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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 6 1995-1998
Copyright © 1997 by The Endocrine Society

Pediatric Endocrinology

Testing the Hypothalamic-Pituitary-Adrenal Axis in Survivors of Childhood Brain and Skull-Based Tumors1

R. Ravi Shankar, Regina I. Jakacki, Anzar Haider, Melissa W. Lee and Ora Hirsch Pescovitz

Department of Pediatrics, Sections of Endocrinology and Diabetology (R.R.S., A.H., O.H.P.) and Hematology-Oncology (R.I.J., M.W.L.), James Whitcomb Riley Hospital for Children, Indiana University Medical Center, Indianapolis, Indiana 46202-5225

Address all correspondence and requests for reprints to: Ora H. Pescovitz, M.D., Departments of Pediatrics, Physiology, and Biophysics, Riley Hospital for Children, Room 5984, 702 Barnhill Drive, Indianapolis, Indiana 46202-5225. E-mail: ora_pescovitz{at}iucc.iupui.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 Note Added in Proof
 References
 
The objective of this study was to determine whether a low dose of ACTH (0.2 µg/kg) improves the sensitivity of ACTH testing in detecting hypothalamic-pituitary-adrenal (HPA) axis abnormalities in survivors of childhood brain and skull-based tumors.

Twenty-two children who had undergone treatment for brain or skull-based tumors were enrolled in a prospective study to extensively evaluate the HPA axis. Five tests of the adrenal axis were evaluated in each patient, including determination of basal serum cortisol, a standard ACTH test (250-µg iv bolus), a low dose ACTH test (0.2 µg/kg iv bolus), an insulin tolerance test, and a single dose metyrapone test.

Cortisol responses to both ACTH tests were nearly identical. Two patients (9%) failed the low dose ACTH test, whereas three (14%) failed the standard ACTH test; five of the children (23%) failed the insulin tolerance test, and five (23%) had abnormal responses to metyrapone. One child who initially passed the metyrapone test failed the test 19 months later after becoming symptomatic. All children with abnormal metyrapone test results had low levels of basal cortisol secretion.

In this study, the low dose ACTH test did not improve the sensitivity of ACTH testing for evaluation of the HPA axis. We conclude that a single morning basal cortisol level is a good screen for testing the HPA axis in children. We recommend confirming HPA axis dysfunction with the single dose metyrapone test, although this test also has limitations.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 Note Added in Proof
 References
 
AS SURVIVAL after treatment for childhood brain tumors improves (1), it has become obvious that neuroendocrine deficiencies are important contributors to long term morbidity (2, 3, 4, 5, 6). GH deficiency (7, 8, 9, 10), secondary and tertiary forms of hypothyroidism (11, 12, 13), and both precocious puberty and hypogonadotropic hypogonadism have been commonly reported (12, 13, 14, 15, 16, 17). However, abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis are rare (6, 10, 12). This may be attributed to the diagnostic difficulty in evaluating the HPA axis.

Of the various stimulatory tests of the HPA axis, the ACTH stimulation test is the most commonly used. It is simple to perform and generally reproducible. In primary adrenal insufficiency, when the gland is completely destroyed or is incapable of responding to ACTH, this test is clearly valuable. Although it is counterintuitive to use ACTH as a stimulus to assess ACTH secretion, this procedure has been employed extensively in the past. The rationale for this lies in the belief that chronic ACTH deficiency will result in atrophy of the adrenal cortex and subsequent inability to secrete cortisol in response to a single ACTH bolus. The reliability of this method is suspect, however, because the test rarely identifies ACTH deficiency even in patients who have evidence of multiple other hypothalamic-pituitary axis abnormalities. We hypothesized that the standard ACTH test is insensitive, especially in children, because the dose of ACTH used is excessive. The levels of ACTH achieved after a bolus of 1 µg/kg are 10 times higher than those reached during insulin-induced hypoglycemia (18). A much lower dose of ACTH (0.2 µg/kg) has been reported to result in integrated serum ACTH levels that more closely approximate levels achieved during insulin tolerance testing (18).

We hypothesized that this lower dose of ACTH would be more sensitive than the standard ACTH test in detecting complete or partial ACTH deficiency, thus providing a simple, but sensitive and specific, test to evaluate the HPA axis. To test this hypothesis, we compared the low dose ACTH test with four other established tests of the HPA axis in children treated for brain or skull-based tumors.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 Note Added in Proof
 References
 
Subjects

Twenty-two children who had undergone either surgical resection and/or radiation therapy involving the hypothalamic-pituitary region for a brain or skull-based tumor were enrolled (Table 1Go). Eighteen subjects had received 3600 centigray units or more to the hypothalamic-pituitary region as part of their treatment, and 12 children had received chemotherapy. Radiotherapy was completed 16–167 months (mean, 48 months) before enrollment. Four children underwent surgical resection without radiotherapy for tumors of the pituitary gland a median of 11 months before the study (Table 1Go). All subjects were documented to be euthyroid at the time of entry into the study.


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  		Table 1. Patient characteristics and tests of hypothalamic-pituitary-adrenal axis

 
Procedures and interpretation

The protocol was approved by the institutional review board of the Indiana University Medical Center. After obtaining informed consent from the parent or legal guardian and assent from the child, the subjects were admitted to the General Clinical Research Center of the Indiana University Medical Center at 0700 h for the 2-day protocol. Five tests of the adrenal axis were evaluated in each patient, including determination of basal serum cortisol, low dose ACTH test (0.2 µg/kg iv bolus), standard ACTH test (250-µg iv bolus), insulin tolerance test (ITT), and a single dose metyrapone test. Interpretation of these tests as pass, fail, or invalid was based on published and/or Indiana University Medical Center laboratory standards. A pass for basal cortisol was a level of 248 nmol/L (9 µg/dL) or more; for the low dose ACTH test, it was a cortisol level of 496 nmol/L (18 µg/dL) or more; for the standard ACTH stimulation test, it was a cortisol level of 496 nmol/L (18 µg/dL) or more (19); for the ITT, it was a serum cortisol level of 496 nmol/L (18 µg/dL) or more (20). If the serum glucose values did not fall to 2.2 mmol/L (40 µg/dL) or less, the test was considered invalid. For the metyrapone test (21, 22), a compound S level of 115 nmol/L (4 µg/dL) or more was interpreted as indicative of a pass, and the test was considered invalid when the compound S level was < 115 nmol/L (4 µg/dL), but the serum cortisol level had been inadequately suppressed [cortisol level, >138 nmol/L (5 µg/dL)].

Determinations

Cortisol was measured by enzyme-linked immunoassay (Abbott Laboratories, North Chicago, CA) at the endocrine laboratory of the Indiana University Medical Center. The lower limit of detection was 27.6 nmol/L (1 µg/dL). At cortisol levels between 110-1100 nmol/L (4 and 40 µg/dL), the interassay coefficient of variance was 4.9%, and the intraassay coefficient of variance was 4.7%. Compound S (11-deoxycortisol) was determined in the carbon tetrachloride extract by competitive protein binding assay (Mayo Medical Laboratory, Rochester, MN). The lower limit of detection was 2.9 nmol/L (0.1 µg/dL). The average interassay coefficient of variance was 13% at a compound S level of 66.4 nmol/L (2.3 µg/dL).

Statistical analysis

Data are expressed as the mean ± SEM unless otherwise stated. The statistical analyses were performed using the Statview 4.0 package for Macintosh computers. Student’s t test was used to compare responses to the tests in children with pituitary and nonpituitary tumors. Linear regression analyses and ANOVA were used to correlate the results of the tests studied with the dose of radiation, the use of chemotherapeutic agents, and the individual diagnoses.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 Note Added in Proof
 References
 
The results of the five tests of the HPA axis are shown in Table 1Go. Children with pituitary tumors had significantly lower responses to all tests compared to children with other tumors (P < 0.05; data not shown) and the correlation of cortisol responses to the low dose ACTH test with the dose of radiation to the pituitary gland approached statistical significance (r2 = 0.25; P = 0.058). There was no apparent effect of chemotherapy on the responses to these tests.

The peak cortisol response to the low dose ACTH test was not different from that to the standard ACTH test. In fact, the cortisol responses to the two ACTH tests were nearly identical in most patients. Linear regression analysis correlating the results of the two tests indicated an r2 of 0.92 (P < 0.0001).

Of the eight children with low basal serum cortisol levels, five failed the metyrapone test, and one had symptoms compatible with adrenal insufficiency. The mean basal serum cortisol levels of these five children was 78 ± 16.5 nmol/L (2.8 ± 0.6 µg/dL). Two of these subjects failed all of the other tests. Two of them failed the ITT [cortisol, 268 and 287 nmol/L (9.7 and 10.4 µg/dL), respectively], but had normal responses to both the low dose [cortisol, 557 and 723 nmol/L (20.2 and 26.2 µg/dL)] and standard [cortisol, 618 and 759 nmol/L (22.4 and 27.5 µg/dL)] ACTH tests. One child passed the ITT and low dose ACTH test, but failed the standard ACTH test. There was one child who failed the ITT and had a low basal cortisol level (138 nmol/L; 5.0 µg/dL), who unequivocally passed the metyrapone test [compound S, 232 nmol/L (8.0 µg/dL)], the low dose ACTH test [cortisol, 990 nmol/L (35.9 µg/dL)], and the standard ACTH test [cortisol, 943.5 nmol/L (34.2 µg/dL)]. These five children were all treated with glucocorticoid replacement therapy.

One child, who had initially passed the metyrapone test [compound S, 129 nmol/L (4.9 µg/dL)] as well as the other tests developed symptoms compatible with acute glucocorticoid insufficiency 19 months after the initial evaluation. A repeat single dose metyrapone test was indicative of HPA axis abnormality [cortisol, <27.6 nmol/L (1 mg/dL); compound S, 103 nmol/L (3.6 µg/dL)]. She was started on glucocorticoid replacement therapy and achieved prompt resolution of her symptoms.


   Discussion
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
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 References
 
Of the tests available to evaluate the HPA axis, many investigators regard the ITT as the gold standard test of stress-induced adrenal responsiveness (20, 23, 24, 25). The advantages of this test include the physiological stress stimulus caused by hypoglycemia on the HPA axis and its usefulness in simultaneously evaluating GH secretion. The main disadvantage of this test, especially in the pediatric population, is that it must be performed under the close supervision of medical staff who can monitor and render emergency care in the case of severe hypoglycemia. Thus, the development of a simple, safe, and accurate test would be useful in evaluating children at risk for HPA axis dysfunction.

The ACTH stimulation test is a very simple procedure, but its usefulness in assessing the HPA axis has not been definitively established (26, 27, 28). We hypothesized that the standard dose of ACTH might be excessive in most children and, therefore, would translate into a test with low sensitivity. We postulated that using a lower, more physiological dose of ACTH would improve the test’s predictive value. The data generated in this study do not support this hypothesis because the cortisol responses to both ACTH doses were nearly identical.

Graybeal and Fang demonstrated that an ACTH dose of 0.2 µg/kg resulted in peak ACTH levels that were much higher than those seen during the ITT, even if the ACTH dynamics and area under the curve were close to those achieved after insulin-induced hypoglycemia (19). Thus, it is possible that the low dose ACTH test may still not be low enough. Recent observations confirm this. Broide et al. found that 16 of 46 patients treated with chronic inhaled corticosteroids had peak serum cortisol levels less than 18.1 µg/dL when stimulated with 0.5 µg/1.73 m2 ACTH, whereas all but one of these subjects were able to achieve peak serum cortisol levels of 18.1 µg/dL or more when a standard dose of ACTH (250 µg/1.73 m2) was used (29). Tordjman et al. compared the peak serum cortisol levels achieved after a challenge with 1 µg ACTH with those achieved after 250- and 5-µg boluses of ACTH (30). They found 100% sensitivity with the 1-µg test in identifying subjects with HPA axis dysfunction, but only 10% sensitivity with the 250-µg test.

The standard metyrapone test is a rather cumbersome test, in which the patient is required to ingest a dose of meytrapone every 4 h for 24 h before measuring compound S and cortisol levels. However, in a modification of this test, metyrapone is given once (between 2300 h and midnight), followed by the measurement of serum cortisol 8 h later (21). As this method appears to be as effective as the longer metyrapone test (31, 32, 33), we chose to use the simpler, single dose metyrapone test. It has been suggested that metyrapone testing identifies more children with secondary or tertiary adrenal insufficiency than the ITT (34, 35, 36) and may be particularly useful in detecting minor degrees of pituitary suppression that would be unrecognized by insulin-induced hypoglycemia (31, 32). Unlike the ITT, the single dose test is relatively easy to perform and carries little risk. The single most important drawback of the metyrapone test in our study was that a significant number of children (35%) experienced nausea and/or vomiting. This resulted in inadequate dosage delivery and, consequently, an invalid test in 18% of our subjects.

Despite this, the number of children with HPA axis abnormalities identified by the metyrapone test in our study is high and is similar to that reported by Constine et al. (10). Four of the five children who failed the metyrapone test had tumors of the pituitary gland, and the fifth had a visual pathway glioma treated with 6000 centigray units of radiation. In addition, these children had evidence of other hypothalamic-pituitary hormone dysfunction (hypothyroidism, n = 5; GH deficiency, n = 4; hypogonadotropic hypogonadism, n = 2; precocious puberty and diabetes insipidus, n = one each).

Some investigators have considered a normal response to ACTH to be a peak cortisol level of more than 552 nmol/L (20 µg/dL) rather than 496 nmol/L (18 µg/dL). Using these criteria, two children who passed the low dose ACTH test and one child who passed the standard ACTH test would be recategorized as failures. Even so, both ACTH tests would only allow identification of three of the five children who failed the metyrapone test. However, if the lower limits of normal cortisol response were increased to 688 nmol/L (25 µg/dL), the ACTH test would have identified four of the five who failed the metyrapone test. All of the children who passed the metyrapone test had peak cortisol levels of more than 688 nmol/L (25 µg/dL) in response to both ACTH tests.

Our study is not without flaws. Ideally, the five tests of the HPA axis should have been administered in random order. However, we chose to perform the high dose ACTH test in the morning and the low dose ACTH test in the afternoon because we reasoned that the higher dose of ACTH might deplete pituitary ACTH stores, thereby increasing the likelihood of failure to respond to the low dose test. The fact that there was nearly perfect correlation between the responses to the two tests supports the validity of the study design.

In summary, in this study, neither the low dose nor the standard ACTH test was a useful diagnostic study because patients with evidence of ACTH deficiency passed these tests. A recent publication in this journal highlights the potential for serious consequences from misinterpreting normal responses to ACTH testing, thus supporting this position (37). Despite yielding a high number of invalid test results, a single dose metyrapone challenge seems to be a very good test for evaluating ACTH and CRH reserve. Until better diagnostic methods can be designed, we suggest measuring basal serum cortisol as a screening test for HPA axis dysfunction. For subjects with basal serum cortisol levels below 248 nmol/L (9 µg/dL), a metyrapone test should be performed to confirm HPA axis dysfunction. If the compound S level is 115 nmol/L (4 µg/dL) or more, the child can be classified as having a normal HPA axis at the time of testing (Fig. 1Go).



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  		Figure 1. Algorithm for the follow-up of children at risk for developing secondary or tertiary adrenal insufficiency [cortisol, 1 µg/dL (27.6 nmol/L); compound S, 1 µg/dL (28.9 nmol/L)].

 

   Note Added in Proof
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Note Added in Proof
References
 
Oberfield et al. reported abnormal peak cortisol responses in 12 of 17 children treated with cranial or craniospinal irradiation for acute leukemia or CNS tumors when tested with ovine corticotropin-releasing factor (Oberfield SE, Nirenberg A, Allen JC, et al. 1997 Hypothalamic-pituitary-adrenal function following cranial irradiation. Horm Res. 47:9–16).


   Acknowledgments
 
The authors thank Dr. Joseph F. Montebello, Department of Radiation Oncology, Indiana University PUI (Indianapolis, IN).


   Footnotes
 
1 This work was supported by Riley Memorial Association Grant 92–12 (to R.I.J.), General Clinical Research Grant NIHM01750 and American Cancer Society Institutional Research Grant IRG-161 F (to R.I.J.). Presented in part at the 63rd Annual Meeting of the SPR, Seattle, WA, May 1994 [Pediatr Res 1994;35:100A (Abstract 586)] Back

Received December 12, 1996.

Revised February 27, 1997.

Accepted March 6, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Note Added in Proof
 References
 

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