We found that IGF-1 had poor accuracy as demonstrated by low AUC, and poor sensitivity, specificity, and DE for the best cutoff of − 1.493 SD. The correlation analysis revealed that none of the items increased the diagnostic power of IGF-1 for GHD screening.
IGF-1 has been reported to be useful in the screening of GHD in some studies [3–7] but not in others [1, 8]. The reason for these contradictory results is that the patient groups and GHD cutoff values differed between these studies. First, the inclusion criteria may create differences in patient backgrounds. In previous studies on the usefulness of IGF-1 for GHD screening, patients were selected according to bone age [2], target height [3, 6], or catch-up growth [3] in addition to short stature and/or height velocity. These variations in inclusion criteria might superficially improve the sensitivity and specificity of IGF-1. Second, different GH cutoff levels for GHD were selected: ≤5 ng/mL [5, 6], ≤ 6 ng/mL [9], ≤ 7 ng/mL [1], ≤ 8 ng/mL [3, 8], and ≤ 10 ng/mL [4]. In the case of ≤ 8 or ≤ 10 ng/mL [3, 8], the prevalence of GHD in patients with short stature was > 30%, which was higher than that in our study (20.1%). Since disease prevalence affects sensitivity, specificity, PPV, and NPV, IGF-1 is not a useful screening test in a patient population with low prevalence of GHD. In the cohort of this study, the prevalence of GHD was decreased to 12.8% when the GH cutoff level of 5 ng/mL was selected. Therefore, when evaluating the efficacy of IGF-1, comparisons should be made at the same GH cutoff levels.
Bone age, target height, and height velocity should be taken into consideration before selecting patients for the GH secretion test [2]. In our study, bone age, target height, and height velocity before the examination were similar between the GHD and non-GHD groups. Even after combining these conditions with IGF-1, the diagnostic power of IGF-1 for GHD screening did not increase. Therefore, it would be difficult to distinguish patients with GHD from those without GHD using those parameters.
To clarify the relationship between pretreatment IGF-1 and response to GH, height velocity (SD) between groups with IGF-1 above (n = 34) and below (n = 26) the cutoff value (− 1.493 SD) was compared. Pre- and posttreatment height velocity (SD) were similar between the groups. IGF-1 was reported to be weakly correlated with the clinical endpoints of GH treatment [14]. Therefore, it would be difficult to predict the degree of improvement prior to GH treatment using pretreatment IGF-1.
We performed the third stimulation test when the results of GH secretion in the first and second tests were different. Although a sufficient GH response in one stimulation test rules out GHD in most cases [2], the utilization and interpretation of the drugs used in the stimulation test depends on the facility [1, 15]. In this study, pre- and posttreatment growth velocities were similar between the patients diagnosed with GHD on the second and third tests (Table 2). In any subgroup, height velocity before and after examination was not significantly different between those diagnosed on two and three tests. This result indicated that patients diagnosed with GHD by the third test have the similar response to growth hormone as those diagnosed by the traditional method. Therefore, the third simulation test may have some significance in diagnosing patients with GHD.
This study had several limitations. First, immunoassay for IGF-1 analysis is not the most sensitive assay. The variations in immunoassays used in different studies may result in variations in the reported efficacy of IGF-1. More accurate assays, such as LC-MS, may reveal the actual usefulness of IGF-1 for GHD screening. Second, the use of a third stimulation test is not a common practice. If one of the tests is normal, there is no need for a third one. Thus, if the cutoff for a normal GH peak is set at 6 ng/ml, all responses above 6 should be considered normal. However, depending on the order of each stimulation test, the diagnosis of GHD may vary among patients. For example, a patient with a peak GH < 6 ng/mL in A and B stimulation tests and ≥ 6 ng/mL in C stimulation test would not be diagnosed with GHD if the order of the stimulation tests were A, C, and B. There is no evidence on the order of stimulation tests, and the order varies from institution to institution. In the present study, the response to GH was similar in patients who had substandard results in two of the two stimulation tests and in those who had substandard results in two of the three stimulation tests. Therefore, it is necessary to accumulate such cases to clarify the significance of the third stimulation test.
In conclusion, IGF-1 level had poor diagnostic accuracy as a screening test for GHD. Correlation analysis revealed that none of the items increased the diagnostic power of IGF-1. Therefore, IGF-1 should not be used alone for the screening of GHD. A predictive biomarker for GHD should be developed in the future.