Individualised growth response optimisation (iGRO) tool: an accessible and easy-to-use growth prediction system to enable treatment optimisation for children treated with growth hormone.

BACKGROUND: Growth prediction models (GPMs) exist to support clinical management of children treated with growth hormone (GH) for growth hormone deficiency (GHD), Turner syndrome (TS) and for short children born small for gestational age (SGA). Currently, no prediction system has been widely adopted. CONTENT: The objective was to develop a stand-alone web-based system to enable the widespread use of an 'individualised growth response optimisation' (iGRO) tool across European endocrinology clinics. A modern platform was developed to ensure compatibility with IT systems and web browsers. Seventeen GPMs derived from the KIGS database were included and tested for accuracy. SUMMARY: The iGRO system demonstrated prediction accuracy and IT compatibility. The observed discrepancies between actual and predicted height may support clinicians in investigating the reasons for deviations around the expected growth and optimise treatment. CONCLUSIONS: This system has the potential for wide access in endocrinology clinics to support the clinical management of children treated with GH for these three indications.

Central laboratory reassessment of IGF-I, IGF-binding protein-3, and GH serum concentrations measured at local treatment centers in growth-impaired children: implications for the agreement between outpatient screening and the results of somatotropic axis functional testing.

BACKGROUND: Childhood GH deficiency, suspected in the presence of decreased height velocity and short stature, is usually characterized by low IGF-I and IGF-binding protein-3 (IGFBP-3) serum concentrations and is conventionally confirmed by diminished GH peak responses to pharmacological stimuli. OBJECTIVE: We evaluated the agreement between different IGF-I (IGFBP-3) assays in predicting GH deficiency and tested whether variability between growth factor screening and pharmacological testing could be diminished by reassessment of growth factor and GH peak concentrations in a single laboratory. DESIGN: Using the Tuebingen IGF-I (IGFBP-3) RIA, 317 (321) sera from children evaluated for growth disorders in 19 centers were reanalyzed. In 103 children with insulin hypoglycemia and arginine tests, we evaluated how the association between the outcome of growth factor screening and functional testing would change if different assays were employed. RESULTS: Locally measured IGF-I correlated better than IGFBP-3 with the results of the central laboratory (Tuebingen) assay (slope of the regression curve 1.05; 95% confidence interval (95% CI) 1.01-1.1 versus 1.18; 95% CI 1.09-1.3). Agreement between local and central laboratory assays in predicting GH deficiency was better for IGF-I than for IGFBP-3 assays (kappa =0.59 versus kappa =0.47). The poor agreement between growth factor screening and GH pharmacological testing was not improved when hormone concentrations were remeasured in the central laboratory (kappa local=-0.0031, central=0.12). CONCLUSIONS: In children with impaired growth, growth factor screening reflects different aspects of GH insufficiency than does functional testing. Agreement between these approaches is poor and could not be improved by reduction of assay-related variability.

Central reassessment of GH concentrations measured at local treatment centers in children with impaired growth: consequences for patient management.

OBJECTIVE: GH deficiency is diagnosed in children if serum GH fails to rise above a predefined cutoff value in response to at least two stimuli. Diagnostic decisions based on this testing are highly variable between centers and depend on the GH assays used. Considering the large spectrum of commercially available GH assays, we wanted to evaluate the agreement between assays, and to test whether assay-related variability of diagnostic decisions could be reduced by reassessment of peak GH concentrations in a reference center. DESIGN: We reanalysed 699 peak GH serum samples obtained after GH testing of 382 children and adolescents from 19 centers using three reference assays and compared these results with those obtained with the local assays. A subgroup of 132 patients tested with the combination of insulin hypoglycemia test and arginine test was evaluated for changes in the assignment to the diagnostic group of GH deficiency. RESULTS: The mean difference between methods ranged from 5.4 to 10.3 mU/l, slopes of the regression lines from 1.28 to 1.65. Significant non-linearity was detected in five of six assay comparisons, indicating that most assay results cannot be interconverted by the use of a factor. Overall agreement between reference and local assays was only moderate. Significant changes in diagnostic assignment occurred when different assays were used on the same patient (P<0.0001-P<0.0023). Based on GH remeasurement by one reference assay, 36 of 132 patients were categorized differently, with 35 patients changing into the GH-deficient group. Similar findings were obtained with the other reference assays. CONCLUSIONS: To decrease variability in GH testing related to assays and cutoff values, we recommend nationwide reassessment of GH peak sera in reference centers. Decisions to treat GH deficiency should incorporate the reference center results.

Re-assessment of growth hormone secretion in young adult patients with childhood-onset growth hormone deficiency.

OBJECTIVE: Patients with childhood-onset GH deficiency (coGHD) need retesting in late adolescence or young adulthood to verify whether they need to continue GH treatment. For this purpose the Growth Hormone Research Society (GRS) recommends the insulin tolerance test (ITT), or as an alternative the arginine + growth hormone releasing hormone test (ARG + GHRH test) as a diagnostic tool in adolescents and adults. However, there are no standardized cut-off levels based on normal GH secretion for determining GHD vs. GH sufficiency in young adults for the ITT, the ARG + GHRH test or the pyridostigmine + GHRH (PD + GHRH) test, a further new GH stimulation test. PATIENTS AND MEASUREMENTS: We studied 43 patients (28 with organic coGHD, 15 with idiopathic coGHD; 30 males, 13 females; aged 20.4 years, range 16.2-25.4; body mass index 23.5, range 16.3-35.8) using the ARG [0.5 g/kg intravenously (i.v.)] + GHRH (1 micro g/kg i.v.) test, the PD (120 mg orally) + GHRH (1 micro g/kg i.v.) test and the ITT (0.1 IU/kg i.v.) and compared these data with the results of 40 healthy age- and weight-matched volunteers. RESULTS: The GH response in patients was significantly lower than in healthy controls: ARG + GHRH test, 0.8 micro g/l (interquartile range 0.3-2.6) vs. 51.8 micro g/l (32.6-71.2) in controls (P < 0.0001); PD + GHRH test, 0.9 micro g/l (0.3-1.9) vs. 40.4 micro g/l (27.1-54.4) in controls (P < 0.0001); ITT, 0.1 micro g/l (0.0-0.8) vs. 20.3 micro g/l (14.7-31.7) in controls (P < 0.0001). In the ARG + GHRH test we found a diagnostic sensitivity of 100% and a specificity of 97.5% for a cut-off range from 15.1 to 20.3 micro g/l, in the PD + GHRH test a sensitivity of 100% and a specificity of 97% (cut-off range 9.1-13.1 micro g/l) and in the ITT a sensitivity and specificity of 100% each within a cut-off range from 2.7 to 8.8 micro g/l. CONCLUSION: There were no marked differences in sensitivity and specificity in young adults among ARG + GHRH test, PD + GHRH test and the ITT in assessing GH secretion. Because of the lack of side-effects, the ARG + GHRH test is the recommended method for re-evaluation of coGHD in young adults when pituitary GHD is suspected. Furthermore, in adult patient groups where organic pituitary coGHD is common, the ITT may be completely replaced by the ARG + GHRH test. Because of the predominance of hypothalamic GHD in childhood, the ITT is commonly performed for the re-evaluation of patients with childhood-onset GHD because of its mechanism of GH stimulation. The present results confirm the high discriminatory capability of the ITT in young adults.