| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Pediatric and Reproductive Endocrinology Branch (S.L.M., E.R., E.C., G.P.C., D.P.M.), Developmental Endocrinology Branch (M.W., J.A.Y.), 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 (M.H., 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 IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Catecholamines influence virtually all tissues. However, the clinical implications of E deficiency in humans are not clear. E appears to play a role in glucose homeostasis especially in young children (5, 6, 7, 8). In animals, bilateral adrenal demedullation results in impaired exercise performance and poor glycemic control during intense or prolonged exercise (9, 10). There is some evidence that a compensatory enhancement of sympathetic nerve activity, and, thus, NE secretion may occur in acquired forms of E deficiency (11, 12, 13). However, recent findings suggest that such a compensatory increase in NE may not occur in patients with CAH (2). Thus, impaired E secretion, if present, may explain the increased risk for hypoglycemia and cardiovascular instability with acute infections or trauma in patients with CAH (14, 15, 16, 17, 18), and the complaints of impaired exercise endurance in some subjects with this condition (personal experience D.P.M.).
Intense exercise is a natural stressor and a quantifiable stimulus of the adrenal medulla as well as of the systemic sympathetic nervous system (3). E responses are similar under conditions of similar relative exercise intensities, in the morning and evening and across different phases of the menstrual cycle (3, 19). E responses to similar relative workloads are higher in males than females (20, 21) and appear to be blunted in obese individuals (22). The goal of this study was to evaluate stress-induced adrenomedullary reserve in patients with classic CAH, compared with healthy controls, and the effects of E deficiency on exercise capacity and tolerance and E-dependent parameters. For this purpose we employed a standardized short-term high-intensity cycle ergometer test.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Nine otherwise healthy patients with CAH (one Hispanic, eight Caucasian, five males) and nine healthy volunteers (all Caucasian, five males), all nonsmokers, matched for gender, age, and percent body fat participated in this study. Eligible patients with CAH were receiving conventional therapy (glucocorticoid, mineralocorticoid) and 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); 4) no new signs or symptoms of virilization in females. 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. Pubertal stage was assessed by physical examination according to the criteria of Tanner for breast development in females (23) and according to a modified genital staging method based on the average volume of both testes in males (24). Specifically, testicular volumes less than 4 ml were defined as stage 1; 4 ml to less than 8 ml, stage 2; 8 ml to less than 12 ml, stage 3; 12 ml to less than 15 ml, stage 4; and at least 15 ml, stage 5. Physical activity level was derived from information on organized sports and free time activities. Subjects were asked how many times per week they engaged in light physical activities, such as golfing or long walks, moderate physical activities, such as hiking or bicycling, and strenuous physical activities, such as running, swimming laps, or playing basketball. 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
Body composition. Before exercise testing, subjects underwent assessment of their body composition by air displacement plethysmography (Bod Pod, Life Measurement Instruments, Concord, CA) according to the manufacturer’s directions and procedures previously described in detail (25). In summary, air displacement plethysmography was performed in the morning after an overnight fast and after voiding with the subjects wearing minimal tight fitting clothing and a swim cap. Thoracic gas volume was measured during tidal breathing and during exhalation against a mechanical obstruction. Percentage fat was determined from body density using the standard two-compartment model (26) and converted into kilograms of body fat before analysis by multiplying percentage fat and total body weight together.
Exercise protocols. Each subject underwent a maximal incremental exercise test to determine maximal aerobic capacity and a standardized exercise test 1–2 d apart. All exercise tests were physician monitored and performed in the morning after an overnight fast (water permitted). Subjects were instructed to abstain from caffeinated foods and drinks, alcohol, and strenuous exercise for at least 24 h before each exercise session. Guidelines for exercise testing published by the American Heart Association were observed (27). About 60 min before each exercise test, participants drank 1 teaspoon of water per kilogram 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, NE, lactate, glucose, insulin, glucagon, GH, cortisol, free fatty acids (FFAs), and K+. Blood was drawn without using a tourniquet and with the subjects continuously pedaling throughout the exercise period. Whole-blood glucose (Lifescan, Johnson and Johnson, New Brunswick, NJ) readings were obtained regularly on site to identify hypoglycemia.
All exercise tests were performed using a cycle ergometer (SensorMedics Ergoline 800, SensorMedics Corp., Yorba Linda, CA). CAH patients received their usual morning dose of hydrocortisone and fludrocortisone one hour before each exercise test. The healthy volunteers did not receive any medication. Subjects were prepped with electrodes for continuous monitoring with a 12 lead electrocardiogram (MAX 1, SensorMedics Corp., Yorba Linda, CA) and fitted with a nose clip and mouthpiece assembly for measurement of oxygen (VO2) uptake and carbon dioxide production by open circuit spirometry (SensorMedics Vmax). Variables measured included VO2, carbon dioxide, heart rate, blood pressure, respiratory exchange ratio, and rating of perceived exertion (RPE). RPE was assessed immediately after the end of each exercise test using the revised Borg scale (28). 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 (VO2max), which was used to determine workload in the subsequent standardized exercise test. 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 farther. The work rate increase for each subject was determined based on predicted maximal power and designed to elicit maximal effort within 8–12 min. the O2 uptake during the final 20 sec of exercise was used as a measure of VO2max. VO2max was defined by at least two of the following criteria: 1) plateau in oxygen uptake of O2 at 2.0 ml/kg·min or less; 2) heart rate within 5% of 195 beats/min; 3) RPE of 17 or greater, respiratory exchange ratio 1.10 or greater; and 4) blood lactate at peak exercise of 7 mmol/liter or greater.
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 VO2max. Only two subjects (one CAH, one control, both 17 yr old competitive high school athletes) were 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 (29). The detection limits of the assays were1–2 pg/ml (to convert to pmol/liter, multiply by 5.458 for E and 5.911 for NE). Glucose, lactate, and K+ were measured in heparinized whole blood by specific sensitive electrodes, FFAs 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 TOSOH (Covance Laboratories, Vienna, VA) and in two subjects by immunochemiluminometric assay (Esoterix Endocrinology, Calabasas Hills, CA). Insulin values obtained with the immunochemiluminometric assay were adjusted by dividing through the upper reference limit (for fasting insulin) of this assay and multiplying with the corresponding upper reference limit of the TOSOH.
Statistical analysis
Height SD score and body mass index -SD score were determined using anthropometric reference data for U.S. children (30). Group differences of parameters with one measurement were assessed using t test. For parameters with more than one serial measurement, overall differences between CAH patients and healthy controls were assessed using repeated-measures ANOVA. In case of statistical significance (P < 0.05), post hoc analysis was performed employing t test to determine the time points at which groups differed. Catecholamines, known to be nonnormally distributed in the general population, were log transformed for analysis. All reported P values were based on two-sided tests.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
). This was also true for male and female subgroups (data not shown). Overall, the CAH patients were slightly more physically active than the healthy controls (light exercise: 1.8 ± 1.9 vs. 1.3 ± 1.8 times per week, moderate exercise: 1.7 ± 1.7 vs. 1.7 ± 1.4 times per week, strenuous exercise: 2.7 ± 1.3 vs. 1.8 ± 1.6 times per week, CAH vs. controls, respectively).
|
). Plasma NE, on the other hand, did not differ between CAH and controls, both before and during exercise (Fig. 1).
|
). CAH patients had baseline blood glucose levels similar to controls but a markedly blunted exercise-induced rise (Fig. 2). None of the subjects became hypoglycemic during exercise or recovery.
|
). Baseline levels of serum cortisol were similar in both groups, but the exercise-induced increase observed in controls was absent in CAH patients (Fig. 3).
|
). During exercise, FFA concentrations decreased in all but one subject in whom a slight increase was noted and were similar for both groups. Serum K+ levels rose in response to exercise and were similar in CAH patients and healthy controls. (Fig. 4).
|
).
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Baseline and stimulated NE levels in the CAH patients did not differ significantly from those in the healthy controls. Therefore, a compensatory increase in sympathetic nerve activity that may occur in adrenalectomized patients (11, 12) and experimental animals (13) was not demonstrated in our patients. Patients with CAH may have inability to up-regulate the sympathetic nervous system to produce higher levels of NE. Congenital forms of cortisol and consequently E deficiency, such as CAH (1, 2), may thus exert effects on the sympathetic nervous system that are different from those seen with cortisol and E deficiency acquired later in life.
Patients with CAH lacked the normal exercise-induced rise in blood glucose levels, which was most likely caused by the insufficient E response (35, 36). E increases blood glucose levels by stimulating hepatic glucose output and gluconeogenesis and decreasing insulin secretion and sensitivity (35, 37). Stimulation of gluconeogenesis may be important for the prevention of hypoglycemia during prolonged exercise when glycogen stores are depleted (9, 10). Cortisol and GH are involved in the defense against prolonged hypoglycemia, but they play a minor role in moment-to-moment glucose regulation, compared with E, insulin, and glucagon.
In adults, counterregulation of hypoglycemia by E is thought not to be critical, provided glucagon and insulin secretion is intact (38). However, in a state of fasting or caloric restriction, the adrenal medulla may have a compensatory role (39). In contrast, glycemic control in children appears to be dependent on intact E secretion (5, 6, 7, 8). In addition, children generally are known to be more prone to hypoglycemia during prolonged exercise than adults (40). Although none of our patients became hypoglycemic during the short-term high-intensity exercise test, CAH patients, particularly children with CAH, might be at increased risk of hypoglycemia during long-term physical stress. This concern is supported by studies in adrenodemedullated animals suggesting that E is essential to prevent hypoglycemia after depletion of liver glycogen and for allowing continuation of exercise (9, 10).
E deficiency may also be responsible for the increased susceptibility to develop hypoglycemia in children with CAH in association with intercurrent illness (14, 15, 16, 17). Hypoglycemia normally elicits a prompt central nervous system-mediated counterregulatory E response, which causes typical warning symptoms such as tremor, palpitations, sweating, and anxiety. With E deficiency, warning symptoms may be diminished or even absent thus masking hypoglycemia (7). Consequently, children with CAH may not only be at increased risk for hypoglycemia but also for delayed recognition and treatment. Carbohydrate and glucose supplementation with prolonged high-intensity exercise or during illness with fever may be warranted in children with CAH.
As expected, CAH patients lacked the normal exercise-induced increase in cortisol. In healthy subjects, glucose levels started to rise early during exercise, well before the ACTH-mediated cortisol increase (41). Therefore, cortisol does not appear to be a major determinant of glucose response during short-term exercise. Moreover, hepatic glucose production during exercise has been shown to be a sum of glycogenolysis and gluconeogenesis regulated by E, glucagon, and insulin, whereas cortisol contributes only minimally to the acute exercise-induced rise in liver glucose output (37).
The exercise-induced overall changes in the glucoregulatory hormones, insulin, glucagon, and GH, were not different between the two groups. However, insulin levels post exercise appeared to be somewhat higher in the healthy controls, most likely due to the higher glucose levels, because blood glucose concentration is the most important determinant of glucoregulatory hormone response. E suppresses insulin and may enhance glucagon secretion during exercise (42). Therefore, E deficiency in the patients with CAH could have been expected to cause decreased glucagon and increased insulin. The fact that insulin levels did not differ between the two groups, despite a clearly blunted glucose response in the patients with CAH, suggests that insulin was too high for the degree of glycemia in the patients with CAH. It may be speculated that in the case of hypoglycemia, glucagon and GH responses may be increased in a state of E deficiency. Because E is the fastest secreted and acting of the counterregulatory hormones in response to hypoglycemia, a glucose-deficient state might be prolonged and more profound in patients with CAH (12).
E increases energy metabolism of exercising muscles by stimulating muscle glycogenolysis, lipolysis, and facilitation of FFA entry (43). Because muscle lacks glucose-6-phosphatase, glucose is metabolized to lactate before release into the circulation. Adrenalectomized adults (36) and adrenodemedullated animals (9) were described to have impaired lactate response to exercise. In our study, stimulated lactate levels were somewhat lower in CAH patients than in healthy controls, but this difference did not reach statistical significance. This discrepancy may be resolved by the fact that our patients were mainly children in whom exercise-induced muscle glycogenolysis is limited and fat utilization enhanced, compared with adults (40, 44). Alternatively, a statistical significant effect might have been seen with a larger sample size.
Contracting muscles release K+ leading to hyperkalemia and a sensation of fatigue (45). E increases K+ uptake into nonexercising muscle and other tissues, thereby ameliorating exercise-induced hyperkalemia. In addition, catecholamines may exert a cardioprotective effect to the arrhythmogenic effects of hyperkalemia during exercise (45). In our study, E deficiency did not affect serum K+ levels, but the duration of exercise and/or the limitation of exercise to the lower part of the body might have been insufficient to fully assess this effect.
Despite clearly demonstrated E deficiency, the CAH patients had normal short-term high-intensity exercise capacity and tolerance. The 5% lower peak heart rate observed in the patients with CAH may be attributed to the lower E response, but this somewhat lower maximal heart rate was not clinically apparent and alternatively might be due to chance. Few other studies have investigated cardiovascular responses to exercise in patients with adrenocortical and adrenomedullary insufficiency yielding inconsistent results including elevated diastolic but normal systolic blood pressure and pulse rate (31), decreased heart rate (36), and normal blood pressure and heart rate (46). These discrepant findings might be explained by differences in exercise intensities, the lack of appropriately matched or not strictly healthy controls, and/or the lack of stringent exercise conditions in these studies.
We conclude that patients with classic CAH have impaired stress-induced adrenomedullary capacity, leading to defective glucose elevation and possibly reduced heart rate during exercise. None of our patients experienced hypoglycemia. It remains to be determined whether E deficiency decreases endurance and/or poses a risk for hypoglycemia during long-term physical stress.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Abbreviations: CAH, Congenital adrenal hyperplasia; E, epinephrine; FFA, free fatty acid; NE, norepinephrine; RPE, rating of perceived exertion; VO2, oxygen uptake; VO2max, maximal aerobic capacity.
Received April 11, 2003.
Accepted October 27, 2003.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  D. P. Merke Approach to the Adult with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 653 - 660. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Green-Golan, C. Yates, B. Drinkard, C. VanRyzin, G. Eisenhofer, M. Weise, and D. P. Merke Patients with Classic Congenital Adrenal Hyperplasia Have Decreased Epinephrine Reserve and Defective Glycemic Control during Prolonged Moderate-Intensity Exercise J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 3019 - 3024. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Kingsley, M. Varman, A. Chatterjee, R. A. Kingsley, and K. S. Roth Immunizations for Patients With Metabolic Disorders Pediatrics, August 1, 2006; 118(2): e460 - e470. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Jacobson, T. Ansari, J. Potts, and O. P. McGuinness Glucocorticoid-deficient corticotropin-releasing hormone knockout mice maintain glucose requirements but not autonomic responses during repeated hypoglycemia Am J Physiol Endocrinol Metab, July 1, 2006; 291(1): E15 - E22. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Jackson, F. L. R. Williams, A. Burchell, M. W. H. Coughtrie, and R. Hume Plasma Catecholamines and the Counterregulatory Responses to Hypoglycemia in Infants: A Critical Role for Epinephrine and Cortisol J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6251 - 6256. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. G. Forest Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency Hum. Reprod. Update, November 1, 2004; 10(6): 469 - 485. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Stewart Adrenal Replacement Therapy: Time for an Inward Look to the Medulla? J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3677 - 3678. [Full Text] [PDF]
|
|
|
|
|
|
M. Weise, B. Drinkard, S. L. Mehlinger, S. M. Holzer, G. Eisenhofer, E. Charmandari, G. P. Chrousos, and D. P. Merke Stress Dose of Hydrocortisone Is Not Beneficial in Patients with Classic Congenital Adrenal Hyperplasia Undergoing Short-Term, High-Intensity Exercise J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3679 - 3684. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
) and in healthy matched controls (
). Data are presented as mean ± SEM. Baseline levels were drawn 10 min before start of exercise test. Peak exercise refers to the 20-min time point according to protocol or the time point of stopping exercise in subjects who were not able to complete the 20 min of exercising. To convert values to pmol/liter, multiply by 5.458 for epinephrine and by 5.911 for norepinephrine. Epinephrine: ANOVA, P < 0.01; t test (post hoc). **, P < 0.01, CAH vs. healthy controls.
). Data are presented as mean ± SEM. Shaded areas indicate time period of exercise. During the maximal exercise test, the number of subjects decreased with increasing time because individual maximal exercise capacity was reached at different time points (no statisitical analysis performed). Time point 0 min refers to the start of the exercise test after a 3-min warm-up without pedaling resistance. For the standardized exercise test, 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 values to mmol/liter, multiply by 0.0555. ANOVA, P < 0.01, t test (post hoc). *, P < 0.05; **, P < 0.01; ***, P < 0.001, CAH vs. healthy controls.
