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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 8 2633-2637
Copyright © 1999 by The Endocrine Society

Original Studies

Low Dose Hexarelin and Growth Hormone (GH)-Releasing Hormone as a Diagnostic Tool for the Diagnosis of GH Deficiency in Adults: Comparison with Insulin-Induced Hypoglycemia Test1

M. Gasperi, G. Aimaretti, G. Scarcello, G. Corneli, C. Cosci, E. Arvat, E. Martino and E. Ghigo

Department of Endocrinology, University of Pisa (M.G., G.S., C.C., E.M.), 56124 Pisa; and the Division of Endocrinology, Department of Internal Medicine, University of Turin (G.A., G.C., E.A., E.G.), 10126 Turin, Italy

Address all correspondence and requests for reprints to: Dr. M. Gasperi, Dipartimento di Endocrinologia, Ospedale Cisanello, Via Paradisa 2, 56124 Pisa, Italy. E-mail: mgasperi{at}endoc.med.unipi.it


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
GH deficiency (GHD) in adults must be shown by provocative testing of GH secretion. Insulin-induced hypoglycemia (ITT) is the test of choice, and severe GHD, treated with recombinant human GH replacement, is defined by a GH peak response to ITT of less than 3 µg/L. GHRH plus arginine (ARG) is a more provocative test and is as sensitive as ITT provided that appropriate cut-off limits are assumed. GH secretagogues are a family of peptidyl and nonpeptidyl GH-releasing molecules that strongly stimulate GH secretion and, even at low doses, truly synergize with GHRH. Our aim was to verify the diagnostic reliability of the hexarelin (HEX; 0.25 µg/kg, iv) and GHRH (1 µg/kg, iv) test for the diagnosis of adult GHD. To this goal, in the present study we 1) defined the normal ranges of the GH response to GHRH+HEX in a group of normal young adult volunteers (NS; n = 25; 18 men and 7 women; age, 28.5 ± 0.6 yr) and in 11 of them verified its reproducibility in a second session, and 2) compared the GH response to GHRH+HEX with that to ITT in a group of normal subjects (n = 33; 12 men and 21 women; age, 34.1 ± 1.5 yr) and hypopituitaric adults with GHD (n = 19; 10 men and 9 women; age, 39.9 ± 2.2 yr; GH peak <5 µg/L after ITT). The GH response to GHRH+ARG was also evaluated in all GHD and in 77 normal subjects (40 men and 37 women; age, 28.1 ± 0.6 yr). The mean GH peak after GHRH+HEX in NS was 83.6 ± 4.5 µg/L; the third and first percentile limits of the normal GH response were 55.5 and 51.2 µg/L, respectively). The GH response to GHRH+HEX in NS showed good intraindividual reproducibility. In GHD the mean GH peak after GHRH+HEX (2.6 ± 0.7 µg/L) was similar to that after GHRH+ARG (3.6 ± 1.0 µg/L), and both were higher (P < 0.001) than that after ITT (0.6 ± 0.1 µg/L); the GH responses to GHRH+HEX were positively associated with those to ITT and GHRH+ARG. Analyzing individual GH responses, 100% had severe GHD after ITT (GH peak, <3 µg/L). After GHRH+HEX all GHD had GH peaks below the third percentile limit of normality appropriate for this test (i.e. 55.5 µg/L). Thirteen of 19 (68.4%) GHD subjects had GH peaks below 3 µg/L after GHRH+HEX but all 19 (100%) had GH peaks below the first percentile limit of normality (i.e. 51.2 µg/L). The GH responses to GHRH+HEX were highly concordant with those after GHRH+ARG. In conclusion, the present results define normal limits of the GH response to stimulation with low dose HEX+GHRH in normal adults and show that this test is as sensitive as ITT for the diagnosis of adult GHD provided that appropriate cut-off limits are considered.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THERE IS now wide consensus that within an appropriate clinical context, GH deficiency (GHD) in adults must be shown biochemically by single provocative testing provided that a reproducible test with clear normative limits is available (1, 2, 3, 4, 5, 6, 7). This statement is based on evidence that the evaluation of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) levels as well as of spontaneous GH secretion are not reliable for the diagnosis of adult GHD. In fact, mean IGF-I and IGFBP-3 levels in GHD adults are reduced, but these parameters show significant overlap between normal and GHD subjects (1, 4, 7, 8). The same picture applies to mean GH concentrations over 24 h, which are reduced in GHD adults but show clear overlap between normal and GHD subjects even when ultrasensitive GH assays are used (1, 10).

Thus, the diagnosis of adult GHD is established only by provocative testing of GH secretion, and insulin-induced hypoglycemia (ITT) has been indicated as the test of choice (1, 2, 3, 5, 8, 11). The lowest limit of GH response to ITT in normal subjects has been reported to be 5 µg/L by some (1, 2, 11), but not other (12, 13), researchers. Severe GHD, treated with recombinant human GH (rhGH) replacement, is defined by a GH peak to ITT lower than the arbitrary cut-off of 3 µg/L (3, 5). Contraindication to ITT are ischemic heart disease, seizure disorders, and aging (3).

Alternative provocative tests of GH secretion have been proposed and have to be used with appropriate cut-off limits (3, 4, 14, 15, 16, 17). Testing with GHRH alone has no diagnostic value (18), but when GHRH is given in combination with arginine (ARG) it becomes one of the most useful, reproducible, and age-independent provocative tests to evaluate the maximal secretary capacity of somatotrope cells (4, 18, 19). In our laboratory, the third percentile limit of the GH response to GHRH+ARG test across the human lifespan is 16.5 µg/L, and our previous data showed that it reproducibly distinguishes between normal and GHD adult and elderly subjects (4, 19). Moreover, we have recently shown that the GHRH+ARG test is at least as sensitive as ITT for the diagnosis of adult GHD, provided that appropriate cut-off limits are considered, and the limit below which severe GHD is demonstrated has been proposed to be 9 µg/L GH peak (first percentile limit in a population between 20–80 yr of age) (7).

GH secretagogues are a family of synthetic peptidyl [GH-releasing peptides (GHRPs)] and nonpeptidyl molecules that possess strong and reproducible GH-releasing activity, particularly in humans (20). GHRPs act on specific receptors at the pituitary and mainly at the hypothalamic level (20, 21, 22). They seem to act at least partially as functional somatostatin antagonists as well as increasing the activity of GHRH-secreting neurons (20, 23, 24). Indeed, GHRPs release more GH than GHRH and, even when administered at low doses, truly synergize with GHRH (20), but these responses are markedly reduced in patients with hypothalamic-pituitary disconnection (25).

The strong GH-releasing activity of GHRPs, both alone and combined with GHRH, was the rational basis of their potential usefulness as provocative test for the diagnosis of GHD in both children and adults (20, 26, 27). However, there is evidence that the GH response to GHRPs, both alone and combined with GHRH, undergoes marked age-related variations, being maximal in pubertal children and adults and decreasing by the fifth decade of life (27, 28, 29). Thus, age-related normative values are needed before evaluating their potential usefulness for the diagnosis of GHD.

Our aim was to verify the diagnostic reliability of testing with coadministration of hexarelin (HEX) and GHRH for the diagnosis of adult GHD. In the present study we 1) defined the normative values of the GH response to GHRH+HEX and verified the reproducibility of the test in normal adult volunteers, and 2) compared the GH response to GHRH+HEX with that to ITT in a group of hypopituitaric adults with GHD. The GH response to GHRH+ARG was also evaluated in all GHD patients.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Eighty-five young and middle-aged normal adult volunteers (NS; age range, 20–50 yr; n = 110; 45 men and 40 women; age, 31.2 ± 1.3 yr; range, 20–50 yr; all within ±15% of ideal body weight) and 19 adult hypopituitaric patients with GHD (n = 19; 10 men and 9 women; age, 39.9 ± 2.2 yr; range, 20–52 yr; body mass index, 24.5 ± 2.1 kg/m2; GH peak, <5 µg/L after ITT) were studied. Among patients, 13 had acquired adult-onset GHD, 18 of them had panhypopituitarism, whereas the other had isolated childhood-onset GHD, which had been already demonstrated in childhood by failure to respond to 2 classical provocative tests. No patient had received rhGH for at least 3 months before testing, whereas all patients with pituitary insufficiencies other than GH had been receiving optimal replacement therapy for at least 3 months with thyroid hormone, cortisone acetate, gonadal steroids, and DDAVP when appropriated.

The local ethical committee approved the study protocol, and all subjects gave their informed consent to participate in the study.

Twenty-five NS and 19 GHD patients underwent testing with GHRH (GEREF Serono, Italy; 1 µg/kg, iv, at 0 min) and HEX (Europeptides, France; 0.25 µg/kg, iv, at 0 min); this test was repeated in 11 NS. Thirty-three NS and all GHD patients also underwent the tests with ITT (regular insulin, Actrapid Novo-Nordisk A/S, Copenhagen, Denmark: 0.1 IU/kg, iv, at 0 min). In all subjects blood glucose levels after insulin administration decreased below 40 mg/dL. The mean GH peak after ITT in NS was 22.1 ± 3.1 µg/L (range, 3.0–84.0 µg/L). The third and first percentile limits of the normal GH response were 5.2 and 3.7 µg/L, respectively (Table 1Go).


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  		Table 1. Individual and mean (±SEM) peak GH responses to GHRH + HEX, GHRH + ARG, and ITT in GHD adults: first and third percentile limits in young and middle-aged normal subjects

 
Seventy-seven NS and all GHD underwent testing with GHRH+ARG (arginine hydrochloride, 0.5 g/kg, iv, over 30 min from 0–30 min). The mean GH peak after GHRH+ARG in NS was 69.5 ± 4.6 µg/L (range, 13.8–171.0 µg/L). The third and first percentile limits of the normal GH response were 17.5 and 15.9 µg/L, respectively (Table 1Go). The majority of young and middle-aged normal subjects tested with GHRH+ARG had been studied before planning the present study, and those results were previously presented (4). All normal subjects who underwent the GHRH+HEX test were also administered ITT and GHRH+ARG. The results for hypopituitaric patients have never been published.

Blood samples for GH assay were taken every 15 min from -15 to 90 min in each test, and the basal IGF-I level was determined. All tests were performed in the morning after an overnight fast, at least 7 days apart.

Serum GH levels (micrograms per L) were assayed at each time point by immunoradiometric assay (HGH-CTK, Sorin, Milan, Italy). All samples from an individual subject were analyzed in the same assay. 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 between 2.9–42.4 and 2.8–41.2 µg/L, respectively.

Basal serum IGF-I levels (micrograms per L) were assayed by RIA (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. In our laboratory, the age-adjusted third percentile limits of normality for IGF-I levels were 108.5 µg/L between 20–30 yr, 129.8 µg/L between 31–40 yr, and 72.3 µg/L between 41–50 yr.

Statistical analysis of the data was performed by paired and unpaired Student’s t test where appropriate. First and third percentile limits were calculated with Microsoft Corp. Excel 7.0 for Windows 95. Results (mean ± SEM) are expressed as absolute values for GH as well as IGF-I.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The mean GH peak after GHRH+HEX in NS was 83.6 ± 4.5 µg/L (range, 49.0–124.0 µg/L). The third and first percentile limits of the normal GH response were 55.5 and 51.2 µg/L, respectively (Fig. 1Go). The GH response to GHRH+HEX in NS showed good intraindividual reproducibility (first vs. second session, 87.7 ± 6.5 vs. 90.0 ± 8.9 µg/L; r = 0.61; P < 0.04; Fig. 2Go). In NS, the mean GH response to GHRH+HEX was similar to that to GHRH+ARG, which, in turn, was higher (P < 0.001) than that to ITT. This was true even considering only the GH responses in the 25 normal subjects who underwent all tests.



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  		Figure 1. Individual peak GH responses to ITT, GHRH+ARG, and GHRH+HEX in GHD adults. The dotted line and dotted boxes represent first and third percentile limits and normal GH responses in normal young and middle-aged subjects, respectively.

 


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  		Figure 2. Intraindividual reproducibility of the GH response to GHRH+HEX in normal adults tested in two sessions (r = 0.61; P < 0.04).

 
Mean IGF-I levels in GHD patients were lower than those in NS (46.9 ± 6.9 vs. 213.3 ± 17.2 µg/L; P < 0.001) with some overlap between the two groups (range, GHD vs. NS, 31.0–116.0 vs. 78.0–375.0 µg/L).

The mean GH peak after GHRH+HEX in GHD patients (2.6 ± 0.7 µg/L) was clearly lower than that in NS (P < 0.001; Table 1Go). In GHD patients, the mean GH response to GHRH+HEX was similar to that after GHRH+ARG (3.6 ± 1.0 µg/L), and both were higher (P < 0.001) than that after ITT (0.6 ± 0.1 µg/L; Table 1Go). In GHD patients, the GH response to GHRH+HEX was positively associated with those to ITT and GHRH+ARG. In the whole population of subjects who underwent all three tests (n = 25), the GH response to different stimuli was positively associated. The GH response to GHRH+HEX and GHRH+ARG, but not to ITT, showed a trend toward a positive association with IGF-I levels.

Analyzing individual GH responses in GHD, 19 of 19 (100%) had GH peaks below 3 µg/L after ITT. After GHRH+HEX, all GHD had GH peak below the third percentile limit of normality appropriate for this test. Thirteen of 19 (68.4%) GHD patients had GH peaks below 3 µg/L, but 19 of 19 (100%) had GH peaks below the first percentile limit of normality (i.e. 51.2 µg/L; Fig. 1Go and Table 1Go). The GH responses to the GHRH+HEX test were highly concordant with those after GHRH+ARG. In fact, after GHRH+ARG all GHD patients had GH peaks below the third percentile limit of normality. Eleven of 19 (57.0%) GHD patients had GH peaks below 3 µg/L, but 18 of 19 (94.7%) had GH peaks below the first percentile limit of normality in adults (Fig. 1Go and Table 1Go).

No significant side-effects were observed. Only mild tachycardia and sweating after ITT and transient facial flushing after GHRH and HEX occurred in the majority of patients. However, no medication was required, and no test had to be stopped.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results of this study allow us to 1) define normal limits of the GH response to stimulation with low dose HEX+GHRH to demonstrate that this test shows good intraindividual reproducibility in healthy adults, and 2) show that this test is as sensitive as ITT as well as the GHRH+ARG test for the diagnosis of GHD in adults, provided that appropriate cut-off limits are considered.

Our present results confirm that ITT as well as GHRH+ARG are reliable provocative tests for the diagnosis of adult GHD, provided that appropriate cut-off limits are considered (4, 5, 7). The diagnosis of adult GHD must be established by provocative testing of GH secretion, and ITT is considered the test of choice (1, 3, 4, 5). Severe GHD, treated with rhGH replacement, is defined by an arbitrary cut-off GH peak response to ITT of less than 3 µg/L, whereas the lowest limit of GH response to ITT in normal individuals has been reported to be 5 µg/L (1). ITT has been found to be poorly reproducible by some (12, 13), but not by other (1, 2), researchers; moreover, it is contraindicated in patients with ischemic heart disease, seizure disorders, and aging (3). This led to looking for alternative provocative tests which, however, must be used with cut-off limits appropriate to their own GH-releasing potency (3, 5). Among alternatives, GHRH given in combination with arginine (4, 7) or pyridostigmine (4, 15, 16), which probably act via inhibition of hypothalamic SS release (30), becomes the most potent and reproducible provocative test to evaluate the pituitary GH releasable pool (15, 16, 18, 19) distinguishing normal from GHD adults (4, 16). It has been recently shown that GHRH+ARG is at least as reliable as ITT for the diagnosis of adult GHD (4, 7).

Looking for another potential test alternative to ITT, we studied the diagnostic reliability of testing with HEX, a GHRP, and GHRH. GHRPs show potent and reproducible GH-releasing activity, release more GH than GHRH, and, even when administered at low doses, truly synergizes with GHRH (20), pointing to their potential usefulness as provocative test for the diagnosis of GH secretion. The combination of GHRP-6 and GHRH has been studied in GHD adults (31), but the results were not evaluated with reference to appropriate cut-off limits.

In the present study we verified the diagnostic reliability of the association between low dose HEX+GHRH (32, 33). We restricted our study to young and middle-aged adults, because a clear reduction of the GH response to GHRPs both alone and combined with GHRH has been demonstrated in elderly subjects by some (27, 28, 29, 34), but not by others (35, 36). Thus, the utility of GHRH+HEX as reliable test for the diagnosis of GHD in elderly remains to be shown.

Our present results confirm that the combined administration of HEX, even at low dose, and GHRH induces an impressive GH response in normal subjects in whom the third percentile limit of normality is much higher than that recorded after ITT and after GHRH+ARG. It has to be emphasized that the GH response to GHRH+HEX as well as that to GHRH+ARG (19) shows good intraindividual reproducibility. Thus, at least in adults, the GHRH+HEX test possesses the characteristics of a reliable test showing clear limits of normality and is reproducible.

In GHD as well as in NS the mean GH response to GHRH+HEX was approximately 3- to 4-fold higher than that to ITT and similar to that after GHRH+ARG, further indicating that cut-off limits of normality appropriate to the potency of each test are needed before evaluating the GH response in patients suspected of having GHD (4, 5, 7).

Analyzing individual GH responses in GHD, it is apparent that, assuming 55.5 µg/L as the appropriate third percentile normal limit, the GHRH+HEX test confirmed GHD in all patients. With respect to the arbitrary cut-off of 3 µg/L, 100% of patients had GH peak below this limit after ITT, and 68.4% of them had GH peak above this limit when tested with GHRH+HEX. Theoretically, one could hypothesize that ITT had given false positive responses, indicating severe GHD. However, this hypothesis is unlikely considering that these patients had multiple pituitary insufficiencies and low IGF-I levels. Indeed, assuming the first percentile of normal response to GHRH+HEX (i.e. 51.2 µg/L), all patients had GH peaks below normal. Interestingly, assuming an appropriate cut-off, the GH responses to GHRH+ARG were highly concordant with those to GHRH+HEX. The marked and reproducible GH response to GHRH+HEX as well as that to GHRH+ARG that generally occur in the first hour after injection suggest that blood sampling should be performed at 0, 30, and 60 min. This implies a less time-consuming and costly procedure.

In conclusion, the results of this study show that the coadministration of low dose HEX+GHRH is a potent and reproducible provocative test of GH secretion and, provided that appropriate cut-off limits are applied, it is as reliable as ITT for the diagnosis of GHD in adults. In fact, ITT is considered the golden standard test for the diagnosis of adult GHD, but alternative tests are needed due to side-effects and contraindications, such as in patients with seizures or cardiac ischemia and in elderly subjects. Testing with GHRH+HEX seems free of side-effects and contraindications, thus further suggesting its reliability for the diagnostic management of adults suspected of having GH deficiency.


   Acknowledgments
 
The authors thank Mrs. M. Taliano for her skillful technical assistance.


   Footnotes
 
1 This work was supported by Grant 9706151106 from Ministero Università e Ricerca Scientifica e Tecnologica (Rome, Italy) and Fondazione Studio Malattie Endocrino Metaboliche (Turin, Italy). Back

Received February 1, 1999.

Revised April 28, 1999.

Accepted May 10, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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