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Growth Hormone (GH) Provocative Retesting of 108 Young Adults with Childhood-Onset GH Deficiency and the Diagnostic Value of Insulin-Like Growth Factor I (IGF-I) and IGF-Binding Protein-3¹

Department of Growth and Reproduction, National University Hospital (A.J., N.E.S.), and the Department of Pediatrics, Hvidovre Hospital, University of Copenhagen (S.A.P.), Copenhagen; and the Department of Pediatrics, Glostrup Amtssygehus (K.W.K.), Glostrup, Denmark

Address all correspondence and requests for reprints to: Anders Juul, M.D., Department of Growth and Reproduction GR 5064, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Serum levels of total insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) reflect the endogenous GH secretion in healthy children and exhibit little diurnal variation, which makes them good diagnostic markers for screening of GH deficiency (GHD) in short children, although some controversy still exists. In adults, the diagnostic value of IGF-I and IGFBP-3 suspected of GHD has been reported in only a few studies.

We performed a GH provocative test, using oral clonidine, in 108 patients who had previously been treated with GH during childhood (73 men and 35 women). Basal IGF-I and IGFBP-3 levels were compared to those in 1237 healthy controls (312 controls >18 yr) as well as to peak GH levels. Seventy-nine patients had peak GH values below a cut-off value of 7.5 µg/L (34 with isolated GHD), whereas 29 patients had a normal GH response (28 with previous isolated GHD), i.e. 45% of patients treated with GH during childhood because of isolated GHD had a normal GH response when retested in adulthood. Multiple regression analysis revealed that peak GH levels were dependent on the degree of hypopituitarism, body mass index, and duration of disease. IGF-I levels were below -2 SD in 60 of 79 GHD patients and above -2 SD in 21 of 29 patients with a normal GH response. IGFBP-3 levels were below -2 SD in 54 of 79 GHD patients and above -2 SD in 23 of 29 patients with a normal GH response. Multiple linear regression analysis demonstrated that IGF-I and IGFBP-3 were significantly dependent on peak GH levels and the number of other pituitary axes affected. In this analysis, duration of disease was significantly associated with both IGF-I and IGFBP-3, whereas body mass index was significantly associated with IGFBP-3, but not with IGF-I.

We conclude that IGF-I and IGFBP-3 determinations predict the outcome of a GH provocative test in adults suspected of GHD and believe that IGF-I as well as IGFBP-3 serum concentrations are valuable diagnostic parameters in the evaluation of GHD in adults with childhood-onset disease.

We suggest that children who have been treated with GH should undergo reassessment of their GH secretory status as young adults by provocative testing as well as by IGF-related peptides before continued adult GH replacement therapy is considered. However, our data suggest that it is not necessary to reconfirm GH deficiency by GH provocative testing in young adults who have two or more pituitary hormone deficiencies in addition to GHD.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
THE BENEFICIAL effects of GH replacement therapy in adults with GH deficiency (GHD) have recently become apparent (1, 2), but the criteria to select patients for replacement therapy remain unclear. Although, adults with untreated GHD share a number of clinical symptoms, such as increased body fat, osteopenia, atherogenic lipid profile, etc. (3), there is no biological end point in adults, such as poor growth in children, to support the diagnosis. Consequently, the referral diagnosis of GHD in adults must include a high index of suspicion; most likely, the population that will be referred for testing will be adults previously treated with GH because of pituitary dwarfism or adults with known or suspected hypothalamic-pituitary disease (4).

In short, poorly growing children, the diagnosis of GHD is conventionally achieved by two separate provocative GH tests, which have been considered the gold standard. However, proper interpretation of these tests is not trivial due to the impact of puberty on the GH response (5, 6), the poor reproducibility of GH response to provocative testing (7, 8), variability of GH levels according to assay (9, 10), as well as differences in the GH response according to stimuli (e.g. oral clonidine, iv arginine or GHRH, insulin-induced hypoglycemia, etc.) (11). In adults suspected of GHD, similar methodological difficulties exist. Furthermore, the degree of abdominal obesity, physical fitness, age, and gender are major determinants of the stimulated GH secretion in adults (12) and have to be taken into account.

We evaluated the diagnostic value of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) determinations in relation to the outcome of GH provocative testing using oral clonidine in 108 patients who had previously been treated with GH in childhood and were reevaluated in young adulthood.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patients

All 251 patients who had been treated with human pituitary-derived GH (Nanormon, Novo Nordisk, Gentofte, Denmark) until 1988 were located through the central register at the Danish Health Authorities to whom application for treatment was originally sent in each case. Files from 173 patients were available for this study, but data from 65 of these patients were excluded (5 patients had died, 40 patients were still treated with GH at the time of the study, 7 had received GH because of hypochondroplasia, and 13 were excluded as they were <18 yr of age), leaving 108 patients for further analysis (Table 1). None of these had been receiving GH replacement for the last 6 months, but were replaced adequately with other pituitary hormones when needed. Pubertal development was examined in 107 of the patients according to the method of Tanner (Table 2). The etiologies of the 108 patients varied: idiopathic (n = 24; 22.2%), possible birth-related asphyxia (n = 34; 31.5%), craniopharyngeoma (n = 9; 8.3%), other intracranial pathology (n = 19; 17.6%), familiar/genetic (n = 8; 7.4%), small for gestational age (n = 6; 5.5%), and other (n = 8; 7.4%).

Controls

5–20 yr old (n = 1038). Healthy children and adolescents in four different primary schools and one grammar school in the Copenhagen area participated in this study. Serum procollagens, IGF-I and IGFBP-3 levels in these healthy subjects have previously been reported (13, 14, 15).

20–70 yr (n = 199). Hospital employees and medical students participated as controls. None had acute or chronic diseases, and none was taking any medication (including oral contraceptives). These results have previously been reported (16).

There was a total of 312 healthy subjects over 18 yr of age.

Blood sampling

Serum levels of IGF-I and IGFBP-3 was determined in a basal blood sample from all 108 individuals and compared to the peak GH value during the GH provocative test. Blood samples were drawn from an antecubital vein and centrifuged, and serum was stored at -20 C until analysis.

Serum analyses

IGF-I. IGF-I was determined in all subjects with a RIA using truncated IGF-I [des(1, 2, 3)-IGF-I] as radioligand as originally described (17) modified by the use of a monoiodinated isomer as tracer [Tyr³¹-des(1, 2, 3)-IGF-I] (14). Serum was extracted by acid-ethanol and cryoprecipitated before analysis to remove interfering binding proteins. Intraassay coefficients of variation (n = 15) were 5.4% [at bound/free ratio (B/B₀) of 0.20], 3.9% (at B/B₀ of 0.4), and 10.3% (at B/B₀ of 0.7), respectively. Interassay coefficients of variation (n = 45) were 10.4% (at B/B₀ of 0.2), 8.7% (at B/B₀ of 0.4), and 14.1% (at B/B₀ of 0.7), respectively.

IGFBP-3. Serum concentrations of IGFBP-3 were measured by a RIA, previously described by Blum et al. (18). Reagents for the IGFBP-3 RIA were obtained from Mediagnost (Tubingen, Germany). Intraassay coefficients of variation (n = 17) were 2.3% (at B/B₀ of 0.3), 2.4% (at B/B₀ of 0.4), and 5.9% (at B/B₀ of 0.8), respectively. Interassay coefficients of variation (n = 144) were 10.7% (at B/B₀ of 0.5) and 7.6% (at B/B₀ of 0.8), respectively.

Serum GH was determined by a commercially available RIA (Pharmacia, Uppsala, Sweden).

Statistical procedures

SD scores were calculated for IGF-I and IGFBP-3 based on previously reported normative data (14, 15).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
GH provocative testing in 108 adults suspected of GHD

Seventy-nine (54 men and 25 women) of the 108 patients who were reevaluated had a peak GH response less than 7.5 µg/L (GHD). Thirty-four of these had isolated GHD, and 45 had multiple pituitary deficiency of varying degree. Twenty-nine patients had a normal GH response to oral clonidine (28 with previous isolated GHD). Consequently, 28 of 62 patients (45%) who were treated during childhood because of isolated GHD had a normal GH response when retested in adulthood. One patient with secondary hypothyroidism had a normal GH response when reevaluated, whereas in the presence of 2 or more additional hormone deficiencies, all patients had a pathological GH response during retesting (Fig. 1 and Table 3). Multiple linear regression analysis revealed that peak GH levels were significantly dependent on duration of disease, degree of hypopituitarism, age, and body mass index (r = 0.41; P < 0.0001).

View larger version (17K): [in this window] [in a new window]   Figure 1. Peak GH levels during GH provocative testing (clonidine) according to degree of hypopituitarism in 108 adults previously treated during childhood with GH.

Serum IGF-I and IGFBP-3 levels in 79 patients with GHD and 29 patients with a normal GH response are shown in Fig. 2, and mean values are shown in Tables 2 and 3. IGF-I as well as IGFBP-3 serum levels (SD score) significantly decreased with increasing degree of hypopituitarism (Fig. 3; all P < 0.001, by ANOVA). In patients with isolated GHD, IGF-I and IGFBP-3 predicted a subnormal peak GH after provocative testing in 17 of 34 (50%) and 18 of 34 (47%) patients, respectively (Fig. 4).

View larger version (28K): [in this window] [in a new window]   Figure 2. Serum levels of IGF-I (top panels) and IGFBP-3 (bottom panels) in 108 patients classified as either GHD (peak GH, <7.5 µg/L; •) or patients with a normal GH response (). Males are shown to the left (females to the right). Lines represent the 95% prediction intervals for IGF-I and IGFBP-3 and are derived from Refs. 14–16.

View larger version (19K): [in this window] [in a new window]   Figure 3. Serum levels of IGF-I (top panel), IGFBP-3 (middle panel), and body mass index (bottom panel; expressed as the SD score) according to degree of hypopituitarism in 79 GHD patients (peak GH, <7.5 µg/L) compared to 29 patients with normal GH responses.

View larger version (17K): [in this window] [in a new window]   Figure 4. Peak GH levels vs. IGF-I SD score (top panel) and IGFBP-3 SD score (bottom panel) in 62 patients previously treated with GH because of isolated GHD who were reevaluated as young adults. The dotted lines represent the two cut-off values corresponding to 7.5 µg/L (for peak GH) and to -2 SD score (for IGF-I and IGFBP-3).

IGF-I levels were below -2 SD in 60 of 79 GHD patients and above -2 SD in 21 of 29 patients with normal GH responses. IGFBP-3 levels were below -2 SD in 54 of 79 GHD patients and above -2 SD in 23 of 29 patients with normal GH responses. Sensitivities and specificities are given in Table 4.

View larger version (28K): [in this window] [in a new window]   Figure 5. Effect of varying the peak GH cut-off value during GH provocative test between 1–10 µg/L on sensitivity (top panel), specificity (middle panel), and test accuracy (bottom panel) for IGF-I and IGFBP-3 (at three different cut-off values). The dashed lines represent the chosen peak GH cut-off value of 7.5 µg/L.

View larger version (17K): [in this window] [in a new window]   Figure 6. Comparison of the diagnostic value of IGF-I vs. IGFBP-3 in all 108 patients who were classified as either GHD (peak GH, <7.5 µg/L; •) or normal (). The lines represent the lower limit (-2 SD) for the analyses.

Multiple linear regression analyses revealed that the peak GH response and the degree of hypopituitarism played a significant role for both parameters, whereas body mass index played a role for IGFBP-3 only (see Table 5).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

A large number of clinical trials have been carried out since 1989 of GH replacement therapy in GHD adults, who have been diagnosed using various provocative tests (insulin tolerance test, arginine, GHRH, clonidine, and glucagon). In the present study we used clonidine, which is an -adrenergic agonist that stimulates GH secretion (24, 25). The peak GH response to oral clonidine is dependent on age (26), obesity, and physical fitness (12, 27). Vahl et al. found that 50% of healthy young adults (aged 27–34 yr) had peak GH levels below the arbitrary cut-off value of 3 µg/L (12). This poor specificity may argue against using clonidine as a diagnostic test in adults. On the other hand, poor specificity has recently been described for the insulin tolerance test (8), which has been regarded as the most reliable provocative test in the diagnosis of GHD in adults (28), leaving unanswered the question of which test to use. Furthermore, varying biochemical criteria for patient selection have been described during the last 6 or 7 yr. Definition of maximal GH response to a stimulus varies enormously from 0.5–10 µg/L (1, 2, 29, 30, 31, 32, 33, 34). Thus, apart from different selection criteria of patients (complete GHD vs. GHD with minor GH secretory capacity), a lack of standardization of GH assays contributes to this variation. These findings strongly argue for each laboratory to construct its own cut-off values (10).

Serum levels of total IGF-I and IGFBP-3 reflect the endogenous GH secretion in healthy children and exhibit little diurnal variation, which makes them good diagnostic markers for screening of GHD in short children. In adults, the diagnostic value of IGF-I and IGFBP-3 suspected of GHD has been reported in a few studies (23, 35, 36, 37, 38, 39, 40) and has recently been questioned (28). Pulsatile GH secretion increases in puberty and declines with increasing age in adulthood (41, 42, 43). Similarly, IGF-I (14, 44, 45, 46) and IGFBP-3 (15, 16, 18) increase in puberty and decline with increasing age, partly due to sex steroids (43), physical fitness (47), and adiposity (46). Consequently, extensive age-related normative data for these two analyses are mandatory, but often lacking. In the present study of 79 adults with childhood-onset GHD, the diagnostic sensitivity of IGF-I and IGFBP-3 determinations was 75.9% and 68.4%, respectively, giving predictive values of a positive test (ability to correctly identify patients with GHD) of 88.2% and 90.0% for IGF-I and IGFBP-3, respectively. Our findings regarding the diagnostic value of total IGF-I are in accord with those of other studies in GHD adults (23, 35, 36, 37), but in contrast to those of Hoffman et al. (28), who found an extremely poor diagnostic value for IGF-I (sensitivity of 39%). This discrepancy may be due to the fact that these researchers (28) studied a relatively small group of patients (n = 23) with GHD of adult onset, who may represent a different population of patients compared to our patients who have childhood-onset GHD. Some patients with childhood-onset GHD never reach final sexual maturation (or with a substantial delay), which may affect the diagnostic value of IGF-I and IGFBP-3. Finally, we found that serum levels of both IGF-I and IGFBP-3 in GHD adults were dependent on the degree of GHD in accordance with previous findings for IGF-I (35). In addition, body mass index played a significant role for IGFBP-3 levels. Manipulating the cut-off limits for GH and IGF, respectively, yielded the highest degree of concordance between the GH provocative test and IGF-I/IGFBP-3 levels using a cut-off value for GH of approximately 3–4 µg/L and cut-off values of -2.0 and -1.0 SD for IGF-I and IGFBP-3, respectively.

We conclude that a subnormal IGF-I or IGFBP-3 serum level in most cases predicts a subnormal GH response to provocative testing using oral clonidine in adult patients who are suspected of having GHD. IGF-I and IGFBP-3 levels were dependent on the duration of GHD, the number of additional hormonal deficits, and peak GH levels. Consequently, we believe that they are valuable tools in the evaluation of adult GHD. We suggest that children who have been treated with GH should undergo reassessment of their GH secretory status as young adults before continued adult GH replacement therapy is considered. However, our data suggest that it is not necessary to reconfirm GHD by GH provocative testing in young adults who have two or more pituitary hormone deficiencies in addition to GHD.

	Acknowledgments

 
We are grateful to Ulla Højelse, Brian Vendelboe, and Kirsten Jørgensen for their skilled technical assistance.

	Footnotes

 
¹ This work was supported by the Michaelsen Foundation (to A.J.) and the Danish Medical Research Council (Grants 12–9361 and 12–1376).

Received October 23, 1996.

Revised December 18, 1996.

Accepted January 6, 1997.

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