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Original Studies |
Division of Endocrinology, Department of Internal Medicine, University of Turin, 10126 Turin Italy
Address all correspondence and requests for reprints to: E. Ghigo, M.D., Divisione di Endocrinologia, Ospedale Molinette, C.so Dogliotti 14, 10126 Torino, Italy
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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There is now wide consensus that, within an appropriate clinical context, GHD in adults must be shown biochemically, by single provocative testing, provided that a reproducible test with clear normative limits is available (9, 10, 11, 12). This statement is based on evidence that the assays of insulin-like growth factor-I (IGF-I) and IGF binding protein-3 per se do not establish the diagnosis of adult GHD. In fact, normal IGF-I and/or IGF binding protein-3 levels do not exclude GHD. This is caused by significant overlap between normal and GHD subjects for these parameters (9, 10, 13). Also, the evaluation of spontaneous GH secretion over 24 h has no diagnostic value in adulthood (9). In fact, it is clearly reduced in GHD, but there is a clear overlap between normal and GHD subjects (even when ultrasensitive GH assays are used) (14).
At present, the diagnosis of adult GHD is established only by provocative testing of GH secretion, and insulin-induced hypoglycemia (ITT) is indicated as the test of choice (1, 9, 11, 12, 13, 15). The lowest limit of GH response to ITT in normal subjects has been reported as 5 µg/L by some (but not by other) authors (1, 9, 15, 16, 17). Severe GHD to be treated with rhGH replacement is defined by a GH peak to ITT lower than the arbitrary cut-off of 3 µg/L (11, 12). Contraindication to ITT are ischemic heart disease, seizure disorders, and aging (12).
Alternative provocative tests of GH secretion have been proposed and have to be used with appropriate cut-off limits (10, 12, 18, 19, 20). The diagnostic value of clonidine provocative testing is limited, whereas arginine (ARG) and glucagon alone could be useful tests but are less discriminatory than ITT (18, 21). Testing with GHRH alone has no diagnostic value (22); but when GHRH is given in combination with ARG, it becomes the most useful, reproducible, and age-independent provocative test to evaluate the maximal secretory capacity of somatotrope cells (10, 22, 23). In our lab, the third centile limit of the GH response to GHRH+ARG test across human lifespan is 16.5 µg/L, and our previous data showed that it reproducibly distinguishes between normal and GHD adult and elderly subjects (10, 23). Based on this evidence, the GHRH+ARG test has been proposed as the most promising alternative to ITT for the diagnosis of GHD (11).
The aim of the present study was to compare the diagnostic reliability of ITT and the GHRH+ARG test in a large population of hypopituitary adults.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Nineteen patients had childhood onset (CO) GHD: eight of them had isolated GHD, whereas the others had panhypopituitarism already diagnosed and treated in childhood. In CO-GHD, the diagnosis had been already demonstrated in childhood by failure to respond to two classical provocative tests.
The etiologies of multiple hypopituitarism other than GH (n = 32) were the following: 24 with pituitary tumors and craniopharingioma before and/or after pituitary surgery or radiotherapy; 4 with idiopathic hypopituitarism; 2 with posttraumatic hypopituitarism; 1 with Sheehan syndrome; and 1 with histiocytosis.
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 (deamino-cys, D-ARG)-vasopressin (DDAVP, desmopressin) when appropriate.
The local ethical committee approved the study protocol, and all patients gave their informed consent to participate in the study.
All patients underwent the following tests, in the morning after an overnight fasting, at least 3 days apart: 1) ITT (regular insulin, Actrapid Novo-Nordisk Denmark: 0.1 U/kg iv at 0 min); and 2) 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).
Blood samples were taken every 15 min from -15 to +90 min.
Serum GH levels were assayed at each time point by immunoradiometric assay (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 laboratory, the third centile limit of normal peak GH response to GHRH+ARG from young adulthood to aging is 16.5 µg/L (evaluated in a population of 74 normal subjects, age 20–80 yr) (10). For ITT, we considered 5 µg/L as the third centile limit of normal peak GH response, based on data in the literature. During ITT, glucose measurement was performed, and a minimum plasma glucose level of 2.2 mmol/L or less was detected (9).
Serum IGF-I levels was assayed basally by RIA (Nichols Institute of 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 laboratory (data derived from 336 normal subjects from 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.
Student’s paired t test and linear regression analysis were used for statistical analysis of the data.
Results (mean ± SEM) are expressed as absolute values for GH, as well as for IGF-I (µg/L).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The 3rd centile limit of the peak GH response to ITT was assumed to be 5 µg/L, based on data from literature (1, 9), whereas in our laboratory, the response to GHRH+ARG provocation was 16.5 µg/L.
The mean peak GH response to ITT (1.5 ± 0.2 µg/L, range
0.1–8.5 µg/L) was lower (P < 0.001) than that to
GHRH+ARG (3.0 ± 0.4 µg/L, range 0.1–12.0 µg/L) (Fig. 1
). The peak GH responses to the two
tests were positively associated (r = 0.61, P <
0.0001), whereas both were independent of age. The peak GH response to
GHRH+ARG (r = 0.35, P < 0.03) [but not the
response to ITT (r = 0.2, P not significant)] was
positively, though weakly, associated with IGF-I levels. The mean peak
GH responses to ITT and GHRH+ARG in CO-GHD (1.3 ± 0.3 and
3.0 ± 0.6 µg/L, respectively) were similar to those in adult
onset-GHD (1.8 ± 0.4 and 3.1 ± 0.6 µg/L, respectively).
Similarly, the mean peak GH responses in patients with
panhypopituitarism (1.9 ± 0.7 and 2.9 ± 0.8 µg/L,
respectively) were similar to those in patients with one to two
pituitary hormonal insufficiencies other than GH (1.8 ± 0.5 and
3.7 ± 1.0 µg/L, respectively).
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and 3).
On the other hand, after GHRH+ARG, all patients had GH peaks lower than
16.5 µg/L, whereas 21/40 (52.5%) had GH peaks higher than 3 µg/L.
It is noteworthy that 73% of the patients with GH peak higher than 3
µg/L after GHRH+ARG had GH peaks below this limit after ITT (Fig. 2 and 3).
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and 3).
Note that those patients with GH peaks higher than 3 µg/L after ITT
or 9 µg/L after GHRH+ARG had multiple pituitary insufficiencies. No significant side effects were observed with both tests. Only mild tachycardia and sweating (after ITT) and transient facial flushing (after GHRH) occurred in the majority of patients. However, no test had to be stopped.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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There is consensus that the diagnosis of adult GHD is established by provocative testing of GH secretion (9, 10). ITT is considered the test of choice (9, 11, 12). In fact, this test has been found to be capable of distinguishing GHD from the reduced GH secretion that accompanies aging and obesity. Following consensus of opinion leaders (11, 12), severe GHD, to be treated with rhGH replacement, is defined by an arbitrary cut-off that is a GH peak response to ITT less than 3 µg/L. Note that the lowest limit of GH response to ITT in normal individuals has been reported as 5 µg/L (9). However, recently, ITT has been found to be poorly reproducible in normal subjects, thus questioning its specificity (16, 17). Moreover, ITT is contraindicated in patients with ischemic heart disease, seizure disorders, and aging (12).
Alternative provocative tests of GH secretion have been proposed, but they must be used with appropriate cut-off limits (11, 12). Among alternatives, other classical provocative tests, as well as GHRH alone, are of less (if any) value, when compared with ITT (18, 21, 22). However, when GHRH is given in combination with ARG or pyridostigmine, which probably act via inhibition of hypothalamic somatostatin release (24), it becomes the most potent and reproducible provocative test to evaluate the pituitary GH releasable pool (19, 20, 22, 23, and present data) distinguishing between normal and GHD adults (10, 20).
In contrast to GHRH+PD, the GH response to GHRH+ARG is not reduced in aging (25, 26, 27). Thus, it has been suggested that the latter stimulus could be proposed as the most promising alternative to ITT.
With respect to its third centile cut-off limit (5.0 µg/L GH peak) (9), ITT demonstrated GHD in 90% of the patients, whereas all of them had insufficient GH response to GHRH+ARG. This picture overlaps with that comparing ITT with GHRH + pyridostigmine in a large population of young and middle-aged GHD subjects (20).
With respect to the arbitrary cut-off of 3 µg/L as the limit below which severe GHD is demonstrated after ITT (11, 12), 83% of the patients were below this limit. Thus, our data confirm the diagnostic reliability of ITT, which, in our hands, gave no serious side effects.
On the other hand, with respect to the arbitrary cut-off of 3 µg/L, 47.5% of the patient population has peak GH results below this limit when tested with GHRH+ARG. Note that 73% of them had had a GH peak lower than 3 µg/L after ITT. Theoretically, one could hypothesize that ITT had given a large number (approximately 50%) of false positive responses, indicating severe GHD. However, this hypothesis is unlikely, considering that the majority of these patients had multiple pituitary insufficiencies and low IGF-I levels.
We would like to emphasize that each test must be used with appropriate cut-off limits. This means also that the arbitrary cut-off point below which severe GHD is demonstrated has to be appropriate to the potency of each provocative test. Because 3 µg/L is the arbitrary cut-off for ITT, the third centile limit of which is 5 µg/L, we arbitrarily considered 9 µg/L as the cut-off point for GHRH+ARG; note that this limit represents the first centile limit of the normal GH response to the GHRH+ARG test, in a large population of normal subjects (10).
Note that 92.5% of the GHD patients had GH peaks, after GHRH+ARG, below the limit of 9 µg/L. This population also included 6/7 of the patients with GH peaks higher than 3 µg/L after ITT. We concluded that all these patients have severe GHD; they are all now treated with rhGH and show benefit from treatment.
On the other hand, we assumed that patients with GH peaks higher than 9 µg/L (7.5%), but lower than 16.5 µg/L, after GHRH+ARG had partial GHD. At present, there is no evidence supporting the hypothesis that partial GHD in adults needs GH replacement.
Finally, we would like to emphasize that, unlike ITT, the GH response to GHRH+ARG in GHD is positively associated with IGF-I levels, which is the best marker of GH secretory status (28). This evidence reinforces the reliability of this provocative test for the diagnosis of severe adult GHD.
In conclusion, our present results show that the GHRH+ARG test is, at least, as reliable as ITT for the diagnosis of adult GHD, provided that appropriate cut-off limits are considered.
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Acknowledgments |
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Footnotes |
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Received November 5, 1997.
Revised January 8, 1998.
Revised February 3, 1998.
Accepted February 10, 1998.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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E. L. Germain-Lee, J. Groman, J. L. Crane, S. M. Jan de Beur, and M. A. Levine Growth Hormone Deficiency in Pseudohypoparathyroidism Type 1a: Another Manifestation of Multihormone Resistance J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4059 - 4069. [Abstract] [Full Text] [PDF]
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W. F. Blum, E. P. Shavrikova, D. J. Edwards, M. Rosilio, M. L. Hartman, F. Marin, D. Valle, A. J. van der Lely, A. F. Attanasio, C. J. Strasburger, et al. Decreased Quality of Life in Adult Patients with Growth Hormone Deficiency Compared with General Populations Using the New, Validated, Self-Weighted Questionnaire, Questions on Life Satisfaction Hypopituitarism Module J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4158 - 4167. [Abstract] [Full Text] [PDF]
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A. Colao, C. Di Somma, S. Spiezia, M. Filippella, R. Pivonello, and G. Lombardi Effect of Growth Hormone (GH) and/or Testosterone Replacement on the Prostate in GH-Deficient Adult Patients J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 88 - 94. [Abstract] [Full Text] [PDF]
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K. H. Darzy, G. Aimaretti, G. Wieringa, H. R. Gattamaneni, E. Ghigo, and S. M. Shalet The Usefulness of the Combined Growth Hormone (GH)-Releasing Hormone and Arginine Stimulation Test in the Diagnosis of Radiation-Induced GH Deficiency Is Dependent on the Post-Irradiation Time Interval J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 95 - 102. [Abstract] [Full Text] [PDF]
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C. Hoybye, A. Hilding, H. Jacobsson, and M. Thoren Metabolic Profile and Body Composition in Adults with Prader-Willi Syndrome and Severe Obesity J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3590 - 3597. [Abstract] [Full Text] [PDF]
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M. Maghnie, F. Cavigioli, C. Tinelli, M. Autelli, M. Arico, G. Aimaretti, and E. Ghigo GHRH Plus Arginine in the Diagnosis of Acquired GH Deficiency of Childhood-Onset J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2740 - 2744. [Abstract] [Full Text] [PDF]
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V. Rochira, A. Balestrieri, M. Faustini-Fustini, S. Borgato, P. Beck-Peccoz, and C. Carani Pituitary Function in a Man with Congenital Aromatase Deficiency: Effect of Different Doses of Transdermal E2 on Basal and Stimulated Pituitary Hormones J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2857 - 2862. [Abstract] [Full Text] [PDF]
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B. M. K. Biller, M. H. Samuels, A. Zagar, D. M. Cook, B. M. Arafah, V. Bonert, S. Stavrou, D. L. Kleinberg, J. J. Chipman, and M. L. Hartman Sensitivity and Specificity of Six Tests for the Diagnosis of Adult GH Deficiency J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2067 - 2079. [Abstract] [Full Text] [PDF]
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A. Colao, C. di Somma, A. Cuocolo, L. Spinelli, N. Tedesco, R. Pivonello, D. Bonaduce, M. Salvatore, and G. Lombardi Improved Cardiovascular Risk Factors and Cardiac Performance after 12 Months of Growth Hormone (GH) Replacement in Young Adult Patients with GH Deficiency J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 1874 - 1881. [Abstract] [Full Text]
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M. Maghnie, B. Salati, S. Bianchi, M. Rallo, C. Tinelli, M. Autelli, G. Aimaretti, and E. Ghigo Relationship between the Morphological Evaluation of the Pituitary and the Growth Hormone (GH) Response to GH-Releasing Hormone Plus Arginine in Children and Adults with Congenital Hypopituitarism J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1574 - 1579. [Abstract] [Full Text]
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G. Aimaretti, C. Baffoni, S. Bellone, L. Di Vito, G. Corneli, E. Arvat, L. Benso, F. Camanni, and E. Ghigo Retesting Young Adults with Childhood-Onset Growth Hormone (GH) Deficiency with GH-Releasing-Hormone-Plus-Arginine Test J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3693 - 3699. [Abstract] [Full Text]
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H. C. Hoeck, P. Vestergaard, P. E. Jakobsen, J. Falhof, and P. Laurberg Diagnosis of Growth Hormone (GH) Deficiency in Adults with Hypothalamic-Pituitary Disorders: Comparison of Test Results Using Pyridostigmine Plus GH-Releasing Hormone (GHRH), Clonidine Plus GHRH, and Insulin-Induced Hypoglycemia as GH Secretagogues J. Clin. Endocrinol. Metab., April 1, 2000; 85(4): 1467 - 1472. [Abstract] [Full Text]
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A. Colao, A. Cuocolo, C. Di Somma, G. Cerbone, A. M. Della Morte, E. Nicolai, R. Lucci, M. Salvatore, and G. Lombardi Impaired Cardiac Performance in Elderly Patients with Growth Hormone Deficiency J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 3950 - 3955. [Abstract] [Full Text]
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A. Colao, C. Di Somma, R. Pivonello, S. Loche, G. Aimaretti, G. Cerbone, A. Faggiano, G. Corneli, E. Ghigo, and G. Lombardi Bone Loss Is Correlated to the Severity of Growth Hormone Deficiency in Adult Patients with Hypopituitarism J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 1919 - 1924. [Abstract] [Full Text]
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A. Colao, G. Cerbone, R. Pivonello, G. Aimaretti, S. Loche, C. Di Somma, A. Faggiano, G. Corneli, E. Ghigo, and G. Lombardi The Growth Hormone (GH) Response to the Arginine Plus GH-Releasing Hormone Test Is Correlated to the Severity of Lipid Profile Abnormalities in Adult Patients with GH Deficiency J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1277 - 1282. [Abstract] [Full Text]
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M. Maghnie, C. Strigazzi, C. Tinelli, M. Autelli, M. Cisternino, S. Loche, and F. Severi Growth Hormone (GH) Deficiency (GHD) of Childhood Onset: Reassessment of GH Status and Evaluation of the Predictive Criteria for Permanent GHD in Young Adults J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1324 - 1328. [Abstract] [Full Text]
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 A. Giustina and J. D. Veldhuis Pathophysiology of the Neuroregulation of Growth Hormone Secretion in Experimental Animals and the Human Endocr. Rev., December 1, 1998; 19(6): 717 - 797. [Abstract] [Full Text]
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