ESPE Yearbook of Paediatric Endocrinology

J Clin Endocrinol Metab, August 2020, 105(8):e2796–e2806. doi: 10.1210/clinem/dgaa287. PMID: 32436961

The aim of this longitudinal study was to investigate the potential long-term adverse effects of combined GnRHa/GH treatment on metabolic and bone health in short SGA children. Reassuring data are found at 5 years after cessation of GH therapy.

Children born small for gestational age (SGA) have weight and/or length at birth less than -2 SDS for gestational age (1),(2). Approximately 10% of SGA children do not catch-up their growth retardation and have permanent short stature. Growth Hormone (GH) treatment is effective in improving the growth outcome of SGA children especially when therapy is started well before the onset of puberty. In children born SGA with predicted adult height less than -2.5 S.D., the combined therapy with GH plus 2-years gonadotropin releasing hormone analogues (GnRHa) has been suggested to postpone puberty and eventually increase adult height (3). Therapy with GnRH analogues may affect fat deposition, BMI and bone density as shown in retrospective studies conducted in children with central precocious puberty.

In this study, insulin sensitivity and β-cell function (by frequently sampled intravenous glucose tolerance tests, FSIGT), blood pressure, serum lipid levels, body composition and bone mineral density (by dual-energy x-ray absorptiometry (DXA) scans), were assessed during the 5 years after cessation of GH therapy in SGA young adults who were treated during childhood with the combination of GH+GnRHa (n=112) compared to those treated with GH alone (n=251) and 145 age-matched adults born appropriate for gestational age (AGA). In the GH treated group, a subgroup (n=95) was randomly assigned to treatment with either GH 1 or 2 mg/m2/day (~ 0.033 or 0.067 mg/kg/d).

At 5 years after discontinuation of GH therapy, the three groups showed no significant differences in fat mass, FSIGT results, blood pressure, serum lipid levels and bone mineral density. Total fat mass and trunk fat were lower, and lean body mass was higher in those treated with 2 mg GH/m²/day, compared to 1 mg GH/m²/day, whereas FSIGT results, limb fat, blood pressure, serum lipid levels, and bone density were similar in both GH-dose groups.

This further elegant study from the Rotterdam team shows that combined GnRHa/GH therapy is not associated with long-term adverse effects on metabolism, body composition and bone mineralization markers. However, the efficacy of the combined GH/GnRHa therapy has to be tested in a larger group of short SGA children before being transferred to clinical practice. Moreover, it has to be pointed out that the available metabolic markers are a surrogate of the real cardiometabolic status. In this regard, two recent studies reporting an increased long-term cardiovascular morbidity (4) and mortality (5) in SGA young adults treated with GH during childhood raises concern about a potential, likely IGF1-mediated, adverse effect on endothelial function, whose detection may elude the standard metabolic assessment (6).

Reference: 1. Saenger P, Czernichow P, Hughes I, Reiter EO. Small for gestational age: short stature and beyond. Endocr Rev. 2007;28(2):219–51.2. Clayton PE, Cianfarani S, Czernichow P, Johannsson G, Rapaport R, Rogol A. Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metab. 2007;92(3):804–10.3. Lem AJ, van der Kaay DC, de Ridder MA, Bakker-van Waarde WM, van der Hulst FJ, Mulder JC, et al. Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog: results of a randomized, dose-response GH trial. J Clin Endocrinol Metab. 2012;97(11):4096–105.4. Sävendahl L, Cooke R, Tidblad A, Beckers D, Butler G, Cianfarani S, et al. Long-term mortality after childhood growth hormone treatment: the SAGhE cohort study. Lancet Diabetes Endocrinol. 2020;8(8):683–92.5. Tidblad A, Bottai M, Kieler H, Albertsson-Wikland K, Sävendahl L. Association of Childhood Growth Hormone Treatment With Long-term Cardiovascular Morbidity. JAMA Pediatr. 2021;175(2):e205199.6. Bach LA. Endothelial cells and the IGF system. J Mol Endocrinol. 2015;54(1):R1–13.