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DOI: 10.1055/s-0030-1253385
© Georg Thieme Verlag KG Stuttgart · New York
Adrenomedullary Function in Patients with Nonclassic Congenital Adrenal Hyperplasia
Publication History
received 14.12.2009
accepted 07.04.2010
Publication Date:
05 May 2010 (online)
Abstract
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is classified into three types based on disease severity: classic salt-wasting, classic simple virilizing, and nonclassic. Adrenomedullary dysplasia and epinephrine deficiency have been described in classic CAH, resulting in glucose dysregulation. Our objective was to investigate adrenomedullary function in nonclassic CAH and to evaluate adrenomedullary function according to disease severity. Adrenomedullary function was evaluated in response to a standardized cycle ergonometer test in 23 CAH patients (14 females, age 9–38 years; 6 salt-wasting, 7 simple virilizing, 5 nonclassic receiving glucocorticoid treatment, 5 nonclassic not receiving glucocorticoid), and 14 controls (7 females, age 12–38 years). Epinephrine, glucose, and cortisol were measured at baseline and peak exercise. CAH patients and controls were similar in age and anthropometric measures. Patients with nonclassic CAH who were not receiving glucocorticoid and controls experienced the expected stress-induced rise in epinephrine, glucose, and cortisol. Compared to controls, patients with all types of CAH receiving glucocorticoid had impaired exercise-induced changes in epinephrine (salt-wasting: p=0.01;simple virilizing: p=0.01; nonclassic: p=0.03), and cortisol (salt-wasting: p=0.004; simple virilizing: p=0.006; nonclassic: p=0.03). Salt-wasting patients displayed the most significant impairment, including impairment in glucose response relative to controls (p=0.03). Hydrocortisone dose was negatively correlated with epinephrine response (r=−0.58; p=0.007) and glucose response (r=−0.60; p=0.002). The present study demonstrates that untreated patients with nonclassic CAH have normal adrenomedullary function. The degree of epinephrine deficiency in patients with CAH is associated with the severity of adrenocortical dysfunction, as well as glucocorticoid therapy.
Key words
glucocorticoids - epinephrine - adrenal cortex - adrenal medulla
References
- 1 Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005; 365 2125-2136
- 2 Speiser PW, Dupont J, Zhu D, Serrat J, Buegeleisen M, Tusie-Luna M, New MI, White PC. Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Invest. 1992; 90 584-595
- 3 Boikos SA, Horvath A, Heyerdahl S, Stein E, Robinson-White A, Bossis I, Bertherat J, Carney JA, Stratakis CA. Phosphodiesterase 11A expression in the adrenal cortex, primary pigmented nodular adrenocortical disease, and other corticotropin-independent lesions. Horm Metab Res. 2008; 40 347-353
- 4 Kuulasmaa T, Jaaskelainen J, Suppola S, Pietilainen T, Heikkila P, Aaltomaa S, Kosma VM, Voutilainen R. WNT-4 mRNA expression in human adrenocortical tumors and cultured adrenal cells. Horm Metab Res. 2008; 40 668-673
- 5 Powers JF, Picard KL, Tischler AS. RET expression and neuron-like differentiation of pheochromocytoma and normal chromaffin cells. Horm Metab Res. 2009; 41 710-714
- 6 Merke DP, Chrousos GP, Eisenhofer G, Weise M, Keil MF, Rogol AD, Van Wyk JJ, Bornstein SR. Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency. N Engl J Med. 2000; 343 1362-1368
- 7 Weise M, Drinkard B, Mehlinger SL, Holzer SM, Eisenhofer G, Charmandari E, Chrousos GP, Merke DP. Stress dose of hydrocortisone is not beneficial in patients with classic congenital adrenal hyperplasia undergoing short-term, high-intensity exercise. J Clin Endocrinol Metab. 2004; 89 3679-3684
- 8 Weise M, Mehlinger SL, Drinkard B, Rawson E, Charmandari E, Hiroi M, Eisenhofer G, Yanovski JA, Chrousos GP, Merke DP. Patients with classic congenital adrenal hyperplasia have decreased epinephrine reserve and defective glucose elevation in response to high-intensity exercise. J Clin Endocrinol Metab. 2004; 89 591-597
- 9 Green-Golan L, Yates C, Drinkard B, VanRyzin C, Eisenhofer G, Weise M, Merke DP. Patients with classic congenital adrenal hyperplasia have decreased epinephrine reserve and defective glycemic control during prolonged moderate-intensity exercise. J Clin Endocrinol Metab. 2007; 92 3019-3024
- 10 Riepe FG, Krone N, Kruger SN, Sweep FC, Lenders JW, Dotsch J, Monig H, Sippell WG, Partsch CJ. Absence of exercise-induced leptin suppression associated with insufficient epinephrine reserve in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Exp Clin Endocrinol Diabetes. 2006; 114 105-110
- 11 Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 1982; 14 377-381
- 12 Eisenhofer G, Goldstein DS, Stull R, Keiser HR, Sunderland T, Murphy DL, Kopin IJ. 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. 1986; 32 2030-2033
-
13
Center for Disease Control.
Epi Info™. In. 3.3.2 ed
2000;
- 14 Ehrhart-Bornstein M, Breidert M, Guadanucci P, Wozniack W, Bocian-Sobkowska J, Malendowicz LK, Bornstein SR. 17 alpha-Hydroxylase and chromogranin A in 6th week human fetal adrenals. Horm Metab Res. 1997; 29 30-32
- 15 Ehrhart-Bornstein M, Bornstein SR. Cross-talk between adrenal medulla and adrenal cortex in stress. Ann N Y Acad Sci. 2008; 1148 112-117
- 16 Wurtman RJ, Pohorecky LA. Adrenocortical control of epinephrine synthesis in health and disease. Adv Metab Disord. 1971; 5 53-76
- 17 Linder BL, Esteban NV, Yergey AL, Winterer JC, Loriaux DL, Cassorla F. Cortisol production rate in childhood and adolescence. J Pediatr. 1990; 117 892-896
- 18 Bidet M, Bellanne-Chantelot C, Galand-Portier M-B, Tardy V, Billaud L, Laborde K, Coussieu C, Morel Y, Vaury C, Golmard J-L, Claustre A, Mornet E, Chakhtoura Z, Mowszowicz I, Bachelot A, Touraine P, Kutten F. Clinical and molecular characterization of a cohort of 161 unrelated women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency and 330 family members. J Clin Endocrinol Metab. 2009; 94 1570-1578
- 19 Charmandari E, Eisenhofer G, Mehlinger SL, Carlson A, Wesley R, Keil MF, Chrousos GP, New MI, Merke DP. Adrenomedullary function may predict phenotype and genotype in classic 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2002; 87 3031-3037
- 20 Marker JC, Hirsch IB, Smith LJ, Parvin CA, Holloszy J O, Cryer PE. Catecholamines in prevention of hypoglycemia during exercise in humans. Am J Physiol. 1991; 260 E705-E712
- 21 Galbo H, Christensen NJ, Mikines KJ, Sonne B, Hilsted J, Hagen C, Fahrenkrug J. The effect of fasting on the hormonal response to graded exercise. J Clin Endocrinol Metab. 1981; 52 1106-1112
- 22 Fellmann N, Coudert J. [Physiology of muscular exercise in children (author's transl)]. Arch Pediatr. 1994; 1 827-840
- 23 Hansen IL, Levy MM, Kerr DS. Differential diagnosis of hypoglycemia in children by responses to fasting and 2-deoxyglucose. Metabolism. 1983; 32 960-970
- 24 Kruse K, Bartels H. [Significance of the 2-deoxy-d-glucose-test on the differentiation of hypoglycemia in childhood (author's transl)]. Klin Padiatr. 1975; 187 308-313
- 25 Sizonenko PC, Paunier L, Vallotton B, Cuendet GS, Zahnd G, Marliss EB. Response to 2-deoxy-D-glucose and to glucagon in “ketotic hypoglycemia” of childhood: evidence for epinephrine deficiency and altered alanine availability. Pediatr Res. 1973; 7 983-993
- 26 Tietze HU, Zurbrugg RP, Zuppinger KA, Joss EE, Kaser H. Occurrence of impaired cortisol regulation in children with hypoglycemia associated with adrenal medullary hyporesponsiveness. J Clin Endocrinol Metab. 1972; 34 948-958
- 27 Bao S, Briscoe VJ, Tate DB, Davis SN. Effects of differing antecedent increases of plasma cortisol on counterregulatory responses during subsequent exercise in type 1 diabetes. Diabetes. 2009; 58 2100-2108
- 28 Zuckerman-Levin N, Tiosano D, Eisenhofer G, Bornstein S, Hochberg Z. The importance of adrenocortical glucocorticoids for adrenomedullary and physiological response to stress: a study in isolated glucocorticoid deficiency. J Clin Endocrinol Metab. 2001; 86 5920-5924
- 29 Artavia-Loria E, Chaussain JL, Bougneres PF, Job JC. Frequency of hypoglycemia in children with adrenal insufficiency. Acta Endocrinol Suppl (Copenh). 1986; 279 275-278
- 30 Hinde FR, Johnston DI. Hypoglycaemia during illness in children with congenital adrenal hyperplasia. Br Med J (Clin Res Ed). 1984; 289 1603-1604
- 31 Donaldson MD, Thomas PH, Love JG, Murray JD, McNinch AW, Savage DC. Presentation, acute illness, and learning difficulties in salt wasting 21-hydroxylase deficiency. Arch Dis Child. 1994; 70 214-218
- 32 Mackinnon J, Grant DB. Hypoglycaemia in congenital adrenal hyperplasia. Arch Dis Child. 1977; 52 591-593
- 33 Charmandari E, Weise M, Bornstein SR, Eisenhofer G, Keil MF, Chrousos G, Merke DP. Children with classic congenital adrenal hyperplasia have elevated serum leptin concentrations and insulin resistance: potential clinical implications. J Clin Endocrinol Metab. 2002; 87 2114-2120
- 34 Bidet M, Bellanne-Chantelot C, Galand-Portier MB, Golmard J-L, Tardy V, Morel Y, Clauin S, Coussieu C, Boudou P, Mowzowicz I, Bachelot A, Touraine P, Kutten F. Fertility in women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2010; 95 1182-1190
Correspondence
D. P. MerkeMD, MS
NIH
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Email: dmerke@nih.gov