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Serum IGF-1 to IGFBP-3 Molar Ratio: A Promising Diagnostic Tool for Growth Hormone Deficiency in Children

This study aimed to evaluate the effectiveness of the serum IGF-1/IGFBP-3 ratio in diagnosing growth hormone deficiency (GHD) in children with short stature (SS). In a 7-year cross-sectional observational study involving 235 children, the participants were divided into GHD and non-GHD groups. The results showed that a low serum IGF-1/IGFBP-3 ratio had the highest sensitivity (87.5%) and comparable specificity (83.0%) for diagnosing GHD among all studied variables. Combining low serum IGF-1, IGFBP-3, and IGF-1/IGFBP-3 ratio yielded the highest specificity for GHD (97.7%). The study suggests that the serum IGF-1/IGFBP-3 ratio is a useful marker for diagnosing GHD in children without other disorders affecting serum IGF-1 levels. However, further large-scale studies are needed to confirm the diagnostic utility of the serum IGF-1/IGFBP-3 ratio.

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This commentary on MyEndoConsult (MEC), written by MEC author Akuffo Quarde, MD, and MEC editor Alan Sacerdote, MD, explores an article titled "Serum IGF-1 to IGFBP-3 Molar Ratio: A Promising Diagnostic Tool for Growth Hormone Deficiency in Children" published in the JCEM.

Commentary

AQ: Hey Alan, I recently read a clinical study on the diagnostic utility of the serum IGF-1 to IGFBP-3 molar ratio for growth hormone deficiency (GHD) in children with short stature (SS). The study was conducted on 235 children over seven years and investigated the diagnostic utility of the IGF-1/IGFBP-3 ratio in diagnosing GHD

AS: That's interesting. So, what did they find about the performance of the IGF-1/IGFBP-3 ratio in diagnosing GHD?

AQ: The study showed that a low serum IGF-1/IGFBP-3 ratio had the highest sensitivity for GHD at 87.5%, with a specificity of 83.0%. When they combined low serum IGF-1, IGFBP-3, and IGF-1/IGFBP-3 ratio, the specificity for GHD increased to 97.7%. On the other hand, the combination of normal serum IGF-1, IGFBP-3, and IGF-1/IGFBP-3 ratio had the highest specificity for a non-GHD cause of SS at 100.0%.

AS: That's quite impressive. It seems like the serum IGF-1/IGFBP-3 ratio could be a useful marker for diagnosing GHD in children without other disorders that may affect serum IGF-1 levels. Did the authors mention any limitations of their study?

AQ: Yes, they acknowledged a few limitations. The study didn't include certain groups of participants, like those with disorders that could affect serum IGF-1 levels and those with a BMI ≥ 25 kg/m2. Additionally, the study was conducted at a single hospital, which might limit the generalizability of the results.

AS: It's good that they recognized those limitations. I suppose further research in other countries and involving more diverse populations would help to confirm the diagnostic utility of the serum IGF-1/IGFBP-3 ratio.

AQ: Absolutely. It would also be interesting to see if a low IGF-1 to IGFBP-3 molar ratio could identify potential responders to GH therapy in cases where GH stimulation tests show optimal responses. This could help to better identify patients who may benefit from GH therapy, especially given the arbitrary nature of traditional GH stimulation tests.

AS: Agreed. The study seems to have opened up some new avenues for research in this area. I look forward to seeing how this field evolves in the coming years.

AQ: Can you shed some light on existing research experience in this area of scientific inquiry?

AS: Absolutely. The literature on the IGF-1/IGFBP-3 molar ratio and its role in diagnosing GHD is quite diverse. As you mentioned earlier, the sensitivity and specificity of IGF-1 and IGFBP-3 as diagnostic tools for GHD vary greatly depending on factors like the cutoff limits, age groups, and immunoassays used. A 2015 meta-analysis of 12 studies actually found that the sensitivities of IGF-1 and IGFBP-3 were 66% and 50%, respectively, while the specificities were 69% and 79%, respectively (1).

Other potential applications of the IGF-1/IGFBP-3 molar ratio have also been explored in the literature, such as its role as a biomarker for compliance and safety of GH therapy (2,3) and its utility in diagnosing GHD in adults (4). Granada et al. investigated the diagnostic role of serum IGF-1/IGFBP-3 molar ratio in 27 adult patients with GHD and found that the sensitivity and specificity for the diagnosis of adult GHD were 37% and 99.3%, respectively (4). The high specificity in their study may be due to the normal health of their control group, which didn't have any chronic disease or disorder affecting the GH-IGF-1 axis.

AQ: That's interesting, Alan. Based on this study and the literature you mentioned, it seems that the IGF-1/IGFBP-3 molar ratio holds promise as a diagnostic tool for GHD in children. However, it's important to note that the study we're discussing has its limitations, such as not including certain participant groups, recruiting participants from a single hospital, and using the World Health Organization growth charts instead of locally tailored growth charts.

AS: You're right, AQ. These limitations do affect the generalizability of the study's findings. However, as the hospital is the main referral medical center for the Ministry of Health medical system in Jordan, the results may still apply to the general population in the country. Further research is needed to investigate the diagnostic utility of the serum IGF-1/IGFBP-3 ratio in larger, more diverse populations, as well as to explore whether a low IGF-1/IGFBP-3 molar ratio can identify potential responders to GH therapy in settings where an optimal response to GH stimulation tests is equivocal.

AQ: There's definitely more research to be done in this area. Nevertheless, this study provides valuable insight into the potential of the IGF-1/IGFBP-3 molar ratio as a diagnostic tool for GHD in children without other disorders affecting serum IGF-1 levels. It'll be interesting to see how this field of research develops in the future.

Reference

  1. Shen Y, Zhang J, Zhao Y, Yan Y, Liu Y, Cai J. Diagnostic value of serum IGF-1 and IGFBP-3 in growth hormone deficiency: a systematic review with meta-analysis. Eur J Pediatr. 2015;174(4):419–427.
  2. Scirè G, del Bianco C, Spadoni GL, Cianfarani S. Growth hormone therapy does not alter the insulin-like growth factor-I/insulin-like growth factor binding protein-3 molar ratio in growth hormone-deficient children. J Endocrinol Invest. 2008;31(2):153–158.
  3. Gaddas M, Périn L, le Bouc Y. 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. J Clin Res Pediatr Endocrinol. 2019;11(3):253–261.
  4. Granada ML, Murillo J, Lucas A, et al.  Diagnostic efficiency of serum IGF-I, IGF-binding protein-3 (IGFBP-3), IGF-I/IGFBP-3 molar ratio and urinary GH measurements in the diagnosis of adult GH deficiency: importance of an appropriate reference population. Eur J Endocrinol. 2000;142(3):243–253.
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