ESPE Yearbook of Paediatric Endocrinology

Brief summary: The objective of this study was to examine whether IGF-I and IGF-binding protein-3 (IGFBP-3) levels track through childhood into adulthood and to estimate the cumulative lifetime exposure to IGF-I in healthy individuals and in individuals with a defined period of increased IGF-I levels because of GH therapy.

Measurement of serum IGF-I is a cornerstone in rhGH treatment monitoring. Keeping serum IGF-I concentrations within the normal reference range is recommended as a safety measure, given the epidemiologic associations between high serum IGF-I and cancer risk (1-2).

Samples from 6459 healthy participants (cross-sectional=5326; longitudinal=1133) aged 0–76 years (9963 serum samples) and 9 patients born small-for-gestational-age (SGA) with 238 serum samples during rhGH treatment were included.

IGF-I and IGFBP-3 levels showed age-dependent changes with a rapid decrease after birth, increasing levels during childhood, and peak levels around puberty followed by a post-pubertal decrease and a continuous subtle decline throughout adulthood.

Individuals were stratified into tertiles based on their mean IGF-I or IGFBP-3 SD score (SDS). Throughout the period of life considered, the majority of the participants stayed within the same tertile, allowing the authors to draw the conclusion that a single measurement of IGF-I (SDS) is a reliable approximation of cumulative lifetime exposure.

As an estimate of cumulative lifetime exposure to IGF-I, the area under the curve (AUC) for 0 to 76 years was calculated. For SGA patients, the actual AUC during the years of rhGH treatment and a predicted AUC (under the hypothesized scenario that rhGH treatment was not used) were calculated.

The estimated cumulative lifetime exposure to IGF-I without GH treatment was below the average in SGA patients, whereas GH treatment increased IGF-I by 0.6 SDS, shifting the patients from having IGF-I levels in the lowest tertile to the middle tertile. However, the cumulative lifetime IGF-I exposure in GH-treated SGA patients remained below the average of the reference population.

In conclusion, IGF-I and IGFBP-3 levels track throughout life, suggesting that a single IGF-I measurement is reliable to assess long-term exposure and rhGH therapy in childhood does not increase the cumulative lifetime exposure to IGF-I beyond levels of healthy individuals. This latter seems to be reassuring in relation to the safety of rhGH treatment, especially in non-GHD children, who more easily reach supraphysiologic IGF-I concentrations during rhGH treatment. However, the reported data clearly show that rhGH treated subjects experience a transient period of exposure to IGF-I levels significantly higher than the genetically determined concentrations thus leaving unanswered the question about a possible detrimental effect of this transitory overexposure.

References: 1. Renehan AG, Zwahlen M, Minder C, O’Dwyer ST, Shalet SM, Egger M. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet. 2004;363(9418):1346–1353. 2. Sävendahl L, Cooke R, Tidblad A, et al. Long-term mortality after childhood growth hormone treatment: the SAGhE cohort study. Lancet Diabetes Endocrinol. 2020;8(8):683–692.