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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 10 3693-3699
Copyright © 2000 by The Endocrine Society

Original Studies

Retesting Young Adults with Childhood-Onset Growth Hormone (GH) Deficiency with GH-Releasing-Hormone-Plus-Arginine Test1

G. Aimaretti, C. Baffoni, S. Bellone, L. Di Vito, G. Corneli, E. Arvat, L. Benso, F. Camanni and E. Ghigo

Division of Endocrinology (G.A., C.B., S.B., L.D.V., G.C., E.A., F.C., E.G.), Department of Internal Medicine, University of Turin; and Chair of Auxopathology (L.B.), Department of Pediatrics, University of Turin, 10126 Torino, Italy

Address correspondence and requests for reprints to: Ezio Ghigo, M.D., Divisione di Endocrinologia, Ospedale Molinette, C.so Dogliotti 14, 10126 Torino, Italy. E-mail: ezio.ghigo{at}unito.it


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Within an appropriate clinical context, severe GH deficiency (GHD) in adults has to be defined biochemically by provocative testing of GH secretion. Patients with childhood-onset GHD need retesting in late adolescence or young adulthood to verify whether they have to continue recombinant human GH treatment. GHRH + arginine (GHRH+ARG) is the most reliable alternative to the insulin-induced hypoglycemia test (ITT) as a provocative test for the diagnosis of GHD in adulthood, provided that appropriate cut-off limits are assumed (normal limits, 16.5 µg/L as 3rd and 9.0 µg/L as 1st centile). We studied the GH response to a single GHRH (1 µg/kg iv) + ARG (0.5 g/kg iv) test in 62 young patients who had undergone GH replacement in childhood, based on the following diagnosis: 1) organic hypopituitarism with GHD (oGHD) [n = 18: 15 male (M), 3 female (F); age, 26.8 ± 2.2 yr; GH peak < 10 µg/L after two classical tests]; 2) idiopathic isolated GHD (iGHD) [n = 23 (15 M, 8 F); age, 23.0 ± 1.5 yr; GH peak < 10 µg/L after two classical tests]; and 3) GH neurosecretory dysfunction (GHNSD) [n = 21 (10 M, 11 F); age, 25.1 ± 1.6 yr; GH peak > 10 µg/L after classical test but mGHc < 3 µg/L]. The GH responses to GHRH+ARG in these groups were also compared with that recorded in a group of age-matched normal subjects (NS) [n = 48 (20 M, 28 F); age, 27.7 ± 0.8 yr]. Insulin-like growth factor I levels in oGHD subjects (61.5 ± 13.7 µg/L) were lower (P < 0.001) than those in iGHD subjects (117.2 ± 13.1 µg/L); the latter were lower than those in GHNSD subjects (210.2 ± 12.9 µg/L), which, in turn, were similar to those in NS (220.9 ± 7.1 µg/L). The mean GH peak after GHRH+ARG in oGHD (2.8 ± 0.8 µg/L) was lower (P < 0.001) than that in iGHD (18.6 ± 4.7 µg/L), which, in turn, was clearly lower (P < 0.001) than that in GHNSD (31.3 ± 1.6 µg/L). The GH response in GHNSD was lower than that in NS (65.9 ± 5.5 µg/L), but this difference did not attain statistical significance. With respect to the 3rd centile limit of GH response in young adults (i.e. 16.5 µg/L), retesting confirmed GHD in all oGHD, in 65.2% of iGHD, and in none of the GHNSD subjects. With respect to the 1st centile limit of GH response (i.e. 9.0 µg/L), retesting demonstrated severe GHD in 94% oGHD and in 52.1% of iGHD. All oGHD and iGHD with GH peak after GHRH+ARG lower than 9 µg/L had also GH peak lower than 3 µg/L after ITT. In the patients in whom GHD was confirmed by retesting, the mean GH peak after GHRH+ARG was higher than that after ITT (3.4 ± 0.5 vs. 1.9 ± 0.4). In conclusion, given appropriate cut-off limits, GHRH+ARG is as reliable as ITT for retesting patients who had undergone GH treatment in childhood. Among these patients, severe GHD in adulthood is generally confirmed in oGHD, is frequent in iGHD, but never occurs in GHNSD.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE BENEFICIAL effects of recombinant human (rh)GH replacement therapy on metabolism and body composition have been clearly shown (1, 2, 3), and now the use of rhGH in adults with severe GH deficiency (GHD) is approved in the majority of countries.

Within an appropriate clinical context, GHD in adults must be shown biochemically by single provocative testing, provided that reproducible test with clear normative limits is available (2). This statement is based on evidence that the assays of insulin-like growth factor (IGF)-I and IGF-binding protein (IGFBP)-3, as well as the evaluation of spontaneous GH secretion, do not establish the diagnosis of adult GHD (2). The diagnosis of severe GHD in adults is established by a GH peak in the insulin-induced hypoglycemia test (ITT) lower than the arbitrary cut-off of 3 µg/L (2, 4, 5, 6, 7). On the other hand, it has been shown that the GHRH + arginine (GHRH+ARG) test is a reliable alternative, being at least as sensitive as ITT, provided that appropriate cut-off limits are considered (2, 4, 5, 7). In fact, the GHRH+ARG test is one of the most potent and reproducible provocative tests of GH secretion and severe GHD in adults is shown by GH peak response below 9 µg/L (5, 8).

Patients with childhood-onset GHD need retesting in late adolescence or young adulthood to verify whether they need to continue rhGH treatment (1, 2, 9, 10, 11, 12, 13). Though the evaluation of spontaneous GH secretion, IGF-I, and IGFBP-3 levels is a critical point in childhood (14), this is not the case in adulthood (2, 6, 15, 16). Thus, how to retest these patients in adolescence or young adulthood is already clarified and represented by provocative testing (2, 6, 12, 13). Studies, so far, performed retesting patients who had been treated with rhGH in childhood have found a different percentage of persistent severe GHD in adulthood, ranging from 12.5–90% (1, 9, 10, 11, 17, 18, 19, 20, 21). However, these studies have generally been performed in a different cohort of GHD patients, with classical provocative tests that have poor reproducibility (8, 14, 17, 19, 22, 23, 24).

Whom to test among children who had been treated with rhGH in childhood is still an open question. Some authors proposed retesting all of them, whereas others proposed avoiding retesting in patients with panhypopituitarism and low IGF-I levels because of certain severe GHD (2, 9, 10, 19, 20, 25, 26).

It is widely accepted that most short children treated with rhGH do not have classical severe GHD (9, 10, 19). Moreover, insufficient somatotroph function for growth in childhood could be enough for metabolic activities in adulthood, and only adults with severe GHD need GH replacement (2, 6). In fact, at present, a benefit from rhGH replacement in adulthood has been shown only in patients with severe childhood-onset GHD (2, 6, 26, 27, 28).

Based on the foregoing, we studied the GH response to a single GHRH+ARG test in 62 young patients who had undergone GH replacement in childhood based on the following diagnosis: 1) organic hypopituitarism with GHD (oGHD); 2) idiopathic isolated GHD (iGHD); or 3) GH neurosecretory dysfunction (GHNSD). All these categories of patients are allowed to undergo GH replacement in childhood in many countries. Noteworthy is the fact that different pathogenesis and endocrinological profiles underlie the impairment of GH secretion in these categories. Patients with organic GHD have severe deficiency of somatotroph secretion because of direct impairment of the pituitary, whereas hypothalamic impairment more frequently underlies the low GH secretion in patients with iGHD; both these categories of patients show lack of GH response to 2 classical provocative tests (6). On the other hand, patients with GH insufficiency caused by GHNSD have normal GH response to provocative tests but impairment of spontaneous GH secretion, probably reflecting alterations in the neurotransmitter control of somatotroph function (6, 29, 30, 31).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Sixty-two young patients, who had undergone GH replacement in childhood, were studied. All subjects had been treated with rhGH in childhood, based on the following diagnosis and criteria: 1) oGHD, n = 18 [15 male (M), 3 female (F)]; age, 26.8 ± 2.2 yr; GH peak < 10 µg/L after two classical tests; GH peak < 4 µg/L in 15 of 18 patients who had been defined as having severe oGHD. Among patients in this group, 14 had panhypopituitarism, whereas the others had 1–2 pituitary deficits. All were in optimized replacement therapy since childhood. The etiologies of multiple hypopituitarism included: pituitary tumors, craniopharingioma, histiocytosis, pituitary surgery and/or radiotherapy, and posttraumatic or idiopathic hypopituitarism; 2) iGHD, n = 23 (15 M, 8 F), 23.0 ± 1.5 yr old, GH peak < 10 µg/L after two classical tests, GH peak < 4 µg/L in 8 of 23 patients who had been defined as having severe iGHD); and 3) GHNSD, n = 21 (10 M, 11 F); age, 25.1 ± 1.6 yr; GH peak > 10 µg/L after classical test but mGHc < 3 µg/L).

All patients underwent GHRH (GHRH29, GEREF, Serono, Italy; 1 µg/kg iv at 0 min) + ARG (ARG hydrochloride, 0.5 g/kg iv over 30 min, from 0 to +30 min) test. Blood samples were taken every 15 min, from -15 to +90 min.

The GH responses to GHRH+ARG in these groups were also compared with that recorded in a group of age-matched normal subjects [NS; n = 48 (20 M, 28 F)].

All patients in whom GHD was confirmed by retesting underwent also ITT (regular insulin; Actrapid, Novo-Nordisk, Bagsvaert, Denmark; 0.1 U/kg iv at 0 min). Blood samples were taken every 15 min, from -15 to +90 min.

All tests were performed in the morning, after an overnight fasting. No patient received rhGH for at least 3 months before testing, whereas all patients with pituitary insufficiencies other than GH had been in optimized replacement therapy for at least 3 months with thyroid hormone, cortisone acetate, gonadal steroids, and DDAVP, when appropriate.

The study protocol had been approved by an independent local ethical committee, and all patients gave their informed consent to participate in the study.

Serum GH levels were assayed ,at each time point, by an immunoradiometric assay method (HGH-CTK, Sorin, Italy). All samples from an individual subject were analyzed together. The sensitivity of the method was 0.15 µg/L. The inter- and intraassay coefficients of variation were 5.1–7.5% and 2.6–5.4%, respectively, at GH levels of 2.9–42.4 and 2.8–41.2 µg/L, respectively.

In our lab, the 3rd centile limit of normal peak GH response to GHRH+ARG from young adulthood to aging is 16.5 µg/L, whereas the 1st centile limit is 9.0 µg/L (evaluated in a population of 74 NS; age, 20–80 yr) (5). For ITT, we considered 5.0 and 3.0 µg/L as 3rd and 1st centile limits of normal peak GH response, based on data in literature (2, 6). During ITT, glucose measurement was performed, and a minimum plasma glucose level of 2.2 mmol/L or less was detected (2).

In all groups, basal serum IGF-I levels were assayed by an RIA method (Nichols Institute Diagnostics, San Juan Capistrano, CA) after acid-ethanol extraction, to avoid interference by binding proteins. The sensitivity of the method was 0.1 µg/L. The inter- and intraassay coefficients of variation were 8.8–10.8% and 5.0–9.5%, respectively, at IGF-I levels of 79.6–766.4 and 79.4–712.5 µg/L, respectively. Age-adjusted 3rd centile limits of normality for IGF-I levels in our lab (data derived from 336 NS, 20–80 yr old) are: 108.5 µg/L between 20–30 yr, 129.8 µg/L between 31–40 yr, 72.3 µg/L between 41–50 yr, 62.4 µg/L between 51–60 yr, 41.5 µg/L between 61–70 yr, and 24.7 µg/L between 71–80 yr (16).

The statistical analysis of the data was carried out by ANOVA and nonparametric Kruskall-Wallis test.

Results (mean ± SEM and/or individual values) are expressed as absolute values for GH, as well as for IGF-I (µg/L).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
IGF-I levels in oGHD (61.5 ± 13.7 µg/L) were lower (P < 0.001) than those in iGHD (117.2 ± 13.0 µg/L); the latter were lower (P < 0.001) than those in GHNSD (210.2 ± 12.9 µg/L), which, in turn, were similar to those in NS (220.9 ± 7.1 µg/L).

The mean GH peak after GHRH+ARG in oGHD (2.8 ± 0.8 µg/L) was lower (P < 0.001) than that in iGHD (18.6 ± 4.7 µg/L) which, in turn, was clearly lower (P < 0.001) than that in GHNSD (31.3 ± 1.6 µg/L) (Table 1Go and Fig. 1Go).


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  		Table 1. Individual peak GH responses in the same subjects who had undergone GH treatment in childhood based on diagnosis of oGHD, iGHD, or GHNSD

 


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  		Figure 1. Mean and individual GH peaks after GHRH+ARG test in subjects who had been treated with GH in childhood as having organic (left) or idiopathic (middle) GHD or GHNSD (right). Lines represent: (—) 3rd and (– – –) 1st centile limits of normal GH response to GHRH+ARG and ( ... ) the limit below which severe GHD is demonstrated by ITT in adults.

 
The GH response in GHNSD was lower than that in NS (65.9 ± 5.5 µg/L), but this difference did not attain statistical significance.

With respect to the 3rd centile limit of GH response in young adults (i.e. 16.5 µg/L), retesting confirmed GHD in all oGHD, in 65.2% of iGHD, and in none of the GHNSD subjects.

With respect to the 1st centile limit of GH response (i.e. 9.0 µg/L), retesting demonstrated severe GHD in 94% of oGHD and in 52.1% of iGHD subjects.

Taking into account the group of subjects classified as iGHD in childhood, those in whom GHD was not confirmed in adulthood had IGF-I levels (150.9 ± 14.6 µg/L), as well as GH peak after GHRH+ARG (43.5 ± 7.6 µg/L) clearly higher (P < 0.05 and P < 0.001, respectively) than those in subjects in whom the somatotroph deficit was apparent (IGF-I, 98.9 ± 16.9 µg/L; GH peak after GHRH+ARG, 5.2 ± 1.1 µg/L).

Considering together organic and idiopathic GHD, retesting with GHRH+ARG confirmed GHD in 81% of the patients, and the somatotroph deficit was severe in 71%. When only patients with severe organic or idiopathic GHD in childhood (GH peak < 4 µg/L) were taken into account, GHD in adulthood was confirmed by GHRH+ARG test in 96%, and the somatotroph deficit was severe in 93%.

All oGHD and iGHD patients with GH peak after GHRH+ARG lower than 9 µg/L had also GH lower than 3 µg/L after ITT. In the patients in whom GHD was confirmed by retesting, the mean GH peak after GHRH+ARG was higher than that after ITT (3.4 ± 0.5 vs. 1.9 ± 0.4 µg/L, P < 0.01) (Fig. 2Go). In these patients, IGF-I levels in iGHD were not statistically different from those in oGHD (98.9 ± 16.9 vs. 61.5 ± 13.7 µg/L) but, as anticipated above, the levels were lower (P < 0.05) than those in subjects in whom the somatotroph deficit was no more apparent (IGF-I, 150.9 ± 14.6 µg/L).



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  		Figure 2. Mean and individual GH peaks after GHRH+ARG or ITT in patients with persistent organic or idiopathic GHD in adulthood. Dotted lines represent the appropriate limits below which severe GHD is shown by GHRH+ARG or ITT.

 
Individual IGF-I levels in patients in whom retesting confirmed or did not show GHD in adulthood are reported in Fig. 3Go.



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  		Figure 3. Individual IGF-I levels in patients in whom retesting confirmed (left) or did not show (right) adult GHD. Shaded areas represent age-related normal IGF-I ranges.

 
In both organic and idiopathic GHD, IGF-I levels were positively, though weekly, associated with the peak GH response to GHRH+ARG (r = 0.42, P < 0.05); this was not the case in GHNSD patients and in NS.

No magnetic resonance imaging (MRI) was performed in patients in whom GHD was not shown at retesting in adulthood. Considering iGHD patients with persistence of GHD in adulthood, subtle MRI alterations were found in 8 of 15 (53%). On the other hand, 14 of 18 patients with oGHD had clear MRI alterations (77.7%).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study shows that, given appropriate cut-off limits, GHRH+ARG is as reliable as ITT for retesting adolescent or young adult patients who had undergone GH treatment in childhood. Among these patients, severe GHD in adulthood is generally confirmed in oGHD, is frequent in iGHD, but never occurs in GHNSD.

The reliability of GHRH+ARG as a provocative test to evaluate the pituitary GH releasable pool has been already shown in children, as well as in adult and elderly subjects (7, 19). In fact, this test has been shown as one of the most potent and reproducible (8, 22, 32). Particularly, it has been shown to be at least as reliable as ITT, the golden standard test (1, 2, 4, 33, 34), for the diagnosis of adult GHD, provided that appropriate cut-off limits are assumed (5). In agreement with this evidence, it is not surprising that, in the present study, we found the GHRH+ARG test to be as reliable as ITT for retesting adolescents and young adults who had been treated with GH in childhood. In fact, all patients in whom GHD was confirmed by retesting with GHRH+ARG showed also impaired somatotroph response to ITT. Actually, we performed ITT only in patients who failed to pass the GHRH+ARG test; because testing with GHRH explores the pituitary secretory capacity, bypassing the CNS pathways controlling GH secretion, we can not definitively rule out the possibility that some patients passing the GHRH+ARG test have persistent hypothalamic dysregulation, leading to their short stature as children.

Based on the recent GHRS consensus of opinion, GHD in adults has to be shown biochemically by provocative testing in the appropriate clinical context (2). This assumption implies that adult GHD must be suspected in all subjects who had been treated with GH in childhood and that these all subjects should undergo retesting with provocative tests.

Previous studies in literature reported discrepant percentages of persistent GHD in adulthood in patients who had been classified as GHD in childhood (1, 9, 10, 11, 17, 18, 19, 20). This evidence led to the statement that there is no justification for the view that patients diagnosed in childhood to be GHD should continue on therapy into adult life without their GH status being reinvestigated and shown to be persistently abnormal (9, 11). Of course, failure in showing severe GHD in adulthood does not imply that the diagnosis of GHD in childhood was a mistake; in fact, the child who is now an adult had poor growth as an indicator of GH insufficiency in childhood.

The inability to confirm GHD in adulthood could reflect transient GHD in childhood, as proposed by some authors (9, 17). On the other hand, it could merely reflect the lack of reproducibility of classical provocative tests, which has been clearly shown by many authors (19, 22, 23, 35, 36). However, it has also to be considered that even patients with normal GH response to provocative tests, but showing impairment of spontaneous GH secretion, are now currently considered as GH insufficients and are treated with rhGH for replacement (22, 29, 30, 31, 37, 38). Thus, it is not surprising that they all showed normal GH response when retested in adulthood with GHRH+ARG. They had been already normally responders to provocative tests in childhood and again showed a clear GH releasable pool. Our present findings indicate that slowly growing children, treated with GH for the so-called GHNSD, probably do not need retesting in adulthood, because the probability that they have severe GHD, if any, is negligible; in fact, in our study, all these patients also had normal IGF-I levels in adulthood.

Taking into account only subjects who had been defined as having organic GHD, our present data agree with previous findings (10, 18, 20) showing that the large majority of them have persistent severe GHD, even when retested in adulthood by a provocative test as potent as GHRH+ARG. It has been already proposed that, in the presence of multiple pituitary deficits, retesting for GHD could be even avoided, based on the persistence of very low IGF-I levels (2, 19). Our present findings could agree with this assumption, because all patients with multiple pituitary deficits were confirmed as having severe GHD and low IGF-I levels.

Retesting with GHRH+ARG showed that the persistence of GHD, particularly of severe deficiency, was much lower in the group of subjects who had been treated in childhood as having idiopathic GHD. The percentage of persistent GHD found in our study by retesting with GHRH+ARG is, however, similar to that recorded in previous studies in which classical provocative tests were used to retest the pituitary GH releasable pool, though with appropriate cut-off levels (9, 10, 11, 20). As in other studies (1, 9, 10, 11, 18, 19), subjects who had been shown to have severe GHD in childhood (GH peak <5 µg/L) generally showed persistency of severe GHD, even when retested with GHRH+ARG. In fact, the majority of subjects who showed normalization of the GH response had been shown to have partial GHD in childhood, in agreement with other authors (1, 9, 11). Once again, normalization of the GH response at retesting could be explained by transient GHD in childhood or by the low reliability of classical provocative tests (17, 22, 39, 40). Anyway, our present data strongly indicate that subjects who had been categorized as having idiopathic GHD and had been treated with GH in childhood represent the group that mostly requires retesting in adulthood to verify the existence of severe GHD and the need of continuing GH replacement in adulthood. At present, we could not rule out the possibility that less severe GHD in adulthood could have clinical significance in adulthood; in fact, it has been already reported that mild GH insufficiency in adults is associated with some alteration in metabolism and structure functions (41, 42, 43).

It is noteworthy that, if we consider together the subjects who received GH treatment for organic or idiopathic GHD in childhood, the percentage of persistent GHD in adulthood (81%) is really remarkable and is very close to that reported by some other authors (10, 18). This percentage clearly decreases (53%) if we include subjects who had been treated in childhood for GHNSD. Because the majority of children and adolescents treated with GH generally have nonclassical GHD, the true percentage of subjects who expected to be persistent GHD in adulthood, among those who received rhGH in childhood, is far lower.

In conclusion, our study shows that, among subjects who had been treated with GH in childhood, in adulthood GHD is never present in GHNSD, is often present in idiopathic GHD, and is generally confirmed in organic GHD. Thus, retesting with provocative tests is mandatory in iGHD but could be avoided in oGHD if IGF-I levels are very low and in the presence of other pituitary deficits.


   Acknowledgments
 
We thank Dr. C. Origlia, L. Quaranta, and D. Gaia for participation in the study and Mrs. M. Talliano for skillful technical assistance.


   Footnotes
 
1 Supported by a grant from the University of Turin and Fondazione per lo Studio delle Malattie Endocrino-Metaboliche (Turin, Italy). Back

Received February 8, 2000.

Revised June 22, 2000.

Accepted June 30, 2000.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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