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Original Studies |
Departments of Pediatrics (M.M., C.S., M.C., F.S.), Biometry-Scientific Direction (C.T.), and Servizio Analisi Chimico Cliniche (M.A.), University, IRCCS Policlinico S. Matteo, I-27100 Pavia; and Servizio di Endocrinologia Pediatrica, Ospedale Regionale per le Microcitemie (S.L.), Cagliari, Italy
Address all correspondence and requests for reprints to: Mohamad Maghnie, M.D., Ph.D., Department of Pediatrics, IRCCS Policlinico S. Matteo, I-27100 Pavia, Italy. E-mail: maghnie{at}smatteo.pv.it
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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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Magnetic resonance imaging (MRI) has been of great value in the diagnosis of disorders of the hypothalamic-pituitary area. MRI studies have allowed a better diagnostic characterization of children with GHD by showing the pituitary size as well as the presence of different morphological abnormalities such as anterior pituitary hypoplasia, pituitary stalk agenesis, and posterior pituitary ectopia (13). Whether the pituitary size and/or the presence of morphological abnormalities could be useful in predicting permanent GHD, however, is not known. Furthermore, few data on retesting in patients with organic GHD have been reported (14).
In this study we reevaluated GH secretion after arginine (ARG), insulin induced-hypoglycemia (ITT), and combined ARG+ITT, insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), and MRI in 35 young adults with childhood-onset GHD of different etiologies. Specifically, we studied the role of pituitary MRI in the prediction of permanent GHD, and the reproducibility of MRI pituitary findings in adult life.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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GH secretion was reevaluated after completion of GH treatment in
35 young adult patients with childhood-onset GHD (23 men and 12 women)
diagnosed at a mean age of 9.0 ± 2.5 yr. The mean duration of GH
treatment was 8.8 ± 2.5 yr, and treatment was stopped at a mean
age of 19.2 ± 3.2 yr. Twenty-three (15 men and 8 women) had
isolated GHD, and 12 had multiple pituitary hormone deficiencies
(MPHD), of whom 8 (5 men and 3 women) had idiopathic hypopituitarism
and 4 had craniopharyngioma. Their main clinical findings are
summarized in Tables 1
and 2. The first MRI studies revealed a
normal pituitary volume (280 ± 59.4 mm3) in 11
patients (group I), a small pituitary gland (163.1 ± 24.4
mm3; group I vs. II, P = 0.0009)
in 7 patients (group II), and pituitary hypoplasia (95.8 ± 39.3
mm3; group I vs. III, P <
0.00001; group II vs. III, P = 0.003),
pituitary stalk agenesis, and posterior pituitary ectopia in 13
patients (group III). Craniopharyngioma was diagnosed in 4 patients
(group IV). Partial GHD (GH peak after insulin and arginine tests,
5.0–9.9 µg/L) was diagnosed in all patients in group I, in 2 of 7
patients in group II, and in 3 of 13 patients in group III, whereas all
of the remaining patients had total GHD (GH peak, <5.0 µg/L). All
patients with MPHD were receiving appropriate hormone replacement
therapy.
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Study design
Evaluation of GH secretion. In all patients, GH treatment was discontinued when growth velocity during the last year dropped to less than 1 cm. A median of 3 months after discontinuation of treatment, GH secretion was reevaluated in all patients by means of ARG and ITT and in 33 patients by sequential ARG+ITT tests performed on 3 separate occasions. Serum IGF-I and IGFBP-3 concentrations were determined in 33 patients at the first retesting; 6, 12, and 24 months after GH withdrawal in the patients with permanent GH deficiency; and 6 months after GH withdrawal in those with normal GH responses to stimuli. Soluble insulin (0.05 U/kg) and ARG (0.5 g/kg) over 30 min were given iv at time zero, and venous blood for GH determinations (and glucose during ITT) was obtained at 0, 30, 60, 90, and 120 min. During the ARG+ITT test, samples were collected in 33 patients 0, 30, and 60 min after the start of a 30-min ARG infusion; immediately upon the collection of the 60-min sample, insulin was given iv, and samples were collected 30, 60, and 120 min after the injection.
MRI. MRI was performed after the achievement of final height and 1–3 months after GH therapy withdrawal, using a spin-echo technique on a 1.5 T superconductive system (Magnetom, Siemens, Germany). Sagittal and coronal T1-weighted images (TR, 400 ms; TE, 15 ms; three excitations) were obtained using 3-mm sections (matrix size, 256 x 256; 20-cm field of view). The pituitary volumes were calculated as previously described (13).
Assay procedures. Serum GH levels were measured by fluoroimmunoassay using a commercial kit (AutoDELFIA hGH, EG&G, Wallac Oy, Finland). The intra- and interassay coefficients of variations were 5.1% and 2.5%, respectively, at 0.430 mU/L, 2.7% and 2.1% at 5.0 mU/L, and 2.2% and 1.4% at 21.1 mU/L. Cross-reactivity was less than 0.001% for PRL and human placental lactogen.
IGF-I was measured by RIA using a commercial kit (SM-C-RIA-CT, BioSource SA, Belgium). The intra- and interassay coefficients of variations were 6.1%, 4.1%, and 4.7% at 54.2 ± 3.3, 194 ± 8, and 491 ± 2 µg/L and 9.9%, 9.6%, and 9.3% at 121 ± 11, 251 ± 24, and 494 ± 46 µg/L. The sensitivity of the assay was 0.25 ± 0.1 µg/L.
The serum IGFBP-3 levels were measured by RIA using a commercial kit (Nichols Institute Diagnostics, San Juan Capistrano, CA). The specific and nonspecific bindings of radiolabeled IGFBP-3 were 33% and 2.9%.
Statistical analysis
Comparisons between groups were performed using the Mann-Whitney U test (when comparing two groups) or Kruskal-Wallis ANOVA (when comparing more than two groups). Comparisons within groups were performed using the Wilcoxon test (for comparing the same group twice) or Friedman ANOVA (for comparing the same group more than twice). Correlations among IGF-I, IGFBP-3, and peak GH after ARG, ITT, and ARG+ITT were analyzed with the Spearman r coefficient. P < 0.05 was considered statistically significant. All tests were two-sided. All data are given as the mean ± SE.
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Results |
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The mean pituitary volume was 392.9 ± 37.0 mm3
in group I, 324.0 ± 113.5 mm3 in group II, and
91.6 ± 33.6 mm3 in group III (Tables 1
and 2). In
particular, pituitary volume had increased to normal limits in six of
seven subjects in group II; the hypothalamic-pituitary MRI studies in
the remaining patients confirmed the initial findings.
GH responses to provocative tests
ARG test. Peak GH was more than 10 µg/L in 11 patients
(31.4%): 6 of 11 in group I (54.5%) and 5 of 7 in group II (71.5%).
In 22 patients (62.8%), the GH peak was less than 5 µg/L: 3 of 11 in
group I (27%) and 2 of 7 in group II (28.5%). In all patients from
groups III and IV, peak GH was less than 3 µg/L (Fig. 1).
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). Blood
sugar with a nadir less than 40 mg/dL or a decrease of about 50% was
documented in all patients. Symptomatic hypoglycemia was documented in
16 of 35 and was severe in MPHD patients (2 of 11 in group I, 2 of 7 in
group II, 10 of 13 in group III, and 2 of 4 in group IV).
ARG+ITT. Peak GH was more than 10 µg/L (51.5%) in 18
patients, all from groups I and II. In all 14 patients in groups III
and IV, the GH peak was less than 3 µg/L (Fig. 1). Blood sugar with a
nadir below 40 mg/dL or a decrease of about 50% was documented in all
patients after insulin administration. Symptomatic hypoglycemia
was documented in 13 of 33 patients and was severe in MPHD patients: 1
of 11 in group I, 1 of 7 in group II, 9 of 11 in group III, and 2 in
group IV.
IGF-I and IGFBP-3
The serum IGF-I levels were more than 300 µg/L in groups I and II and less than 250 µg/L in groups III and IV 1–3 months after GH therapy withdrawal. The mean IGF-I level was 382.8 ± 42.1 µg/L in group I (vs. group III, P = 0.00007; vs. group IV, P = 0.0004), 378.2 ± 46.7 µg/L in group II (vs. group III, P = 0.0005; vs. group IV, P = 0.008), 173.9 ± 34.9 µg/L in group III, and 196.3 ± 20.9 µg/L in group IV (Fig. 2).
The mean IGF-I level remained unchanged in groups I (356.2 ± 34.9
µg/L) and II (367.4 ± 37.1 µg/L) 6 months after GH therapy
withdrawal. It was significantly decreased in groups III and IV after 6
months (78.6 ± 26.7 and 59.0 ± 20.3 µg/L;
P = 0.0003) and 12 months (38.0 ± 8.6 and
38.2 ± 27.6 µg/L; P = 0.0004), but remained
unchanged after 24 months (35.8 ± 8.7 and 38.2 ± 1.5
µg/L; P < 0.0001; Fig. 2).
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). A significant positive correlation was found between IGF-I and
IGFBP-3 levels obtained 1–3 months after GH withdrawal and peak GH
responses to ARG (r = 0.86; P < 0.00001 and
r = 0.67; P = 0.0002), ITT (r = 0.82;
P < 0.00001 and r = 0.66; P =
0.0002), and ARG+ITT (r = 0.78; P < 0.00001 and
r = 0.77; P < 0.00001). A significant correlation
was found between IGF-I and IGFBP-3 levels (r = 0.76;
P < 0.00001). |
Discussion |
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Our findings of a low GH response to provocative tests in the patients with congenital pituitary abnormalities are in agreement with the findings in the patients described by Juul and co-workers (7). Although they have not reported MRI findings, we suppose that many of their GH-unresponsive patients had the same hypothalamic-pituitary abnormalities as those described in our cases.
We found that the pituitary volume after MRI reevaluation was within the normal range in six of seven patients with small anterior pituitary gland at diagnosis. The physiological age-related increase in pituitary size reported in healthy volunteers (15) is, however, surprising in such patients. This finding raises the question of the real meaning of an isolated small pituitary gland in children with GHD, i.e. whether a small pituitary represents a pathological finding or is just a normal variant. We believe that the role of puberty (FSH and LH secretion associated with pituitary hyperplasia) cannot be disregarded. Nagel et al. (16) have recently reported a significant positive correlation between pituitary height and GH secretion in children with short stature, a finding that was not confirmed in this study. We believe that the pituitary size in children has a broader normal range than has been previously described, and that the sample sizes for normal MRI pituitary appearance, although convincingly established for the first 2 yr of life (17), have yet to be defined between this age and the onset of puberty.
The ITT is considered the most reliable provocative test in the diagnosis of GHD in adulthood; GH responses less than 3 µg/L are considered diagnostic of severe GHD, with an accuracy of 100% (18, 19, 20). The fact that all patients with congenital or acquired GHD failed to increase the GH response above 3 µg/L after ARG, ITT, and ARG+ITT confirms that this cut-off limit is adequate for the definition of permanent GHD of childhood onset. It has been recently reported that the severity of hormone deficiency in adults is related to the number of additional pituitary hormone deficiencies (21), and that all patients with two or more additional pituitary hormone deficiencies had subnormal GH responses at retesting (7). In our study we found that among patients with congenital abnormalities at MRI the GH response at retesting was similar in those with IGHD and those with MPHD. Furthermore, there was no tendency to a downward trend in the peak GH response in patients with MPHD, compared with IGHD, as reported in adults (21). Our findings suggest that the severity of GHD is related not only to the number of pituitary hormone deficits, but also to the MRI findings. In this regard, we have previously shown that the GH response to a GHRH infusion in patients with pituitary stalk agenesis and ectopic posterior pituitary lobe was low regardless of whether they had IGHD or MPHD (22).
We observed a significant correlation between the GH peak after provocative tests and serum IGF-I and IGFBP-3 concentrations as well as between IGF-I and IGFBP-3 at retesting. A significant correlation has been recently reported between IGF-I and the GH response to the combined administration of ARG and GHRH, but not to insulin (23). Our patients, however, were younger than those studied by Aimaretti et al. (23). Moreover, mean IGF-I concentrations in our patients were higher than those reported in healthy age-matched normal subjects (1, 23, 24). The regulation of IGF-I secretion and action is complex, and many factors, such as age, endogenous GH secretion, body mass index, physical fitness, glucocorticoids, PRL, testosterone, and increased IGFBP-3 binding capacity, are reported to be potential determinants of IGF-I serum concentration (24). We believe that in our patients the decline in IGF-I that occurred within a relatively short time cannot be a consequence of aging (25) and that some other regulatory factors may play a role at least in the early period after withdrawal of GH treatment.
In conclusion, we have confirmed that a high proportion of children with IGHD with normal or small pituitary glands show normalization of GH secretion at the completion of GH treatment, whereas GHD was permanent in all patients with congenital anatomical abnormalities, such as pituitary hypoplasia, pituitary stalk agenesis, and posterior pituitary ectopia, at MRI. IGF-I and IGFBP-3 determinations shortly after GH withdrawal had limited value in the diagnosis of GHD of childhood onset associated with congenital hypothalamic-pituitary abnormalities, but became accurate after 6–12 months. Our results suggest that patients with GHD and congenital hypothalamic-pituitary abnormalities do not require further investigation of GH secretion, whereas patients with IGHD and normal or small pituitary at MRI should be retested well before the attainment of adult height.
Received October 2, 1998.
Revised November 18, 1998.
Accepted November 30, 1998.
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