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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 8 3679-3684
Copyright © 2004 by The Endocrine Society

Special Feature

Stress Dose of Hydrocortisone Is Not Beneficial in Patients with Classic Congenital Adrenal Hyperplasia Undergoing Short-Term, High-Intensity Exercise

Martina Weise, Bart Drinkard, Sarah L. Mehlinger, Stuart M. Holzer, Graeme Eisenhofer, Evangelia Charmandari, George P. Chrousos and Deborah P. Merke

Pediatric and Reproductive Endocrinology Branch (S.L.M., S.M.H., E.C., G.P.C., D.P.M.), Developmental Endocrinology Branch (M.W.), National Institute of Child Health and Human Development, The Warren Grant Magnuson Clinical Center (B.D., D.P.M.) and Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke (G.E.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Deborah P. Merke, M.D., National Institutes of Health Clinical Center, Building 10, Room 13S260, 10 Center Drive MSC 1932, Bethesda Maryland 20892-1932. E-mail: dmerke{at}nih.gov.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Classic congenital adrenal hyperplasia (CAH) is associated with impaired function of the adrenal cortex and medulla leading to decreased production of cortisol and epinephrine. As a result, the normal exercise-induced rise in blood glucose is markedly blunted in such individuals. We examined whether an extra dose of hydrocortisone, similar to that given during other forms of physical stress such as intercurrent illness, would normalize blood glucose levels during exercise in patients with CAH. We studied hormonal, metabolic, and cardiorespiratory parameters in response to a standardized high-intensity exercise protocol in nine adolescent patients with classic CAH. Patients were assigned to receive either an additional morning dose of hydrocortisone or placebo, in addition to their usual glucocorticoid and mineralocorticoid replacement in a randomized, double-blind, crossover design 1 h before exercising. Although plasma cortisol levels approximately doubled after administration of the additional hydrocortisone dose compared with the usual single dose, fasting and exercise-induced blood glucose levels did not differ. In addition, no differences were observed in the serum concentrations of the glucose-modulating hormones epinephrine, insulin, glucagon, and GH and of the metabolic parameters lactate and free fatty acids. Although maximal heart rate was slightly higher after stress dosing (193 ± 3 vs. 191 ± 3 beats/min, mean ± SEM, P < 0.05), this did not affect exercise performance or perceived exertion. We conclude that patients with classic CAH do not benefit from additional hydrocortisone during short-term, high-intensity exercise. Although this has not been tested with long-term exercise, a high degree of caution should be used when considering the frequent use of additional hydrocortisone administration with exercise, given the adverse side effects of glucocorticoid excess.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CONGENITAL ADRENAL HYPERPLASIA (CAH), a disease traditionally thought to be restricted to the adrenal cortex, has also been shown recently to be associated with impaired functioning of the adrenal medulla (1, 2). Proper glucocorticoid secretion of the adrenal cortex appears to be necessary for normal organogenesis of the adrenal medulla as well as induction and maintenance of the production of its main hormone epinephrine (E) (3). The latter is a classic stress hormone that affects virtually all tissues. Still, the clinical implications of E deficiency in humans are not well understood. The finding of E deficiency in children with otherwise unexplained episodes of hypoglycemia (4, 5, 6, 7) and the observation of reduced exercise performance due to poor glycemic control during intense or prolonged exercise in adrenally demedullated animals (8, 9) suggest that E is important for glucose homeostasis.

Patients with CAH often complain of impaired exercise tolerance (personal experience, D.P.M.). Some practitioners recommend extra steroid dosing in such patients when participating in endurance sports (10). However, studies demonstrating a beneficial effect of extra hydrocortisone in such situations have not been performed. We recently found that the normal exercise-induced rise in blood glucose is markedly impaired in patients with classic CAH (2). Indeed, these patients lacked the normal exercise-induced rise of two glucose-modulating hormones, namely cortisol and E, which explains the deficient glucose response. The individual impact of each of these hormone deficiencies was unclear. Thus, we tested the hypothesis that an extra dose of hydrocortisone would increase blood glucose levels in response to exercise and would also exert beneficial effects on exercise tolerance and capacity in patients with classic CAH. For this purpose, we used a standardized, short-term, high-intensity cycle ergometer test in a randomized, double-blind, crossover design study.


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

Nine adolescent patients with CAH in otherwise good health and receiving conventional therapy (glucocorticoid, mineralocorticoid) participated in this study. Nine healthy volunteers matched for gender, age, and body mass index (BMI) SD score also participated in this protocol and have been previously reported (2). Eligible patients with classic 21-hydroxylase deficiency were in good clinical control as defined by the criteria: 1) 17-OH-progesterone level between 100 and 1500 ng/dl (to convert to nmol/liter, multiply by 0.03); 2) plasma renin activity within the normal reference range; 3) growth rate within 2 SD for age (children); and 4) no new signs or symptoms of virilization in females. Six of the nine patients had age-appropriate serum androstenedione levels. The remaining three patients had androstenedione levels that were slightly increased for their chronological age but appropriate for their bone age and below the upper limit of normal for adults (normal adult range, 40–210 ng/dl). All subjects underwent a screening visit including medical history, physical examination, pregnancy test in females, and a baseline electrocardiogram to establish eligibility for high-intensity exercise testing. The study was approved by the National Institute of Child Health and Human Development Institutional Review Board, and written informed consent was obtained from all adult subjects and the parents of participating children. All children gave their assent.

Study protocol

The details of the study protocol have been reported previously (2).

Exercise protocols

Each subject underwent a total of three exercise sessions, one maximal incremental exercise test to determine maximal aerobic capacity and two identical standardized exercise tests on three consecutive mornings, 24 h apart. Subjects received their usual morning dose of hydrocortisone and fludrocortisone 1 h before each exercise test. In addition, they received either an additional morning dose of hydrocortisone or placebo before the standardized exercise tests in a randomized, double-blind, crossover design. Upon completion of the series of exercise tests, patients were asked during which session they believed the extra dose of hydrocortisone was given.

All exercise tests were physician-monitored and performed after an overnight fast (water permitted). Subjects were instructed to abstain from caffeinated foods and drinks, alcohol, and strenuous exercise for the 24 h before each exercise session. Guidelines for exercise testing published by the American Heart Association were observed (11). About 60 min before each exercise test, participants drank 1 teaspoon of water per kilogram of body weight to provide adequate hydration. An indwelling line, placed in the forearm at least 45 min before each test, was used for drawing blood at baseline with the subject resting for at least 20 min in the supine position and at predetermined time points during the exercise tests and recovery periods for measurements of E, norepinephrine (NE), lactate, glucose, insulin, glucagon, GH, cortisol, ACTH, and free fatty acids (FFA). Blood was drawn without using a tourniquet and with the subjects continuously pedaling throughout the exercise period. Whole-blood glucose (Lifescan; Johnson & Johnson, New Brunswick, NJ) readings were obtained regularly onsite to identify hypoglycemia.

All exercise tests were performed using a cycle ergometer (SensorMedics Ergoline 800; SensorMedics Corp., Yorba Linda, CA). Subjects were prepped with electrodes for continuous monitoring with a 12-lead electrocardiogram (SensorMedics MAX 1, Sensormedics Corp.) and fitted with a nose clip and mouthpiece assembly for measurement of oxygen (VO2) uptake and carbon dioxide (VCO2) production by open-circuit spirometry (SensorMedics Vmax). Variables measured included VO2, VCO2, heart rate, blood pressure, respiratory exchange ratio, and rating of perceived exertion. Rating of perceived exertion was assessed immediately after the end of each exercise test using the revised Borg scale (12). After exercising, subjects recovered by pedaling with unloaded resistance until heart rate returned to less than 120 beats/min and subsequently by sitting in a chair.

All subjects underwent a maximal incremental cycle ergometer test to volitional exhaustion to document their maximal aerobic capacity (VO2 max), which was used to determine workload in the subsequent standardized exercise tests. The maximal test involved a 3-min warm-up (with unloaded pedaling resistance) followed by a continuous increase in work rate until the subject could go no further. The work rate increase for each subject was determined based on predicted maximal power and designed to elicit maximal effort within 8–12 min. O2 uptake during the final 20 sec of exercise was used as a measure of VO2 max. The standardized 20-min exercise test included a 3-min warm-up, followed by 5 min at 50%, 10 min at 70%, and then 5 min at 90% of the previously determined individual VO2 max. Only one subject, a 17-yr-old competitive high school athlete, was able to finish the 20 min of exercising according to protocol. Thus, the majority of subjects did not complete the 20 min of exercise due to exhaustion.

Assays

Plasma E and NE were determined by liquid chromatography with electrochemical detection (13). The detection limits of the assays were 1–2 pg/ml (to convert to pmol/liter, multiply by 5.458 for E and by 5.911 for NE). Glucose and lactate were measured in heparinized whole blood by specific sensitive electrodes, FFA by colorimetric assay (detection at 546 nm), GH and cortisol by chemiluminescence immunoassay, all at the Clinical Center laboratories at the National Institutes of Health. Serum concentrations of glucagon were determined by RIA (Esoterix Endocrinology, Calabasas Hills, CA). Serum insulin was measured by a two-site enzyme immunoassay (TOSOH Bioscience Inc., San Francisco, CA) and ACTH by RIA after extraction (both at Covance Laboratories, Vienna, VA).

Statistical analyses

Height SD score and BMI SD score were determined using anthropometric reference data for U.S. children (14). For comparison of some of the results to normal, data from an age-, gender-, and BMI-matched healthy control group undergoing the same procedures except for hydrocortisone administration were used. Only those results that were previously found to significantly differ between CAH patients receiving standard replacement therapy and healthy controls are presented (2). Details of this control group are described elsewhere (2). The effect of hydrocortisone dose and differences between CAH patients and healthy controls were assessed by using repeated measures two-way ANOVA and testing for interactions when indicated. For variables with only one measurement per period (e.g. duration of exercise), P values were derived from two-sample t tests for period differences in the two sequences. Statistical significance was accepted for two-sided P < 0.05. Catecholamines (E and NE), known to be nonnormally distributed in the general population, were log-transformed for analysis.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline characteristics of the patients are shown in Table 1Go. Eight patients were on glucocorticoid replacement therapy with hydrocortisone, and one adult patient was on dexamethasone (0.35 mg/d). The patient on dexamethasone received hydrocortisone 17 mg/m2·d in place of her usual dexamethasone during the study. All patients received fludrocortisone.


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  		TABLE 1. Baseline characteristics of CAH patients

 
Administration of an additional morning dose of hydrocortisone resulted in an approximate doubling of plasma cortisol levels (Fig. 1Go) and a concomitantly marked suppression of the exercise-induced ACTH rise (Fig. 1Go). Cortisol levels decreased over time in the patients with CAH, as opposed to the normal exercise-induced rise in cortisol observed in the matched healthy controls (Fig. 1Go).



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  		FIG. 1. Plasma cortisol, ACTH, and blood glucose concentrations during the standardized exercise test and recovery period in patients with CAH after administration of a single ({circ}) or double (•) morning dose of hydrocortisone 1 h before exercising and in healthy matched controls (dotted line) not having received any medication. Data are presented as mean ± SEM. Shaded areas indicate time period of exercise. Time point 0 min refers to the start of the exercise test after a 3-min warm-up without pedaling resistance. The 20-min time point also refers to the time of peak exercise in patients who were not able to complete the 20 min of exercising. ANOVA for double vs. single dose of hydrocortisone: cortisol, P < 0.001; ACTH, P < 0.004; glucose, P = 0.5. Conversion factors for calculation of SI units: cortisol, micrograms per deciliter x 27.59 = nanomoles per liter; ACTH, picograms per milliliter x 0.2202 = picomoles per liter; glucose, milligrams per deciliter x 0.0555 = millimoles per liter.

 
The extra hydrocortisone did not affect blood glucose levels (Fig. 1Go). Exercise-induced glucose concentrations in the CAH patients remained well below those observed in matched healthy controls, both when CAH patients took their usual dose of hydrocortisone (Fig. 1Go; P < 0.001) (2) and when they took double their usual dose (Fig. 1Go; P = 0.001). The normal exercise-induced rise in glucose observed in the matched healthy controls did not occur in the patients with CAH.

Plasma levels of E and NE and serum concentrations of other glucose-modulating hormones, such as glucagon, insulin, and GH (Fig. 2Go), were largely unaffected by stress dosing (P > 0.40 for all). Although the mean peak E level after double dose of hydrocortisone was about half of that observed after single dose, the decrease was not significant due to the large variation. Exercise-induced E concentrations in the CAH patients remained well below those observed in matched healthy controls, both when CAH patients took their usual dose of hydrocortisone (Fig. 2Go; P < 0.01) (2) and when they took double their usual dose (Fig. 2Go; P < 0.01). Plasma levels of NE, glucagon, insulin, and GH were not different from those of normal controls (data not shown) (2). The metabolic parameters lactate and FFA also were unaffected by the administration of additional hydrocortisone (Fig. 3Go) and also were previously found not to differ from normal controls (data not shown) (2).



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  		FIG. 2. Serum or plasma levels of the glucose modulating hormones E, NE, glucagon, insulin, and GH during the standardized exercise test and recovery period in patients with CAH after administration of a single ({circ}) or double (•) morning dose of hydrocortisone 1 h before exercising. For comparison, plasma levels from matched healthy controls (dotted line) undergoing the same exercise procedures except for hydrocortisone administration are shown for E, the only variable shown which was previously found to significantly differ between patients with CAH and healthy controls (2 ). Data are presented as mean ± SEM. Shaded areas indicate time period of exercise. Time point 0 min refers to the start of the exercise test after a 3-min warm-up without pedaling resistance. The 20-min time point also refers to the time of peak exercise in patients who were not able to complete the 20 min of exercising. Conversion factors for calculation of SI units: E, picograms per milliliter x 5.458 = picomoles per liter; NE, picograms per milliliter x 5.911 = picomoles per liter; glucagon, picograms per milliliter x 1 = nanograms per liter; insulin, microunits per milliliter x 7.175 = picomoles per liter; GH, nanograms per milliliter x 1 = micrograms per liter.

 


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  		FIG. 3. Serum levels of the catecholamine-dependent parameters lactate and FFA during the standardized exercise test and recovery period in patients with CAH after administration of a single ({circ}) or double (•) morning dose of hydrocortisone 1 h before exercising. Data are presented as mean ± SEM. Shaded areas indicate time period of exercise. Time point 0 min refers to the start of the exercise test after a 3-min warm-up without pedaling resistance. The 20-min time point also refers to the time of peak exercise in patients who were not able to complete the 20 min of exercising. To convert FFA values to millimoles per liter, multiply by 1.1.

 
Doubling of the usual hydrocortisone dose did not influence exercise capacity, perceived exertion, or cardiorespiratory responses to exercise except for peak heart rate, which was somewhat (minimally but significantly) higher after the double dose of hydrocortisone than after the single dose (mean increase, 2.2 beats/min; 95% confidence interval, 0.5–3.9 beats/min) (Table 2Go). Only one patient made a correct assumption about during which session he had received the extra dose of hydrocortisone. The remaining patients made a wrong assumption (n = 3) or said they did not notice a difference (n = 5).


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  		TABLE 2. Exercise capacity and cardiorespiratory response during the standardized exercise test in hormone-replaced CAH patients receiving an extra dose of hydrocortisone vs. placebo

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our data suggest that patients with classic CAH do not benefit from extra hydrocortisone during short-term, high-intensity exercise. Particularly, the abnormal exercise-induced blood glucose levels observed in these patients are not normalized by stress dosing.

Although in patients with CAH, administration of stress doses of hydrocortisone is undoubtedly crucial in situations of severe and prolonged physical stress, such as intercurrent infections or trauma, the usefulness of extra hydrocortisone in situations of short-term physical stress, such as exercise, has not been demonstrated. Some practitioners advise their CAH patients to take extra hydrocortisone for exercise or endurance sports, but there are no clear-cut general recommendations (10), and controlled clinical studies demonstrating beneficial effects have not been performed.

We recently found that patients with classic CAH have reduced E reserve and blood glucose levels in response to short-term, high-intensity exercise (2). Because such patients are not able to mount a normal endogenous cortisol response to stress, we sought to determine whether an exogenous extra dose of hydrocortisone would normalize their blood glucose levels during exercise or would exert beneficial effects on their exercise capacity. The CAH patients received hydrocortisone tablets 1 h before starting exercise based on the known pharmacokinetics of oral hydrocortisone (15, 16) and with the goal to reach maximal serum cortisol levels during exercise. However, exogenous hydrocortisone does not mimic normal physiology. After oral administration of hydrocortisone, serum cortisol concentrations reach a peak within 1–2 h and decline to very low cortisol concentrations 4–6 h later (16). Unlike the healthy controls in whom the stimulation of the hypothalamic-pituitary-adrenal (HPA) axis led to the expected ACTH-mediated increase in serum cortisol, cortisol levels were highest at baseline, about twice as high as in the healthy controls, and declined rapidly thereafter in the CAH patients.

ACTH levels were somewhat higher in patients with CAH who received single-dose hydrocortisone when compared with healthy controls. This finding is in agreement with previous observations of decreased sensitivity of the HPA axis to glucocorticoid-induced negative feedback inhibition in patients with CAH (17). Despite receiving "standard" glucocorticoid replacement, patients with classic CAH have been described to have elevated basal ACTH and ACTH hyperresponsiveness to CRH stimulation (17). This decreased sensitivity to feedback inhibition may be due to the inevitable periods of under- and overexposure to glucocorticoids during replacement therapy or to intrauterine glucocorticoid deficiency. However, the HPA axis of our patients with classic CAH was responsive to negative feedback inhibition, because higher doses of hydrocortisone resulted in a marked suppression of ACTH concentrations.

Although the double dose of hydrocortisone increased plasma cortisol levels by approximately 2-fold compared with the single dose, it did not affect blood glucose levels, which remained significantly lower than in the healthy controls. In addition, serum concentrations of the glucose-modulating hormones E, NE, insulin, glucagon, and GH remained largely unchanged. These findings support the notion that cortisol is not a major player in acute blood sugar regulation (18) and further strengthen our previously stated view that E deficiency (rather than cortisol deficiency) is mostly responsible for the impaired glucose response to exercise observed in patients with CAH (2). Cortisol has been shown to decrease glucose clearance; however, the overall effect of cortisol on glucose levels is small compared with that produced by E (18). Moreover, E, glucagon, and cortisol interact synergistically, and their combination increases glucose much more than the sum of the individual hormonal effects (18). Therefore, in the presence of E deficiency, it is doubtful that additional hydrocortisone would have a significant impact on glucose levels. Whether extra hydrocortisone would have normalized plasma glucose concentrations in our patients when given at a different time point before or during exercise, with frequent but modest doses of hydrocortisone, or with some other variation of administration of the hydrocortisone remains to be determined.

Although E replacement during physical stress would be the most physiological approach in patients with E deficiency, this is not currently possible due to the necessary parenteral application and the short plasma half-life of only 3 min for E, which would require multiple dosing or constant infusion. In addition, an appropriate "replacement dose" has not been established, and possible adverse reactions include cardiac arrhythmias, tachycardia, hypertension, seizures, pulmonary edema, anxiety, nausea, and vomiting.

Although hypoglycemia did not occur in our patients during short-term exercise, E-induced stimulation of gluconeogenesis may be important for prevention of hypoglycemia during prolonged exercise, when glycogen stores are depleted (8, 9). Particularly, children with CAH might be at high risk for developing hypoglycemia during prolonged exercise. This concern is based on the observation that glycemic control in children appears to be dependent on intact E secretion (4, 5, 6, 7) and on the fact that children in general are more prone to hypoglycemia during exercise than adults (19).

Whether extra hydrocortisone is beneficial for reduction of hypoglycemia risk during long-term exercise in patients with CAH remains to be determined. Alternatively, intake of carbohydrates may be an easy and effective way of preventing hypoglycemia and maintaining endurance in such patients as demonstrated in an animal model of E deficiency (9). Because E deficiency may also be responsible for the increased susceptibility to develop hypoglycemia in children with CAH in association with intercurrent illness (20, 21, 22, 23), carbohydrate and glucose supplementation may also be warranted in such situations.

Additional hydrocortisone did not influence exercise performance or tolerance in our patients with CAH. Cardiorespiratory responses to exercise also remained unchanged except for a statistically significant but clinically insignificant increase in maximal heart rate (which might be due to chance). All except one patient made wrong assumptions about during which session they had received the extra dose of hydrocortisone or could not find a notable difference in their ability to perform. This finding further supports the lack of beneficial effects of stress dosing with hydrocortisone during short-term, high-intensity exercise.

Unnecessary excessive hydrocortisone use in patients with CAH may exert the well-known adverse effects on body composition, skin, bone, cardiovascular system, and carbohydrate metabolism. In addition, it may further impair adrenomedullary functioning (24, 25) in these patients, by suppressing any remaining endogenous cortisol synthesis known to be necessary for induction and maintenance of E production (3). Therefore, in the absence of a clear benefit and presence of possible adverse effects, caution should be exercised regarding the frequent use of stress doses of hydrocortisone for exercise in patients with CAH.

We conclude that in patients with CAH the use of extra hydrocortisone is not beneficial during short-term, high-intensity exercise. Moreover, the impaired exercise-induced glycemic response characteristic of classic CAH cannot be corrected by stress dosing. Because the repeated use of supraphysiological glucocorticoid doses may exert adverse effects, stress dosing in this setting does not seem to be justified. Whether extra hydrocortisone is beneficial for reduction of hypoglycemia risk and exercise performance during long-term exercise in patients with CAH remains to be determined. E administration might be more effective in raising blood glucose levels but is not currently possible. Alternatively, intake of carbohydrates may be an easy and effective way of preventing hypoglycemia and maintaining endurance in such patients.


   Acknowledgments
 
The authors thank the patients and their families for participating in this study, Ms. Donna Peterson for assistance in data management, Dr. Robert Wesley for assistance with data analysis, and the 9 West Day Hospital Nursing Staff of the Warren Grant Magnuson Clinical Center for assistance with the exercise testing.


   Footnotes
 
D.P.M. is a commissioned officer in the United States Public Health Service.

Abbreviations: BMI, Body mass index; CAH, congenital adrenal hyperplasia; E, epinephrine; FFA, free fatty acids; HPA, hypothalamic-pituitary-adrenal; NE, norepinephrine; VCO2, measurement of carbon dioxide production; VO2, measurement of oxygen uptake; VO2 max, maximal aerobic capacity.

Received November 26, 2003.

Accepted April 25, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Merke DP, Chrousos GP, Eisenhofer G, Weise M, Keil MF, Rogol AD, Van Wyk JJ, Bornstein SR 2000 Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency. N Engl J Med 343:1362–1368[Abstract/Free Full Text]
  2. Weise M, Mehlinger SL, Drinkard B, Rawson E, Charmandari E, Hiroi M, Eisenhofer G, Yanovski JA, Chrousos GP, Merke DP 2004 Patients with classic congenital adrenal hyperplasia have decreased epinephrine reserve and defective glucose elevation in response to high intensity exercise. J Clin Endocrinol Metab 89:591–597[Abstract/Free Full Text]
  3. Wurtman RJ, Pohorecky LA 1971 Adrenocortical control of epinephrine synthesis in health and disease. Adv Metab Disord 5:53–76[Medline]
  4. Sizonenko PC, Paunier L, Vallotton B, Cuendet GS, Zahnd G, Marliss EB 1973 Response to 2-deoxy-D-glucose and to glucagon in "ketotic hypoglycemia" of childhood: evidence for epinephrine deficiency and altered alanine availability. Pediatr Res 7:983–993
  5. Tietze HU, Zurbrugg RP, Zuppinger KA, Joss EE, Kaser H 1972 Occurrence of impaired cortisol regulation in children with hypoglycemia associated with adrenal medullary hyporesponsiveness. J Clin Endocrinol Metab 34:948–958[Abstract/Free Full Text]
  6. Kruse K, Bartels H 1975 Die Bedeutung des 2-Desoxy-Glucose-Tests für die Differenzierung kindlicher Hypoglykamien [Significance of the 2-deoxy-D-glucose-test on the differentiation of hypoglycemia in childhood (author’s translation)]. Klin Padiatr 187:308–813[Medline]
  7. Hansen IL, Levy MM, Kerr DS 1983 Differential diagnosis of hypoglycemia in children by responses to fasting and 2-deoxyglucose. Metabolism 32:960–970[CrossRef][Medline]
  8. Yang HT, Hammer RL, Sellers TL, Arogyasami J, Carrell DT, Winder WW 1988 Adrenodemedullation affects endurance but not hepatic fructose 2,6-bisphosphate. Am J Physiol 254:R572–R577
  9. Winder WW, Yang HT, Jaussi AW, Hopkins CR 1987 Epinephrine, glucose, and lactate infusion in exercising adrenodemedullated rats. J Appl Physiol 62:1442–1447[Abstract/Free Full Text]
  10. Joint LWPES/ESPE CAH Working Group 2002 Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. J Clin Endocrinol Metab 87:4048–4053[Free Full Text]
  11. Washington RL, Bricker JT, Alpert BS, Daniels SR, Deckelbaum RJ, Fisher EA, Gidding SS, Isabel-Jones J, Kavey RE, Marx GR 1994 Guidelines for exercise testing in the pediatric age group. From the Committee on Atherosclerosis and Hypertension in Children, Council on Cardiovascular Disease in the Young, the American Heart Association. Circulation 90:2166–2179[Abstract/Free Full Text]
  12. Borg GA 1982 Psychophysical bases of perceived exertion. Med Sci Sports Exerc 14:377–381[Medline]
  13. Eisenhofer G, Goldstein DS, Stull R, Keiser HR, Sunderland T, Murphy DL, Kopin IJ 1986 Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma, and their responses to inhibition of monoamine oxidase. Clin Chem 32:2030–2033[Abstract/Free Full Text]
  14. Najjar MF, Rowland M 1987 Anthropometric reference data and prevalence of overweight, United States, 1976–80. Vital Health Stat 11:1–73
  15. Patel RB, Rogge MC, Selen A, Goehl TJ, Shah VP, Prasad VK, Welling PG 1984 Bioavailability of hydrocortisone from commercial 20 mg tablets. J Pharm Sci 73:964–966[CrossRef][Medline]
  16. Charmandari E, Johnston A, Brook CG, Hindmarsh PC 2001 Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Endocrinol 169:65–70[Abstract]
  17. Speiser PW, Heier L, Serrat J, New MI, Nass R 1995 Failure of steroid replacement to consistently normalize pituitary function in congenital adrenal hyperplasia: hormonal and MRI data. Horm Res 44:241–246[Medline]
  18. Shamoon H, Hendler R, Sherwin RS 1981 Synergistic interactions among antiinsulin hormones in the pathogenesis of stress hyperglycemia in humans. J Clin Endocrinol Metab 52:1235–1241[Abstract/Free Full Text]
  19. Fellmann N, Coudert J 1994 Physiology of muscular exercise in children. Arch Pediatr 1:827–840[Medline]
  20. Hinde FR, Johnston DI 1984 Hypoglycaemia during illness in children with congenital adrenal hyperplasia. Br Med J (Clin Res Ed) 289:1603–1604
  21. Mackinnon J, Grant DB 1977 Hypoglycaemia in congenital adrenal hyperplasia. Arch Dis Child 52:591–593[Abstract/Free Full Text]
  22. Donaldson MD, Thomas PH, Love JG, Murray GD, McNinch AW, Savage DC 1994 Presentation, acute illness, and learning difficulties in salt wasting 21-hydroxylase deficiency. Arch Dis Child 70:214–218[Abstract/Free Full Text]
  23. Artavia-Loria E, Chaussain JL, Bougneres PF, Job JC 1986 Frequency of hypoglycemia in children with adrenal insufficiency. Acta Endocrinol Suppl (Copenh) 279:275–280[Medline]
  24. Badder EM, Santen R, Samojlik E, Harrison TS 1980 Adrenal medullary epinephrine secretion: effects of cortisol alone and combined with aminoglutethimide. J Lab Clin Med 96:815–821[Medline]
  25. Brown MR, Fisher LA 1986 Glucocorticoid suppression of the sympathetic nervous system and adrenal medulla. Life Sci 39:1003–1012[CrossRef][Medline]



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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals