ISSN 1662-4009 (Online)

ESPE Yearbook of Paediatric Endocrinology (2019) 16 4.5 | DOI: 10.1530/ey.16.4.5

The beneficial effect of combined GH/GnRHa therapy in increasing adult height outcome in children with ISS

Lazar L, Levy S, Oron T, Meyerovitch J, de Vries L, Shalitin S, Tenenbaum A, Phillip M & Lebenthal Y.



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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