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Growth Hormone Testing for the Diagnosis of Growth Hormone Deficiency in Childhood: A Population Register-Based Study

Association France Hypophyse (J.-C.C., J.-L.C., Y.L., J.-C.J.) and Institut de Recherche Thérapeutique (J.-P.T., M.L.) and Departement de Biostatistique et d’Informatique Médicale (J.C.), Hôpital Cochin, Paris, France

Address all correspondence and requests for reprints to: Dr. Jean-Claude Carel, INSERM U-342 and Department of Pediatric Endocrinology, Hôpital Saint Vincent de Paul, 82 avenue Denfert Rochereau, 75014 Paris, France. E-mail: jccarel{at}infobiogen.fr

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Evaluation of GH secretion using pharmacological GH stimulation tests (GHST) remains a current practice, although the reliability of GHST has been questioned, and many pitfalls have been pointed out. We have analyzed all of the 6373 GH stimulation tests that led to the initiation of GH therapy in 3233 children treated in France from 1973–1989. Tests and GH measurements were performed by individual centers and collected by the Association France-Hypophyse. GH deficiency (GHD) was due to craniospinal irradiation (11%), was due to organic causes or associated with multiple deficiencies (22%), or was considered idiopathic (65%); 2% of the patients were considered non-GHD. Eleven different pharmacological tests were used, and 62 of the 66 theoretical pairs of tests were used at least once. The most frequent combination of tests (ornithine in one instance and insulin in another) was used in 12.7% of patients. The reliability of the GH peak measured by comparing the results of 2 tests in the same patient was poor, as measured by intraclass correlation coefficients below 0.8. Multivariate analysis identified several parameters positively or negatively associated with peak plasma GH: calendar year of initiation of treatment, etiology of GHD, height SD score, bone age SD score, puberty, weight SD score, genetic target height SD score, and the nature of the pharmacological agent used. We believe that several of these factors (weight SD score, genetic target height SD score, and nature of the agent) identify biases in the diagnosis of GHD. We conclude that GHST should be performed with a very limited number of agents, interpreted after the establishment of reference values in age-matched normal children, and associated with other clinical and biochemical parameters for establishing the diagnosis of GHD.

	Introduction

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THE RELIABILITY of pharmacological tests used for evaluating GH secretion have repeatedly been questioned (1, 2, 3, 4) for the lack of normal age-related reference values, the use of variable cut-off values with time, the use of different pharmacological stimuli, the dependence on physiological parameters (age, puberty, and body weight), poorly reproducible results, and the use of different laboratory methods and standards for the measurement of plasma GH. Although the diagnosis of GH deficiency (GHD) involves the analyses of height, growth velocity, GH secretion, and GH-dependent plasma proteins and the search for an etiology (4, 5, 6, 7), GH stimulation tests (GHST) are still one of the essential elements of diagnosis. GHST are used to regulate the use of GH in most countries, with the exception of Australia (8). How several potentially confounding factors can influence the results of GHST, the diagnosis, the decision to initiate GH substitutive therapy, and ultimately the results of treatment have not, to our knowledge, been analyzed in a population-based cohort of treated patients.

The organization for GH distribution in France allowed the centralized collection of relevant parameters for all patients treated in the country since the early 1970s. We have analyzed the results of all GHST that led to the initiation of treatment in 3233 children from 1973 to December 1989.

	Subjects and Methods

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In France, from 1973 onward, the distribution of GH (initially extracted GH and then recombinant GH) has been organized nationwide under the medical control of Association France Hypophyse. Physicians were required to provide relevant data on a standard form. All children whose GH treatment was started up to December 31, 1989 were included in this analysis, with the exception of patients with Turner’s syndrome. The principal baseline characteristics of these 3233 children are presented in Table 1. Ninety-two percent of the patients were considered GHD based on the results of 2 GHST, 6% were classified as having GH neurosecretory dysfunction, and 2% were non-GHD, severely growth-retarded children. All patients were maintained in this analysis to allow an exhaustive evaluation of practices over a period of time.

The following data were collected: date of initiation of GH treatment, height, weight, chronological age, bone age according to Greulich and Pyle (9) assessed by individual physicians, pubertal stage (10, 11), and parents’ heights. Dates of initiation of treatment were grouped into three periods (1973–1980, 1981–1984, and 1985–1989) after verification of the homogeneity of variables within these periods. SD scores of height and weight for age were calculated (12). The genetic target height SD score was calculated as the average of the parental SD scores, using standards obtained in the late 1960s (13). Patients were coded as pubertal if Tanner stage was P2B2 or more (girls) or P2G2 or more (boys). The etiology of short stature was coded in four categories: craniospinal irradiation-induced GHD, other organic GHD or multihormonal deficiencies, idiopathic GHD, and short stature without GHD.

GH stimulation tests

The results of two GH stimulation tests performed using national guidelines had to be provided to Association France Hypophyse to initiate GH treatment. The various stimuli used were: arginine, clonidine, L-DOPA, glucagon, insulin-induced hypoglycemia, ornithine, GHRH, arginine- and insulin-induced hypoglycemia, clonidine and betaxolol, glucagon and betaxolol, glucagon and propranolol, or other stimuli. GHRH tests were maintained in this analysis, although normal GH peaks during this test are much higher than those after conventional pharmacological tests (14). GH measurements were performed by local laboratories. The peak GH value during the test was recorded even if the peak value was observed at the baseline measurement.

Criteria used for the attribution of GH treatment

As only the data from patients ultimately treated with GH are analyzed and reported here, the criteria used to decide the attribution of GH treatment influenced our results. At the beginning of the collection of this dataset (1973), two peak GH values less than 5 ng/mL (complete GHD) were required; from 1980 onward, the threshold was progressively moved to 10 ng/mL (partial GHD). After the description of GH neurosecretory dysfunction (15), patients with peak GH of 10 ng/mL or more and subnormal spontaneous GH secretion were considered GH deficient (Table 1). A small number (n = 68; 2%) of non-GHD children were treated on a compassionate basis.

Statistical methods

Intraclass correlation coefficients (r) and their 95% confidence intervals were computed to analyze the reliability of GHST (16). The intraclass correlation coefficient expresses the relative magnitude of the two components of total variability, i.e. biological variability (between-subject variability, ²_BS) and random error (method error, ²_ER), in a series of measurements in different subjects. The relationship between the measurement error and its true value, estimated by the mean, was illustrated as described previously (17).

To identify factors associated with peak GH during GHST, we randomly selected one test for each patient to avoid analyzing duplicates of patient’s data (two GHST for the same patient). A univariate analysis was initially performed after adjustment of the calendar year of the test and the diagnosis. Factors significantly associated with peak GH in the univariate analysis were then used to construct a multivariate regression model in several stages. First, the model had to take into account the calendar year of testing, as criteria for initiation of treatment varied with time. Second, the etiology of GHD was introduced. Third, information about the child (chronological and bone age, height and weight SD scores, and puberty) were introduced in the model as well as genetic target height SD score. Last, the nature of the stimulus used in the GHST was added to significant predictors of the preceding stage. Categorial variables were dichotomized (equal to 1 if the condition was true or to 0). The computations were performed with the SAS statistical package (SAS Institute, Cary, NC) (18).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Description of GH stimulation tests (Tables 2 and 3)

Five of the 11 different stimuli were used in more than 80% of the 6373 tests: ornithine, arginine- and insulin-induced hypoglycemia, insulin-induced hypoglycemia, arginine, and glucagon and propranolol. Of the 66 theoretical pairs of tests (not counting other tests), 62 were actually used at least once. The most frequent association (ornithine/insulin-induced hypoglycemia) was used in 12.7% of the patients, and the 10 most frequent associations of tests encompassed 70.5% of the patients.

Reliability of tests (Figs. 1 and 2)

Reliability was calculated for patients who had undergone the same test twice, for the most frequent associations of tests, and for all pairs of tests (reliability of any pair of tests used). Intraclass correlation coefficients (r) and 95% confidence intervals are presented in Fig. 1. In all cases, r was inferior to 0.8, a commonly admitted threshold for satisfactory reliability. As expected, r was generally higher in patients who had the same test twice than in patients who had two different tests. Figure 2 displays this variability for six of the pairs of tests and allows the evaluation of reliability at various levels of plasma GH. Reliability appeared good for very low peak GH values and decreased with increasing GH values. The 95% confidence interval of the difference between the two tests is between -5 and 5. This indicates that patients with a mean peak plasma GH of 5 ng/mL could have values of approximately 0 and 10 ng/mL as well as two values around 5 ng/mL. The losangic shapes of the plots suggests an improvement of reliability around peak GH values of 10 ng/mL. This artifact is due to the inclusion in this cohort of 92% of patients with two GH peaks below 10 ng/mL; there is little room for variability when a patient has an average and a maximum GH peak close to 10 ng/mL.

View larger version (29K): [in this window] [in a new window]   Figure 1. Intraclass correlation coefficients (r) and 95% confidence intervals for pairs of tests performed in the same patient. The legend indicates the nature of the pharmacological stimuli and the number of patients is shown in parentheses. Intraclass correlation coefficients can be interpreted as the correlation coefficient between measurements for a subject. Values of 0.8 or more are considered satisfactory.

View larger version (32K): [in this window] [in a new window]   Figure 2. Reliability of GH stimulation tests for selected pairs of tests illustrated by the method of Altman and Bland (17). The x-axis represents the mean of the two measurements, and the y-axis shows the difference between the two measurements. Horizontal lines in the plots represent the mean ± 2 sd of the difference.

In the univariate analysis, the following parameters were associated with peak GH: age, bone age, puberty, height SD score, weight SD score, genetic target height SD score, and nature of the pharmacological stimulus. These factors were then used to construct the multiple regression model presented in Table 4. As expected, peak GH increased with the calendar year of diagnosis of GHD, subdivided into three time periods. Diagnosis was an independent predictor of peak GH, with organic GHD or multiple pituitary deficiencies associated with the lowest GH values and idiopathic GHD associated with the highest, with the exception of non-GHD patients. Several clinical characteristics of the patients were independently associated with peak GH in our model. Height SD score was positively associated with peak plasma GH. Height SD score had a ß coefficient of 0.47, indicating that when height decreased by 1 SD score unit, peak GH decreased by 0.47 ng/mL. Bone age and puberty were independently associated with peak GH. Age itself, associated with peak GH in the univariate analysis, was not an independent predictor of peak GH in the multivariate model due to its interaction with bone age. Genetic target height SD score had a negative ß, indicating that patients with shorter parents secreted more GH. Body weight SD score was also negatively associated with peak GH, indicating that overweight patients had lower peak GH responses. Last, the nature of the stimulus was a strong independent predictor of peak GH response, with ß coefficients ranging from -0.80 to 1.43 (excluding the GHRH test). As these results had been obtained after randomly selecting one test per patient (see Subjects and Methods), we performed the same analysis on the other half of the dataset; essentially similar results were obtained for all variables, including the nature of the pharmacological stimulus, except for rarely used tests (tests with n < 162; Table 4). Therefore, after correction for all other parameters, the nature of the stimulus could alter peak GH by approximately 2 ng/mL. It should be underlined that the predictive parameters identified here only accounted for 19% of the variance of peak GH.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Over the years, several GH secretion tests have been developed using single or multiple pharmacological stimuli (1, 3, 4). Our results confirm a very heterogeneous use of these stimuli; in the Kabi International Growth Study, 32 different tests were used in 3896 children, with wide variations between countries (19). Although all of these agents influence GH through hypothalamic GHRH secretion (20), some of them are considered stronger than others (21), but their relative potencies have never been systematically examined (22, 23). Reports from the Kabi International Growth Study (19) and by Rochiccioli et al. (24) have shown differences between stimuli, but no correction was made for other variables influencing peak GH. In our multivariate analysis, the nature of the stimulus was independently associated with peak GH, and patients tested with arginine had, on the average, 1.88 ng/mL lower peak GH values than those tested with glucagon-betaxolol. As GH secretion seems to be continuously distributed between normal and idiopathic GHD, the choice of the stimulus can influence the diagnosis if a single cut-off value is used.

Several clinical parameters were also independently associated with peak GH, namely bone age, height SD score, puberty, weight SD score, and genetic target height SD score. Younger, prepubertal patients with severe height deficits and tall parents were more likely to have low peak GH values. The correlations of GH secretion or plasma insulin-like growth factor I (IGF-I) with height SD score have been previously reported (25, 26, 27). The similar finding made in our dataset reinforces the concept that GH secretion is a quantitative trait that plays a role in the multifactorial variation of growth. The positive association of peak GH with bone age and pubertal status probably reflects the problems in making the diagnosis of GHD around puberty. Older, pubertal patients had higher GH values, consistent with transient early pubertal decrease in GH secretion (28, 29, 30, 31, 32). As discussed previously (33), our findings document the negative impact of adipose tissue on GH secretion and the risk of overdiagnosing GHD in overweight patients. Several hypotheses can be made for the negative association of genetic target height SD score and peak GH. Most likely, patients with borderline criteria for GHD (those with the highest peak GH values) were not GH deficient and had genetically determined short stature. Alternatively, genetically determined quantitative variations in peripheral GH sensitivity could play a role, as demonstrated recently in patients with idiopathic short stature (34). Our analysis only explained 19% of the variance of peak plasma GH, indicating the existence of other unrecognized factors influencing GH secretion.

Finally, our study also allowed evaluation of the reliability of GHST. All intraclass correlation coefficients (r) were below 0.8, indicating poor reliability. It should be stressed that our results overestimate the reliability of GHST performed in children evaluated for GHD, because patients treated for GHD were selected for concordant peak GH values. The data presented in Fig. 2 clearly depict the difficulty in defining any cut-off value for peak plasma GH due to the very wide intrasubject variability.

Last, our study has several methodological limitations. First, GH tests and measurements were performed at a large number of centers with different laboratory methods over a period of almost 2 decades. Due to the various reagents and standards used over this period, GH levels, expressed in nanograms per mL, actually represent variable amounts of active GH (35, 36). Second, we could only analyze data from patients treated with GH and had no access to patients evaluated for possible GHD. Third, the criteria used to include patients in this study (i.e. the decision to initiate GH treatment) were not uniform over time. However, the introduction of the calendar year in the multivariate analysis corrects the impact of the evolution of medical practices. Fourth, our results describe French practices that might be different from those used in other countries. However, the centralized database of the Association France-Hypophyse presented the unique opportunity of performing an exhaustive analysis of GH-testing practices in a given country over almost 2 decades.

The conclusions that can be derived from our study are in line with recent recommendations for diagnosis and treatment of GHD (4, 6). We should select a very limited number of GHST or perhaps just a single powerful one (glucagon and propranolol or glucagon and betaxolol from our study). The lack of reliability of a GHST should be taken into account and might be improved by performing the same test twice rather than two different ones in a given patient. By decreasing the number of tests, we will obtain more data on reliability and distribution in short children evaluated for possible GHD, and we should try to obtain normal age-matched values (37, 38). Last, alternative or complementary approaches to the diagnosis and definition of GHD should be developed, including the reliance on GH-dependent proteins such as IGF-I and IGF-binding protein-3 or increased reliance on auxological parameters (8).

	Acknowledgments

 
The authors thank the many pediatric endocrinologists and laboratory biologists who collected the clinical and biochemical data and contributed to their validation.

Received October 22, 1996.

Revised February 26, 1997.

Accepted April 18, 1997.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Carel, J.-C. Articles by Coste, J. Search for Related Content PubMed PubMed Citation Articles by Carel, J.-C. Articles by Coste, J.