Evaluation of IGF1/IGFBP3 Molar Ratio as an Effective Tool for Assessing the Safety of Growth Hormone Therapy in Small-for-gestational-age, Growth Hormone-Deficient and Prader-Willi Children

Abstract

Objective: IGF1 concentration is the most widely used parameter for the monitoring and therapeutic adaptation of recombinant human growth hormone (rGH) treatment. However, more than half the variation of the therapeutic response is accounted for by variability in the serum concentrations of IGF1 and IGFBP3. We therefore compared the use of IGF1/IGFBP3 molar ratio with that of IGF1 concentration alone.

Methods: We selected 92 children on rGH for this study and assigned them to three groups on the basis of growth deficiency etiology: small for gestational age (SGA), GH deficiency (GHD) and Prader-Willi syndrome (PWS). Plasma IGF1 and IGFBP3 concentrations and their molar ratio were determined.

Results: Before rGH treatment, mean IGF1/IGFBP3 molar ratio in the SGA, GHD and PWS groups was 0.14±0.04, 0.07±0.01 and 0.12±0.02, respectively. After the initiation of rGH treatment, these averages were 0.19±0.07, 0.20±0.08 and 0.19±0.09, within the normal range for most children, even at puberty and despite some significant increases in serum IGF1 levels.

Conclusion: We consider IGF1/IGFBP3 molar ratio to be a useful additional parameter for assessing therapeutic safety in patients on rGH, and for maintaning the values within the normal range for age and pubertal stage.

Keywords: GH therapy; IGF1/IGFBP3 molar ratio; growth hormone deficiency; small for gestational age; Prader-Willi syndrome.

Figure 1

Distribution of IGF1/IGFBP3 ratio in the three groups before (A) and after (B) recombinant human growth hormone treatment. Rectangles represent values between +1 and -1 standard deviation scores (SDS) and bars represent SDS values SGA: small for gestational age, GHD: growth hormone deficiency, PWS: Prader-Willi syndrome

Figure 2

Distribution of IGF1 concentration (A) and IGF1/IGFBP3 molar ratio (B), in small for gestational age (SGA) children during growth hormone treatment. The IGF1 values have been distributed according to the standard deviation scores (SDS) intervals established by Bidlingmaier et al (10). In the SGA group, two children had IGF1 concentrations >+2 SDS, but IGF1/IGFBP3 molar ratios in the normal range (arrows)

Figure 3

Distribution of IGF1 (A) and IGF1/IGFBP3 molar ratio (B), in children with growth hormone deficiency (GHD) during GH treatment. In the GHD group, eight children had IGF1 concentrations >+2 SDS (circled cases), but IGF1/IGFBP3 molar ratios in the reference range. Conversely, one five-year-old child had an IGF1 concentrations in the reference range but a very high molar ratio due to a very low IGFBP3 concentration (<-2 SDS; arrow)

Figure 4

Distribution of IGF1 (A) and IGF1/IGFBP3 molar ratio (B), in children with Prader-Willi syndrome (PWS) during growth hormone (GH) treatment. In the PWS group, three children had discrepancies between serum IGF1 levels [expressed in standard deviation scores (SDS)] and IGF1/IGFBP3 molar ratio. 1^st case (arrow 1): 1.4-year-old child with PWS and an IGF1 concentration in the normal range (expressed in SDS) but a low molar ratio (due to very high IGFBP3 concentration >+2 SDS). 2^nd case (arrow 2): 5.4-year-old child with PWS and an IGF1 concentration in the normal range (expressed in SDS) but a high IGF1/IGFBP3 molar ratio (due to low IGFBP3 concentration). 3^rd case (arrow 3): 11.4-year-old child with a high IGF1 concentration (expressed in SDS) and an IGF1/IGFBP3 molar ratio in the reference range (IGFBP3 concentration towards the upper end of the reference range)