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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 7 3149-3154
Copyright © 2003 by The Endocrine Society

Assessment of the Hypothalamo-Pituitary-Adrenal Axis in Patients Treated with Radiotherapy and Chemotherapy for Childhood Brain Tumor

M. Schmiegelow, U. Feldt-Rasmussen, A. K. Rasmussen, M. Lange, H. S. Poulsen and J. Müller

Department of Growth and Reproduction (M.S., J.M.) and Pediatric Clinic II (M.S.), Juliane Marie Center; Department of Endocrinology, Abdominal Center (U.F.-R., A.K.R., M.L.); and Section of Radiation Biology, Department of Oncology, Finsen Center (H.S.P.), University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Marianne Schmiegelow, M.D., Department of Growth and Reproduction 5064, Juliane Marie Center, University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: mschmiegelow{at}hotmail.com.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The impact of cranial irradiation (CIR) and chemotherapy on the hypothalamo-pituitary (HP)-adrenal (HPA) axis was assessed in a population-based follow-up study of patients treated for childhood brain tumor not directly involving the HP axis.

HPA function was evaluated and compared with that in healthy controls (n = 17), measuring basal cortisol and the peak cortisol response to an insulin tolerance test (ITT) and an ACTH test. The cortisol cut-off level was 500 nmol/liter. The biological effective dose (BED) of radiotherapy was determined for the HP region and spine and was expressed in Gray units, as BED gives a means of expressing the biological effects of different dosage schedules in a uniform way.

Seventy-three children (46 males and 27 females), less than 15 yr of age when diagnosed during 1970–1997 in the Eastern part of Denmark, were included. The median age at time of radiotherapy was 8.4 yr (range, 0.8–14.9). The median length of follow-up was 15 yr (range, 2–29).

Fourteen patients (19%) had basal cortisol levels below 500 nmol/liter and did not respond with a peak cortisol above the cut-off level to either an ACTH test (30 or 60 min) or an ITT, and thus, they had insufficiency of the HPA axis. Even though a peak cortisol above 500 nmol/liter was reached in the rest of the cohort (n = 59) after either an ACTH test (30 or 60 min) or an ITT, they had significantly lower peak cortisol levels compared with controls (P = 0.0099). Thirteen patients failed the ACTH test (30 min), but passed the ACTH test (60 min), implying a risk of misinterpreting the cortisol capacity of the patient if only the ACTH test (30 min) is obtained. The basal cortisol levels and the cortisol levels in the ACTH test (30 min) and the ACTH test (60 min) were significantly lower in the patient group compared with controls. There was a significant correlation between the peak cortisol after the ITT compared with the peak cortisol after the ACTH test (30 or 60 min; rs = 0.56; P = 0.0006), but 48% failed the ITT, and there was discordance in 10 of 33 (30%) patients who passed the ACTH but failed the ITT, indicating the recommendation of continuous use of the ITT as the gold standard for evaluation of the HPA axis. Stepwise backward multiple linear regression analysis showed that the best-fit model to predict the peak cortisol level after an ITT included BED (P = 0.04) and length of follow-up (P = 0.06). In contrast, age at RT, chemotherapy, BED to the spine, and gender were not included in the model.

In conclusion, these data suggest that CIR for a childhood brain tumor may affect the HPA axis, resulting in secondary adrenal insufficiency, whereas adjuvant chemotherapy does not seem to add to the deleterious effect of CIR. We recommend life-long surveillance of the HPA axis and performing regular ITTs.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE SURVIVAL rate of children with brain tumors has increased to about 65% (1, 2); however, the improvement in prognosis has been achieved at the expense of serious late effects. Children treated for brain tumors with radiotherapy (RT) and chemotherapy (CT) are at risk of developing endocrine deficits when the hypothalamus-pituitary (HP) axis falls within the fields of radiation, which may result in GH deficiency and gonadal and thyroid dysfunction (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15). Yet evaluation of the HP-adrenal (HPA) axis has only been reported in a few studies (6, 12, 16). Partial ACTH deficiency due to HPA axis dysfunction is often asymptomatic, but during stressful stimuli, failure to mount a biologically sufficient cortisol response may lead to deleterious consequences and endanger survival.

The mode of assessment of the HPA axis remains controversial. The insulin tolerance test (ITT) has been considered the golden standard when assessing the HPA axis. A blood glucose level of 2.2 mmol/liter or less results in neuroglycopenia, which activates the hypothalamus with secretion of CRH, resulting in secretion of ACTH from the pituitary gland. The ITT in adults is regarded as a safe test in experienced hands (17, 18); however, case reports have demonstrated potential risks using the ITT in children (19, 20). Therefore, the ACTH test is used in children and in patients with cardiac disease or epilepsy. The conventional ACTH test using synthetic corticotropin assesses the function of the adrenal cortex. Chronic ACTH deficiency results in atrophy of the adrenal cortex and failure to respond to exogenous corticotropin. The ACTH test is thus an indirect measurement of the function of the pituitary gland. Cranial irradiation (CIR) may cause ACTH secretory abnormalities if the HP axis has been irradiated. It could be anticipated that scattered irradiation from a spinal field to the adrenal cortex might result in primary adrenal dysfunction. However, to our knowledge craniospinal irradiation (CSI) itself, as in children treated for medulloblastoma, has not been reported to damage adrenal function (10). Radiobiological approaches to the understanding of the long-term side-effects of late responding tissues, such as nerve tissue, have shown that the biological effects depend for any given total dose on the fractionation size (21). The normal tissue reaction of the nerve tissue within the fields of radiation is dependent on the biological effective dose (BED) received, as the BED gives a means of expressing the biological effect of various treatment schedules in a uniform way, as previously described (7, 22). A possible effect of CT on the HPA axis and/or the adrenal cortex has to our knowledge not been reported.

The aim of the study was to assess the impact of RT and CT on the HPA axis in a population-based follow-up study of children treated for brain tumor. We have measured basal cortisol levels and the peak cortisol response to an ITT and an ACTH test and evaluated the possible relation of BED to the HP region and spine.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

The study included all patients who were 1) diagnosed and treated for brain tumor in the eastern part of Denmark, including all counties of Sealand, the Faroe Islands, and Greenland; 2) diagnosed from January 1970 through February 1997; 3) aged less than 15 yr at the time of diagnosis of a primary brain tumor not directly involving the HP axis; 4) treated with cranial or craniospinal RT and with or without CT; 5) more than 1 yr from end of treatment at the time of follow-up; and 6) in remission at the time of follow-up. Four patients were excluded from the study at time of follow-up: two patients had emigrated, one was living in Greenland, and one had his case record missing.

Ninety-one patients met the criteria and were asked to participate in the study. Seventy-six patients (84%) agreed to participate. The 15 nonparticipants did not differ significantly with respect to histological diagnosis of the tumor, age of the child at the time of RT, total dose of RT, dose per fraction of RT, or length of follow-up. Of the 76 patients who met the inclusion criteria and agreed to participate (49 males and 27 females), 2 males were excluded due to hypofunction of the HPA axis detected at the time of diagnosis. Finally, 1 male was excluded because he had not discontinued his hydrocortisone medication at the time of follow-up. Thus, 73 patients were included (46 males and 27 females). The median age at the time of RT was 8.4 yr (range, 0.8–14.9 yr), and the median length of follow-up was 15 yr (range, 2–29 yr). The median age at time of follow-up was 21.6 yr (range, 6.2–43.5 yr). The tumor diagnoses were astrocytoma (n = 31), medulloblastoma (n = 23), ependymoma (n = 5), germ cell tumor (n = 3), glioma (n = 3), pinealoma (n = 1), hemangiopericytoma (n = 1), primitive neuroectodermal tumor (n = 1), and nonhistological verified diagnoses (n = 5). These latter 5 patients were assumed to have chiasma glioma (n = 4) and an infiltrating fossa posterior tumor regarded to be a medulloblastoma (n = 1) according to diagnostic imaging. By the WHO classification, 37 patients had benign tumor, and 31 patients had malignant tumor (23). Twenty-eight patients had hydrocephalus at the time of diagnosis to such a degree that they had a shunt operation performed. Four patients were receiving hydrocortisone treatment when included in the study. They discontinued their medication the same morning they were tested, and as the metabolic clearance rate of hydrocortisone is 2 h, we assumed that there would be no iatrogenic alteration in the HPA axis in this subset. Twenty-nine patients were receiving other hormone replacement treatments, which included GH (n = 20), T4 (n = 20), estradiol (n = 8), and testosterone (n = 2).

The controls (n = 17) were healthy individuals from the hospital staff (eight men and nine women), with a median age at time of investigation of 31 yr (range, 24–64 yr).

Treatment

Surgery. Sixty-eight children had biopsy or total or partial resection of the tumor performed in addition to RT.

RT.
Fifteen children had been treated with 60Co units, and 58 children had been treated with external conventional 4-, 6-, or 8-megavoltage RT delivered by a linear accelerator. Thirty children were treated with CSI, 14 were treated with whole brain irradiation only, and 29 children were treated with focal cranial irradiation. The overall treatment time differed according to different treatment schedules used from 1970 to 1997 from 1 fraction every second day to 1 fraction/day, 5 times a week, and the dose per fraction differed from an increment strategy starting at very low doses increasing over the treatment period to the administration of uniform fractions during the whole treatment period.

CT.
In addition to RT, 30 children were treated pre- and/or postoperatively with adjuvant CT. Children treated during the late seventies and eighties were given lomustine, vincristine, and methotrexate as single drugs or in combination. Later in the nineties, children with a germinal cell tumor received cisplatin and bleomycin, and etoposide (VP16), and children with a medulloblastoma received vincristine, carboplatin, endoxan, and VP16 according to the International Society of Pediatric Oncology II protocol (24)

Methods

Assessment of cortisol response. Beginning between 0800–1000 h all patients (n = 73) eligible for inclusion in the study underwent an ACTH test. Of the 73 patients, 46 were 18 yr of age or older at the time of follow-up; however, of these, 13 had seizure disorders in which an ITT is contraindicated. Twenty-one were children less than 18 yr of age, in whom it is our routine to assess the HPA axis using the ACTH test due to case reports having demonstrated potential risks using the ITT test. The remaining 33 patients (>=18 yr of age at the time of follow-up) also had an ITT performed beginning between 0800–1000 h after an 8-h fasting period on a different day. The median time interval between the ACTH test and the ITT was 5 months (range, 2 wk and 15 months). There was significantly difference between the 33 patients vs. the 40 patients with respect to age at follow-up and, hence, length of follow-up, whereas no significant difference was found with respect to the age of the child at the time of RT or the BED to the HP region. Controls had an ACTH test performed, and cortisol levels were measured at 0, 30, and 60 min, but no ITT was performed.

Definition of response. A peak cortisol response of 500 nmol/liter or more was considered adequate both in the ACTH test and as a peak response to hypoglycemia of 2.2 mmol/liter or less on ITT (25, 26).

Procedures. For the ACTH test, 250 µg Synachten were administered iv as a bolus, with sampling at 0, 30, and 60 min. The ITT was carried out according to a standard protocol; 0.10–0.15 U/kg soluble insulin was administered iv by a cannula inserted in the antecubital fossa, producing a blood glucose nadir of 2.2 mmol/liter or less. Serum samples for cortisol estimation were drawn at -15, 0, 15, 30, 45, 60, and 75 min.

Assays. The cortisol concentrations were measured by a time-resolved fluoroimmunoassay (AutoDELFIA cortisol assay, Wallac Oy, Inc., Turku, Finland) or for patients tested with ACTH before 1998 (n = 20) with HPLC. For the AutoDELFIA, the intraassay coefficient of variation was 3.6% at 212 nmol/liter, 2.9% at 520 nmol/liter, and 3.2% at 781 nmol/liter, and the interassay coefficient of variation was 1.9% at 212 nmol/liter, 0.8% at 520 nmol/liter, and 1.4% at 781 nmol/liter. For the HPLC, the intraassay coefficient of variation was 10.6% at 104 nmol/liter, 1.9% at 496 nmol/liter, and 2.9% at 734 nmol/liter. To ensure the stability of the analysis, the DELFIA assays were calibrated against the HPLC at regular intervals.

BED. To obtain a uniform comparison of the different treatment regimens we used BED of RT, which gives a means of comparing different RT schedules (22). BED received by the HP region and the spine was determined by the linear quadratic model as previously described (7).

Statistics. Because the data for the patient population had a skewed distribution, we used median and range. Correlations between variables were tested with the nonparametric Spearman’s correlation analysis (rs = correlation coefficient) (27). We performed the Kruskal-Wallis test to analyze the variance by ranks comparing three unpaired groups, and only in the case of significant difference was a post hoc Mann-Whitney U test used for comparing data from two independent groups. The relationship between the independent variables, age at time of RT, time elapsed since RT, BED to the HP region, BED to the spine, and chemotherapy (given = 1, not given = 0), and the dependent variable peak cortisol after an ITT was analyzed by stepwise backward multiple regression analysis. The validity of the regression model was checked using standard tests. These included assessing the distribution of the residuals and testing for normality and checking the linearity assumptions in the model by means of standard scatter plots. Data analyses were performed with SPSS statistical software (SPSS, Inc., Chicago, IL) (28). Two-sided P < 0.05 was regarded as significant.

Ethics. Adults and children (or their parents when appropriate) gave their informed consent. The study was in accordance with the Declaration of Helsinki II and was approved by the local ethical committee of Copenhagen, Denmark.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Fourteen patients (19%) had basal cortisol levels below 500 nmol/liter and did not respond with a peak cortisol above the cut-off level to either an ACTH test (30 or 60 min) or an ITT; thus, they had insufficiency of the HPA axis. A peak cortisol of 500 nmol/liter or greater was reached in the rest of the cohort (n = 59) after either an ACTH test (30 or 60 min) or an ITT, but they still had significantly lower peak cortisol levels compared with controls (P = 0.0099). The median and range of peak cortisol responses are summarized in Table 1Go. Of the 14 patients who had a peak cortisol response below 500 nmol/liter, 10 (71%) had been treated with CIR only, and 4 patients (29%) had been treated with CSI. There was no significant difference between the median peak level of cortisol in the 2 groups.


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  		TABLE 1. Cortisol response to the ACTH test and to the insulin tolerance test (ITT) in patients and to the ACTH test in controls (number and percentage)

 
As previously reported, the cohort also had GH and thyroid status determined (7, 15), and of the 14 patients with insufficiency of the HPA axis, 13 also had developed GH deficiency, and 5 had hypothyroidism as well.

Twenty-eight patients had hydrocephalus and were shunted, but only four of them had insufficiency of the HPA axis.

Basal cortisol levels as well as cortisol levels after an ACTH test (30 and 60 min) were significantly lower in the patient group compared with controls (Fig. 1Go).



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  		FIG. 1. Basal cortisol levels as well as cortisol levels after an ACTH test (30 and 60 min) were significantly lower in the patient group compared with controls.

 
Thirty-three patients of the total cohort also had an ITT performed. Sixteen patients (48%) failed the ITT with a peak cortisol response less than 500 nmol/liter, whereas a peak cortisol of 500 nmol/liter or greater was reached in 17 patients (Table 1Go). There was a significant correlation between the ITT and the peak ACTH test (rs = 0.56; P = 0.0006). There was discordance in 10 of 33 (30%) patients who passed the ACTH test, but failed the ITT (Fig. 2Go). The 10 patients had a median peak cortisol response to the ITT of 445 nmol/liter (range, 380–490 nmol/liter) and a median peak cortisol response to the ACTH test of 605 nmol/liter (range, 500–740 nmol/liter). Eight of the 10 patients had a cortisol response to the ITT between 400–500 nmol/liter (Fig. 2Go).



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  		FIG. 2. Thirty-three patients of the total cohort also had an ITT performed. Sixteen patients (48%) failed the ITT with a peak cortisol response less than 500 nmol/liter, whereas a peak cortisol of 500 nmol/liter or greater was reached in 17 patients (Table 1Go). There was a significant correlation between the ITT and the peak ACTH test (rs = 0.56; P = 0.0006). There was discordance in 10 patients (of 33, 30%) who passed the ACTH test, but failed the ITT.

 
Thirteen patients failed the ACTH test (30 min) but passed the ACTH test (60 min; Fig. 3Go); however, of these 13 patients only 5 had an ITT performed, and 4 of the 5 patients also had a peak cortisol response of 500 nmol/liter or greater.



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  		FIG. 3. Thirteen patients failed the ACTH test (30 min) but passed the ACTH test (60 min); however, of these 13 patients only 5 had an ITT performed, and 4 of the 5 patients also had a peak cortisol response of 500 nmol/liter or greater.

 
Twenty patients had basal cortisol and 60 min cortisol levels measured by the HPLC method. However, we found no significant difference between these cortisol levels and those in the 53 patients who had their cortisol levels analyzed by RIA.

The median BED to the HP region was 73 Gy (range, 0–94 Gy). BED was not significantly related to peak cortisol after a 30-min ACTH test (rs = 0.02), a 60-min ACTH test (rs = -0.05), or an ITT (rs = -0.02). The median BED to the spine was 55 Gy (range, 27–78 Gy). We found no significant correlation between BED to the spine and peak cortisol (rs = 0.24).

Stepwise backward multiple linear regression analysis showed that the best-fit model to predict the peak cortisol level after an ITT included BED (P = 0.04) and length of follow-up (P = 0.06). In contrast, age at RT, CT, BED to the spine, and gender were not included in the model (Table 2Go).


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  		TABLE 2. Multiple linear regression analysis of factors of possible correlation to peak cortisol after an insulin tolerance test (ITT)

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In the present population-based study, 19% had a basal cortisol level less than 500 nmol/liter and did not respond with a peak cortisol above the cut-off level to either an ACTH test (30 or 60 min) or an ITT and thus had insufficiency of the HPA axis. This is contradictory to other studies, which have demonstrated only subtle abnormalities in adrenal function after RT for childhood brain tumor (6, 12, 16). In the study by Constine et al. (12), the HPA axis was evaluated with a mean interval between therapy and testing of 7 yr (range, 2–13 yr) by means of the ACTH test together with a CRH test and a metyrapone test. The CRH test is supposed to demonstrate evidence of hypothalamic dysfunction, whereas the metyrapone test works by stimulating the release of ACTH by lowering cortisol secretion. Constine et al. (12) found normal cortisol responses to the ACTH test as well as a mean peak ACTH response to the CRH test within the normal range and normal serum cortisol responses; however, 35% of the patients had a low 11-deoxycortisol response to the administration of metyrapone. In the study by Oberfield et al. (16), the median follow-up was 5 yr (range, 0.1–20 yr), and they evaluated the HPA axis with a CRH test and found significantly lower basal cortisol levels as well as peak cortisol responses, but the mean integrated values for cortisol (area under the curve) and the ACTH responses to CRH were not different from the control values. Livesey et al. (6) evaluated the HPA axis with a mean interval between therapy and testing of 9.6 yr (range, 2–26 yr) and evaluated the HPA axis by means of the ITT; they found only 4 of 90 subjects (4%) with diminished cortisol responses. In the present study 48% failed the ITT, but of the 33 patients who had both an ITT as well as an ACTH performed, there were 10 discrepancies (30%), who passed the ACTH test, but failed the ITT. By regarding the ITT as the gold standard, it appeared that the ACTH test was less reliable in assessing the HPA axis in patients who have been treated with CIR and therefore are at risk of hypothalamic damage. It is important to underline that no failure of the ITT to detect HPA axis impairment was proven, as we found no patients with a cortisol response to the ITT of 500 nmol/liter or greater who had a cortisol response to the ACTH test below 500 nmol/liter. These results should rise the question of whether the ACTH test should be abandoned as a first line test, as the 10 patients who passed the ACTH test, but failed the ITT, might be at risk during fever episodes or in case of emergencies that endanger survival. The fact that 8 of the 10 patients who did not respond to the ITT (<500 nmol/liter) had a cortisol response between 400–500 nmol/liter indicates a partial defect and the appropriateness of repeating the ITT within a short space of time in this borderline group. These results are in line with those of some other studies, which recommended continuous use of the ITT as the gold standard for evaluation of the HPA axis in patients with pituitary disease (25, 29, 30, 31, 32). This is, however, contradictory to other studies, which have come to the conclusion that the ACTH test can substitute for the ITT (33, 34, 35, 36, 37, 38, 39). An explanation for these contradictory reports could be that data from different centers have employed different assays and different criteria used to define states of adrenal deficiency: different cut-off values and mixed patient populations with regard to diagnosis and treatment. We have been able to undertake a population-based study of radiation-induced hypopituitarism in a large series of patients treated for primary brain tumors not directly involving the HP axis using the same assays tested in the same laboratories.

As for treatment with different RT schedules, total radiation dose and dose per fraction are both important. High doses per fraction will, for any given total dose, increase the severity of the late effects after RT, and we made the different treatments compatible using the BED received by the HP region (7). The ITT results in the release of both ACTH and GH via the hypothalamus, contrary to the ACTH test, which only indirectly reflects the HPA axis by expressing the functional state of the adrenal cortex. This difference is reflected in the fact that the multiple linear regression analysis showed that the best-fit model to predict the peak cortisol level after an ITT included the BED. As mentioned above, only a few other studies concerning the relationship between the irradiation of the HPA axis in children and hypoadrenalism exist. In the study by Constine et al. (12) the doses of radiation to the HP region ranged from 39.2–70.2 Gy, with no information of fractionation. In the study by Livesey et al. (6) the median dose of radiation to the hypothalamic region was 48 Gy (range, 10–56 Gy) in 34 fractions (range, 20–42 fractions), indicating different fractionation schemes. In a study by Crowne et al. (40) no significant disruption of the HPA axis was found in children treated with low dose, whole brain CIR (18–24 Gy, 1.8–2.0 Gy/fraction to the HP region) for acute lymphoblastic leukemia. Comparing this with our study indicates fractionated dose-dependent development of HPA dysfunction, and prospective studies incorporating BED and specific dosimetry to the HP region are needed to obtain threshold doses of radiation capable of damaging the HP axis. Scattered irradiation of RT to the spine had no significant influence on the adrenal glands, as we found no significant correlation between BED to the spine and cortisol levels. To our knowledge there has been no reports on the possible contribution of CT to adrenal dysfunction, and in the present study it could not be established that CT added to the deleterious effects of RT.

Corticotropin deficiency was also seen to develop progressively over the period of follow-up, as the stepwise backward multiple linear regression analysis showed that the best-fit model to predict peak cortisol after an ITT included length of follow-up in the model, in contrast to age at time of RT. This is in very good accord with the pathophysiology of radiation-induced changes in nerve tissue. Over time a decline is seen due to both vascular changes with degeneration and mitotic cell death of capillary endothelial cells, which fail to nourish the nerve tissue, resulting in parenchymal cell loss. With a median length of follow-up in the present study of 15 yr we would expect to have established the number of patients with adrenal dysfunction. However, as longer-term results of children with brain tumors are not yet available, we suggest that HPA function should be followed life-long after CIR.

The median peak cortisol level after an ACTH test (30 or 60 min) was significantly lower in the HPA axis-insufficient group compared with controls as well as in the group of patients with a peak cortisol level above the cut-off level compared with controls. This group may potentially be at risk of becoming HPA axis insufficient, and even though the median follow-up was 15 yr, this underlies the need for life-long follow-up of patients who have been treated with CIR.

As previously reported, the cohort also had GH and thyroid status determined (7, 15); 93% of patients with insufficient HPA axis also had GH deficiency, and 36% had thyroid dysfunction as well. The occurrence of GH deficiency as the earliest endocrine abnormality in children who have undergone CIR suggests that this axis is the most vulnerable to RT, but in addition to GH deficiency there are different reports of the sequence of other anterior pituitary hormone deficits after irradiation in childhood. Constine et al. (12) concluded from their study with a median follow-up of 7 yr (range, 2–13 yr) that hypothyroidism and gonadal dysfunction were the most frequent changes, whereas only subtle abnormalities in adrenal dysfunction could be shown. Livesey et al. (6) reported from their retrospective study with a median follow-up of 9.6 yr (range, 2–26 yr) that 86% had GH deficiency, 8% had primary hypothyroidism, and 15% had gonadal dysfunction. The prevalence of endocrine disorders described above confirms the importance of long-term follow-up, including regular observations of growth and appropriate investigations, in all children treated with CIR.

We found significantly lower basal cortisol levels in patients compared with controls. Likewise, the cortisol response to the ACTH test at both 30 and 60 min was significantly lower in patients compared with controls. It should be noted that no controls responded with less than 500 nmol/liter at either 30 or 60 min. We found a significant correlation between the ACTH test for 30 and that for 60 min, but 13 patients were what could be called slow responders, in that their cortisol levels at 30 min were less than 500 nmol/liter, but increased at 60 min to 500 nmol/liter or more. This implies that in patients who have been treated for childhood brain tumor with CIR and therefore are at risk of being HPA insufficient, a 30 min determination after the ACTH test with a cut-off value of 500 nmol/liter might give a misinterpretation of the cortisol capacity of the patient, and a 60 min determination should be obtained; otherwise, life-long substitution with hydrocortisone can be the consequence.

The established reference test for assessment of the HPA axis has been the ITT for many years, but due to potential side-effects of the ITT, the ACTH test, which is quick and safe, has become the first line test in many units. The conventional ACTH test incorporates 250 µg ACTH, a dose regarded as supraphysiological, and several investigators have published evidence for a more sensitive ACTH test using a lower dose of 1 µg ACTH (26, 41, 42, 43). However, it is hoped that ongoing studies will determine whether this test could be the gold standard for assessing the HPA.

In conclusion, these data suggest that CIR for childhood brain tumor may affect the HPA axis, resulting in secondary adrenal insufficiency, whereas adjuvant CT does not add to the deleterious effect of RT. We recommend life-long surveillance of the HPA axis in long-term survivors of childhood brain tumor who have been treated with CIR and regular performance of an ITT.


   Acknowledgments
 
The skillful technical assistance of Kirsten Jørgensen (Department of Growth and Reproduction, Juliane Marie Center) and Lisbeth Kirkegaard (Department of Endocrinology, Abdominal Center, National University Hospital, Rigshospitalet, Copenhagen, Denmark) is greatly appreciated.


   Footnotes
 
This work was supported by The Otto Christensen Foundation, The Frænkel Foundation, The Danish Children Cancer Foundation, The Gangsted Rasmussen Foundation (Grant 8436), The Lundbeck Foundation (Grant 39/96), The Olga Boel Foundation, The Rosalie Petersen Foundation (Grant 62036-3), The Ville Heise Foundation (Grant M1-96), and The Haensch Foundation.

Abbreviations: BED, Biological effective dose; CIR, cranial irradiation; CSI, craniospinal irradiation; CT, chemotherapy; HP, hypothalamo-pituitary; HPA, hypothalamo-pituitary-adrenal; ITT, insulin tolerance test.

Received December 17, 2002.

Accepted March 31, 2003.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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