: 1235–1240.
  15. Boepple PA, Frisch LS, Wierman ME, et al. Growth, final height, and reproduction function following GnRH agonist-induced pituitary-gonadal suppression in central precocious puberty. Proc of the 75th Annual Meet of The Endocrine Society. 1993, 10.
  16. Oostdijk W, Rikken B, Schreuder S, et al. 1996 Final height in central precocious puberty after long term treatment with a slow release GnRH agonist. Arch Dis Child. 75: 292–297.
  17. Kauli R, Korneich L, Laron Z. 1990 Pubertal development, growth and final height in girls with sexual precocity after therapy with the GnRH analog D-TRP-6-LHRH. Horm Res.33:11–17.



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