The Efficacy of GnRHa Alone or in Combination with rhGH for the Treatment of Chinese Children with Central Precocious Puberty

Mengjie Wang, Youjie Zhang, Dan Lan, Jennifer W Hill, Mengjie Wang, Youjie Zhang, Dan Lan, Jennifer W Hill

Abstract

The addition of recombinant human growth hormone (rhGH) to GnRH agonist (GnRHa) to treat central precocious puberty (CPP) is controversial. We systemically reviewed and evaluated the efficacy and safety of the rhGH and GnRHa adjunctive therapy in Chinese children with CPP and assessed the influence of age and therapy duration on the efficacy of the combined treatment. A total of 464 patients were included from 14 studies. Compared with baseline, administration of GnRHa plus rhGH led to a significant increase in height, predicted adult height (PAH) and height standard deviation for bone age (HtSDS-BA), corresponding to a weighted mean difference (WMD) (95%CI) of 9.06 cm (6.41, 11.70), 6.5 cm (4.47, 8.52), and 0.86 (0.58, 1.14) respectively. Subgroup analysis showed the combined therapy had increased efficacy in subjects with initial treatment age younger than 10 years old or with treatment lasting over 12 months. Compared with GnRHa alone treatment, the combined treatment led to a significant increase in height, PAH and HtSDS-BA, corresponding to a WMD (95% CI) of 3.56 cm (2.54, 4.57), 3.76 cm (3.19, 4.34) and 0.56 (0.43, 0.69). The combined treatment exhibited no safety concerns. Our findings may aid clinicians in making treatment decisions for children with CPP.

Figures

Figure 1. Flow chart showing the process…
Figure 1. Flow chart showing the process of literature screening.
Figure 2. Random effects meta-analysis of GnRHa…
Figure 2. Random effects meta-analysis of GnRHa plus rhGH adjunctive treatment on Height, PAH and HtSDS-BA.
The vertical line indicated no treatment effect. Squares and horizontal lines represent the point estimated with associated 95% CI for each comparison, respectively. Diamonds represent the random effects pooled WMD for each outcome. WMD, weighted mean difference; PAH, predicted adult height; HtSDS-BA, height standard deviation score for bone age.
Figure 3. Fixed-effects meta-analysis of GnRHa plus…
Figure 3. Fixed-effects meta-analysis of GnRHa plus rhGH vs. GnRHa alone treatment on Height, PAH and HtSDS-BA.
The vertical line indicated no treatment effect. Squares and horizontal lines represent the point estimated with associated 95% CI for each comparison, respectively. Diamonds represent the random effects pooled WMD for each outcome. WMD, weighted mean difference; PAH, predicted adult height; HtSDS-BA, height standard deviation score for bone age.
Figure 4. Fixed-effects meta-analysis of GnRHa plus…
Figure 4. Fixed-effects meta-analysis of GnRHa plus rhGH adjunctive treatment on BMI.
The vertical line indicated no treatment effect. Squares and horizontal lines represent the point estimated with associated 95% CI for each comparison, respectively. Diamonds represent the random effects pooled WMD for each outcome. WMD, weighted mean difference; BMI, body mass index.

References

    1. Carel J. C. & Leger J. Clinical practice. Precocious puberty. N Engl J Med 358, 2366–2377, doi: 10.1056/NEJMcp0800459 (2008).
    1. Parent A. S. et al.. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr Rev 24, 668–693, doi: 10.1210/er.2002-0019 (2003).
    1. Kim S. H., Huh K., Won S., Lee K. W. & Park M. J. A significant increase in the incidence of central precocious puberty among Korean girls from 2004 to 2010. Plos One 10, e0141844, doi: 10.1371/journal.pone.0141844 (2015).
    1. Kletter G. B. & Kelch R. P. Clinical review 60: Effects of gonadotropin-releasing hormone analog therapy on adult stature in precocious puberty. J Clin Endocrinol Metab 79, 331–334, doi: 10.1210/jcem.79.2.8045943 (1994).
    1. Oostdijk W. et al.. Final height in central precocious puberty after long term treatment with a slow release GnRH agonist. Arch Dis Child 75, 292–297 (1996).
    1. Oerter K. E. et al.. Adult height in precocious puberty after long-term treatment with deslorelin. J Clin Endocrinol Metab 73, 1235–1240, doi: 10.1210/jcem-73-6-1235 (1991).
    1. Carel J. C. et al.. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics 123, e752–762, doi: 10.1542/peds.2008-1783 (2009).
    1. Klein K. O., Barnes K. M., Jones J. V., Feuillan P. P. & Cutler G. B. Jr. 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, doi: 10.1210/jcem.86.10.7915 (2001).
    1. Walvoord E. C. & Pescovitz O. H. Combined use of growth hormone and gonadotropin-releasing hormone analogues in precocious puberty: theoretic and practical considerations. Pediatrics 104, 1010–1014 (1999).
    1. Tato L. et al.. Use of combined Gn-RH agonist and hGH therapy for better attining the goals in precocious puberty treatment. Horm Res 44 Suppl 3, 49–54 (1995).
    1. Saggese G., Bertelloni S., Baroncelli G. I., Di Nero G. & Battini R. Growth velocity and serum aminoterminal propeptide of type III procollagen in precocious puberty during gonadotropin-releasing hormone analogue treatment. Acta Paediatr 82, 261–266 (1993).
    1. Pasquino A. M. et al.. Combined treatment with gonadotropin-releasing hormone analog and growth hormone in central precocious puberty. J Clin Endocrinol Metab 81, 948–951, doi: 10.1210/jcem.81.3.8772556 (1996).
    1. Muller J., Juul A., Andersson A. M., Sehested A. & Skakkebaek N. E. Hormonal changes during GnRH analogue therapy in children with central precocious puberty. J Pediatr Endocrinol Metab 13 Suppl 1, 739–746 (2000).
    1. Wu J. M., Yu J. & Yang Y. Gene expression related to growth axis and gonadal axis in puberty rats. Zhong Xi Yi Jie He Xue Bao 1, 35–38 (2003).
    1. Cara J. F., Burstein S., Cuttler L., Moll G. W. Jr. & Rosenfield R. L. Growth hormone deficiency impedes the rise in plasma insulin-like growth factor I levels associated with precocious puberty. J Pediatr 115, 64–68 (1989).
    1. Pasquino A. M., Pucarelli I., Segni M., Matrunola M. & Cerroni F. Adult height in girls with central precocious puberty treated with gonadotropin-releasing hormone analogues and growth hormone. J Clin Endocrinol Metab 84, 449–452, doi: 10.1210/jcem.84.2.5431 (1999).
    1. Kohn B., Julius J. R. & Blethen S. L. Combined use of growth hormone and gonadotropin-releasing hormone analogues: the national cooperative growth study experience. Pediatrics 104, 1014–1018 (1999).
    1. Oostdijk W. et al.. Long-term results with a slow-release gonadotrophin-releasing hormone agonist in central precocious puberty. Dutch-German Precocious Puberty Study Group. Acta Paediatr Scand Suppl 372, 39–45; discussion 46 (1991).
    1. Volta C., Regazzi C., Ndaka J., Vitale R. & Bernasconi S. Combined therapy with luteinizing hormone releasing hormone agonist (LHRHa) and growth hormone (GH) in central precocious puberty. Acta Biomed 76, 73–78 (2005).
    1. Luo X. Clinical effect of GnRHa combined with recombinant human growth hormone (rhGH) in the treatment of idiopathic central precocious puberty (ICPP) in girls. China Modern Medicine 22, 107–109 (2015).
    1. Li Y., Liang L., Sun L. & Dong G. Treatment of post-menarche idiopathic central precocious puberty in girls with combined gonadotropin-releasing hormone analog and growth hormone. Chinese Journal of Pediatrics 43, 108–112 (2005).
    1. Wei Q., Zhou Z. & Li Y. Effects of treatment on idiopathic central precocious puberty with gonadotropin-releasing hormone analogue and growth hormone. Medical Information 16, 328–329 (2003).
    1. Zhang L. & Chen Z. The observation of combined use of gonadotropin-releasing hormone analogues and growth hormone in central precocious puberty. Fudan University Master’s Thesis (2012).
    1. Zhao Y., Zhang Q. & Gao X. The effect of recombinant human growth hormone on height during the GnRHa treatment for idiopathic central precocious puberty. Shandong Medical Journal 51, 60–61 (2011).
    1. Zheng P. et al.. Final adult height in girls with idiopathic central precocious puberty treated with gonadotropin-releasing hormone analogue and growth hormone. Chinese Journal of Endocrinology and Metabolism 27, 287–291 (2011).
    1. Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration (2011).
    1. Higgins J. P., Thompson S. G., Deeks J. J. & Altman D. G. Measuring inconsistency in meta-analyses. BMJ 327, 557–560, doi: 10.1136/bmj.327.7414.557 (2003).
    1. Deeks J A. D. & Bradburn M. Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. In Egger M. (eds) London: BMJ Books (2001).
    1. Egger M., Davey Smith G., Schneider M. & Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 315, 629–634 (1997).
    1. Sutton A. J., A. K., Jones D. R., Sheldon T. A. & Song F. Methods for meta-analysis in medical research. Chichester: Wiley. (2000).
    1. Bai H. Effect of combined treatment with gonadotropin-releasing hormone analogues and growth hormone in central precocious puberty. Shandong Medical Journal 53, 89–90 (2013).
    1. Liu H. & Wang Z. The efficacy of growth hormone in idiopathic central precocious puberty. Strait Journal of Preventive Medicine 19, 80–81 (2013).
    1. Sun X., Wu J., Yang F., Li P. & Wang X. Effects of treatment on female idiopathic central precocious puberty with gonadotrophine-releasing hormone analogue and growth hormone. Chinese Journal of Child Health Care 20, 731–734 (2012).
    1. Wu Q. The efficacy observation of combining GnRHa with rhGH to treat the big bone age female idiopathic precocious puberty. China Modern Medicine 19, 75–76 (2012).
    1. Liu C. & Li G. The effect of height improvement treated with GnRHa and rhGH in girls with big bone age of idiopathic central precocious puberty. Shandong University Master’s Thesis (2011).
    1. Ma H., Du M., Li Y., Su Z. & Chen S. Evaluation of combined treatment of gonadotropin-releasing hormone analog with recombinant human growth hormone in girls with central precocious puberty. Clin J Endocrinol Metab 22, 252–255 (2006).
    1. Fang L., Yao G., Jin Y., Zhu Z. & Zheng Z. Effect of short term of combined treatment with Gonadotropin-releasing hormone analogues and Growth hormone in central precocious puberty. Journal of Biology 18, 19–20 (2001).
    1. Wang C. et al.. Effects of gonadotropin releasing hormone analog and growth hormone on height in girls with idiopathic centralprecocious puberty. Chin J Contemp Pediatr 16, 25–30 (2014).
    1. Tonini G. & Lazzerini M. Side effects of GnRH analogue treatment in childhood. J Pediatr Endocrinol Metab 13 Suppl 1, 795–803 (2000).
    1. Carel J. C. et al.. Treatment of central precocious puberty by subcutaneous injections of leuprorelin 3-month depot (11.25 mg). J Clin Endocrinol Metab 87, 4111–4116, doi: 10.1210/jc.2001-020243 (2002).
    1. van Gool S. A. et al.. Final height outcome after three years of growth hormone and gonadotropin-releasing hormone agonist treatment in short adolescents with relatively early puberty. J Clin Endocrinol Metab 92, 1402–1408, doi: 10.1210/jc.2006-2272 (2007).
    1. Lem A. J., van der Kaay D. C. & Hokken-Koelega A. C. Bone mineral density and body composition in short children born SGA during growth hormone and gonadotropin releasing hormone analog treatment. J Clin Endocrinol Metab 98, 77–86, doi: 10.1210/jc.2012-2492 (2013).
    1. Liu H. et al.. Systematic review: the safety and efficacy of growth hormone in the healthy elderly. Ann Intern Med 146, 104–115 (2007).
    1. Saggese G. et al.. Effect of combined treatment with gonadotropin releasing hormone analogue and growth hormone in patients with central precocious puberty who had subnormal growth velocity and impaired height prognosis. Acta Paediatr 84, 299–304 (1995).
    1. Toumba M., Bacopoulou I., Savva S. C. & Skordis N. Efficacy of combined treatment with growth hormone and gonadotropin releasing hormone analogue in children with poor prognosis of adult height. Indian Pediatr 44, 497–502 (2007).
    1. Gyon Y., Yun Y. J., Kim Y. D. & Han H. S. Age at menarche and near final height after treatment with gonadotropin-releasing hormone agonist alone or combined with growth hormone in Korean girls with central precocious puberty. Clin Pediatr Endocrinol 24, 175–183, doi: 10.1297/cpe.24.175 (2015).
    1. Pucarelli I., Segni M., Ortore M., Arcadi E. & Pasquino A. M. Effects of combined gonadotropin-releasing hormone agonist and growth hormone therapy on adult height in precocious puberty: a further contribution. J Pediatr Endocrinol Metab 16, 1005–1010 (2003).
    1. Pucarelli I. et al.. Combined therapy with GnRH analog plus growth hormone in central precocious puberty. J Pediatr Endocrinol Metab 13 Suppl 1, 811–820 (2000).
    1. Tuvemo T. et al.. Final height after combined growth hormone and GnRH analogue treatment in adopted girls with early puberty. Acta Paediatr 93, 1456–1462, doi: 10.1080/08035250410021793 (2004).
    1. Mul D., Oostdijk W., Waelkens J. J., Schulpen T. W. & Drop S. L. Gonadotrophin releasing hormone agonist treatment with or without recombinant human GH in adopted children with early puberty. Clin Endocrinol (Oxf) 55, 121–129 (2001).
    1. Li P., Li Y. & Yang C. Gonadotropin releasing hormone agonist treatment to increase final stature in children with precocious puberty: a meta-analysis. Medicine (Baltimore) 93, e260, doi: 10.1097/MD.0000000000000260 (2014).
    1. Mauras N. et al.. Anastrozole increases predicted adult height of short adolescent males treated with growth hormone: a randomized, placebo-controlled, multicenter trial for one to three years. J Clin Endocrinol Metab 93, 823–831, doi: 10.1210/jc.2007-1559 (2008).
    1. 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, doi: 10.1210/jc.2007-0321 (2007).
    1. Growth Hormone Research, S. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. GH Research Society. J Clin Endocrinol Metab 85, 3990-3993, doi: 10.1210/jcem.85.11.6984 (2000).
    1. Toumba M., Kokotsis V., Savva S. C. & Skordis N. Expensive therapies in children: benefit versus cost of combined treatment of recombinant human growth hormone and gonadotropin-releasing hormone analogue in girls with poor height potential. J Pediatr Endocrinol Metab 27, 311–316, doi: 10.1515/jpem-2013-0210 (2014).
    1. Onuma T. A. et al.. Regulation of temporal and spatial organization of newborn GnRH neurons by IGF signaling in zebrafish. J Neurosci 31, 11814–11824, doi: 10.1523/JNEUROSCI.6804-10.2011 (2011).
    1. Divall S. A. et al.. Divergent roles of growth factors in the GnRH regulation of puberty in mice. J Clin Invest 120, 2900–2909, doi: 10.1172/JCI41069 (2010).
    1. Neal-Perry G., Yao D., Shu J., Sun Y. & Etgen A. M. Insulin-like growth factor-I regulates LH release by modulation of kisspeptin and NMDA-mediated neurotransmission in young and middle-aged female rats. Endocrinology 155, 1827–1837, doi: 10.1210/en.2013-1682 (2014).
    1. Tam C. S., de Zegher F., Garnett S. P., Baur L. A. & Cowell C. T. Opposing influences of prenatal and postnatal growth on the timing of menarche. J Clin Endocrinol Metab 91, 4369–4373, doi: 10.1210/jc.2006-0953 (2006).
    1. Sorensen K., Aksglaede L., Petersen J. H., Andersson A. M. & Juul A. Serum IGF1 and insulin levels in girls with normal and precocious puberty. Eur J Endocrinol 166, 903–910, doi: 10.1530/EJE-12-0106 (2012).

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