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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0493
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 8 3019-3024
Copyright © 2007 by The Endocrine Society

Patients with Classic Congenital Adrenal Hyperplasia Have Decreased Epinephrine Reserve and Defective Glycemic Control during Prolonged Moderate-Intensity Exercise

Liza Green-Golan, Catherine Yates, Bart Drinkard, Carol VanRyzin, Graeme Eisenhofer, Martina Weise and Deborah P. Merke

National Institutes of Health Clinical Center (L.G.-G., C.V., D.P.M.), Pediatric Endocrinology (C.Y.), Walter Reed Army Medical Center, Washington, D.C. 20307; and Rehabilitation Medicine Department (B.D.), Clinical Neurocardiology Section (G.E.) of National Institute of Neurological Disorders and Stroke, Reproductive Biology and Medicine Branch (M.W., D.P.M.) of National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Deborah P. Merke, M.D., M.S., National Institutes of Health Clinical Center, Building 10-CRC, Room 1-2740, Bethesda, Maryland 20892-1932. E-mail: dmerke{at}mail.nih.gov.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Patients with classic congenital adrenal hyperplasia (CAH) have adrenomedullary dysplasia and hypofunction, and their lack of adrenomedullary reserve has been associated with a defective glucose response to brief high-intensity exercise.

Objective: Our objective was to assess hormonal, metabolic, and cardiovascular response to prolonged moderate-intensity exercise comparable to brisk walking in adolescents with classic CAH.

Subjects and Methods: We compared six adolescents with classic CAH (16–20 yr old) with seven age-, sex-, and body mass index group-matched controls (16–23 yr old) using a 90-min standardized ergometer test. Metabolic, hormonal, and cardiovascular parameters were studied during exercise and recovery.

Results: Glucose did not change throughout exercise and recovery for controls, whereas CAH patients showed a steady decline in glucose during exercise with an increase in glucose in the postexercise period. Glucose levels were significantly lower in CAH patients at 60 (P = 0.04), 75 (P = 0.01), and 90 (P = 0.03) min of exercise and 15 (P = 0.02) min post exercise, whereas glucose levels were comparable between the two groups early in exercise and at 30 min (P = 0.19) post exercise. As compared with controls, CAH patients had significantly lower epinephrine (P = 0.002) and cortisol (P ≤ 0.001) levels throughout the study and similar norepinephrine, glucagon, and GH levels. Patients with CAH and controls had comparable cardiovascular parameters and perceived level of exertion. Despite having lower glucose levels, insulin levels were slightly higher in CAH patients during the testing period (P = 0.17), suggesting insulin insensitivity.

Conclusion: CAH patients have defective glycemic control and altered metabolic and hormonal responses during prolonged moderate-intensity exercise comparable to brisk walking.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CONGENITAL ADRENAL HYPERPLASIA (CAH) due to 21-hydroxylase deficiency is an autosomal recessive disease characterized by cortisol and aldosterone deficiency and androgen excess. The adrenal medulla, which synthesizes and secretes epinephrine, has been shown to be morphologically and functionally impaired in patients with classic CAH (1, 2). These adrenomedullary abnormalities are most likely due to a deficit in adrenal cortical glucocorticoid secretion because glucocorticoid secretion is necessary for adrenomedullary organogenesis and adrenomedullary epinephrine synthesis (3).

Catecholamines are released in response to physical stressors such as illness, trauma, or exercise. Plasma epinephrine is almost exclusively derived from the adrenal medulla, whereas plasma norepinephrine is predominantly derived from sympathetic nerve endings. Epinephrine influences heart rate and blood pressure and helps regulate blood glucose levels. We previously reported that patients with CAH had decreased epinephrine secretion with a lack of the normal exercise-induced rise in blood glucose during high-intensity short-term exercise (2). Patients with classic CAH have also been shown to lack the normal exercise-induced leptin suppression during high-intensity short-term exercise (4). This abnormal leptin response was also associated with insufficient epinephrine reserve and secretion. In general, catecholamines are thought to be most important under conditions of high metabolic stress, such as intense exercise, but less important in low intensity stress (5). The physiological response to low-intensity and/or long-term exercise in CAH patients is unknown.

Although several physical stressors are capable of eliciting physiological responses in the body, exercise is natural, quantifiable in terms of workload and duration, and a known stimulus of the adrenal medulla and systemic sympathetic nervous system (6). The clinical implications of epinephrine deficiency in humans are not fully understood. To evaluate further the metabolic and hormonal consequences of epinephrine deficiency, we evaluated adrenomedullary response, counterregulatory hormones, and cardiovascular and metabolic parameters in patients with classic CAH, compared with healthy controls, during a standardized 90-min moderate intensity exercise test comparable to brisk walking.


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

Six (three male) adolescent patients with classic CAH (age 16–20 yr) and seven (four male) age-, sex- and body mass index (BMI) group-matched controls (age 16–23 yr) participated in this study. All patients with CAH were otherwise healthy and receiving conventional therapy (glucocorticoid and mineralocorticoid). Patients with CAH were receiving glucocorticoid replacement with hydrocortisone (mean dose, 15.7 mg/m2·dl; range, 13.2–17.9 mg/m2·d) and fludrocortisone (mean dose, 105 µg/d; range, 75–150 µg/d). All were in good clinical control as defined by the following criteria: 1) 17-OH-progesterone levels between 100 and 1500 ng/dl (3 and 45 nmol/liter), 2) plasma renin activity within the normal reference range, and 3) no new signs or symptoms of virilization in females. Screening visits included a medical history, physical examination, pregnancy test in females, and a baseline electrocardiogram to establish eligibility for exercise testing, as defined by the American Heart Association (7). Pubertal stage was assessed by physical examination according to the criteria of Tanner for breast development in females (8) and according to a modified genital staging method based on the average volume of both testes in males (9). Specifically, testicular volumes less than 4 ml were defined as stage 1; 4 ml to less than 8 ml were defined as stage 2; 8 ml to less than 12 ml were defined as stage 3; 12 ml to less than 15 ml were defined as stage 4; and at least 15 ml, stage 5. The study was approved by the National Institute of Child Health and Human Development Institutional Review Board. All adult subjects and parents of participating children gave written informed consent. All children gave their assent.

Study protocol

All exercise tests were performed in the morning after an overnight fast (water permitted), and subjects were instructed to avoid caffeinated foods and drinks, alcohol, and strenuous exercise for at least 24 h before each exercise session. One hour before each test, subjects drank one teaspoon of water per kilogram body weight to provide adequate hydration and received their usual morning hydrocortisone dose. Also at this time, an indwelling line was placed in the forearm of each subject so that blood could be drawn before, during, and after exercise testing. Blood was analyzed for epinephrine, norepinephrine, glucose, insulin, cortisol, ACTH, glucagon, and GH. To identify hypoglycemia, whole-blood glucose (Lifescan; Johnson and Johnson, New Brunswick, NJ) readings were obtained regularly during exercise. A recovery period followed each exercise session. Subjects pedaled with unloaded resistance until heart rate returned to less than 120 beats/min and subsequently rested in a chair.

A cycle ergometer (SensorMedics Ergoline 800; SenseorMedics Corp., Yorba Linda, CA) was used for all exercise testing. Subjects were prepped with electrodes for continuous monitoring with a 12-lead electrocardiogram (MAX 1; SensorMedics) and fitted with a nose clip and mouthpiece assembly for measurement of oxygen uptake (VO2) 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. To assess rating of perceived exertion at the end of each testing session, subjects used a Borg Scale rating (10).

All subjects completed two exercise sessions, a maximal test on d 1 and a 90-min standardized test on d 2. The maximal test was an incremental exercise test to exhaustion to document maximal aerobic capacity (VO2) and anaerobic threshold (AT). The maximal test included a 3-min warm-up (with unloaded pedaling resistance) followed by a continuous increase in workload until the subject reached exhaustion. Based on predicted maximal power, the work rate for each subject increased to elicit maximal effort within 8–12 min. Oxygen uptake during the final 20 sec of exercise was used as a measure of VO2 max, and the V-slope (11) method was used to determine the AT. The VO2 max and AT levels obtained from the d-1 maximal test were used to standardize the d-2 90-min exercise test and to ensure that each subject exercised at the same level of intensity (comparable to brisk walking). The d-2 standardized session included a 3-min warm-up, 90 min of exercise at 80% of the individual’s previously determined AT, and a 5-min cool-down (pedaling without resistance).

Assays

Plasma epinephrine and norepinephrine were determined by HPLC with electrochemical detection (12). The detection limits of the assay were 1–2 pg/ml (5.5–10.9 pmol/liter). Cortisol, insulin, and ACTH were measured using a competitive chemiluminescence immunoassay, and glucose was measured in heparinized whole blood by specific sensitive electrodes. The cortisol assay has a sensitivity of 1 µg/dl and has interassay coefficients of variation (CV) of 11.1, 7.5, and 10% at 3.3, 22.4, and 35.6 µg/dl, respectively. The insulin assay has a sensitivity of 2 µU/ml and CV of 6.2 and 4.9% at 8.13 and 61.7 µU/ml, respectively. The ACTH assay has a sensitivity of less than 5 pg/ml and CV of 1.7 and 2.3% at 26.5 and 379 pg/ml, respectively. The glucose assay has a sensitivity of 3 mg/dl and CV of 2.7, 1.6, and 1.3% at 11.43, 98, and 251 mg/dl, respectively. Lactate levels were measured using the Synchron Systems LX-20 assay. This assay has a sensitivity of 0.3 mmol/liter and CV of 2.5, 2.5, and 2.6% at 1.1, 3.7, and 4.8 mmol/liter, respectively. These tests were performed at the Department of Laboratory Medicine of the National Institutes of Health Clinical Center (Bethesda, MD). Serum glucagon and GH assays were performed at Esoterix, Inc. (Calabasas Hills, CA). Glucagon concentrations were determined by double-antibody RIA with a sensitivity of 10 pg/ml. The CVs were 6.7, 5.0, and 3.4% at 47, 66, and 154 pg/ml, respectively. GH concentrations were determined by a two-site immunometric assay with a minimal detectable concentration of 0.05 ng/ml. The CV were 14, 5.2, and 3.8% at 0.08, 0.94, and 2.5 ng/ml respectively.

Statistical analysis

Height SD score, weight SD score, and BMI SD score were determined using anthropometric reference data for U.S. children (13). Differences between CAH patients and healthy controls were assessed using a t test for parameters with one measurement and a two-factor repeated-measures ANOVA for parameters with serial measurements. In the case of statistical significance (P < 0.05) for serial measurements, post hoc analysis was performed using a t test to determine the time point 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
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Patients with CAH and healthy controls were similar in age, height, weight, BMI, and pubertal stage (Table 1Go). These similarities held for male and female subgroups (data not shown). Patients with CAH and healthy controls had comparable systolic (P = 0.57) and diastolic (P = 0.95) blood pressure and heart rate (P = 0.63) throughout exercise and recovery (Fig. 1Go). Perceived levels of exertion based on the Borg scale (P = 0.31) and VO2 max (P = 0.31) were similar between patients and controls. Patients and controls had similar metabolic equivalent values as defined by the ratio of work metabolic rate to a standard resting metabolic rate (14). Based on this scale, patients and controls exercised at an energy expenditure rate comparable to brisk walking (14). Plasma lactate levels were similar between patients and controls throughout exercise and recovery (P = 0.47). Thus, both groups had comparable tolerance for exercise.


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  		TABLE 1. Group characteristics of patients with CAH and healthy controls

 

Figure 1
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  		FIG. 1. Systolic and diastolic BP and heart rate during exercise and recovery in patients with CAH (•) and in healthy matched controls ({circ}). Data are presented as mean ± SEM. Shaded areas indicate time period of exercise.

 
Compared with healthy controls, patients with CAH had significantly lower plasma epinephrine levels throughout exercise and recovery (P = 0.002) (Fig. 2AGo). Norepinephrine levels, however, were similar between patients and controls throughout the entire testing session (P = 0.54) (Fig. 2BGo).


Figure 2
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  		FIG. 2. Serum or plasma levels of epinephrine, norepinephrine, glucose, insulin, cortisol, ACTH, glucagon, and GH in patients with CAH (•) and healthy matched controls ({circ}). Data are presented as mean ± SEM. Shaded areas indicate time period of exercise. Conversion factors for calculation of SI units are as follows: epinephrine, pg/ml x 5.461 = pmol/liter; norepinephrine, pg/ml x 5.911 = pmol/liter; glucose, mg/dl x 0.055 = mmol/liter; insulin, µU/ml x 7.175 = pmol/liter; cortisol, µg/dl x 27.586 = nmol/liter; ACTH, pg/ml x 0.222 = pmol/liter; glucagon, pg/ml x 1 = ng/liter; GH, ng/ml x 1 = µg/liter. *, P < 0.05; **, P ≤ 0.01, post hoc analysis.

 
Patients with CAH and healthy controls had similar baseline glucose levels (P = 0.44), but glucose levels were different between the two groups throughout the study (P = 0.05). Glucose did not change throughout exercise and recovery for healthy controls, whereas patients with CAH showed a steady decline in glucose during exercise with an increase in levels during recovery (Fig. 2CGo). In the analysis of specific time points, glucose levels were significantly lower in patients with CAH at 60 (P = 0.04), 75 (P = 0.01), and 90 (P = 0.03) min of exercise and 15 min (P = 0.02) post exercise (Fig. 2CGo). CAH patients did not have overt hypoglycemia at any point during exercise testing and did not experience any glucopenic symptoms. Despite having lower glucose levels, insulin levels were slightly higher in CAH patients during the testing period, but this difference failed to reach statistical significance (P = 0.17) (Fig. 2DGo).

Similarly, patients with CAH and healthy controls had similar baseline cortisol levels (P = 0.67), but overall cortisol levels differed between the two groups (P = 0.001). As expected, CAH patients experienced a decline in cortisol during exercise, whereas healthy controls experienced an increase in cortisol after 60 min of exercise (Fig. 2EGo). ACTH levels were similar between the two groups throughout exercise and recovery (P = 0.57) but tended to be higher in the patients with CAH.

During exercise and recovery, glucagon levels tended to be higher in healthy controls (P = 0.14) (Fig. 2GGo) and GH levels somewhat higher in patients with CAH (P = 0.11) (Fig. 2HGo), but these differences did not reach statistical significance. In both groups, GH levels rose during the first part of exercise, peaked, and declined during the second half of exercise and recovery.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our data demonstrate that patients with classic CAH have reduced epinephrine reserve and a decline in blood glucose levels in response to long-term moderate-intensity exercise that is equivalent to brisk walking. Patients with classic CAH failed to maintain the normal flat glucose response to moderate long-term exercise and instead experienced a progressive decline in blood glucose levels. Nevertheless, blood glucose in CAH patients increased to levels comparable to controls post exercise. To our knowledge, this is the first study to examine the physiological, hormonal, and metabolic measures to moderate-intensity prolonged exercise in patients with CAH.

Our epinephrine results are in agreement with current literature describing the dependence of adrenomedullary function on proper adrenocortical glucocorticoid output (15, 16). This output is chronically impaired in patients with CAH, and thus, as in previous studies (1, 2, 4), markedly low levels of plasma epinephrine were observed at baseline. Previous exercise studies in patients with classic CAH reported decreased epinephrine reserve in CAH patients during short-term high-intensity exercise. Our current study supports the notion that impaired epinephrine secretion is also observed with mild to moderate stressors or in situations other than high-intensity physical stressors.

There are few data regarding the clinical significance of low epinephrine levels. Epinephrine is thought to be most important under conditions of high metabolic stress, such as intense exercise or severe illness. Low levels of epinephrine most likely play a role in hypoglycemic crises reported in some patients with CAH during severe illness. One large population study suggests that low resting plasma epinephrine levels were associated with an unfavorable survival rate (17); this finding, however, may be a function of the lower levels of epinephrine in older individuals (18). In our study, epinephrine levels increased approximately 2-fold in our healthy controls. Previous studies of healthy controls reveal a 10- to 20-fold increase in epinephrine during high-intensity exercise. In this setting of mild to moderate epinephrine stimulation, our CAH patients experienced abnormal glucoregulatory control, suggesting that the clinical implications of epinephrine deficiency extend beyond situations of high metabolic stress. Along these lines, chronic epinephrine deficiency has been suggested to play a role in the insulin insensitivity and hyperleptinemia observed in patients with classic CAH (4, 19).

Compensatory increases in sympathetic nerve activity resulting in an increase in norepinephrine secretion have been reported in adrenalectomized patients (20) and patients with Addison’s disease (21) but not in patients with CAH (2, 4). Similarly, in our current study, no significant differences in norepinephrine levels between CAH patients and controls were observed. However, previous exercise studies in patients with CAH used a short-term high-intensity exercise paradigm. Thus, when given a longer time frame (90 min) of exercise, CAH patients were still unable to up-regulate the sympathetic nervous system to produce higher levels of norepinephrine, despite low levels of epinephrine. This supports the notion that the discrepancy in results between patients with CAH and those who acquire cortisol/epinephrine deficiencies later in life may be due to the congenital nature of CAH (1).

In accordance with previous studies (2, 4), CAH patients experienced defective glycemic control during exercise. Multiple factors likely played a role. Most important, the normal exercise-induced rise in epinephrine was absent in the CAH patients. During exercise, epinephrine stimulates gluconeogenesis and glycogenolysis (22) by increasing hepatic glucose output. Glucose progressively declined in patients with CAH, suggesting that the progressive decline in cortisol and lack of adequate counterregulatory response also contributed. The observed decline in cortisol levels during exercise in the CAH patients reflects metabolism of exogenously administered hydrocortisone. Exercise-induced changes in the pancreatic secretion of glucagon and insulin play an important role in the stimulation of hepatic glucose production during long-term exercise, and both glucagon and insulin are influenced by catecholamines. Epinephrine increases glucagon secretion and inhibits insulin secretion via adrenergic receptors (23). Interestingly, controls experienced more of a rise in glucagon and more of a decrease in insulin than patients with CAH, suggesting possible indirect effects of low epinephrine. The lack of statistical significance between the two groups on measures of glucagon and insulin may have been due to our small sample size.

By the end of recovery, glucose levels were comparable between patients and controls, suggesting that other factors besides epinephrine and cortisol were eventually able to aid in the production of glucose once the physical stressor was stopped. GH may have played a protective role in stimulating glucose production because of its ability to stimulate hepatic glucose synthesis. GH, although not significantly different between the two groups, was higher in patients with CAH during exercise and recovery. Although epinephrine increases energy metabolism of exercising muscles by stimulating muscle glycogenolysis during exercise, muscle glycogenolysis can occur in the absence of epinephrine (24). It is likely that factors not measured in this study and possibly even factors independent of hormone levels, played an important role in the prevention of hypoglycemia and the postexercise increase in glucose observed in our CAH patients.

Despite the low glucose levels of patients during exercise, hypoglycemia did not occur at any point during exercise or recovery. However, the progressive decline in glucose levels observed in patients during extended exercise became significant starting at 60 min. Fasting before long periods of exercise and/or during severe illness should be discouraged in patients with classic CAH and would put patients at risk for hypoglycemia. Despite having lower glucose levels, insulin levels were higher in patients with CAH. This difference was not statistically significant but suggests a degree of insulin resistance previously reported in patients with CAH (19, 25).

The clinical question of whether extra hydrocortisone should be administered before exercise was not addressed in this study but was addressed in a previous study of short-term high-intensity exercise (26). In this previous study, diminished adrenomedullary output was not overcome with an extra dose of exogenous hydrocortisone, suggesting that high intraadrenal glucocorticoid levels are needed for proper epinephrine synthesis (26), and alterations in adrenomedullary development and structure may also play a role (1). In our current study of moderate-intensity long-term (90 min) exercise, glucose progressively declined in patients with CAH, suggesting that the progressive decline in cortisol may have played a role. However, despite having a progressive decline in cortisol levels due to metabolism of exogenously administered hydrocortisone, our patients had a rise in blood glucose post exercise. Thus, although it would be prudent to take a usual dose of hydrocortisone before exercise, there is no evidence that additional hydrocortisone before exercise would be beneficial.

Studies describing cardiorespiratory parameters in children and adolescents with CAH and patients with other forms of adrenal insufficiency have yielded mixed results. Under resting conditions, children with CAH have been reported to have elevated daytime systolic and diastolic blood pressure (BP) and to lack a normal dip in nocturnal systolic BP (27). Compared with controls, elevated diastolic BP was reported during exercise in children with isolated glucocorticoid deficiency due to ACTH unresponsiveness (16). Decreased heart rate in response to exercise has been reported in adrenalectomized adults (28). In our previous short-term high-intensity exercise study, we reported that patients had a 5% lower peak heart rate than controls with a normal systolic and diastolic BP (2). Discrepancy of results may be due to different patient populations, different testing protocols, or different treatment practices. We conclude, however, that despite abnormal adrenal function and epinephrine deficiency, patients with CAH have intact cardiorespiratory functioning during prolonged moderate-intensity exercise.

The small sample size of classic CAH patients and controls is an obvious limitation to our study. However, previous exercise studies in patients with CAH (2, 4, 26) and other exercise studies used comparable sample sizes to investigate similar parameters.

We conclude that patients with CAH have defective glycemic control evident in prolonged moderate-intensity exercise. Moreover, CAH patients have difficulty maintaining glucose levels as exercise duration increases. Although the clinical implications of epinephrine deficiency remain to be determined, our study demonstrates altered metabolic and hormonal response in CAH patients during a moderate-intensity stressor equivalent to brisk walking. This suggests that the clinical implications of cortisol and epinephrine deficiency extend beyond situations of extreme physical stress. The adrenal medulla plays an important physiological role that warrants further investigation.


   Acknowledgments
 
We thank the patients and their families for participation in this study.


   Footnotes
 
This research was supported (in part) by the Intramural Research Program of the National Institutes of Health and (in part) by the CARES Foundation.

D.P.M. and B.D. are Commissioned Officers in the U.S. Public Health Service.

Disclosure Statement: L.G.-G., C.Y, B.D, C.V., G.E., M.W., and D.P.M have nothing to declare.

First Published Online May 29, 2007

Abbreviations: AT, Anaerobic threshold; BMI, body mass index; BP, blood pressure; CAH, congenital adrenal hyperplasia; CV, coefficients of variation; VO2, oxygen uptake.

Received March 5, 2007.

Accepted May 22, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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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.
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