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Endocrine Care |
Pediatric Endocrinology (L.A., R.B.) and Neurosurgery (C.S.-R.) Departments, Physiology Laboratory (C.T.), Université René Descartes and Hôpital Necker-Enfants Malades, Assistance Publique-Hopitaux de Paris; Pediatric Oncology Department (J.M.Z.), Institut Curie, Paris; and Pediatric Oncology Department (O.H.), Institut Gustave Roussy, Villejuif, France
Address all correspondence and requests for reprints to: R. Brauner, M.D., 211 avenue Daumesnil, 75012 Paris, France.
Abstract
Cranial irradiation alters hypothalamic-pituitary function. We reevaluated 90 patients with GH deficiency caused by fractionated cranial irradiation performed at age 4.9 ± 0.4 (SE) yr when they were 15.7 ± 0.2 yr old. Group 1 received 18 Grays (Gy) (7 cases) or 24 Gy (21 cases) for acute lymphoblastic leukemia; group 2, 30–40 Gy for medulloblastoma (22 cases); group 3, 45–60 Gy for optic glioma and various tumors (30 cases); and group 4, 40–50 Gy for retinoblastoma (10 cases).
The mean GH peaks after an arginine insulin test in group 3 (1.9 ± 0.4 µg/liter) was lower than in groups 1 (4.8 ± 0.5 µg/liter, P < 0.001) and 2 (3.4 ± 0.5 µg/liter, P < 0.03). The mean plasma IGF-I concentrations in group 3 [-3.8 ± 0.2 z score (zs)] was lower than in groups 1 (-2.4 ± 0.3 zs, P < 0.001) and 2 (-3.1 ± 0.2 zs, P < 0.02), as was the mean in group 4 (-3.9 ± 0.3 zs, P < 0.01 compared with group 1 and P < 0.05 compared with group 2). GH peaks and IGF-I were correlated positively (P = 0.0001) and negatively with dose (P < 0.001 for GH and P = 0.0001 for IGF-I), but not with age at irradiation. Among the 43 patients with GH peaks below 3 µg/liter, 41 (95%) had plasma IGF-I less than -2 zs. The body mass index (BMI), plasma insulin, and leptin were similar in the four groups. They were positively correlated with each other (P < 0.001 for BMI compared with insulin and with leptin, respectively, and P < 0.01 for insulin compared with leptin), but not with age or dose of irradiation, or with markers of GH secretion.
In conclusion, in patients with GH deficiency caused by cranial irradiation, the residual GH secretion and plasma IGF-I depend on the dose. Almost all the patients with severe GH deficiency had low plasma IGF-I. BMI, leptin, and insulin seem to be independent of GH status.
CRANIAL IRRADIATION DURING childhood alters hypothalamic-pituitary (HP) function; the most frequent change is GH deficiency. Many patients treated by cranial irradiation for leukemia or cancer during childhood have now become young adults. Before transferring their follow-up to adult departments, it is important to establish the factors influencing their residual GH secretion, and how to evaluate them. The plasma concentrations of IGF-I and its GH-dependent binding protein (IGFBP-3) are diagnostic markers of permanent idiopathic GH deficiency during childhood (1), but reports indicate that they are poor diagnostic tests of GH deficiency after cranial irradiation (2, 3, 4) and in adults (5, 6).
This study of young adults with GH deficiency caused by cranial irradiation during childhood was done to evaluate the effect of age and dose of irradiation on the development and severity of GH deficiency, the frequency of other HP abnormalities, and the frequency of low IGF-I and IGFBP-3 in the patients with severe GH deficiency. We also assessed the relationship between GH secretion and the body mass index (BMI), plasma insulin, and leptin concentrations, which are also used as markers of changes in the HP function. Our goal is to better understand the pathophysiological process that results from HP irradiation.
Materials and Methods
Patients
Ninety (53 males and 37 females) consecutive patients with GH
deficiency caused by fractionated cranial irradiation performed at
4.9 ± 0.4 (range, 0.3–14.6) yr of age for disorders not
involving the HP area were reevaluated when they were 15.7 ± 0.2
(13.5–19.1) yr old and had completed GH therapy. None of them had any
central nervous system involvement or recurrence. All were monitored by
one of us (R.B.) at the Pediatric Endocrinology Department. They were
assigned to one of four groups according to their initial disorder and
their physical calculated dose of HP radiation (Table 1
), given as five fractions per week over
5–7 wk. Group 1 patients were given 18 Grays (Gy) (7 cases) or 24 Gy
(21 cases) of prophylactic cranial irradiation for acute lymphoblastic
leukemia; group 2 patients were given 30–40 Gy for medulloblastoma (22
cases); group 3 patients were given 45–60 Gy for optic glioma (19
cases), astrocytoma (4 cases), pinealoma (2 cases), brain stem tumor (1
case), or pharyngeal rhabdomyosarcoma (4 cases); and group 4 patients
(10 cases) were given 40–50 Gy for retinoblastoma. This group was set
up because the irradiation was given laterally and the patients were
very young at irradiation. Group 2 was also given spinal irradiation.
Four group 1 patients were also given bilateral testicular irradiation
for testicular involvement. The criteria for GH therapy were a GH peak
lower than 10 µg/liter after two stimulation tests (except for nine
patients who were evaluated with one test), using arginine insulin for
the first test and ornithin for the second test, and also total height
loss greater than 1 SD (7). The TSH response
to TRH was determined at the first evaluation in 6 patients from group
1, 16 patients from group 2, 22 patients from group 3, and 10 patients
from group 4. Those with early puberty had also been treated with GnRH
analog (8). The GH therapy had been completed for at least
1 month (0.5 ± 0.1 yr, 0.1–4.5 yr), but the other hormonal
replacement therapies (including sex steroids) were continuing. All
patients had reached their adult height (<1 cm growth during the
preceding year and a bone age over 15 yr in girls and 16 yr in boys)
and completed their puberty. The patients and their parents were
informed that the testing was being performed to evaluate residual GH
secretion and to adjust the replacement therapy (other than GH) before
reducing endocrine follow-up, and to prepare for the transfer of their
follow-up to adult departments. They were also advised that their test
results would be part of an ongoing study. They gave their consent for
the evaluation.
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The evaluation was performed in a single morning with patients in a fasting state and included a physical examination plus measurements of height and weight. Blood samples were obtained at 0800 h for measurements of free T4, cortisol, PRL (except in 10 cases), T (in males), and E2 (in females, except in 6 cases). TSH were measured in patients given spinal irradiation, to look for thyroid injury; gonadotropins were measured in those given spinal irradiation and/or chemotherapy, to look for gonadal injury. The concentrations of cortisol were not measured in the patients given hydrocortisone replacement therapy; nor were sex steroids or gonadotropins in the patients given sex steroids. An arginine insulin stimulation test (third GH evaluation) was performed to evaluate the GH peak response. An aliquot of plasma was frozen at -20 C to measure IGF-I (except in 12 cases), IGFBP-3 (except in 8 cases), insulin (except in 12 cases), and leptin (except in 15 cases). In the patients with no progression of puberty, the HP-gonadal axis was also evaluated by measuring basal and GnRH-stimulated (100 µg/m2, maximal dose 150 µg) gonadotropin (FSH and LH) peaks.
Methods
The BMI (weight in kilograms/height in meters squared) was expressed as the z score (zs) (9). Commercial immunoassays were used to measure GH (human GH, immunoradiometric assay; Immunotech, Marseille, France), IGF-I (IGF-I-RIACT; Cis Bio, Gif sur Yvette, France), IGFBP-3 (IGFBP-3, immunoradiometric assay; Diagnostic Systems Laboratories, Inc., Webster, TX), insulin (Phasedeph Insulin RIA; Pharmacia & Upjohn, Inc., St. Quentin en Yvelines, France), and leptin (human Leptin RIA; Linco Research, Inc., St. Charles, MO) (10). The control group for plasma IGF-I concentrations included 31 adolescents aged 14–16 yr and 30 young adults aged 17–20 yr. All had normal height and weight and spontaneous pubertal development. Plasma IGF-I concentrations were expressed as zs to overcome the age-related fluctuations in IGF-I concentrations. The normal data for IGFBP-3 were given in the kit insert provided by the manufacturers with -2 SD at 2 mg/liter. The normal limits were 12–28 pmol/liter for plasma free T4, 5–20 µg/liter for PRL, and 0.6–4 mU/liter for basal plasma TSH, 14 ± 7 mU/liter for TSH peak, and less than 9 for TSH at 120 min after the TRH stimulation.
The results are expressed as means ± SE. Groups were
compared with the Kruskal-Wallis test, followed by Mann-Whitney
U tests and a Wilcoxon rank test for GH peaks in the four
groups, and by the 
2 test for percentages.
Correlations were analyzed using Spearman’s test.
Results
GH secretion
The group 1 patients were significantly younger than those of
groups 2 and 3 at irradiation, and those of group 4 were the youngest
of all (Table 1
). The ages at the last evaluation were similar in all
four groups. The mean GH peak in group 3 was significantly lower than
in groups 1 and 2 (Fig. 1). The mean
plasma IGF-I concentrations in groups 3 and 4 were significantly lower
than those of groups 1 and 2. The mean plasma IGFBP-3 concentrations in
group 4 were significantly lower than those of the other groups. When
groups 3 and 4 were analyzed together, because they had been given the
highest HP irradiation doses, the means of GH peaks and plasma IGF-I
concentrations in these groups were also significantly lower than those
of groups 1 and 2. Fewer patients in group 1 (69%) had low (<-2 zs)
plasma IGF-I concentrations than in groups 2 (83%), 3 (89%), and 4
(100%, P < 0.05). Fewer patients in groups 1 (40%),
2 (15%), and 3 (29%) had low (<-2 SD) plasma
IGFBP-3 concentrations than in group 4 (67%, P <
0.02).
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), but not with age at
irradiation. The plasma IGFBP-3 concentration was correlated positively
with the IGF-I concentration (r = 0.54, P =
0.0001), but not with the GH peak or with the irradiation dose.
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). The
mean height of the GH peak for the whole population was greater at the
first (6.1 ± 0.4 µg/liter) evaluation than at the second
(5.0 ± 0.4 µg/liter, P < 0.01), performed
after an interval of 1.0 ± 0.2 yr. Both values were significantly
higher than that at the third evaluation (3.5 ± 0.3 µg/liter,
P < 0.001). When each group was analyzed separately,
there was a significant decrease in the GH peak between the first and
the third evaluations in groups 1, 2, and 3, but not in group 4.
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No patient had clinical signs of hypothyroidism. The TSH response
to TRH at the first evaluation was low and/or prolonged in 6 of 16
group 2 patients, 11 of 22 group 3 patients, and 4 of 10 group 4
patients. At the last evaluation, 30 patients were given replacement
T4 treatment because of low
T4 and/or abnormal TSH concentrations (Table 2). ACTH deficiency was found in three
group 3 patients who had been given irradiation at 5.8 ± 2 yr of
age and also had TSH and gonadotropin deficiencies. Early puberty
occurred in 33 patients (9 girls in group 1, 5 girls and 2 boys in
group 2, and 7 girls and 10 boys in group 3) who had been treated with
GnRH analog. No progression of secondary sexual characteristics, and/or
rare menstruations or primary amenorrhea in girls, were seen in 11
patients (2 boys), 9 of them having had an early puberty. Their
gonadotropin response to GnRH test was subnormal (six cases), normal
(two cases), or above-normal (two cases). In addition, two boys had
Leydig cell deficiency following testicular irradiation. The basal
plasma FSH concentration was increased (>9 IU/liter) in 12 boys,
indicating tubular deficiency caused by testicular irradiation (4 group
1 patients) and/or chemotherapy (4 group 2, 2 group 3, and 2 group 4
patients). Patients who lacked sex steroids were given T heptylate
(four boys), estroprogestin (six girls), or progestin alone (three
girls) because of spontaneous E secretion and normal gonadotropin
response to GnRH test in two of them, but oligomenorrhea. The basal
plasma PRL concentrations were increased (22–42 µg/liter) in two
patients in group 2 and two patients in group 3. The means of these
concentrations in groups 2 and 3 were significantly higher than those
in groups 1 and 4 (Table 1). They were positively correlated with age
at irradiation (r = 0.35, P < 0.001) and
negatively correlated with the time between irradiation and evaluation
(r = -0.38, P < 0.001), but not with the
irradiation dose.
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The mean BMI, plasma insulin, and leptin concentrations were
similar in the four groups (Table 1). Fewer patients in groups 1 (3%)
and 4 (0%) had BMI greater than 2 zs than in groups 2 (18%) and 3
(27%, P < 0.01). The figures for boys and girls were
similar. The three parameters were positively correlated (Fig. 4). No correlation was found between
these parameters and age or dose of irradiation, GH peak, plasma IGF-I,
or IGFBP-3 concentrations.
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We find that the dose of HP irradiation determines the residual GH secretion, the frequency of low plasma IGF-I concentration in GH-deficient patients, and the frequency of other HP abnormalities. Almost all the patients with severe GH deficiency caused by cranial irradiation had low plasma IGF-I. The positive correlation between the GH peak and plasma IGF-I suggests that this parameter can be used to monitor residual GH secretion.
The threshold dose of fractionated irradiation for a risk of GH deficiency has not been determined. We (11) found that the GH peak after an arginine insulin test was below 10 µg/liter in 63% of the patients given 18 Gy and evaluated during childhood, and Cicognani et al. (12) used magnetic resonance imaging to show that the mean height of the pituitary anterior lobe was reduced. This was correlated with the GH peak and the area under the curve after an arginine test, and with the mean nocturnal GH concentration. Talvensaari et al. (13) and Tillman et al. (14) both reported a negative correlation between the dose (15–46 Gy) and the nocturnal GH peak and the integrated nocturnal GH secretion. Schmiegelow et al. (15) also found that the GH peak after an arginine test in 16 patients given cranial irradiation for disorders not involving the HP area was negatively correlated with the dose delivered to 90% of the volume of the pituitary. Patients who, by the 90% dose volume, were given more than 37.5 Gy to the HP area had an accumulated risk of GH deficiency of 87% 2.5 yr after irradiation. The growth rate of patients with GH deficiency caused by cranial irradiation depends on the cranial dose (16), which suggests that the degree of GH deficiency depends on the irradiation dose. The present study shows that the GH peaks decreased with the time since irradiation, except in the group given irradiation when very young. This decrease was also reported by Brennan et al. (4) after 18–25 Gy. Clayton and Shalet (17) found that the late incidence of GH deficiency (peak <7.5 µg/liter) was similar over the whole dose range (27–47.5 Gy in 82 patients), but the speed of onset over the first few years depended on dose. We have found that the frequencies of TSH, ACTH, and gonadotropin deficiencies increase with the HP dose. The HP secretions, other than GH, were also examined by Constine et al. (18), who found a negative correlation between the dose (39.6–70.2 Gy) and the serum total T4 and triiodothyronine concentrations, as well as the basal and stimulated serum TSH concentrations.
This study comparing groups with GH deficiency caused by various HP irradiation doses shows that the frequency of low plasma IGF-I concentration depends on the HP dose. This may partly explain the reports indicating normal plasma IGF-I and IGFBP-3 concentrations in GH deficiency caused by cranial irradiation, as the majority of these reports evaluated patients given low HP doses. Thus, the plasma IGF-I and IGFBP-3 concentrations were not correlated with the GH peak in the patients given 18 Gy (11) or 24 Gy (19) prophylactic cranial irradiation for leukemia and evaluated during childhood. However, the mean plasma IGF-I concentration in GH-deficient patients was significantly lower than that of GH-sufficient ones in those given 24 Gy (19), but not in those given 18 Gy (11). Brennan et al. (4) evaluated 32 adults given 18–25 Gy during childhood for lymphoblastic leukemia, and found a significantly (P < 0.01) lower IGF-I than in controls, but there was no significant difference between those with severely insufficient and normal GH peaks. Sklar et al. (2) evaluated 15 patients with a GH peak of less than 10 µg/liter 2.7 yr after 18 Gy to more than 60 Gy, and found a low IGFBP-3 in only 3 patients. Tillman et al. (3) found that none of 27 patients with radiation-induced GH deficiency had an IGFBP-3 less than -1.5 SD. Achermann et al. (20) evaluated 14 adults given high-dose irradiation (>30 Gy) during childhood for disorders not involving the HP area and found a significantly lower GH peak and IGF-I and IGFBP-3 concentrations than in controls; but the difference in IGF-I between irradiated and controls was greater than in IGFBP-3.
It is difficult to diagnose GH deficiency in adults. Hoffman et al. (5) found 70% of the IGF-I and 72% of the IGFBP-3 concentrations within the normal range in adults with a GH peak below 5 µg/liter after an insulin test. But de Boer et al. (6) found figures of 4% and 8%, respectively for the same parameters. These differences might be due to the ages at onset (adult vs. childhood) and to the causes of the GH deficiency: pituitary adenoma, cranial irradiation, and other causes in the study by Hoffman et al. (5); idiopathic in the study by Boer et al. (6). In this study, when the cut-off was 3 µg/liter for GH peak and -2 zs for IGF-I, there was a dissociation between normal IGF-I despite a profound GH deficiency in only 2 of 43 patients. To further evaluate the role of the age at onset and of the causes of GH deficiency, we compared the plasma IGF-I concentrations in GH deficiency caused by cranial irradiation at 4.9 yr to those of nine young adults with congenital GH deficiency caused by pituitary stalk interruption syndrome. In this group, the concentrations of IGF-I were -2.8 ± 0.9 zs in the five patients with adult range plasma sex steroids concentrations and -4.8 ± 0.2 zs in the four patients with low plasma sex steroids concentrations secondary to associated congenital gonadotropin deficiency. These concentrations are similar to those of patients given high HP irradiation doses.
The BMI, insulin, and leptin concentrations were positively correlated with each other, but not with age or dose of irradiation or with markers of GH secretion. Obesity has been reported to be more frequent in adults given prophylactic cranial irradiation for acute lymphoblastic leukemia during childhood (21, 22), without any difference in BMI between 18 and 21–24 Gy (21), and with no correlation with GH secretion (23). Leptin concentrations were significantly higher in patients given cranial irradiation than in the nonirradiated patients treated for acute lymphoblastic leukemia, with a positive correlation between BMI and leptin concentrations (24). Young adults given 18 or 24 Gy cranial irradiation during childhood had a BMI and an absolute fat mass that were no different from those of controls; but their absolute lean masses were significantly lower and their leptin concentrations higher. The maximum GH peak response to either provocative test showed a negative correlation with leptin, which does not agree with our data.
Our current policy for young adults given cranial irradiation during childhood takes account of the cranial dose. Those given 18 or 24 Gy cranial irradiation do not need replacement therapy (unless they have been given testicular irradiation) and are followed by their physicians because only a few had a GH peak less than 3 µg/liter and none of them had an HP pituitary deficiency other than GH 11.8 yr after irradiation. They are seen in our department if they have a medical problem, or routinely every 3–5 yr for physical examination and assays of plasma T4 and IGF-I. Those given higher doses are seen every 1 or 2 yr, particularly if they are on hydrocortisone and/or sex steroids. The evaluation includes a clinical examination, cycle regularity in females, assays of plasma T4, T (in boys), or E2 and PRL if cycles are abnormal in girls, cortisol at 0800 h, and IGF-I. The decision to treat patients with GH throughout life should take account of this variable. Other pituitary deficiencies should also be treated.
In conclusion, this study shows that the alteration of the HP function caused by cranial irradiation depends on the HP dose. Normal plasma IGF-I concentrations despite a GH deficiency are seen almost exclusively after low (18 or 24 Gy) HP doses. This suggests that plasma IGF-I can be used as a marker of the changes in the HP caused by cranial irradiation and that high doses of cranial irradiation decrease plasma IGF-I to values similar to those found in congenital idiopathic GH deficiency. Plasma IGFBP-3 concentrations were not correlated with the GH peak or with the irradiation dose and were less frequently decreased than those of IGF-I. This has previously been suggested, but remains unexplained.
Acknowledgments
We thank Prs. S. Blanche and G. Leverger for sending us five and four patients, respectively; J. C. Souberbielle for helpful advice; M. C. Perret and M. C. Manolioux (Physiology Laboratory) for technical assistance; the nurses of the Pediatric Endocrinology Department (M. Faivre, M. Couzi, and C. Robertson) for carrying out the tests; and Drs. G. Watts and O. Parkes for editorial help.
Footnotes
This work was presented in part at the 39th Annual Meeting of the European Society for Pediatric Endocrinology, Brussels, Belgium, 2000.
Abbreviations: BMI, Body mass index; HP, hypothalamic-pituitary; IGFBP, IGF-binding protein.
Received August 29, 2000.
Accepted August 15, 2001.
References
This article has been cited by other articles:
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