ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Endocrinol Metab. 2019;104:3287-3295.

The current definition of idiopathic short stature (ISS) refers to a heterogeneous group of short children, in the absence of any underlying detectable cause, including both normal variants of growth and pathological conditions. ISS subjects have been reported to reach an average final height of −1.5 SDS in boys and −1.6 SDS in girls [1,2], but with wide variability due to the different underlying conditions. In 2003, the FDA approved the use of GH in ISS children in USA, but its efficacy seems modest [3]. By slowing bone maturation and pubertal progression, gonadotropin-releasing hormone analogues (GnRHa) may prolong the time available for growth and there could be a rationale for their use as therapeutic agents in children with ISS. Studies on the efficacy of GnRHa in ISS subjects have provided conflicting results [4,5,6]. The effects of combination therapy with GnRHa and rhGH are variable [8,9] and not all studies have assessed data on adult height. Consequently, the combined treatment of GnRHa and rhGH is not currently recommended for ISS children [7].

This retrospective observational study reports the efficacy of combined GH + GnRHa therapy in a cohort of 192 ISS subjects treated either with GH alone (70%) or with the combined therapy (30%). Combined therapy was administered for 1.5 to 3 years in the prepubertal group (n=31), to children with relatively early pubertal onset (chronological age: boys >9.5 and <11; girls >8.5 and <10) and fast transition (<1 year) from Tanner stage 2 to 3; and in the pubertal group (n=27), to adolescents who were already in mid-puberty (Tanner stage 3–4) at referral. Both GH alone and combined treatment were effective in improving adult height compared to predicted adult and target height; the benefits were more pronounced in children who were prepubertal at baseline. However, the adult height achieved by GH-treated patients was within the normal population range irrespective of the treatment regimen and most of the children, whether treated by GH alone or by combined GH/GnRHa, reached an adult height within their mid-parental height range.

These findings strongly suggest that most of the children enrolled in the trial had a constitutional delay of growth and puberty (CDGP), a normal variant of growth which does not affect the achievement of a normal adult height. Indeed, the current definition of ISS encompasses many children with CDGP who do not need any treatment for achieving a normal adult height. In this respect, this study lacks a control group of untreated ISS children. Another major limitation lies in the retrospective observational design and the consequent absence of a close matching between the study groups. Finally, a recent randomized controlled study has raised a safety issue for the potential negative impact of such combined therapy on the incidence of bone fractures [10].

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2. Rekers-Mombarg LT, Wit JM, Massa GG, Ranke MB, Buckler JM, Butenandt O, Chaussain JL, Frisch H, Leiberman E. Spontaneous growth in idiopathic short stature. European Study Group. Arch Dis Child 1996;75:175–180.

3. Deodati A, Cianfarani S. Impact of growth hormone therapy on adult height of children with idiopathic short stature: systematic review. Bmj 2011;342:c7157.

4. Yanovski JA, Rose SR, Municchi G, Pescovitz OH, Hill SC, Cassorla FG, Cutler GB, Jr. Treatment with a luteinizing hormone-releasing hormone agonist in adolescents with short stature. N Engl J Med 2003;348:908–917.

5. Municchi G, Rose SR, Pescovitz OH, Barnes KM, Cassorla FG, Cutler GB, Jr. Effect of deslorelin-induced pubertal delay on the growth of adolescents with short stature and normally timed puberty: preliminary results. J Clin Endocrinol Metab 1993;77:1334–1339.

6. Carel JC, Hay F, Coutant R, Rodrigue D, Chaussain JL. Gonadotropin-releasing hormone agonist treatment of girls with constitutional short stature and normal pubertal development. J Clin Endocrinol Metab 1996;81:3318–3322.

7. Carel JC, Eugster EA, Rogol A, Ghizzoni L, Palmert MR, Antoniazzi F, Berenbaum S, Bourguignon JP, Chrousos GP, Coste J, Deal S, de Vries L, Foster C, Heger S, Holland J, Jahnukainen K, Juul A, Kaplowitz P, Lahlou N, Lee MM, Lee P, Merke DP, Neely EK, Oostdijk W, Phillip M, Rosenfield RL, Shulman D, Styne D, Tauber M, Wit JM. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics 2009;123:e752–762.

8. Balducci R, Toscano V, Mangiantini A, Municchi G, Vaccaro F, Picone S, Di Rito A, Boscherini B. Adult height in short normal adolescent girls treated with gonadotropin-releasing hormone analog and growth hormone. J Clin Endocrinol Metab 1995;80:3596–3600.

9. Kamp GA, Mul D, Waelkens JJ, Jansen M, Delemarre-van de Waal HA, Verhoeven-Wind L, Frolich M, Oostdijk W, Wit JM. A randomized controlled trial of three years growth hormone and gonadotropin-releasing hormone agonist treatment in children with idiopathic short stature and intrauterine growth retardation. J Clin Endocrinol Metab 2001;86:2969–2975.

10. Benabbad I, Rosilio M, Tauber M, Paris E, Paulsen A, Berggren L, Patel H, Carel JC. Growth hormone in combination with leuprorelin in pubertal children with idiopathic short stature. Endocr Connect 2018;7:708–718.