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  • Clinical Research Article
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Gonadotropin-releasing hormone analogs treatment in girls with central precocious puberty and early fast puberty

Pediatric Research volume 95, pages 1051–1059 (2024)Cite this article

Abstract

Background

Gonadotropin-releasing hormone analog (GnRHa) is the standard treatment for children with central precocious puberty (CPP). We assessed efficacy and safety of GnRHa treatment in girls with CPP and early fast puberty (EFP).

Methods

This retrospective observational study included anthropometric, clinical and laboratory data retrieved from medical files of girls with CPP or EFP, treated with GnRHa and followed at a tertiary endocrine clinic during 2007–2021.

Results

For both CPP (n = 144) and EFP (n = 231) groups, mean height-SDS at GnRHa initiation and termination and at the last follow-up visit was greater than mid-parental height-SDS (P < 0.001). Only among girls with EFP, mean BMI-SDS was higher at treatment termination than initiation (P = 0.025). Median ages at menarche of the CPP and EFP groups were 11.8 and 12.0 years. Menstrual irregularities were reported in 20.3% of girls with CPP and in 18.7% of those with EFP. Adverse effects to treatment were reported in 3.5% and 3.9% of girls with CPP and EFP, respectively.

Conclusions

In this large cohort, GnRHa treatment in girls with EFP was effective without significant adverse effects as in those with CPP. A randomized controlled trial is required to examine the psychological impact of GnRHa treatment of variant early puberty.

Impact statement

  • Gonadotropin-releasing hormone analog (GnRHa) is the standard treatment for central precocious puberty (CPP).

  • We assessed efficacy and safety of GnRHa treatment in girls with early fast puberty (EFP), characterized by pubertal signs between ages 8–9 years with fast pubertal signs advancement and accelerated growth and bone maturation and in girls with CPP.

  • We found in this large cohort that GnRHa treatment in girls with EFP was effective and safe as in those with CPP. A prospective randomized controlled trial is required to examine the psychological impact of GnRHa treatment of variant early puberty.

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Fig. 1: Vertical scatter plot with median (IQR) representing height-standard deviation score in girls with CPP and EFP, at three time points compared to mid-parental height.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Fuqua, J. S. Treatment and outcomes of precocious puberty: an update. J. Clin. Endocrinol. Metab. 98, 2198–2207 (2013).

    CAS  PubMed  Google Scholar 

  2. Lazar, L., Kauli, R., Pertzelan, A. & Phillip, M. Gonadotropin-suppressive therapy in girls with early and fast puberty affects the pace of puberty but not total pubertal growth or final height. J. Clin. Endocrinol. Metab. 87, 2090–2094 (2002).

    CAS  PubMed  Google Scholar 

  3. Kauli, R. et al. 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 (1997).

    CAS  PubMed  Google Scholar 

  4. Blumenthal, H. et al. Elevated social anxiety among early maturing girls. Dev. Psychol. 47, 1133–1140 (2011).

    PubMed  PubMed Central  Google Scholar 

  5. Brito, V. et al. Central precocious puberty: revisiting the diagnosis and therapeutic management. Arch. Endocrinol. Metab. 60, 163–172 (2016).

    PubMed  Google Scholar 

  6. Krishna, K. B. et al. Use of Gonadotropin releasing hormone alalogs in children: update by an international consortium. Horm. Res. Paediatr. 91, 357–372 (2019).

    Google Scholar 

  7. Klein, K. O., Barnes, K. M., Jones, J. V., Feuillan, P. P. & Cutler, G. B. 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 (2001).

    CAS  PubMed  Google Scholar 

  8. Swaiss, H. H., Khawaja, N. M., Farahid, O. H., Batieha, A. M. & Ajlouni, K. M. Effect of gonadotropin-releasing hormone analogue on final adult height among Jordanian children with precocious puberty. Saudi Med. J. 38, 1101–1107 (2017).

    PubMed  PubMed Central  Google Scholar 

  9. Głąb, E., Wikiera, B., Bieniasz, J. & Barg, E. The influence of GnRH analog therapy on growth in central precocious puberty. Adv. Clin. Exp. Med. 25, 27–32 (2016).

    PubMed  Google Scholar 

  10. Brito, V. N. et al. Factors determining normal adult height in girls with gonadotropin-dependent precocious puberty treated with depot gonadotropin-releasing hormone analogs. J. Clin. Endocrinol. Metab. 93, 2662–2669 (2008).

    CAS  PubMed  Google Scholar 

  11. Lazar, L., Padoa, A. & Phillip, M. Growth pattern and final height after cessation of gonadotropin-suppressive therapy in girls with central sexual precocity. J. Clin. Endocrinol. Metab. 92, 3483–3489 (2007).

    CAS  PubMed  Google Scholar 

  12. Miller, B. S. & Shukla, A. R. Sterile abscess formation in response to two separate branded long-acting gonadotropin-releasing hormone agonists. Clin. Ther. 32, 1749–1751 (2010).

    PubMed  Google Scholar 

  13. Guaraldi, F., Beccuti, G., Gori, D. & Ghizzoni, L. Management of endocrine disease: long-term outcomes of the treatment of central precocious puberty. Eur. J. Endocrinol. 174, R79–R87 (2016).

    CAS  PubMed  Google Scholar 

  14. Park, J. & Kim, J. H. Change in body mass index and insulin resistance after 1-year treatment with gonadotropin-releasing hormone agonists in girls with central precocious puberty. Ann. Pediatr. Endocrinol. Metab. 22, 27–35 (2017).

    PubMed  PubMed Central  Google Scholar 

  15. Leite, A. L. et al. Do GnRH agonists really increase body weight gain? Evaluation of a multicentric Portuguese cohort of patients with central precocious puberty. Front. Pediatr. 10, 816635 (2022).

    ADS  PubMed  PubMed Central  Google Scholar 

  16. Xiaoping, L. et al. An open label, multicenter clinical trial that investigated the efficacy and safety of leuprorelin treatment of central precocious puberty in Chinese children. Medicine 100, e28158 (2021).

    Google Scholar 

  17. Kim, H. R., Nam, H. K., Rhie, Y. J. & Lee, K. H. Treatment outcomes of gonadotropin-releasing hormone agonist in obese girls with central precocious puberty. Ann. Pediatr. Endocrinol. Metab. 22, 259–265 (2017).

    PubMed  PubMed Central  Google Scholar 

  18. De Sanctis, V., Soliman, A. T., Di Maio, S., Soliman, N. & Elsedfy, H. Long-term effects and significant Adverse Drug Reactions (ADRs) associated with the use of Gonadotropin-Releasing Hormone analogs (GnRHa) for central precocious puberty: a brief review of literature. Acta Biomed. 90, 345–359 (2019).

    PubMed  PubMed Central  Google Scholar 

  19. Willemsen, R. H., Elleri, D., Williams, R. M., Ong, K. K. & Dunger, D. B. Pros and cons of GnRHa treatment for early puberty in girls. Nat. Rev. Endocrinol. 10, 352–363 (2014).

    CAS  PubMed  Google Scholar 

  20. Kuczmarski, R. J. et al. CDC growth charts for the United States: methods and development. Vital-. Health Stat. 246, 1–190 (2002). 11.

    Google Scholar 

  21. Lee, P. A., Luce, M. & Bacher, P. Monitoring treatment of central precocious puberty using basal luteinizing hormone levels and practical considerations for dosing with a 3-month leuprolide acetate formulation. J. Pediatr. Endocrinol. Metab. 29, 1249–1257 (2016).

    CAS  PubMed  Google Scholar 

  22. Bayley, N. & Pinneau, S. Tables for predicting adult height from skeletal age. J. Pediatr. 14, 432–441 (1952).

    Google Scholar 

  23. Borges, M. F. et al. Evaluation of central precocious puberty treatment with GnRH analogue at the Triangulo Mineiro Federal University (UFTM). Arch. Endocrinol. Metab. 59, 515–522 (2015).

    PubMed  Google Scholar 

  24. López-Miralles, M., Lacomba-Trejo, L., Valero-Moreno, S., Benavides, G. & Pérez-Marín, M. Psychological aspects of pre-adolescents or adolescents with precocious puberty: a systematic review. J. Pediatr. Nurs. 64, e61–e68 (2022).

    PubMed  Google Scholar 

  25. Michaud, P. A., Suris, J. C. & Deppen, A. Gender-related psychological and behavioral correlates of pubertal timing in a national sample of Swiss adolescents. Mol. Cell Endocrinol. 25, 172–178 (2006).

    Google Scholar 

  26. Tremblay, L. & Frigon, J. Y. Precocious puberty in adolescent girls: a biomarker of later psychosocial adjustment problems. Child Psychiatry Hum. Dev. 36, 73–94 (2005).

    PubMed  Google Scholar 

  27. Xie, L. L. et al. A clinical study of girls with idiopathic central precocious puberty and psychological behavior problems. Clin. Pediatr. 62, 914–918 (2023).

    Google Scholar 

  28. Shoelwer, M. et al. Psychological assessment of mothers and their daughters at the time of diagnosis of precocious puberty. Int. J. Pediatr. Endocrinol. 5, 1–5 (2015).

    Google Scholar 

  29. Loochi, S. A. et al. Gonadotropin releasing hormone analogue therapy in girls with idiopathic precocious puberty/early-fast puberty: dynamics in adiposity indices, eating habits and quality of life. J. Pediatr. Endocrinol. Metab. 34, 373–383 (2021).

    PubMed  Google Scholar 

  30. Kendirci, H. N. et al. Evaluating the efficacy of treatment with a GnRH analogue in patients with central precocious puberty. Int. J. Endocrinol. 2015, 247386 (2015).

    PubMed  PubMed Central  Google Scholar 

  31. Knific, T. et al. Final adult height in children with central precocious puberty- a retrospective study. Front. Endocrinol. (Lausanne) 2, 1008474 (2022).

    Google Scholar 

  32. Yoon, J. W., Park, H. A., Lee, J. & Kim, J. H. The influence of gonadotropin-releasing hormone agonists on anthropometric change in girls with central precocious puberty. Korean J. Pediatr. 60, 395–402 (2017).

    PubMed  PubMed Central  Google Scholar 

  33. Arrigo, T. et al. Reduction of baseline body mass index under gonadotropin-suppressive therapy in girls with idiopathic precocious puberty. Eur. J. Endocrinol. 150, 533–537 (2004).

    CAS  PubMed  Google Scholar 

  34. van der Sluis, I. M., Boot, A. M., Krenning, E. P., Drop, S. L. & de Muinck Keizer-Schrama, S. M. Longitudinal follow-up of bone density and body composition in children with precocious or early puberty before, during and after cessation of GnRH agonist therapy. J. Clin. Endocrinol. Metab. 87, 506–512 (2002).

    PubMed  Google Scholar 

  35. Paterson, W. F., McNeill, E., Young, D. & Donaldson, M. D. Auxological outcome and time to menarche following long-acting goserelin therapy in girls with central precocious or early puberty. Clin. Endocrinol. (Oxf.) 61, 626–634 (2004).

    CAS  PubMed  Google Scholar 

  36. Vuralli, D., Ozon, Z. A., Gonc, E. N., Alikasifoglu, A. & Kandemir, N. Long-term effects of GnRH agonist treatment on body mass index in girls with idiopathic central precocious puberty. J. Pediatr. Endocrinol. Metab. 33, 99–105 (2020).

    PubMed  Google Scholar 

  37. Wolters, B., Lass, N. & Reinehr, T. Treatment with gonadotropin-releasing hormone analogues: different impact on body weight in normal-weight and overweight children. Horm. Res. Paediatr. 78, 304–311 (2012).

    CAS  PubMed  Google Scholar 

  38. Baek, J. W. et al. Age of menarche and near adult height after long-term gonadotropin-releasing hormone agonist treatment in girls with central precocious puberty. Ann. Pediatr. Endocrinol. Metab. 19, 27–31 (2014).

    PubMed  PubMed Central  Google Scholar 

  39. Lazar, L., Meyerovitch, J., de Vries, L., Phillip, M. & Lebenthal, Y. Treated and untreated women with idiopathic precocious puberty: long-term follow-up and reproductive outcome between the third and fifth decades. Clin. Endocrinol. 80, 570–576 (2014).

    Google Scholar 

  40. Faienza, M. F. et al. Metabolic outcomes, bone health, and risk of polycystic ovary syndrome in girls with idiopathic central precocious puberty treated with gonadotropin-releasing hormone analogues. Horm. Res. Paediatr. 87, 162–169 (2017).

    CAS  PubMed  Google Scholar 

  41. Luo, X. et al. Long-term efficacy and safety of gonadotropin-releasing hormone analog treatment in children with idiopathic central precocious puberty: a systematic review and meta-analysis. Clin. Endocrinol. (Oxf.) 94, 786–796 (2021).

    CAS  PubMed  Google Scholar 

  42. Barros, B. S., Kuschnir, M. C. M. C., Bloch, K. V. & Silva, T. L. N. D. ERICA: age at menarche and its association with nutritional status. J. Pediatr. (Rio J.) 95, 106–111 (2019).

    PubMed  Google Scholar 

  43. Flash-Luzzatti, S., Weil, C., Shalev, V., Oron, T. & Chodick, G. Long-term secular trends in the age at menarche in Israel: a systematic literature review and pooled analysis. Horm. Res. Paediatr. 81, 266–271 (2014).

    CAS  PubMed  Google Scholar 

  44. Cantas-Orsdemir, S. & Eugster, E. A. Update on central precocious puberty: from etiologies to outcomes. Expert Rev. Endocrinol. Metab. 14, 123–130 (2019).

    CAS  PubMed  Google Scholar 

  45. Tonini, G. & Lazzerini, M. Side effects of GnRH analogue treatment in childhood. J. Pediatr. Endocrinol. Metab. 13, 795–803 (2000).

    PubMed  Google Scholar 

  46. Gu, Q., Luo, Y., Ye, J. & Shen, X. Comparative efficacy and safety of three current clinical treatments for girls with central precocious puberty: a network meta-analysis. Endocr. Pr. 25, 717–728 (2019).

    Google Scholar 

  47. Kirkgoz, T. et al. Management of systemic hypersensitivity reactions to gonadotropin-releasing hormone analogues during treatment of central precocious puberty. Horm. Res. Paediatr. 93, 66–72 (2020).

    CAS  PubMed  Google Scholar 

  48. Warnock, J. K. & Bundren, J. C. Anxiety and mood disorders associated with gonadotropin-releasing hormone agonist therapy. Psychopharmacol. Bull. 33, 311–316 (1997).

    CAS  PubMed  Google Scholar 

  49. Menk, T. A. S. et al. Assessment of stress levels in girls with central precocious puberty before and during long-acting gonadotropin-releasing hormone agonist treatment: a pilot study. J. Pediatr. Endocrinol. Metab. 30, 657–662 (2017).

    PubMed  Google Scholar 

  50. Franceschi, R. et al. Prevalence of polycystic ovary syndrome in young women who had idiopathic central precocious puberty. Fertil. Steril. 93, 1185–1191 (2010). 1.

    PubMed  Google Scholar 

  51. Magiakou, M. A. et al. The efficacy and safety of gonadotropin-releasing hormone analog treatment in childhood and adolescence: a single center, long-term follow-up study. J. Clin. Endocrinol. Metab. 95, 109–117 (2010).

    CAS  PubMed  Google Scholar 

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Funding

Research reported in this publication was supported by a research grant from Debiopharm Biopharmaceutical Company. The content is solely the responsibility of the authors.

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Authors and Affiliations

  1. The Jesse Z. and Sara Lea Shafer Institute of Endocrinology and Diabetes, National Center for Childhood Diabetes Schneider Children’s Medical Center of Israel, Petah Tikva, Israel

    Leiat Lerman, Michal Yackobovitch-Gavan, Moshe Phillip & Shlomit Shalitin

  2. Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Michal Yackobovitch-Gavan, Moshe Phillip & Shlomit Shalitin

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  1. Leiat Lerman
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Contributions

L.L.—Substantial contributions to acquisition of data, analysis and interpretation of data, drafting the article, and final approval of the version to be published. M.Y.G.—Substantial contributions to analysis and interpretation of data, revising the article critically for important intellectual content, and final approval of the version to be published. M.P.—Substantial contributions to acquisition of data, revising the article critically for important intellectual content, and final approval of the version to be published. S.S.—Substantial contributions to conception and design, acquisition of data, analysis and interpretation of data, revising it critically for important intellectual content, and final approval of the version to be published.

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Correspondence to Shlomit Shalitin.

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Lerman, L., Yackobovitch-Gavan, M., Phillip, M. et al. Gonadotropin-releasing hormone analogs treatment in girls with central precocious puberty and early fast puberty. Pediatr Res 95, 1051–1059 (2024). https://doi.org/10.1038/s41390-023-02879-6

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