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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 12 5969-5975
Copyright © 2003 by The Endocrine Society

Defect in Epinephrine Production in Children with Craniopharyngioma: Functional or Organic Origin?

Régis Coutant, Hélène Maurey, Stéphanie Rouleau, Elisabeth Mathieu, Philippe Mercier, Jean Marie Limal and Anne Le Bouil

Departments of Pediatrics (R.C., H.M., S.R., J.M.L.), Biochemistry (E.M.), Neurosurgery (P.M.), and Pharmacology (A.L.B.), University Hospital, 49000 Angers, France

Address all correspondence and requests for reprints to: Dr. Régis Coutant, Department of Pediatrics, University Hospital, 15 Rue Larrey, 49000 Angers, France. E-mail: recoutant{at}chu-angers.fr.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Despite pituitary hormone replacement, patients with craniopharyngioma often complain of fatigue. They may have deficient control of catecholamine secretion caused by hypothalamic lesion. Another hypothesis is a functional defect in catecholamine production through either glucocorticoid deficiency because high intraadrenal glucocorticoid concentration is necessary for epinephrine synthesis or unrecognized hypoglycemia, which can intrinsically alter epinephrine secretion. We measured catecholamine response to insulin-induced hypoglycemia and orthostasis, and 24-h urinary catecholamine excretion, in 16 children with craniopharyngioma (patients) and 27 sex- and age-matched short children. We also studied the influence of a 4-fold increase in the usual daily dose of hydrocortisone on catecholamine excretion (50 vs. 12 mg/m2 of body surface area) in the glucocorticoid-deficient patients. Last, we compared 24-h continuous sc glucose in patients and 10 sex- and age-matched healthy children. The results are expressed as medians (25th, 75th). For a similar blood glucose nadir after insulin administration, peak plasma epinephrine in response to hypoglycemia was lower in patients vs. controls [420 (120, 715) vs. 730 (460, 1200) ng/liter, P < 0.01], whereas peak plasma norepinephrine was higher [390 (280, 550) vs. 270 (180, 280) ng/liter, P < 0.05]. Catecholamine response to orthostasis did not differ between groups. Urinary epinephrine was significantly lower in patients (P < 0.001), whereas urinary norepinephrine was similar. The extent of epinephrine deficiency correlated with neither tumor size nor hypothalamic involvement. A 4-fold higher hydrocortisone dose did not correct the defective epinephrine excretion in the glucocorticoid-deficient patients. Last, the 24-h sc glucose values were similar between patients and controls. In conclusion, children with craniopharyngioma have a defect in epinephrine but not norepinephrine production. There is no proof of a univocal origin, either organic or functional. Whether abnormal catecholamine secretion alters glucose level during fasting or acute illness, or hampers adaptation to exercise, requires further studies.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
AFTER SURGICAL RESECTION of craniopharyngioma, patients usually have hypopituitarism (1) and, despite adequate replacement with pituitary hormones, they frequently complain of fatigue. Because the hypothalamus is believed to play a role in triggering the release of hormones in response to stress, this lack of resistance may be due to hypothalamic lesion (2).

Hypoglycemia, one of the most frequently used stressors, has been shown to induce a prompt counterregulatory hormone response to recover normal blood glucose level (2, 3). Studies in rats (4, 5, 6) suggest that the ventromedial hypothalamus plays a central role in stimulating epinephrine, norepinephrine, and glucagon responses to hypoglycemia. In humans, the few studies undertaken in patients with hypopituitarism, with or without hypothalamic involvement, have shown divergent results, with most indicating an alteration in catecholamine response to hypoglycemia and others showing a relative preservation of this response. In none of these studies has a clear link with the presence or extent of a hypothalamic lesion been noted (7, 8, 9, 10, 11, 12, 13). A recent study (14) showed that the responses to hypoglycemia of GH, cortisol, epinephrine, norepinephrine, and glucagon were markedly attenuated in a patient with hypothalamic sarcoidosis. An impaired adrenergic response to hypoglycemia was also shown in five of eight adult patients with craniopharyngioma extending to the hypothalamic region, thus supporting the hypothesis of hypothalamic involvement in hypoglycemia-induced activation of the sympathoadrenal axis in humans (15). However, it was unclear why the adrenergic response was spared in three patients, despite similar hypothalamic involvement. In addition, the observation that the noradrenergic and glucagon responses to hypoglycemia were unimpaired in all the study patients was puzzling.

An alternative explanation for these discrepancies may be that the defective adrenergic response to hypoglycemia in patients with pituitary/hypothalamus involvement is of functional origin. High intraadrenal glucocorticoid concentrations are needed to induce the enzymes that drive adrenal catecholamine synthesis, such as phenylethanolamine N-methyltransferase, which converts norepinephrine to epinephrine (9, 16, 17). Patients with Addison’s disease or congenital adrenal hyperplasia have decreased urinary epinephrine excretion, whereas their norepinephrine excretion is either increased or normal (18, 19). Another hypothesis is that patients with hypopituitarism have reduced plasma epinephrine responses owing to mild hypoglycemia because mild hypoglycemia has been shown to intrinsically alter epinephrine secretion (20).

To address these questions, we evaluated the plasma epinephrine and norepinephrine responses to insulin-induced hypoglycemia and orthostasis as well as the 24-h urinary catecholamine excretion in 16 children with craniopharyngioma, 14 of whom had hypothalamic involvement. We then compared these data with those from 27 short sex- and age-matched children. In addition, the 24-h urinary catecholamine excretion was measured in the children with craniopharyngioma and glucocorticoid deficiency while they were taking their usual dose of hydrocortisone (12 mg/m2 body surface area per day) as well as at a 4-fold higher dose (50 mg/m2 body surface area per day). Last, we evaluated whether a continuous sc glucose monitoring system (CGMS) detected asymptomatic hypoglycemia in the children with craniopharyngioma and compared these data with those from 10 healthy sex-, age-, and body mass index (BMI)-matched children.


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

Children with craniopharyngioma. Sixteen children with craniopharyngioma (eight males, eight females) were studied; 14 had undergone transcranial surgery and two, transnasal surgery. They were aged 6.3–15.9 yr [median (25th; 75th), 13.6 (11.0; 14.8) yr]. Fourteen had had a tumor with hypothalamic involvement. Median height was 0.2 (-0.1; 0.6) SD score and median BMI was 0.5 (0.1; 1.8) SD score (21, 22). Surgery had been performed 0–6 yr [0.8 (0.2; 3.3) yr] before the study. Postoperatively, all the children had at least one pituitary hormone deficiency (15 with GH deficiency, 16 with TSH deficiency, 14 with corticotropin deficiency, 15 with certain or probable gonadotropin deficiency, and 13 with diabetes insipidus) and were receiving appropriate hormone replacement therapy.

Control group for catecholamine study. Twenty-seven healthy short children (13 males and 14 females) were studied. They were aged 7.9–15.7 yr [11.6 (10.1; 13.7) yr, P > 0.05 vs. craniopharyngioma group]. These children had primarily been referred for assessment of GH secretion using an insulin tolerance test (ITT) because of short stature and/or decreasing growth velocity. Median height was -2.2 (-2.6; -1.6) SD score and median BMI was -0.9 (-1.4; -0.4) SD score (P < 0.05 vs. craniopharyngioma group for both comparisons). GH deficiency was ruled out (GH peak to the ITT or the arginine-insulin test > 20 mUI/liter). The children were all in good health. None of them had gonadotropin deficiency, hypothyroidism, chromosomal abnormalities, dysmorphic syndromes, skeletal dysplasia, chronic illness, or any endocrine or metabolic disease. None was taking medication.

Control group for CGMS. In a group of 10 healthy children (five males, five females), aged 8.0–14.3 yr [11.6 (9.5; 14.2) yr, P > 0.05 vs. craniopharyngioma group], continuous sc glucose monitoring was performed. Median height was +0.7 (0.0; 1.3) SD score and median BMI was +1.1 (-0.8.; 2.3) SD score (P > 0.05 vs. craniopharyngioma group for both comparisons).

Protocols were approved by our institutional review board. All subjects and families gave their informed consent.

Study design

Insulin-induced hypoglycemia test. A standardized ITT was performed in the children after a physiologic overnight fast. Hormone replacement therapy was not given the morning of the test. After placement of a catheter in a peripheral vein, regular insulin was injected iv at a dose of 0.1 U/kg at 0800 h. Blood samples were collected at time 0, 30, and 60 min for epinephrine, norepinephrine, cortisol, and ACTH measurement and at time 0, 15, 30, 45, 60, and 120 min for GH measurement. Blood was also collected for glucose measurement at time 0, 5, 10, 15, 30, 45, and 60 min. Plasma was stored at -70C until the assays were performed. Blood was also sampled at baseline for measurement of IGF-I, IGFBP3, TSH, free T4, FSH, LH, testosterone, and estradiol.

Urinary specimen collection. Twenty-four-hour urine specimens were obtained for catecholamine measurement, whereas the patients were taking their usual hormone replacement doses. For the 14 children with glucocorticoid deficiency, a 24-h urine specimen was also collected while the patients were taking a 4-fold higher dose of hydrocortisone (oral hydrocortisone 50 mg/m2 body surface area per day four times daily instead of 12 mg/m2 per day three times daily).

Orthostatic test. After the insulin-induced hypoglycemia test, the subjects were allowed to stand up, and after 5 min blood samples were taken for the measurement of plasma catecholamines.

Glucose sensor. The MiniMed (Sylmar, CA) CGMS was used for sc glucose monitoring. The system consists of a sc sensor connected by a cable to a pager-sized glucose monitor. Glucose readings are acquired by the monitor every 10 sec, and an average glucose value is stored in the monitor memory once every 5 min (up to 288 measurements per day). Each glucose sensor provides glucose information for up to 72 h. The stored values in the monitor are downloaded by the MiniMed Com-Station and presented in graphical and statistical form via a computer program. While using the CGMS, the test participants had to perform at least six blood glucose self-monitoring (SBGM) tests per day (three before meals, three 1–2 h after meals) and enter these values into the CGMS monitor. All blood glucose self-monitoring tests were performed using the One Touch Ultra meter and One Touch Ultra glucose strips (Lifescan, Inc., Milpitas, CA).

Magnetic resonance imaging (MRI). Pituitary MRI was performed with a 0.5-tesla superconductive system with a head coil, a 256 x 256 reconstruction matrix and a 20-cm field of view. T1-weighted images (spin echo repetition x 400, echo x 200) were obtained in the sagittal and coronal planes using 3-mm sections for determination of tumor size.

Assays

Plasma epinephrine and norepinephrine were measured by HPLC with electrochemical detection, as described (23, 24). Sensitivity was 50 ng/liter (0.27 nmol/liter), and the intra- and interassay coefficients of variation were less than 5% and 10%, respectively, at every level. Serum GH was measured by immunoradiometric assay (Immunotech/Beckman Coulter, Villepinte, France). Sensitivity was 0.05 µg/liter, and the intra- and interassay coefficients of variation were 1.5% and 14.03%, respectively. The GH results are expressed in IRP 66/217 U, for which 2 mU = 1 µg. Plasma ACTH was measured by immunoradiometric assay (Nichols Institute, San Juan Capistrano, CA). Sensitivity was 1 ng/liter (0.22 pmol/liter), and the intra- and interassay coefficients of variation were 3.7% and 5.1%, respectively. Serum cortisol was measured by electrochemiluminescence immunoassay on the Elecsys System 2010 (Roche Diagnostics, Mannheim, Germany). Sensitivity was 1 nmol/liter and the intra- and interassay coefficients of variation were 1% and 5.5%, respectively. Plasma glucose was measured with a Hitachi 917 analyzer (Roche Diagnostics Co., Meylan, France).

Urinary epinephrine and norephinephrine, urinary dopamine, and urinary catecholamine metabolite (vanillylmandelic acid) were measured by HPLC with electrochemical detection, as described (25). Detection limits for epinephrine, norephinephrine, dopamine, and vanillylmandelic acid were 1 µg/liter (5.5 nmol/liter), 1 µg/liter (5.9 nmol/liter), 10 µg/liter (63 nmol/liter), and 0.25 mg/liter (1.25 µmol/liter), respectively. Intra- and interassay coefficients of variation for catecholamines and their metabolites were less than 3% and 7%, respectively.

All samples were assayed in duplicate.

Statistics

Data are presented as medians (25th percentile; 75th percentile). The slope of the increase in plasma glucose was calculated by least square analysis from the glucose concentrations between 15 and 60 min after insulin injection during the ITT. The Mann-Whitney U test and Wilcoxon signed-rank test were used for comparison between groups. Spearman’s rank-order correlations were performed, with plasma catecholamine peak in response to ITT as the studied variable. P < 0.05 was considered significant. Statistical tests were performed with the SPSS 9.0 statistical package (SPSS, Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Insulin-induced hypoglycemia

The median glucose value at baseline was 4.3 (3.9; 4.9) mmol/liter in the craniopharyngioma group and 4.6 (4.3; 4.9) mmol/liter in the control group (NS). The glucose nadir was observed at 15 min and was similar in the two groups [1.8 (1.6; 2.3) vs. 1.6 (1.3; 2.1) mmol/liter, craniopharyngioma vs. controls, NS]. All subjects recovered spontaneously from hypoglycemia; however, the slope of the increase in plasma glucose concentration from 15 to 60 min after iv insulin injection was lower in the craniopharyngioma group [+ 0.037 (0.029; 0.042) vs. + 0.054 (0.042; 0.057) mmol/liter·min, P = 0.001]. This was likely related to the defect in counterregulatory hormone secretion in these patients.

Plasma catecholamines during ITT

There was no difference in baseline plasma epinephrine between the two groups. Peak plasma epinephrine was lower in the craniopharyngioma group, compared with controls (P < 0.01) (Table 1Go and Fig. 1Go). Hypoglycemia caused a 4.1 (1.2; 7.1)-fold increase in plasma epinephrine in the craniopharyngioma group, compared with a 6.9 (3.6; 11.7)-fold increase in the control group (P < 0.05). By contrast, peak plasma norepinephrine was significantly higher in the craniopharyngioma group (P < 0.05) (Table 1Go, Fig. 1Go), whereas baseline plasma norepinephrine was marginally higher in this group: 220 (150, 410) vs. 180 (130, 270) ng/liter [1.30 (0.89; 2.43) vs. 1.06 (0.77; 1.60) nmol/liter] (P = 0.09). Hypoglycemia caused a 1.4 (1.1; 1.9)-fold increase in plasma norepinephrine in the craniopharyngioma group, compared with a 1.4 (1.2; 1.8)-fold increase in the control group (NS).


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  		TABLE 1. Plasma and urinary catecholamines in patients with craniopharyngioma and controls

 


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  		FIG. 1. Plasma epinephrine and norepinephrine peaks in response to an insulin tolerance test in children with craniopharyngioma and controls. Boxes indicate 25th and 75th percentiles, with the horizontal line representing the median value. a, P < 0.001 vs. craniopharyngioma group. b, P < 0.05 vs. craniopharyngioma group. To convert values to nanomoles per liter, divide by 183 for epinephrine and 169 for norepinephrine.

 
Other hormones during ITT

Peak plasma GH, ACTH, and cortisol were lower in the craniopharyngioma group, compared with the control group (P < 0.001 for all comparisons).

Orthostatic test

Orthostasis caused a 2.0 (1.4; 2.6)-fold increase in plasma norepinephrine in the craniopharyngioma group, compared with a 1.9 (1.6; 2.2)-fold increase in the control group (NS); there was no detectable change in plasma epinephrine in either group.

Urinary catecholamines and their metabolites

Urinary epinephrine excretion, expressed as amount per day per unit of body surface area, was lower in the craniopharyngioma group, compared with the control group (P < 0.001) (Table 1Go). There was no difference in urinary norepinephrine excretion between groups (Table 1Go). Urinary dopamine and vanillylmandelic acid were lower in the craniopharyngioma patients (P < 0.05 for both comparisons) (Table 1Go). All these differences remained significant when the urinary catecholamines and their metabolites were expressed as amounts per gram of creatinine.

Relationships between catecholamine responses to ITT and clinical and biological variables

There was no correlation between the peak plasma epinephrine or norepinephrine response to ITT and age, gender, height SD score, or BMI SD score in either patients or controls. There was no correlation between the peak plasma epinephrine or norepinephrine response to ITT and tumor height or width as measured by MRI. The two children who had had a tumor with no hypothalamic involvement had a low plasma epinephrine response to hypoglycemia.

In the control group, there were positive relationships between the peaks of plasma epinephrine and plasma norepinephrine ({rho} = 0.51, P < 0.01), plasma ACTH ({rho} = 0.37, P < 0.05), and plasma cortisol ({rho} = 0.38, P < 0.05) in response to ITT, thus suggesting a link between catecholamine and cortisol productions. These relationships were not seen in the craniopharyngioma group (Fig. 2Go).



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  		FIG. 2. Significant simple correlations between peaks of plasma epinephrine in response to ITT and plasma norepinephrine ({rho} = 0.51, P < 0.01), plasma ACTH ({rho} = 0.37, P < 0.05), and serum cortisol ({rho} = 0.38, P < 0.05) in controls ( ). No correlation was seen between these variables in the children with craniopharyngioma ({blacksquare}). To convert values to nanomoles per liter, divide by 183 for epinephrine and 169 for norepinephrine. To convert values to picomoles per liter, divide by 4.54 for ACTH.

 
Urinary catecholamine excretion after increase in hydrocortisone dose

We investigated whether a 1-d higher hydrocortisone dose (50 mg/m2·d instead of 12 mg/m2·d) in glucocorticoid-deficient patients (n = 14) would reverse the defect in epinephrine synthesis: No difference in urinary epinephrine [3.2 (1.3; 5.5) vs. 4.4 (2.0; 7.1) µg/d·m2; 17.5 (7.1; 30.0) vs. 24.0 (10.9; 38.8) nmol/d·m2], norepinephrine [13.1 (10.0; 20.1) vs. 15.1 (13.3; 30.6) µg/d·m2; 77.4 (59.1; 118.8) vs. 89.2 (786.0; 181.8) nmol/d·m2], or dopamine [130 (95, 195) vs. 150 (120, 204) µg/day·m2; 849 (620; 1273) vs. 980 (784; 1332) nmol/day·m2] excretion was seen after the 4-fold increase in hydrocortisone (increased dose vs. usual dose, NS for all comparisons).

CGMS

Median 24-h blood glucose and median individual SD for 24-h blood glucose measurements were 4.7 (4.4; 5.1) mmol/liter and 1.0 (0.9; 1.3) mmol/liter in patients, compared with 4.7 (4.5; 5.1) mmol/liter and 1.0 (0.9; 1.1) mmol/liter in controls (NS). Median nocturnal blood glucose (between 2200 and 0600 h) and median individual SD for nocturnal blood glucose measurements were 4.6 (4.1; 4.7) mmol/liter and 0.9 (0.6; 1.2) mmol/liter in patients, compared with 4.1 (3.9; 4.3) mmol/liter and 0.6 (0.5; 0.8) mmol/liter in controls (NS).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study showed that the epinephrine response to insulin-induced hypoglycemia was decreased in children with craniopharyngioma, in agreement with the lower 24-h urinary epinephrine excretion in these children, compared with controls: This likely indicates a defect in adrenal medulla function. Conversely, the norepinephrine response to hypoglycemia was increased in the patients, whereas the 24-h urinary norepinephrine excretion was spared. No difference in catecholamine response to orthostasis was seen between groups. According to a lesional hypothesis, an alteration in the hypothalamic locus involved in hypoglycemia detection would explain the decrease in the epinephrine response to hypoglycemia. However, the discrepancies between the epinephrine and norepinephrine responses to hypoglycemia do not favor this explanation. In addition, no correlation between the extent of epinephrine deficiency and tumor size or hypothalamic involvement was found. According to a functional hypothesis, low intraadrenal glucocorticoid concentration could alter epinephrine synthesis. Although significant correlations between cortisol and peak epinephrine response to hypoglycemia were found in controls, they were not observed in patients. However, a 4-fold increase in hydrocortisone dose was not able to restore the daily epinephrine excretion in children with craniopharyngioma and glucocorticoid deficiency. Another functional hypothesis is that mild hypoglycemia alters the epinephrine secretion. Although the slope of blood glucose recovery during insulin-induced hypoglycemia was lower in the children with craniopharyngioma, mean sc glucose, both daily and nocturnal, was similar in patients and controls in normal settings.

In animals, brain hypoglycemia induced the release of epinephrine, norepinephrine, and glucagon (26, 27). In rats, ventromedial hypothalamic lesion prevented this release, whereas local ventromedial hypothalamus glucose perfusion blocked counterregulation during systemic hypoglycemia (5, 6). In dogs, selective hypoglycemia in the anterior and posterior brain regions was able to induce counterregulation (28). Overall, these data support the implication of the hypothalamus in hypoglycemia detection; however, this may not be the sole site involved in triggering the release of counterregulatory hormones in response to hypoglycemia.

We found that the epinephrine response to insulin-induced hypoglycemia and the 24-h urinary epinephrine excretion were reduced by about half in the children with craniopharyngioma, compared with controls. Because circulating epinephrine originates mainly in the adrenal medulla, this likely demonstrates an alteration in adrenomedullary function in these children (29). Urinary vanillylmandelic acid, which arises from epinephrine and norepinephrine catabolism through monoamine oxidase and catechol O-methyltransferase actions, and urinary dopamine were also decreased in our children with craniopharyngioma. Because norepinephrine and dopamine partly originate in the adrenal medulla, this may indicate a defect in its function; however, they also arise from widespread regions of the central nervous system and the sympathetic or dopaminergic peripheral nervous system, so the hypothesis of decreased metabolism of these amines in the nervous system remains possible (29). An alteration in epinephrine response to ITT has been reported in adults with craniopharyngioma (15) and in a single patient with hypothalamic sarcoidosis (14), suggesting that hypothalamic centers are involved in hypoglycemia-induced activation of the sympatho-adrenal axis. However, it has also been described in most patients with hypopituitarism of congenital (7, 8, 12) or acquired origin (10, 11, 13), with no obvious hypothalamic involvement, although not in every case (10). In our patients, the epinephrine defect was not related to tumor size or hypothalamic involvement. As a whole, these data are insufficient to prove hypothalamic involvement in altered epinephrine production.

The norepinephrine response to hypoglycemia changed in the opposite direction in our patients with craniopharyngioma because we observed an increase in baseline and peak norepinephrine response to ITT, whereas no change in daily urinary norepinephrine excretion was seen. Similar findings have been described in patients with Sheehan’s syndrome (11), whereas norepinephrine response to hypoglycemia and/or daily norepinephrine excretion were preserved in most studies in patients with hypopituitarism (7, 9, 10, 12, 13). In only one patient suffering from hypothalamic sarcoidosis was norepinephrine response decreased (14). In contrast, in animal models of hypothalamic lesion or selective prevention of brain hypoglycemia, both norepinephrine and epinephrine responses to insulin-induced hypoglycemia were consistently impaired (4, 5, 6, 27, 28). Therefore, the discrepancies between epinephrine and norepinephrine responses to hypoglycemia generally seen in humans with hypopituitarism, whether there is a hypothalamic lesion, do not strongly support the hypothesis of the hypothalamus as the primary site for defective counterregulation.

Circulating norepinephrine originates mainly in the sympathetic nervous system and then from the adrenal medulla (29). The response of norepinephrine to acute hypoglycemia, however, is believed to derive largely from the adrenal medulla, whereas the norepinephrine response to upright position mainly reflects sympathetic nervous system activity (29, 30, 31). In our children with craniopharyngioma, as in adults, the norepinephrine response to upright position was conserved (15). Actually, in these children both the higher plasma norepinephrine response to hypoglycemia contrasting with the decreased epinephrine response and the preserved urinary norepinephrine excretion contrasting with the decreased urinary epinephrine recall the observations in subjects with adrenal disease.

In patients with autoimmune Addison’s disease or isolated glucocorticoid deficiency, plasma norepinephrine concentration, norepinephrine:epinephrine ratio, norepinephrine response to upright position, or norepinephrine excretion tended to be higher than that of controls (18, 32, 33). Experimental studies have shown that phenylethanolamine N-methyltransferase, the enzyme that converts norepinephrine to epinephrine, is induced by high intraadrenal glucocorticoid concentrations (17, 34, 35), therefore supporting a high adrenomedullary norepinephrine:epinephrine ratio in cases of glucocorticoid deficiency. However, intraadrenal glucocorticoid has also been shown to be involved in earlier steps of epinephrine synthesis, such as activation of tyrosine hydroxylase and dopamine-ß-hydroxylase, and studies of adrenal tissue have shown a decrease in content of both norepinephrine and epinephrine in animals and humans with glucocorticoid deficiency, such as in adrenal hyperplasia (19, 36, 37, 38). By contrast, subjects with adrenalectomy had higher plasma and urinary norepinephrine concentrations than controls (19, 31). Overall, these results favor the hypothesis of compensatory increases in sympathetic nerve activity and norepinephrine secretion to overcome an adrenomedullary defect. The similarities in catecholamine changes in subjects with primary adrenal disease and our children with craniopharyngioma suggest that the catecholamine defect in the latter might originate from the adrenal medulla, likely secondary to glucocorticoid deficiency, whereas sympathetic nervous system activity is preserved.

A positive correlation between peak epinephrine and peak cortisol and ACTH responses to hypoglycemia was found in the controls, thus supporting the hypothesis of a link between adrenocortical and medullary functions (36, 39). However, there was no clear association between the cortisol and epinephrine deficiencies in the children with craniopharyngioma (see Fig. 2Go). In addition, no change in catecholamine excretion was seen after a 4-fold increase in hydrocortisone dose in the glucocorticoid-deficient children. One study in children with isolated GH deficiency or hypopituitarism found epinephrine deficiency only in the hypocorticotropic subjects, and this was not corrected by the usual glucocorticoid replacement dose (9). Because cortisol concentration in adrenal veins was shown to be 4–8 times higher than that in peripheral veins, it is possible that the 4-fold increase in hydrocortisone dose for 1 d was insufficient to increase intraadrenal cortisol concentration enough to reverse the defect in epinephrine production (40). At the very least, this indicates that increasing the hydrocortisone dosage, as is done during stress or infectious disease, is not a simple way to reverse the epinephrine defect. Alternatively, it remains possible that intraadrenal glucocorticoid deficiency is not finally involved in the epinephrine defect.

We observed a failure in blood glucose recovery after insulin-induced hypoglycemia in the children with craniopharyngioma. A rapid counterregulation of glucose is believed to depend on glucagon and epinephrine responses, whereas GH and cortisol have a delayed effect on blood glucose (41). The epinephrine defect was therefore quite likely involved in the lower blood glucose recovery. We did not measure glucagon in this study; hence, its role remains to be determined. In adults with craniopharyngioma, no deficiency in glucagon response to hypoglycemia was found (15). It is noteworthy that hypoglycemia itself may alter counterregulation (20, 42). In healthy humans, moderate hypoglycemia (2.9 mmol/liter for 2 h) significantly blunted the epinephrine, norepinephrine, glucagon, cortisol, and GH responses to a subsequent hypoglycemia induced 2 h later (42). In our study, however, we did not find any difference in 24-h continuous sc glucose between children with craniopharyngioma and controls matched for age, gender, and BMI. This indicates that mild unrecognized hypoglycemia probably did not generally contribute to the epinephrine defect in the children with craniopharyngioma and that the defect in counterregulatory hormones in these same children did not induce hypoglycemia in normal settings. This result does not preclude the possibility of hypoglycemia during fasting or intercurrent illness.

In this study, patients and controls were matched for age and sex because both variables were associated with changes in the sympathoadrenal system (43). The BMI was different between children with craniopharyngioma and short children used as controls for catecholamine measurements: Median BMI was 0.5 SDs in craniopharyngioma vs. -0.9 SD in controls. This difference may hamper the interpretation of our findings because BMI might influence catecholamine secretion. However, we found no relationship between catecholamine response to ITT or catecholamine excretion and BMI in either patients or controls. Conflicting data have been published about catecholamine secretion in relation to fat mass. According to some authors, obesity was associated with a lower baseline concentration of norepinephrine and a failure to increase norepinephrine, not epinephrine, in response to insulin-induced hypoglycemia (44, 45), whereas we observed the opposite response in the children with craniopharyngioma. Others have shown a similar catecholamine response to hypoglycemia in obese and lean subjects (46). Similarly, urinary epinephrine and norepinephrine have been found to be increased, normal, or reduced in obese subjects (47, 48). In our study, the children with craniopharyngioma were not markedly obese, and we believe that the differences in catecholamine production between these children and the controls are valid.

In conclusion, our data indicate that children with craniopharyngioma have a defect in epinephrine production, whereas norepinephrine production is either increased or normal. No single origin, either organic or functional, could account for these abnormalities: 1) They were not related to tumor size or hypothalamic involvement; 2) they were not present only in children with cortisol deficiency nor were they corrected by a 4-fold increase in the usual hydrocortisone dose; and 3) they were not associated with hypoglycemia in normal settings. To determine whether the abnormalities in catecholamine secretion alter blood glucose level during fasting or acute illness, or hamper adaptation to exercise, will require further study.


   Acknowledgments
 
The authors thank Anne Liger, Claire Baril, Sophie Dublé, and Martine Chiffoleau, who provided care to the subjects who participated in the study.


   Footnotes
 
Abbreviations: BMI, Body mass index; CGMS, continuous sc glucose monitoring system; ITT, insulin tolerance test; MRI, magnetic resonance imaging.

Received March 31, 2003.

Accepted August 24, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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S. Morita, M. Otsuki, M. Izumi, N. Asanuma, S. Izumoto, Y. Saitoh, T. Yoshimine, and S. Kasayama
Reduced epinephrine reserve in response to insulin-induced hypoglycemia in patients with pituitary adenoma
Eur. J. Endocrinol., September 1, 2007; 157(3): 265 - 270.
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