Interpretation of growth hormone provocative tests: comparison of cut-off values in four European laboratories

Andersson, Anna‐Maria; Ørskov, Hans; Ranke, Michael B.; Shalet, S; Skakkebæk, Niels E.

doi:10.1530/eje.0.1320340

Cited by 63 publications

(45 citation statements)

References 7 publications

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“…Even in our patients, where cutoff values suggested by the assay manufacturers were used, the diagnostic assignment of patients varied considerably between assays. This finding is in contrast to earlier reports, in which the use of specific cutoff values prevented major non-agreement in diagnostic assignment among some assays (25).…”

Section: Discussioncontrasting

confidence: 99%

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

Hauffa

Lehmann

Bettendorf

et al. 2004

European Journal of Endocrinology

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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 assayrelated 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.European Journal of Endocrinology 150 291-297

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Section: Discussioncontrasting

confidence: 99%

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

Hauffa

Lehmann

Bettendorf

et al. 2004

European Journal of Endocrinology

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“…When the same serum samples are tested in different assays, there is wide variability in the absolute values reported. As a result, the classification of individual subjects as normal or GH deficient may change (32,33).…”

Section: Discussionmentioning

confidence: 99%

Sensitivity and Specificity of Six Tests for the Diagnosis of Adult GH Deficiency

Biller

Samuels

Zagar

et al. 2002

The Journal of Clinical Endocrinology &Amp; Metabolism

320

156

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Although the use of the insulin tolerance test (ITT) for the diagnosis of adult GH deficiency is well established, diagnostic peak GH cut-points for other commonly used GH stimulation tests are less clearly established. Despite that fact, the majority of patients in the United States who are evaluated for GH deficiency do not undergo insulin tolerance testing. The aim of this study was to evaluate the relative utility of six different methods of testing for adult GH deficiency currently used in practice in the United States and to develop diagnostic cut-points for each of these tests. Thirty-nine patients (26 male, 13 female) with adult-onset hypothalamic-pituitary disease and multiple pituitary hormone deficiencies were studied in comparison with age-, sex-, estrogen status-, and body mass index-matched control subjects (n ‫؍‬ 34; 20 male, 14 female). A third group of patients (n ‫؍‬ 21) with adult-onset hypothalamic-pituitary disease and no more than one additional pituitary hormone deficiency was also studied. The primary end-point was peak serum GH response to five GH stimulation tests administered in random order at five separate visits: ITT, arginine (ARG), levodopa (L-DOPA), ARG plus L-DOPA, and ARG plus GHRH. Serum IGF-I concentrations were also measured on two occasions. For purposes of analysis, patients with multiple pituitary hormone deficiencies were assumed to be GH deficient. Three diagnostic cut-points were calculated for each test to provide optimal separation of multiple pituitary hormone deficient and control subjects according to three criteria: 1) to minimize misclassification of control subjects and deficient patients (balance between high sensitivity and high specificity); 2) to provide 95% sensitivity for GH deficiency; and 3) to provide 95% specificity for GH deficiency. The greatest diagnostic accuracy occurred with the ITT and the ARG plus GHRH test, although patients preferred the latter (P ‫؍‬ 0.001). Using peak serum GH cut-points of 5.1 g/liter for the ITT and 4.1 g/liter for the ARG plus GHRH test, high sensitivity (96 and 95%, respectively) and specificity (92 and 91%, respectively) for GH deficiency were achieved. To obtain 95% specificity, the peak serum GH cutpoints were lower at 3.3 g/liter and 1.5 g/liter for the ITT and ARG plus GHRH test, respectively. There was substantial overlap between patients and control subjects for the ARG plus L-DOPA, ARG, and L-DOPA tests, but test-specific cutpoints could be defined for all three tests to provide 95% sensitivity for GH deficiency (peak GH cut-points: 1.5, 1.4 and 0.64 g/liter, respectively). However, 95% specificity could be achieved with the ARG plus L-DOPA and ARG tests only with very low peak GH cut-points (0.25 and 0.21 g/liter, respectively) and not at all with the L-DOPA test. Although serum IGF-I levels provided less diagnostic discrimination than all five GH stimulation tests, a value below 77.2 g/liter was 95% specific for GH deficiency. In conclusion, the diagnosis of adult GH deficiency can be made without performing ...

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“…The reasons for developing a model that excluded this parameter pertain to the inconsistencies that can exist between investigational centers in the methods used for provocation testing and assaying GH (16). It was anticipated that a model excluding this parameter might give better growth predictions for individual patients when there was any uncertainty about their maximum GH secretory capacity.…”

Section: Growth Predictors and Growth Prediction Modelsmentioning

confidence: 99%

Derivation and Validation of a Mathematical Model for Predicting the Response to Exogenous Recombinant Human Growth Hormone (GH) in Prepubertal Children with Idiopathic GH Deficiency

Ranke¹,

Lindberg²,

Chatelain³

et al. 1999

The Journal of Clinical Endocrinology & Metabolism

213

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Postmarketing surveillance studies of recombinant human GH therapy, such as the Kabi Pharmacia International Growth Study (KIGS; Pharmacia & Upjohn, Inc., International Growth Database), have accumulated extensive data concerning the characteristics and growth outcomes of children with various causes of short stature. These data provide an opportunity to analyze the factors that determine responsiveness to GH and allow the development of diseasespecific growth prediction models. We undertook a multiple regression analysis of height velocity (centimeter per yr) with various patient parameters of potential relevance using data from a cohort of 593 prepubertal children with idiopathic GH deficiency (GHD) from the KIGS database. Our aim was to produce models that would have practical utility for predicting prepubertal growth during each of the first 4 yr of GH replacement therapy. These models were validated by a prospective comparison of predicted and observed growth outcomes in an additional 3 cohorts of prepubertal children with idiopathic GHD: 237 additional KIGS patients, 29 patients from the Australian OZGROW study, and 33 patients from Tubingen, Germany. The most influential variable for first year growth response was the natural log (ln) of the maximum GH response during provocation testing, which was inversely correlated with height velocity. The first year growth response was also inversely correlated with chronological age and height SD score minus midparental height SD score. First year growth was positively correlated with body weight SD score, weekly GH dose (ln), and birth weight SD score. Two first year models were developed using these parameters, 1 including and 1 excluding the maximum GH response to provocative testing. The former model explained 61% of the response variability, with a SD of 1.46 cm; the latter model explained 45% of the variability, with a SD of 1.72 cm. The two models gave similar predictions, although the model excluding the maximum GH response to testing tended to underpredict the growth response in patients with very low GH secretory capacity. For the second, third, and fourth year growth responses, 4 predictors were identified: height velocity during the previous year (positively correlated), body weight SD score (positively correlated), chronological age (negatively correlated), and weekly GH dose (ln; positively correlated). The models for the second, third, and fourth year responses explained 40%, 37%, and 30% of the variability, respectively, with SDs of 1.19, 1.05, and 0.95 cm, respectively. When the models were applied prospectively to the other cohorts, there were no significant differences between observed and predicted responses in any of the cohorts in any year of treatment. The fourth year response model gave accurate prospective growth predictions for the fifth to the eighth prepubertal years of GH treatment in a subset of 48 KIGS patients. Analyses of Studentized residuals provided further validation of the models. The parameters used in our models do no...

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Interpretation of growth hormone provocative tests: comparison of cut-off values in four European laboratories

Cited by 63 publications

References 7 publications

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

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

Sensitivity and Specificity of Six Tests for the Diagnosis of Adult GH Deficiency

Derivation and Validation of a Mathematical Model for Predicting the Response to Exogenous Recombinant Human Growth Hormone (GH) in Prepubertal Children with Idiopathic GH Deficiency

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