Absence of Exercise-Induced Leptin Suppression Associated with Insufficient Epinephrine Reserve in Patients with Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

Abstract

Objective: Patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency suffer from glucocorticoid and mineralocorticoid deficiency. They have insufficient epinephrine reserves and increased basal leptin levels and are often insulin resistant. In healthy subjects, an inhibitory effect of acute catecholamine elevation on the leptin plasma concentrations has been reported. However, it is not yet known how leptin levels respond to exercise in CAH patients. Methods: We performed a cycle ergometer test in six CAH patients to measure the response of plasma leptin, glucose and the catecholamines, epinephrine (E) and norepinephrine (N), as well as their respective metabolites, metanephrine (M) and normetanephrine (NM), to intense exercise. Results: Baseline leptin concentrations in CAH patients were not different from those of controls. Leptin levels decreased significantly with exercise in healthy controls, whereas they remained unchanged in CAH patients. In contrast to controls, CAH patients showed no rise of plasma glucose. Basal and stimulated E and M levels were significantly lower in CAH patients compared to controls. Baseline and stimulated N and NM levels were comparable, showing a significant rise after exercise. Peak systolic blood pressure and peak heart rate in both groups were comparable. Conclusion: CAH patients do not manifest exercise-induced leptin suppression. The most probable reason for this is their severely impaired epinephrine stress response. In addition, epinephrine deficiency is leading to secondary changes in various catecholamine dependent metabolic pathways, e. g., energy balance. Although obvious clinical sequelae are so far unknown, the catecholamine-deficient state and the resulting hyperleptinemia might contribute to the severity of the disease in CAH.

Congenital adrenal hyperplasia - leptin - physical exercise

References

• 1 Biason-Lauber A, Zachmann M, Schoenle E J. Effect of leptin on CYP17 enzymatic activities in human adrenal cells: new insight in the onset of adrenarche.  Endocrinology. 2000;  141 1446-1454
• 2 Blum W F, Englaro P, Hanitsch S, Juul A, Hertel N T, Muller J, Skakkebaek N E, Heiman M L, Birkett M, Attanasio A M, Kiess W, Rascher W. Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone.  J Clin Endocrinol Metab. 1997;  82 2904-2910
• 3 Bornstein S R, Breidert M, Ehrhart-Bornstein M, Kloos B, Scherbaum W A. Plasma catecholamines in patients with Addison's disease.  Clin Endocrinol (Oxf). 1995;  42 215-218
• 4 Bornstein S R, Tajima T, Eisenhofer G, Haidan A, Aguilera G. Adrenomedullary function is severely impaired in 21-hydroxylase-deficient mice.  FASEB J. 1999;  13 1185-1194
• 5 Bottner A, Eisenhofer G, Torpy D J, Ehrhart-Bornstein M, Keiser H R, Chrousos G P, Bornstein S R. Lack of leptin suppression in response to hypersecretion of catecholamines in pheochromocytoma patients.  Metabolism. 1999;  48 543-545
• 6 Bottner A, Haidan A, Eisenhofer G, Kristensen K, Castle A L, Scherbaum W A, Schneider H, Chrousos G P, Bornstein S R. Increased body fat mass and suppression of circulating leptin levels in response to hypersecretion of epinephrine in phenylethanolamine-N-methyltransferase (PNMT)-overexpressing mice.  Endocrinology. 2000;  141 4239-4246
• 7 Carulli L, Ferrari S, Bertolini M, Tagliafico E, Del Rio G. Regulation of ob gene expression: evidence for epinephrine-induced suppression in human obesity.  J Clin Endocrinol Metab. 1999;  84 3309-3312
• 8 Charmandari E, Weise M, Bornstein S R, Eisenhofer G, Keil M F, Chrousos G P, Merke D P. 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
• 9 Cohen P, Miyazaki M, Socci N D, Hagge-Greenberg A, Liedtke W, Soukas A A, Sharma R, Hudgins L C, Ntambi J M, Friedman J M. Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss.  Science. 2002;  297 240-243
• 10 Cryer P E. Adrenaline: a physiological metabolic regulatory hormone in humans?.  Int J Obes Relat Metab Disord. 1993;  17 S43-46 S68 (discussion)
• 11 Davies C T, Few J D. Effects of exercise on adrenocortical function.  J Appl Physiol. 1973;  35 887-891
• 12 Ehrhart-Bornstein M, Bornstein S R, Gonzalez-Hernandez J, Holst J J, Waterman M R, Scherbaum W A. Sympathoadrenal regulation of adrenocortical steroidogenesis.  Endocr Res. 1995;  21 13-24
• 13 Eisenhofer G, Friberg P, Pacak K, Goldstein D S, Murphy D L, Tsigos C, Quyyumi A A, Brunner H G, Lenders J W. Plasma metadrenalines: do they provide useful information about sympatho-adrenal function and catecholamine metabolism?.  Clin Sci (Lond). 1995 a;  88 533-542
• 14 Eisenhofer G, Rundquist B, Aneman A, Friberg P, Dakak N, Kopin I J, Jacobs M C, Lenders J W. Regional release and removal of catecholamines and extraneuronal metabolism to metanephrines.  J Clin Endocrinol Metab. 1995 b;  80 3009-3017
• 15 Galbo H, Holst J J, Christensen N J. The effect of different diets and of insulin on the hormonal response to prolonged exercise.  Acta Physiol Scand. 1979;  107 19-32
• 16 Glasow A, Haidan A, Hilbers U, Breidert M, Gillespie J, Scherbaum W A, Chrousos G P, Bornstein S R. Expression of Ob receptor in normal human adrenals: differential regulation of adrenocortical and adrenomedullary function by leptin.  J Clin Endocrinol Metab. 1998;  83 4459-4466
• 17 Groschl M, Wagner R, Dorr H G, Blum W, Rascher W, Dotsch J. Variability of leptin values measured from different sample matrices.  Horm Res. 2000;  54 26-31
• 18 Halaas J L, Gajiwala K S, Maffei M, Cohen S L, Chait B T, Rabinowitz D, Lallone R L, Burley S K, Friedman J M. Weight-reducing effects of the plasma protein encoded by the obese gene.  Science. 1995;  269 543-546
• 19 Halleux C M, Servais I, Reul B A, Detry R, Brichard S M. Multihormonal control of ob gene expression and leptin secretion from cultured human visceral adipose tissue: increased responsiveness to glucocorticoids in obesity.  J Clin Endocrinol Metab. 1998;  83 902-910
• 20 Hebestreit H, Lawrenz W, Zelger O, Kienast W, Jüngst B K. Ergometry in childhood and adolescence.  Monatsschr Kinderheilkd. 1997;  145 1326-1336
• 21 Kain Z N, Zimolo Z, Heninger G. Leptin and the perioperative neuroendocrinological stress response.  J Clin Endocrinol Metab. 1999;  84 2438-2442
• 22 Kindermann W, Schnabel A, Schmitt W M, Biro G, Cassens J, Weber F. Catecholamines, growth hormone, cortisol, insulin, and sex hormones in anaerobic and aerobic exercise.  Eur J Appl Physiol Occup Physiol. 1982;  49 389-399
• 23 Kosaki A, Yamada K, Kuzuya H. Reduced expression of the leptin gene (ob) by catecholamine through a G(S) protein-coupled pathway in 3T3-L1 adipocytes.  Diabetes. 1996;  45 1744-1749
• 24 Merke D P, Chrousos G P, Eisenhofer G, Weise M, Keil M F, Rogol A D, Van Wyk J J, Bornstein S R. Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency.  N Engl J Med. 2000;  343 1362-1368
• 25 Miell J P, Englaro P, Blum W F. Dexamethasone induces an acute and sustained rise in circulating leptin levels in normal human subjects.  Horm Metab Res. 1996;  28 704-707
• 26 Miller W L. Clinical review 54: Genetics, diagnosis, and management of 21-hydroxylase deficiency.  J Clin Endocrinol Metab. 1994;  78 241-246
• 27 Pralong F P, Roduit R, Waeber G, Castillo E, Mosimann F, Thorens B, Gaillard R C. Leptin inhibits directly glucocorticoid secretion by normal human and rat adrenal gland.  Endocrinology. 1998;  139 4264-4268
• 28 Reinken L, van Oost G. Longitudinal physical development of healthy children 0 to 18 years of age. Body length/height, body weight and growth velocity.  Klin Padiatr. 1992;  204 129-133
• 29 Rudman D, Moffitt S D, Fernhoff P M, Blackston R D, Faraj B A. Epinephrine deficiency in hypocorticotropic hypopituitary children.  J Clin Endocrinol Metab. 1981;  53 722-729
• 30 Slieker L J, Sloop K W, Surface P L, Kriauciunas A, LaQuier F, Manetta J, Bue-Valleskey J, Stephens T W. Regulation of expression of ob mRNA and protein by glucocorticoids and cAMP.  J Biol Chem. 1996;  271 5301-5304
• 31 Speiser P W, White P C. Congenital adrenal hyperplasia.  N Engl J Med. 2003;  349 776-788
• 32 van Aggel-Leijssen D P, van Baak M A, Tenenbaum R, Campfield L A, Saris W H. Regulation of average 24 h human plasma leptin level; the influence of exercise and physiological changes in energy balance.  Int J Obes Relat Metab Disord. 1999;  23 151-158
• 33 Weise M, Mehlinger S L, Drinkard B, Rawson E, Charmandari E, Hiroi M, Eisenhofer G, Yanovski J A, Chrousos G P, Merke D P. 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
• 34 Willemsen J J, Ross H A, Jacobs M C, Lenders J W, Thien T, Swinkels L M, Benraad T J. Highly sensitive and specific HPLC with fluorometric detection for determination of plasma epinephrine and norepinephrine applied to kinetic studies in humans.  Clin Chem. 1995;  41 1455-1460
• 35 Willemsen J J, Sweep C G, Lenders J W, Ross H A. Stability of plasma free metanephrines during collection and storage as assessed by an optimized HPLC method with electrochemical detection.  Clin Chem. 2003;  49 1951-1953
• 36 Wortsman J, Frank S, Cryer P E. Adrenomedullary response to maximal stress in humans.  Am J Med. 1984;  77 779-784
• 37 Wurtman R J, Axelrod J. Control of enzymatic synthesis of adrenaline in the adrenal medulla by adrenal cortical steroids.  J Biol Chem. 1966;  241 2301-2305
• 38 Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman J M. Positional cloning of the mouse obese gene and its human homologue.  Nature. 1994;  372 425-432
• 39 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