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Original Studies |
Department of Endocrinology, Christie Hospital National Health Service Trust, Manchester, United Kingdom M20 4BX
Address all correspondence and requests for reprints to: Prof. S. M. Shalet, Department of Endocrinology, Christie Hospital National Health Service Trust, Wilmslow Road, Manchester, United Kingdom M20 4BX.
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Abstract |
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One hundred and sixty-one nonacromegalic patients were identified who had undergone an arginine stimulation test (AST) and an ITT within a 3-month period as part of routine testing between 1975 and 1999. They were divided into those tested before (n = 81; 48 males) and those tested after (n = 80; 36 males) completion of growth and puberty. Patients were considered for inclusion in the study if they had a history of cranial irradiation and a GH response to one provocative test of less than 8 µg/L, taken as indicating that some damage to the GH axis may have occurred. The patients were compared with 2 control groups. The first comprised 35 adults (18 males) and the second consisted of 16 prepubertal children (10 males).
The median peak (range) GH response to the ITT was significantly greater (P < 0.0001) than that to the AST in the adult controls: 24.9 (4.1–76.9) vs. 12.2 (0.88–35.0) µg/L, respectively. However, in the patients the GH responses were similar (P = 0.28): 2.2 (0.2–25.7) vs. 1.4 (0.2–12.8) µg/L to the ITT and AST, respectively. In contrast to the pattern seen in the adult controls, the response to an ITT in childhood controls was of similar magnitude (P = 0.5) to that to the AST: 17.5 (8.1–40.0) vs. 19.4 (7.3–53.8) µg/L, respectively. However in the patients, the GH response to the AST was greater than that to the ITT (P < 0.0001): 4.3 (0.7–17.2) vs. 3.0 (0.4–18.1) µg/L, respectively.
In summary, we have shown that the impact of irradiation on GH responsiveness to provocative agents is stimulus dependent. The GH response to an AST appears to be more resistant to the effects of irradiation than that to the ITT. When investigating the impact of irradiation on GH secretory status, the GH response to an AST may be a less sensitive guide to the functional ability of the GH axis.
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Introduction |
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At present, the insulin tolerance test (ITT) is the gold standard for the biochemical diagnosis of severe GH deficiency. The ITT provokes a pronounced GH response in normal individuals, allows the pituitary-adrenal axis to be tested at the same time, and the morbidity associated with performance of the test is low in experienced units; furthermore, it has excellent diagnostic sensitivity and specificity (2) when used to distinguish adults with extensive organic pituitary disease from normal subjects. There are, however, a wide variety of other stimulation tests used in clinical practice, either as a second test in patients in whom the diagnosis of severe GH deficiency remains difficult and/or as a safer alternative to the ITT. Each provocative test necessitates the use of a specific cut-off derived from normative data, but there remains a widely held view that the implications from a "failed" test are independent of the nature of the stimulus.
Individuals with radiation-induced GH deficiency represent an increasingly large proportion of the GH-deficient population as survival rates after childhood malignancies improve and radiotherapy continues to play an important role in the management of pituitary adenomas in adults. These patients provide a diagnostic challenge as GH deficiency is frequently the only pituitary problem noted after cranial irradiation, and GH-dependent markers such as IGF-I and IGF-binding protein-3 (IGFBP-3) have less diagnostic specificity after radiation-induced damage (3, 4) than in other forms of hypopituitarism. Thus, we sought to examine whether the pattern of responsiveness to the ITT and the arginine stimulation test (AST), another popular and widely used GH provocative test, was the same in normal individuals and in those with radiation-induced damage to the somatotropic axis and, hence, whether the implication of a subnormal GH response is affected by the mechanism of damage to the hypothalamic-pituitary axis.
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Subjects and Methods |
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The adult patients consisted of 80 subjects (36 males), aged 15–59
(median, 26) yr. The body mass index (BMI) ranged from 18.1–41.7
(median, 24.7) kg/m2. Fourteen (18%) patients
were gonadotropin deficient, 11 (14%) were TSH deficient, and 21
(26%) were ACTH deficient. These individuals had a wide variety of
underlying pathophysiologies (Table 1
),
and the hypothalamic-pituitary region had received a median radiation
dose of 3750 (range, 1800–5500) cGy at a median time of 14.5 (range,
0.4–33.9) yr before provocative testing. All patients were receiving
conventional hormone replacement therapy for pituitary deficits other
than GH.
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. The whole
cohort received a median irradiation dose of 3000 (range, 1200–5000)
cGy to the hypothalamic-pituitary region at a median time of 3.1
(range, 0.1–13.5) yr before provocative testing. The results obtained in the patient groups were compared with 2 control groups. The first comprised 35 healthy medical Student’s (18 males; median age, 21.6 yr; range, 21–25 yr), who underwent an ITT and AST. These individuals had a median (range) BMI of 23.4 (19.0–26.8) kg/m2. Ethical committee approval and written consent were obtained. All subjects underwent physical examination to exclude a previously undiagnosed medical condition. The only medication received by the controls was the oral contraceptive pill in the case of 8 female subjects.
In the light of ethical constraints, the second control group was derived from our own published historical data (7). It included 16 children (10 males; median age, 3.5 yr; range, 3–16 yr), all of whom were prepubertal. Eleven had ALL and were studied when off all drug therapy, in remission, and clinically well and before receiving cranial irradiation. The diagnosis in the remaining 5 children was normal short stature. Although the historical nature of these controls means that it is difficult to compare absolute values between the patients tested in childhood and the childhood controls, there is no reason to suspect that the pattern of responsiveness to GH provocative tests changes with time.
All subjects underwent both an ITT and AST on 2 different mornings after an overnight fast. Soluble insulin (Actrapid; 0.2 IU/kg, iv) or arginine (20 g/m2, iv, as a 20% solution over 30 min) was administered after the insertion of an iv cannula. During the ITT, satisfactory hypoglycemia was documented clinically and biochemically.
Assays
Serum GH levels were measured by a two-site RIA, with a limit of sensitivity of 0.4 µg/L. The reference preparation used was NIBSC 66/217 until March 1990 when the results were reported using NIBSC 80/505. This produced results 1.2 times those obtained with the previous preparation. GH levels from the patients who were assessed before January 2, 1990 have been multiplied by a factor of 1.2 to allow comparison with the GH levels obtained after this date. Within- and between-batch coefficients of variation were less than 15% at all measurable analyte concentrations.
Statistics
Data were expressed as a median (range). The Mann-Whitney
rank-sum test and the Wilcoxon signed rank test were used to compare
unpaired and paired data, respectively. The 
2
test/Fisher’s exact test were used to compare the proportion of
individuals achieving greater GH responses to either the ITT or AST.
p < 0.05 was taken as significant. Values below the
sensitivity of the GH assay were described as 0.2 µg/L for
statistical purposes.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The GH response to the ITT was significantly greater
(P < 0.0001) than that to the AST in the control
subjects (Fig. 1A). However in the
patients, the GH responses were similar (P = 0.28; Fig. 1B).
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2 test). To
examine the clinical significance of these results, we calculated the
number of patients who would be excluded from therapy with GH if the
AST in addition to the ITT was used as the basis by which GH deficiency
was diagnosed: 8 patients had a response to an ITT of less than 3
(median, 2.3; range, 1.0–2.9) µg/L, but a response to an AST of
greater than 3 (median, 5.2; range, 3.5–12.6) µg/L. If the adult control group was divided by gender, greater GH responses to the ITT were seen in male compared with female controls (P < 0.001). A smaller difference was seen between the responses to an ITT in male and female patients (P < 0.05). In contrast, female control subjects generate a larger GH response to arginine stimulation (P < 0.02). However, in the patient subgroup the response to an AST is not significantly different between male and female subjects (P = 0.9).
The effect of gender on the pattern of responsiveness to the 2 GH provocation tests was examined. In the female control subjects, 11 of 17 (64.7%) demonstrated a peak response to the ITT that was greater than that achieved to the AST, and in 6 subjects the converse was true. In the male control subjects, all 18 subjects demonstrated a peak GH response to the ITT greater than that achieved to the AST. These results were compared and were significantly different (P < 0.01, by Fisher’s exact test). In contrast, within the adult patients, no significant difference between male and female individuals was found.
Children
In contrast to the pattern seen in the adult control subjects, the
GH response to an ITT in childhood control subjects was of similar
magnitude (P = 0.5) to that to the AST (Fig. 2A). However, in the patients, the GH
response to the AST was greater than that to the ITT (P
< 0.0001; Fig. 2B).
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No gender-related differences were seen in the GH response to the ITT and AST in either the pediatric control group or the patient group. Neither was an effect of gender found on the pattern of responsiveness to the two provocative tests in either cohort.
Comparison between adult and childhood cohorts
The historical nature of the pediatric control subjects means that
comparison between the actual values obtained in the adult and
pediatric control subjects is invalid. However, the proportion of
subjects achieving greater responses to the ITT than to the AST and
vice versa is significantly different between the two
control cohorts (P < 0.005, by Fisher’s exact test).
Similarly, if the pattern of responsiveness seen in the adult and
pediatric patients is compared, a significant difference is seen
(P < 0.001, by 2 test). The
number of patients in whom the GH response to the AST was greater than
that achieved to the ITT is larger in the pediatric cohort (55 of 81
patients, 67.9%) than in the adult cohort (31 of 81 patients,
38.3%).
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Discussion |
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In our adult control subjects, the median GH response to an ITT is 2-fold larger than that to arginine stimulation. In contrast, the median GH response in the irradiated adult cohort was of similar magnitude in both tests. In addition, the pattern of responsiveness within each individual was significantly different in the control and irradiated groups, with 82.9% of control subjects and only 46.9% of irradiated subjects generating their most profound GH response to the ITT. This supports the hypothesis that in adults, radiotherapy preferentially damages the GH response to an ITT, resulting in equalization of the normally more exuberant GH response to that in response to arginine stimulation. In children, the pattern is slightly different, but also supports the view that the GH response to an ITT is more sensitive to irradiation than that to arginine. In the pediatric control subjects, the median GH responses to both provocative tests were similar, whereas in the children who had received irradiation, the median GH response to the AST was of greater magnitude than that to the ITT. The pattern of responsiveness among children in the control and irradiated groups was not significantly different, with approximately 30% of children demonstrating a maximal response to the ITT. This was in contrast to the different pattern found between adult patients and controls. That in normal children GH responses to the ITT and AST were of similar magnitude is in keeping with the published literature (9), although normative data in children are relatively scarce. Our pediatric control cohort is small, including only 16 individuals. It is possible that this explains our failure to find a difference in the pattern of responsiveness to arginine stimulation and an ITT between the irradiated and normal children.
The finding in adults that the GH response to an ITT is more profound
than that to arginine stimulation has been reported previously
(10, 11, 12, 13). The equalization of the responses after
irradiation and, hence, the suggestion that the mechanism by which an
ITT induces GH release is more susceptible to irradiation than that of
the AST are also supported by other researchers, but only in studies of
small numbers of children. Ahmed et al. (14)
studied 14 children, aged 9–17 yr, all of whom received cranial
radiation doses greater than 2400 cGy to the hypothalamic-pituitary
axis. There was a reduction in the mean 24-h level of GH in all
children; all had blunted responses to an ITT, but 2 of the 14 had
normal (
8 µg/L) GH responses to an AST. Romshe et al.
(15) studied 9 children who had received 24–50 Gy cranial
irradiation and subsequently experienced decreased growth velocity.
With arginine stimulation, 6 of 9 patients had a normal GH response
(>7 µg/L), but only 2 of 9 patients had a normal response to an ITT.
Dickinson et al. (16) examined the GH responses
to arginine and to an ITT in 13 patients with neoplastic disease after
treatment with radiation and chemotherapy. Patients who received
intensive cranial radiation (>2400 cGy) showed no response to either
arginine or an ITT; those who received moderate cranial radiation
(
2400 cGy) showed a GH response to arginine but not to an ITT;
patients receiving no cranial radiation responded to both arginine and
an ITT. These data support the hypothesis that the GH response to an
ITT is more vulnerable to cranial irradiation than that to arginine
infusion, reflecting the different mechanisms involved in the GH
responses to these 2 provocative agents.
The differential sensitivities of the two provocative tests used in
this study to radiation damage are probably secondary to divergent
neuroregulatory mechanisms governing GH responsiveness to arginine
vs. hypoglycemia. Arginine stimulation is thought to induce
GH release by inhibiting somatostatin secretion, whereas the mechanism
of action of insulin-induced hypoglycemia is complex and not yet fully
elucidated, being thought to act through
2-adrenergic pathways, somatostatin
suppression, and GHRH release. The basomedial hypothalamus is thought
to contain the neurons responsible for promoting neuroendocrine
responses to hypoglycemia. As the cortisol response to hypoglycemia
remains intact, it must be regulatory mechanisms downstream of this
center that are damaged in irradiated individuals.
In the published literature discussed previously (14, 15), data suggest that it is the GH response to the ITT that changes in parallel with other measures of GH activity, namely growth velocity and 24-h GH profiles, whereas the GH response to an AST remains unimpaired. Thus, patients who fail to respond to an ITT while responding normally to an AST may still be functionally GH deficient and potentially benefit from GH replacement. Eight adults and 14 children in this study would have been excluded from potential GH therapy if the GH response to an AST was used as the defining test. The impact of this in children, in particular, is irreversible. It is important, therefore, that interpretation of the results of GH provocative testing should take into account the etiology of GH deficiency.
Our study is cross-sectional rather than longitudinal. Although this allows a large number of individuals to be studied, it means that factors other than a history of irradiation may play a role in the differences we have demonstrated. Ideally, a longitudinal study would allow the effect of irradiation on the pattern of responsiveness to provocative testing to be examined more fully and may, if growth was also monitored, indicate which test provides the more accurate reflection of GH secretion in vivo.
These data are in keeping with the published literature. In 1969, Merimee et al. (17) demonstrated that women respond to arginine with greater increases in serum GH than men. As treatment of men with estrogen augmented the GH response to arginine, whereas testosterone pretreatment did not decrease the response in women, it was concluded that this was an estrogen effect, possibly through an effect on somatostatin tone. In contrast, the GH response to an ITT is more pronounced in males (18, 19, 20, 21).
In our pediatric cohort, these gender differences in the magnitude of the GH response to arginine and an ITT and in the pattern of responsiveness to GH provocative tests were absent. This is consistent with the hypothesis that these effects are secondary to an increase in sex steroid levels at puberty. This is also likely to explain the different GH responses seen when the adult and childhood cohorts are compared, although the fact that the childhood patients were assessed at a shorter time interval after irradiation than the adult cohort may also play a role.
In summary, we have shown that the impact of irradiation on GH responsiveness to provocative agents is stimulus dependent. The GH response to an AST appears to be more resistant to the effects of irradiation than that to the ITT. Our data do not allow us to determine which test provides the better estimation of the functional ability of the somatotropic axis in vivo. However, the work of others suggests that it is the GH response to an ITT that changes in concert with 24-h profiles and growth failure, whereas the response to an AST is discordant. In our cohort of 161 patients, 22 individuals, 14 children, and 8 adults would be excluded from the potential benefits of GH therapy if the AST was used to define GH deficiency. As a general rule, the etiology of the insult to the somatotropic axis should be taken into account when interpreting the results of a GH stimulation test. More specifically, when investigating the impact of irradiation on GH secretory status, the GH response to arginine stimulation may be a less sensitive guide to the functional ability of the somatotropic axis.
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Acknowledgments |
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Footnotes |
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Received February 21, 2000.
Revised May 23, 2000.
Revised July 18, 2000.
Accepted July 20, 2000.
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References |
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