help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cappa, M.
Right arrow Articles by Müller, E. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cappa, M.
Right arrow Articles by Müller, E. E.
The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 12 4426-4430
Copyright © 1999 by The Endocrine Society

Special Articles

Somatostatin Infusion Withdrawal: Studies in Normal Children and in Children with Growth Hormone Deficiency

Marco Cappa, Antonello E. Rigamonti, Carla Bizzarri, Ottavia Porzio, Patrizia Civolani, Silvano G. Cella, Sandro Loche and Eugenio E. Müller

Divisione di Pediatria (M.C., C.B., O.P.), Ospedale Bambino Gesù, IRCCS, 00050 Roma, Italy; Dipartimento di Farmacologia, Chemioterapia e Tossicologia Medica (A.E.R., S.G.C., E.E.M.), Università di Milano, Milan 20129, Italy; and Servizio di Endocrinologia Pediatrica (P.C., S.L.), Ospedale Microcitemico, 09100 Cagliari, Italy

Address correspondence and requests for reprints to: Eugenio E. Müller, Dipartmento di Farmacologia, Universitá Degli Studi di Milano, Via Vanvitelli, 32, Milan 20129, Italy.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Withdrawal of a somatostatin infusion (SSIW) is followed by a rebound rise of GH in both animals and normal adult men, a phenomenon likely mediated by endogenous GHRH function. In the present study, we have evaluated the GH response to SSIW in a group of 28 prepubertal children (18 boys and 10 girls; aged 3.7–11.1 yr). Six children had GH deficiency [GHD; GH responses to pyridostigmine (PD)+GHRH and to clonidine <20 and <7 µg/L, respectively], 4 children had GH neurosecretory dysfunction (GHND; GH responses to PD+GHRH and to clonidine >=20 and >7 µg/L, respectively; mean integrated nighttime GH concentrations <3 µg/L), and 18 children were short normal children [normal controls (NC)]. All children received a constant infusion of SS at the dose of 3 µg/Kg·h for 90 min.

SSIW elicited a clear-cut GH rise in NC children (13.7 ± 1.0 µg/L), but not in GH-deficient children, regardless of the underlying etiology (GHD, 1.6 ± 0.4 µg/L; GHND, 2.4 ± 0.3 µg/L). The GH response to SSIW was similar between GHD and GHND children. There was no overlapping of the maximum SSIW-stimulated GH peaks between NC and GHD or GHND children.

In conclusion, we have demonstrated that SSIW elicits a significant GH rise in NC children, but not in GH-deficient children, regardless of the underlying etiology (GHD or GHND). This resulted in complete discrimination of NC from GHD or GHND children. Were these present findings confirmed on a larger number of children, SSIW, because of its testing efficaciousness and safety, procedural simplicity, and economy holds promise of being a useful diagnostic tool for GH-dependent growth disorders.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PULSATILE SECRETION of GH is subject to stimulatory and inhibitory regulation by hypothalamic GH-releasing hormone (GHRH) and somatostatin (SS), respectively (1). SS has a role in generating pulsatile GH release, and there is agreement that troughs in a sinusoidal pattern of SS release allow episodic secretion of GH via GHRH release (2). Reportedly, withdrawal of SS infusion either in animals (3, 4, 5, 6) or humans (7, 8) produces a rebound GH rise, and some observations indicate that this may be due to disinhibition of GHRH neuronal function (3, 5, 6, 8, 9, 10). Were this the case, the rebound GH rise following SS infusion withdrawal (SSIW) may be an inferential probe of endogenous GHRH function and a potential tool in the diagnosis of growth disorders due to GH hyposecretory states.

Although biochemical tests for GH secretion clearly distinguish children with severe GH deficiency (GHD) of pituitary origin, recognition of more subtle forms of GH insufficiency still represents a diagnostic dilemma (11). In fact, among short children with the clinical picture of GHD, some may have partial GHD, whereas others may have normal GH responses to stimulation but low spontaneous secretion [GH neurosecretory dysfunction (GHND); 12, 13]. Much of the difficulty in the diagnosis of GHD lies in the poor reproducibility of GH stimulation tests (14, 15) as well as in the fact that they do not reflect spontaneous GH secretion (16, 17, 18).

In the present study, we have evaluated the GH response to 90-min SS infusion in a group of children with normal GH secretion [normal controls (NC)], in children with GHD, and in children with GHND. Our results indicate that the GH response to SSIW might be helpful in the differential diagnosis of growth disorders.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
A total of 28 prepubertal children were studied (18 boys and 10 girls; aged 3.7–11.1 yr). They were referred to our institutions for evaluation of growth. Their main clinical and hormonal characteristics are summarized in Table 1Go. Some children had normal height and were studied either because they reported a decrease in height velocity (HV; subsequently to be found normal) or because they were short relative to their midparental height. The study was carried out under institutionally approved protocols, and informed consent was obtained from the legal guardians of the children.


View this table:
[in this window]
[in a new window]
  		Table 1. Clinical and hormonal characteristics of the 28 children studied

 
A pyridostigmine (PD; Mestinon, Roche, Milan, Italy) plus GHRH (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29) (Geref, Serono, Rome, Italy) test, with PD (60 mg) orally administered 60 min before a bolus injection of 1 µg/Kg GHRH, and an oral clonidine test (Catapresan; Boehringer Ingelheim, Florence, Italy; 0.150 mg/m2) were performed in all patients. The two tests were separated by a 7–14-days interval. In one case, the clonidine test had to be stopped because of severe hypotension, and the arginine test (arginine chloridrate; Damor, Naples, Italy; 0.5 g/Kg iv infusion in 30 min) was instead performed. Plasma insulin-like growth factor-I (IGF-I) concentrations were determined in all children. A peak GH response to PD+GHRH and to clonidine more than or equal to 20 and more than or equal 7 µg/L, respectively, was considered normal (19). Normal values for IGF-I in our laboratory for prepubertal children of either sex are more than 50 µg/L.

Spontaneous nocturnal GH secretion studies with sampling every 30 min from 2300 to 0700 h were performed in all children with a GH response to PD+GHRH and to clonidine less than 20 and less than 7 µg/L, respectively, and in all children with normal GH responses to stimulation, but with height SD score (SDS) less than 2.0, HV less than 4.3 cm/yr, and IGF-I concentrations less than 60 µg/L. Normal mean integrated GH concentration (MGHC) for prepubertal children in our laboratory are more than or equal to 3 µg/L (20).

On the basis of the results of provocative tests and spontaneous GH secretion studies the children were divided into three groups: 18 NC (12 boys and 6 girls; aged 8.0–11.1 yr; peak GH responses to PD+GHRH and to clonidine more than or equal to 20 and more than or equal to 7 µg/L, respectively); 6 children with GHD (4 boys and 2 girls; aged 3.7–7.5 yr; peak GH responses to PD+GHRH less than 20 and less than 7 µg/L, respectively); 4 children with GHND (2 boys and 2 girls; aged 7.0–10.6 yr; peak GH responses: to PD+GHRH and to clonidine more than or equal to 20 and more than or equal to 7 µg/L, respectively; MGHC less than 3 µg/L). The boy who performed the arginine test belongs to the NC group. Magnetic resonance imaging (MRI) studies of the hypothalamic-pituitary area were performed in all GHD and GHND patients.

In the SSIW experiments, after an overnight fast, starting between 0800 and 0900 h, all children received a 90-min infusion of the peptide (from -90 to 0 min of the study). Subjects remained supine and awake throughout the procedure. A two-way iv cannula inserted into the forearm vein was used to draw blood samples and to infuse SS (Stilamin, Serono; 3 µg/Kg·h). At 0 min SS infusion was stopped. Blood samples were drawn at -120 min and 0, 15, 30, 45, 60, 75, and 90 min after infusion for GH determination. No adverse effects were observed during or after SS infusion, except in one case, who had symptomatic hypoglycemia that normalized spontaneously by stopping SS infusion.

GH was measured by an immunoradiometric assay (HGH-CTK-IRMA; Sorin, Saluggia, Italy). The sensitivity of the assay was 0.2 µg/L, with an intra- and interassay coefficient of variation of 4.5% and 7.9%, respectively. IGF-I was measured by RIA after acid-ethanol extraction (Nichols Institute Diagnostic, San Juan Capistrano, CA). The limit of sensitivity was 10 µg/L with a intra- and interassay coefficients of variation of 2.8% and 7.0%, respectively. All postinfusion GH values have been expressed as maximum GH peak or as area under the curve (AUC), calculated by trapezoidal integration. Statistical analysis of the results was carried out using Tukey’s test, preceded by ANOVA, to determine the significance of all pairwise multiple comparisons. A Student’s t test for unpaired data was used to compare groups and to detect any gender intragroup differences. Correlations were performed by the Pearson product moment method. A P value less than 0.05 was considered statistically significant. All values are given as mean ± SE.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go reports the main clinical characteristics of the children of our study. All parameters, except for body mass index, were significantly higher in NC than GHD or GHND children (P < 0.05). Age, height, HV and bone age were lower in GHD than GHND children (P < 0.05). The younger age in GHD and GHND than NC children is probably related to the earlier appearance of symptoms in the GH-deficient children. No gender-related intragroup differences were found. MRI studies in the GHD patients showed the absence of the pituitary stalk in three (nos. 2, 5, and 6), the presence of an empty sella in two (nos. 1 and 3), and a pituitary hypoplasia in one (no. 4). MRI studies were normal in all GHND children (data not shown).

Basal GH concentrations (-120 min) were significantly higher in NC than GHD or GHND children (3.1 ± 0.6 vs 0.6 ± 0.1 or 0.6 ± 0.1 µg/L, P < 0.05). IGF-I levels were significantly lower in GHD and GHND than NC children (24.3 ± 4.3 µg/L or 45.5 ± 4.3 µg/L vs 182.4 ± 25.3 µg/L, P < 0.01 and P < 0.05, respectively).

Mean peak GH concentrations after PD+GHRH or clonidine were higher in NC children than those observed in GHD children (36.6 ± 3.3 vs 6.3 ± 1.0 µg/L, P < 0.05; 13.3 ± 0.9 vs 1.7 ± 0.4 µg/L, P < 0.001, respectively). Peak GH response to PD+GHRH was higher in GHND than in GHD children (28.8 ± 3.5 vs 6.3 ± 1.0 µg/L, P < 0.01), whereas NC children had higher peak GH levels to clonidine testing than GHND subjects (13.3 ± 0.9 vs 7.2 ± 0.1 µg/L, P < 0.01). Peak GH response to clonidine testing was lower in GHD than GHND children (1.7 ± 0.4 vs 7.2 ± 0.1 µg/L, P < 0.05). No significant difference was observed in peak GH concentrations to PD+GHRH testing between NC and GHND children, and no difference in MGHC between GHD and GHND children was present (1.2 ± 0.1 vs 1.6 ± 0.2 µg/L) (Fig. 1Go).



View larger version (13K):
[in this window]
[in a new window]
  		Figure 1. Individual GH peaks after SSIW, PD+GHRH, and clonidine in the 28 children of the study. The dotted lines identify the levels of 7 and 20 µg/L, respectively.

 
GH secretory profiles after SSIW are shown in Fig 2Go. SSIW in NC children resulted in an unequivocal rise in plasma GH levels to a peak value of 13.7 ± 1.1 µg/L at 37.5 ± 3.0 min, with a significant difference vs GHD (1.6 ± 0.4 µg/L at 42.5 ± 9.0 min) and GHND (2.4 ± 0.3 µg/L at 57.0 ± 3.0 min) children (P < 0.001). The mean AUC of NC subjects (104.3 ± 7.6 µg/L·min) was significantly higher than those of GHD and GHND groups (12.9 ± 2.9 and 18.0 ± 2.0 µg/L·min, respectively, P < 0.001). No statistically significant difference was present in GH peak concentrations and mean AUC between the GHD and GHND groups. Scrutiny of individual values showed that the maximum GH peak after SSIW ranged between 8.5–25 µg/L in NC, between 1.6–2.8 µg/L in GHND, and between 0.5–3.4 µg/L in GHD. Thus, there was no overlapping in the peak GH responses to SSIW between NC children and GH-deficient children, regardless of the underlying etiology (GHD or GHND) (Fig 1Go).



View larger version (12K):
[in this window]
[in a new window]
  		Figure 2. Left, Rebound GH rise (0–90 min) after SSIW in the 28 children of our study. Right, Area under the curve. *P < 0.001 vs corresponding value.

 
No intragroup correlation was found between the GH response to SSIW and auxological parameters nor with IGF-I concentrations. A significant correlation (r = 0.94; P < 0.05) was found between the GH response to SSIW and the GH response to clonidine in the GHND group.

No adverse effects were elicited by the drugs or peptides, except for hypotension in one subject, following clonidine.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present study, SSIW induced a clear-cut increase in plasma GH levels in NC children but not in children with GHD or GHND. The data in our NC children are in agreement with those reported by Hindmarsh et al. (7) and degli Uberti et al. (8) in normal young men. Failure of SSIW to promote the rebound GH rise in children with GHD is likely related to the unavailability of a readily releasable pituitary GH pool, as also demonstrated in the same children by the absence of a GH response to the PD+GHRH test, which probes directly the pituitary freed by SS influences (19). Therefore, GHD in these children is related to an impairment of pituitary somatotrope development and/or structure and/or function, as also indicated by their MRI findings.

Absence of a GH response to SSIW in GHND children cannot be explained by a pituitary defect because they had a normal GH response to provocative tests as well as normal MRI findings. The GHND in these children is thought to result from a congenital (developmental) or acquired abnormality and/or a neuroregulatory alteration of hypothalamic GHRH function (21). Hence, the lack of the GH rebound rise after SSIW in our GHND children might be taken to support the view of a (primary) alteration of GHRH function. It is noteworthy in this context that in the dog fasting, which enhances GHRH function, results in a more brisk GH rebound rise after SSIW (6). Furthermore, administration of an antiserum to GHRH in rats almost abolishes the post-SS rebound in GH secretion (4). The significant correlation between the GH response to clonidine and to SSIW in GHND children might also indicate that the two stimuli share a common mechanism of action, i.e. stimulation of endogenous GHRH release/function (22, 23).

In children with short stature and poor growth the diagnosis of GH deficiency is classically established when GH concentrations do not reach an arbitrary cut-off value (usually between 7 and 10 µg/L) after two pharmacological stimuli (11). One of the major problems of the provocative tests lies in their poor reproducibility (14, 15) and in the great number of false negative responses frequently observed also in normal children (24, 25). The reason for this variability has been attributed to the periodic secretion of SS, which may influence the somatotrope response to the stimulus (26). Furthermore, the GH responses to stimulation may also be influenced by the pattern of GH secretion preceding the stimulus, i.e. whether the latter is administered during a spontaneous trough or peak of GH secretion (26). Measurement of spontaneous GH secretion offers no diagnostic advantage over pharmacological tests in the diagnosis of GHD (27). However, short children with a clinical picture overlapping that of GHD might have GHND, which can only be recognized by studies of spontaneous GH secretion (11, 12, 13). Measurement of IGF-I or IGF binding protein-3 alone or in combination does not have sufficient specificity in the diagnosis of GHD in children (28, 29). Moreover, demonstration of a biochemical defect in GH secretion is needed for the short patient to be eligible to receive GH replacement (11). So far, no single test for GH secretion/function has sufficient specificity to discriminate short normal children from children with disorders of GH secretion, and a proper diagnosis rests on a combination of auxological and biochemical findings.

We have shown in this study that the GH secretion after SSIW did discriminate short normal children from children with GHND. In fact, none of the children with GHND achieved a GH peak above 7 µg/L after SSWI, whereas all short normal children did. Recently, Tzanela et al. (30) reported that the GH response to GHRH after pretreatment with the long-acting SS analog, SMS 201-995, was capable to discriminate GHD from NC children. Children with GHND were not included in their study. However, testing with GHRH probes exclusively, the sensitivity of the pituitary to exogenous GHRH and not, which is critical, the endogenous hypothalamic GHRH function, alteration of which is likely responsible for GHND (21). Furthermore, their testing procedure is costly and unpractical in children, being too long (7 h) and necessitating many blood samples, i.e. 16. By contrast, SSIW has the advantage of a great simplicity, requires few blood samples (theoretically only one blood sample drawn at 45 or 60 min postinfusion would be sufficient), and has no side effects. This last point is of major importance in the clinical setting, when considering that many of the tests for GH secretion commonly used are not devoid of side effects (31, 32).

However, SSIW is unable per se to distinguish GHND from GHD children, the differential diagnosis between GHD and GHND, thus requiring a second GH stimulation test. Testing with GHRH after pretreatment with PD (19) or arginine (25) would then differentiate between the two GH hyposecretory states.

In conclusion, we have demonstrated that SSIW elicits a significant GH rise in NC children, but not in GH-deficient children, regardless of the underlying etiology (GHD or GHND). This results in complete discrimination of NC from GHD or GHND children. Were these findings confirmed on a larger number of children, SSIW, because of its effectiveness and safety, procedural simplicity, and economy, holds promise of being a useful diagnostic tool in GH-dependent growth disorders.

Received September 14, 1999.

Accepted October 13, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Muller EE, Locatelli V, Cocchi D. 1999 Neuroendocrine control of growth hormone secretion. Physiol Rev. 79:511–607.[Abstract/Free Full Text]
  2. Tannenbaum GS, Painson JC, Lapointe M, Gurd W, McCarthy GF. 1990 Interplay of somatostatin and growth hormone-releasing hormone in genesis of episodic growth hormone secretion. Metabolism. 39(Suppl 2):35–39.
  3. Miki N, Ono M, Shizume K. 1988 Withdrawal of endogenous somatostatin induces secretion of growth hormone-releasing factor in rats. J Endocrinol. 117:245–252.[Abstract/Free Full Text]
  4. Sugihara H, Minami S, Wakabayashi I. 1988 Post-somatostatin rebound secretion of growth hormone is dependent on growth hormone-releasing factor in unrestrained female rats. J Endocrinol. 122:583–591.
  5. Robinson IC, Jeffery S, Clark RG. 1990 Somatostatin and its physiological significance in regulating the episodic secretion of growth hormone in the rat. Acta Paediatr Scand. 367(Suppl.):87–92.
  6. Cella SG, Luceri M, Cattaneo L, Torsello A, Muller EE. 1996 Somatostatin withdrawal as generator of pulsatile GH release in the dog: a possible tool to evaluate the endogenous GHRH tone? Neuroendocrinology. 63:481–488.[Medline]
  7. Hindmarsh PC, Brain CE, Robinson IC, Matthews DR, Brook CG. 1991 The interaction of growth hormone releasing hormone and somatostatin in the generation of a GH pulse in man. Clin Endocrinol (Oxf). 35:353–360.[Medline]
  8. degli Uberti EC, Ambrosio MR, Cella SG, et al. 1997 Defective hypothalamic growth hormone (GH)-releasing hormone activity may contribute to declining GH secretion with age in man. J Clin Endocrinol Metab. 82:2885–2888.[Abstract/Free Full Text]
  9. Plotsky PM, Vale W. 1985 Patterns of growth hormone-releasing factor and somatostatin secretion into the hypophysial-portal circulation of the rat. Science. 230:461–463.[Abstract/Free Full Text]
  10. Katakami H, Downs TR, Frohman LA. 1988 Inhibitory effect of hypothalamic medial preoptic area somatostatin on growth hormone-releasing factor in the rat. Endocrinology. 123:1103–1109.[Abstract]
  11. Hintz RL. 1998 The role of auxologic and growth factor measurements in the diagnosis of growth hormone deficiency. Pediatrics. 102:524–526.[Abstract/Free Full Text]
  12. Spiliotis BE, August GP, Hung W, Sonis W, Mendelson W, Bercu BB. 1984 Growth hormone neurosecretory dysfunction: a treatable cause of short stature. JAMA. 251:2223–2230.[Abstract]
  13. Zadik Z, Chalew SA, Raiti S, Kowarski AA. 1985 Do short children secrete insufficient growth hormone? Pediatrics. 76:355–360.[Abstract/Free Full Text]
  14. Tassoni P, Cacciari M, Cau M, et al. 1990 Variability of growth hormone response to pharmacological and sleep tests performed twice in short children. J Clin Endocrinol Metab. 71:230–234.[Abstract]
  15. Mazza E, Ghigo E, Goffi S, et al. 1989 Effect of the potentiation of cholinergic activity on the variability in individual GH response to GH-releasing hormone. J Endocrinol Invest. 12:795–798.[Medline]
  16. Bercu BB, Shulman D, Root AW, Spiliotis BE. 1986 Growth hormone (GH) provocative testing frequently does not reflect endogenous GH secretion. J Clin Endocrinol Metab. 63:709–716.[Abstract]
  17. Chalew S, Armour KM, Levin PA, Thorner MO, Kowarski AA. 1986 Growth hormone (GH) response to GH-releasing hormone in children with subnormal integrated concentrations of GH. J Clin Endocrinol Metab. 62:1110–1115.[Abstract]
  18. Seminara S, Filpo A, Piccinini P, et al. 1997 Growth hormone (GH) response to GH-releasing hormone in short children: lack of correlation with endogenous nocturnal GH secretion. J Endocrinol Invest. 20:118–121.[Medline]
  19. Ghigo E, Imperiale E, Boffano GM, et al. 1990 A new test for the diagnosis of growth hormone deficiency due to primary pituitary impairment: combined administration of pyridostigmine and growth hormone-releasing hormone. J Endocrinol Invest. 13:307–316.[Medline]
  20. Dammacco F, Boghen MF, Camanni F, et al. 1993 Somatotropic function in short stature: evaluation by integrated auxological and hormonal indices in 214 children. J Clin Endocrinol Metab. 77:68–72.[Abstract]
  21. Reiter EO, Ron RG. 1998 Normal and aberrant growth. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds. Williams textbook of endocrinology, 9th ed. W. B. Saunders Company; 1427–1507.
  22. Miki N, Ono M, Shizume K. 1984 Evidence that opiatergic and {alpha}-adrenergic mechanisms stimulate rat growth hormone release via growth hormone-releasing factor. Endocrinology. 114:1950–1952.[Abstract]
  23. Hanew K, Tanaka A, Utsumi A, Sugawara A. 1996 The inhibitory effects of growth hormone-releasing hormone (GHRH)-antagonist on GHRH, L’dopa, and clonidine-induced GH secretion in normal subjects. J Clin Endocrinol Metab. 81:1952–1955.[Abstract]
  24. Loche S, Cappa M, Ghigo E, et al. 1993 Growth hormone response to oral clonidine test in normal and short children. J Endocrinol Invest. 16:899–902.[Medline]
  25. Ghigo E, Bellone J, Aimaretti J, et al. 1996 Reliability of provocative tests to assess GH secretory status. Study in 472 normally growing children. J Clin Endocrinol Metab. 81:3323–3327.[Abstract]
  26. Devesa J, Lima L, Lois N, Lechjga MJ, Arce V, Tresguerres JAF. 1989 Reasons for the variability in the growth hormone (GH) responses to GHRH challenge: the endogenous hypothalamic-somatotroph rhythm (HSR). Clin Endocrinol (Oxf). 30:367–377.[Medline]
  27. Rose SR, Ross JL, Uriarte M, Barnes KM, Cassorla FG, Cutler GB Jr. 1988 The advantage of measuring stimulated as compared with spontaneous growth hormone levels in the diagnosis of growth hormone deficiency. N Engl J Med. 319:201–207.[Abstract]
  28. Cianfarani S, Boemi S, Spagnoli A, et al. 1995 Is IGF binding protein-3 assessment helpful for the diagnosis of GH deficiency? Clin Endocrinol (Oxf). 43:43–47.[Medline]
  29. Mitchell H, Dattani MT, Nanduri V, Hindmarsh PC, Preece MA, Brook CGD. 1999 Failure of IGF-I and IGFBP-3 to diagnose growth hormone insufficiency. Arch Dis Child. 80:443–447.[Abstract/Free Full Text]
  30. Tzanela M, Guyda H, Van Vliet G, Tannenbaum GS. 1996 Somatostatin pretreatment enhances growth hormone (GH) responsiveness to GH-releasing hormone: a potential new diagnostic approach to GH deficiency. J Clin Endocrinol Metab. 81:2487–2494.[Abstract]
  31. Shah A, Stanhope R, Matthew D. 1992 Hazards of pharmacological tests of growth hormone secretion in childhood. BMJ. 304:173–174.
  32. Tillmann V, Buckler JM, Kibirige MS, et al. 1997 Biochemical tests in the diagnosis of childhood growth hormone deficiency. J Clin Endocrinol Metab. 82:531–535.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Clin. Endocrinol. Metab.Home page
J. D. Veldhuis, S. M. Anderson, J. T. Patrie, and C. Y. Bowers
Estradiol Supplementation in Postmenopausal Women Doubles Rebound-Like Release of Growth Hormone (GH) Triggered by Sequential Infusion and Withdrawal of Somatostatin: Evidence that Estrogen Facilitates Endogenous GH-Releasing Hormone Drive
J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 121 - 127.
[Abstract] [Full Text] [PDF]

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

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals