ESPE Yearbook of Paediatric Endocrinology

JAMA Pediatr. 2021;175(2):e205199. doi: 10.1001/jamapediatrics.2020.5199. PMID: 33346824

This nationwide population-based study assessed the long-term risk of cardiovascular events in patients who had received rhGH therapy during childhood and adolescence. The study cohort comprised 3.408 subjects treated under the GHD, SGA or ISS indications, and 50 036 age-, sex-, and region-based matched controls. Median follow-up was 14.9 years (to age 25 years) with a total of 795 125 person-years. Patients in each diagnostic group had a significant higher risk for cardiovascular events than controls (hazard ratio 1.69; 95% CI, 1.30–2.19), especially women (HR, 2.95; 95%CI, 1.31–3.20) and those treated for SGA (HR, 1.97, %CI, 1.28-3.04). The increased risk was found in all treated groups and was associated with longer therapy duration and cumulative rhGH dose. The most common severe cardiovascular events were ischemic heart disease, cardiomyopathy and stroke.

GH has pleiotropic effects on the cardiovascular system (1). Acromegaly, a pathological model of exposure to high GH concentrations, is characterized by an increased cardiovascular mortality (2). The results of this study are consistent with previous data from French SAGhE cohort showing higher cerebrovascular mortality (3) and a higher risk of hemorrhagic stroke in subjects receiving rhGH for GHD, SGA and ISS indications during childhood (4). The authors wondered whether the observed increased cardiovascular risk might have been caused by discontinuation of rhGH treatment in adulthood in GHD patients rather than treatment during childhood. However, a further analysis of data from patients who continued therapy after completion of growth confirmed the increased cardiovascular morbidity.

These results are consistent with those reported by the SAGHE consortium (see paper 4.6). It should be noted that neither of these study designs can separate effects of rhGH therapy from risks related to the underlying condition. However, they further suggest the need of a long-term close cardiovascular monitoring in children treated with rhGH, especially in women and those treated for the SGA indication.

Reference: 1. Caicedo D, Díaz O, Devesa P, Devesa J. Growth Hormone (GH) and Cardiovascular System. Int J Mol Sci. 2018;19(1).2. Brevetti G, Marzullo P, Silvestro A, Pivonello R, Oliva G, di Somma C, et al. Early vascular alterations in acromegaly. J Clin Endocrinol Metab. 2002;87(7):3174–9.3. Carel JC, Ecosse E, Landier F, Meguellati-Hakkas D, Kaguelidou F, Rey G, et al. Long-term 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(2):416–25.4. Poidvin A, Touze E, Ecosse E, Landier F, Bejot Y, Giroud M, et al. Growth hormone treatment for childhood short stature and risk of stroke in early adulthood. Neurology. 2014;83(9):780–6.