Editorial
HOR MON E RE SE ARCH I N PÆDIATRIC S
Horm Res Paediatr 2014;82:143–144 DOI: 10.1159/000363108
Published online: August 28, 2014
Is High-Dose Growth Hormone Treatment during Puberty Worthwhile? Stefano Cianfarani
Growth hormone (GH) production markedly increases during puberty, almost doubling the prepubertal circulating levels. This increase in mean levels occurs earlier in girls than in boys, is evident at night and is due to an increase in pulse amplitude rather than a change in pulse frequency [1]. This evidence has prompted some authors to mimic what occurs in physiology to test the efficacy of high-dose GH therapy in pubertal GH-deficient patients [2, 3]. It must be noted that reproducing the normal physiological patterns of GH secretion and activity is impossible with currently available modes and routes of administration of exogenous GH [4]. Nevertheless, preliminary results were indeed promising, showing a significant increase in pubertal height gain and near adult height [2, 3]. Subsequent divergent results [5] and the high cost-effectiveness ratio have limited the clinical application of this therapeutic approach. In this issue of Hormone Research in Paediatrics, Albertsson-Wikland et al. [6] report the favorable impact that high-dose GH treatment during puberty has on height gain and the adult height of children with idiopathic isolated GH deficiency (GHD). The authors conducted a nation-wide, multicenter, randomized, controlled trial, allocating the study cohort (111 intention-to-treat and 85 per-protocol patients) to three different treatment regimens at the onset of puberty: a standard dose (33 μg/kg/ day) or a double dose (67 μg/kg/day) injected once or twice daily. The results of this study show a significant increase in adult height (+0.4 SDS, corresponding to a mean © 2014 S. Karger AG, Basel 1663–2818/14/0823–0143$39.50/0 E-Mail [email protected] www.karger.com/hrp
of 2.4 cm) in the children treated with the higher dose, with no difference between the once- and twice-daily regimens. They conclude that the high-dose treatment regimen, due to high costs, should be limited to children who start replacement therapy late or who have more severe growth retardation at the onset of puberty. Although this is an original and well-designed study with potential clinical implications, it raises a number of issues which should be critically addressed. First, the diagnosis of GHD was based on the peak GH responses to two stimulation tests 3 SDS, but they do not report the percentage for whom the upper limit of normal range (2 SDS) was exceeded, i.e. the safety threshold dur-
ing GH therapy. They disregard the French data showing increased overall mortality in subjects treated with GH in childhood and adolescence [12] and the warning from the European Medicines Agency that followed, i.e. to stick to the approved GH doses for the different indications and avoid doses >50 μg/kg/day. A recent systematic review and meta-analysis has confirmed the higher all-cause mortality risk related to GH treatment [13]. Fourth, this article raises the pharmacoeconomic issue of the cost-effectiveness ratio of this therapeutic approach. The results show a mean final difference of 2.4 cm in adult height between treated and untreated children after 5 years on double-dose treatment. Considering that the average annual cost of GH therapy is about EUR 20,000 per year of treatment at standard doses, the final figure is more than EUR 80,000 per gained centimeter with high doses. Finally, practitioners and policy makers need to address the clinical importance and value of the possible extra 2.4 cm height gain in relation to the goals of treatment. Consideration of additional factors will be important for deciding whether such high doses should be used in GH-deficient children, including the impact of this small height gain on the physical and psychosocial wellbeing of the patients, their expectations, and adverse effects and cost of therapy.
1 Rose SR, Municchi G, Barnes KM, Kamp GA, Uriarte MM, Ross JL, et al: Spontaneous growth hormone secretion increases during puberty in normal girls and boys. J Clin Endocrinol Metab 1991;73:428–435. 2 Mauras N, Attie KM, Reiter EO, Saenger P, Baptista J: High-dose recombinant human growth hormone (GH) treatment of GH-deficient patients in puberty increases near-final height: a randomized, multicenter trial. Genentech Inc. Cooperative Study Group. J Clin Endocrinol Metab 2000;85:3653–3660. 3 Riddick L, Alter C, Davis DA, Frane J, Lippe B, Bakker B: A stepwise increase in recombinant human growth hormone dosing during puberty achieves improved pubertal growth: a national cooperative growth study report. J Pediatr Endocrinol Metab 2009;22:623–628. 4 Drake WM, Howell SJ, Monson JP, Shalet SM: Optimizing GH therapy in adults and children. Endocr Rev 2001;22:425–450. 5 Coelho R, Brook CG, Preece MA, Stanhope RG, Dattani MT, Hindmarsh PC: A randomised study of two doses of biosynthetic human growth hormone on final height of
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pubertal children with growth hormone deficiency. Horm Res 2008;70:85–88. Albertsson-Wikland K, Kriström B, Lundberg E, Aronson AS, Gustafsson J, Hagenäs L, Ivarsson SA, Jonsson B, Ritzén M, Tuvemo T, Westgren U, Westphal O, Åman J: Growth Hormone Dose-Dependent Pubertal Growth: A Randomized Trial in Short Children with Low Growth Hormone Secretion. Horm Res Paediatr 2014; 82: 158–170. Lazar L, Phillip M: Is sex hormone priming in peripubertal children prior to growth hormone stimulation tests still appropriate? Horm Res Paediatr 2010;73:299–302. Cacciari E, Tassoni P, Parisi G, Pirazzoli P, Zucchini S, Mandini M, et al: Pitfalls in diagnosing impaired growth hormone (GH) secretion: retesting after replacement therapy of 63 patients defined as GH-deficient. J Clin Endocrinol Metab 1992;74:1284–1289. Tauber M, Moulin P, Pienkowski C, Jouret B, Rochiccioli P: Growth hormone (GH) retesting and auxological data in 131 GH-deficient patients after completion of treatment. J Clin Endocrinol Metab 1997;82:352–356.
Horm Res Paediatr 2014;82:143–144 DOI: 10.1159/000363108
10 Inzaghi E, Cianfarani S: The challenge of growth hormone deficiency diagnosis and treatment during the transition from puberty into adulthood. Front Endocrinol (Lausanne) 2013;20:4:34. 11 Reiter EO, Price DA, Wilton P, AlbertssonWikland K, Ranke MB: Effect of growth hormone (GH) treatment on the near-final height of 1,258 patients with idiopathic GH deficiency: analysis of a large international database. J Clin Endocrinol Metab 2006; 91: 2047–2054. 12 Carel JC, Ecosse E, Landier F, MeguellatiHakkas D, Kaguelidou F, Rey G, et al: Longterm mortality after recombinant growth hormone treatment for isolated growth hormone deficiency or childhood short stature: preliminary report of the French SAGhE study. J Clin Endocrinol Metab 2012;97:416–425. 13 Deodati A, Baldini Ferroli B, Cianfarani S: Association between growth hormone therapy and mortality, cancer and cardiovascular risk: systematic review and meta-analysis. Growth Horm IGF Res 2014, DOI: 10.1016/j.ghir. 2014.02.001.
Cianfarani
Downloaded by: Mount Sinai School of Medicine 146.203.151.55 - 12/8/2014 9:17:42 AM
References
HOR MON E RE SE ARCH I N PÆDIATRIC S
Horm Res Paediatr 2014;82:143–144 DOI: 10.1159/000363108
Published online: August 28, 2014
Is High-Dose Growth Hormone Treatment during Puberty Worthwhile? Stefano Cianfarani
Growth hormone (GH) production markedly increases during puberty, almost doubling the prepubertal circulating levels. This increase in mean levels occurs earlier in girls than in boys, is evident at night and is due to an increase in pulse amplitude rather than a change in pulse frequency [1]. This evidence has prompted some authors to mimic what occurs in physiology to test the efficacy of high-dose GH therapy in pubertal GH-deficient patients [2, 3]. It must be noted that reproducing the normal physiological patterns of GH secretion and activity is impossible with currently available modes and routes of administration of exogenous GH [4]. Nevertheless, preliminary results were indeed promising, showing a significant increase in pubertal height gain and near adult height [2, 3]. Subsequent divergent results [5] and the high cost-effectiveness ratio have limited the clinical application of this therapeutic approach. In this issue of Hormone Research in Paediatrics, Albertsson-Wikland et al. [6] report the favorable impact that high-dose GH treatment during puberty has on height gain and the adult height of children with idiopathic isolated GH deficiency (GHD). The authors conducted a nation-wide, multicenter, randomized, controlled trial, allocating the study cohort (111 intention-to-treat and 85 per-protocol patients) to three different treatment regimens at the onset of puberty: a standard dose (33 μg/kg/ day) or a double dose (67 μg/kg/day) injected once or twice daily. The results of this study show a significant increase in adult height (+0.4 SDS, corresponding to a mean © 2014 S. Karger AG, Basel 1663–2818/14/0823–0143$39.50/0 E-Mail [email protected] www.karger.com/hrp
of 2.4 cm) in the children treated with the higher dose, with no difference between the once- and twice-daily regimens. They conclude that the high-dose treatment regimen, due to high costs, should be limited to children who start replacement therapy late or who have more severe growth retardation at the onset of puberty. Although this is an original and well-designed study with potential clinical implications, it raises a number of issues which should be critically addressed. First, the diagnosis of GHD was based on the peak GH responses to two stimulation tests 3 SDS, but they do not report the percentage for whom the upper limit of normal range (2 SDS) was exceeded, i.e. the safety threshold dur-
ing GH therapy. They disregard the French data showing increased overall mortality in subjects treated with GH in childhood and adolescence [12] and the warning from the European Medicines Agency that followed, i.e. to stick to the approved GH doses for the different indications and avoid doses >50 μg/kg/day. A recent systematic review and meta-analysis has confirmed the higher all-cause mortality risk related to GH treatment [13]. Fourth, this article raises the pharmacoeconomic issue of the cost-effectiveness ratio of this therapeutic approach. The results show a mean final difference of 2.4 cm in adult height between treated and untreated children after 5 years on double-dose treatment. Considering that the average annual cost of GH therapy is about EUR 20,000 per year of treatment at standard doses, the final figure is more than EUR 80,000 per gained centimeter with high doses. Finally, practitioners and policy makers need to address the clinical importance and value of the possible extra 2.4 cm height gain in relation to the goals of treatment. Consideration of additional factors will be important for deciding whether such high doses should be used in GH-deficient children, including the impact of this small height gain on the physical and psychosocial wellbeing of the patients, their expectations, and adverse effects and cost of therapy.
1 Rose SR, Municchi G, Barnes KM, Kamp GA, Uriarte MM, Ross JL, et al: Spontaneous growth hormone secretion increases during puberty in normal girls and boys. J Clin Endocrinol Metab 1991;73:428–435. 2 Mauras N, Attie KM, Reiter EO, Saenger P, Baptista J: High-dose recombinant human growth hormone (GH) treatment of GH-deficient patients in puberty increases near-final height: a randomized, multicenter trial. Genentech Inc. Cooperative Study Group. J Clin Endocrinol Metab 2000;85:3653–3660. 3 Riddick L, Alter C, Davis DA, Frane J, Lippe B, Bakker B: A stepwise increase in recombinant human growth hormone dosing during puberty achieves improved pubertal growth: a national cooperative growth study report. J Pediatr Endocrinol Metab 2009;22:623–628. 4 Drake WM, Howell SJ, Monson JP, Shalet SM: Optimizing GH therapy in adults and children. Endocr Rev 2001;22:425–450. 5 Coelho R, Brook CG, Preece MA, Stanhope RG, Dattani MT, Hindmarsh PC: A randomised study of two doses of biosynthetic human growth hormone on final height of
144
6
7
8
9
pubertal children with growth hormone deficiency. Horm Res 2008;70:85–88. Albertsson-Wikland K, Kriström B, Lundberg E, Aronson AS, Gustafsson J, Hagenäs L, Ivarsson SA, Jonsson B, Ritzén M, Tuvemo T, Westgren U, Westphal O, Åman J: Growth Hormone Dose-Dependent Pubertal Growth: A Randomized Trial in Short Children with Low Growth Hormone Secretion. Horm Res Paediatr 2014; 82: 158–170. Lazar L, Phillip M: Is sex hormone priming in peripubertal children prior to growth hormone stimulation tests still appropriate? Horm Res Paediatr 2010;73:299–302. Cacciari E, Tassoni P, Parisi G, Pirazzoli P, Zucchini S, Mandini M, et al: Pitfalls in diagnosing impaired growth hormone (GH) secretion: retesting after replacement therapy of 63 patients defined as GH-deficient. J Clin Endocrinol Metab 1992;74:1284–1289. Tauber M, Moulin P, Pienkowski C, Jouret B, Rochiccioli P: Growth hormone (GH) retesting and auxological data in 131 GH-deficient patients after completion of treatment. J Clin Endocrinol Metab 1997;82:352–356.
Horm Res Paediatr 2014;82:143–144 DOI: 10.1159/000363108
10 Inzaghi E, Cianfarani S: The challenge of growth hormone deficiency diagnosis and treatment during the transition from puberty into adulthood. Front Endocrinol (Lausanne) 2013;20:4:34. 11 Reiter EO, Price DA, Wilton P, AlbertssonWikland K, Ranke MB: Effect of growth hormone (GH) treatment on the near-final height of 1,258 patients with idiopathic GH deficiency: analysis of a large international database. J Clin Endocrinol Metab 2006; 91: 2047–2054. 12 Carel JC, Ecosse E, Landier F, MeguellatiHakkas D, Kaguelidou F, Rey G, et al: Longterm mortality after recombinant growth hormone treatment for isolated growth hormone deficiency or childhood short stature: preliminary report of the French SAGhE study. J Clin Endocrinol Metab 2012;97:416–425. 13 Deodati A, Baldini Ferroli B, Cianfarani S: Association between growth hormone therapy and mortality, cancer and cardiovascular risk: systematic review and meta-analysis. Growth Horm IGF Res 2014, DOI: 10.1016/j.ghir. 2014.02.001.
Cianfarani
Downloaded by: Mount Sinai School of Medicine 146.203.151.55 - 12/8/2014 9:17:42 AM
References
