ESPE Yearbook of Paediatric Endocrinology

The adrenal cortex and medulla are intimately linked both anatomically and functionally in the adrenal gland (1, 2). Glucocorticoids are essential for the survival and maintenance of chromaffin cells, as well as the production of epinephrine (3, 4). At the transcriptional level, the expression of phenylethanolamine N-methyltransferase (PNMT), the enzyme that converts norepinephrine to epinephrine, depends on glucocorticoids (5). The effect of impaired adrenal function on sympatho-adrenomedullary function has been studied previously in ACTH deficiency (6) and in mice (7) or humans (8) with 21-hydroxylase deficiency. Severe impairment of adrenomedullary function was characterized by alterations in chromaffin cell migration, development, structure, and catecholamine synthesis.

The aim of the present study was to examine the hypothesis that in patients with isolated glucocorticoid deficiency, epinephrine would be suppressed despite replacement therapy, that norepinephrine might be compensatory, and that the physiological response would reflect these changes.

To this end, patients with isolated glucocorticoid deficiency were subjected to three levels of acute stress: assumption of upright posture, cold pressor and exercise. Their catecholamine and physiological response were monitored. Patients with isolated glucocorticoid deficiency had severe adrenomedullary dysfunction, characterized by a minimal resting production of epinephrine (6±2 pg/mL compared with 64±22 pg/mL of the controls) and a minimal response to stress. A slight compensatory increase of norepinephrine was noted in response to cold pressor test (754±200 pg/mL compared with 431±73 pg/mL of the control). The physiological response is characterized by low systolic blood pressure and high pulse rate in rest and mild stress and in a pressor response to exercise (diastolic 87±5 mmHg, compared with 73±2 mmHg of the control).

These findings suggest that intra-adrenal glucocorticoids are essential for epinephrine secretion, that norepinephrine may be compensatory, and that these result in a distinct physiological response. The implications of the pressor response to exercise, the declining pulse pressure, and the increased pulse response indicate a lower physical fitness in patients with adrenal insufficiency.

This group of patients with ACTH unresponsiveness has been reported previously to have early and extreme postnatal clinical hypoglycemia. Although isolated glucocorticoid deficiency might contribute to neonatal hypoglycemia (9), the medullary underdevelopment and epinephrine deficiency might also contribute to its severity. Furthermore, adrenocortical insufficiency is often characterized by changes in cardiac function and blood pressure, which can be partly reestablished by glucocorticoid replacement therapy (10). This study showed for the first time that the adrenal medulla is an essential player in the fine-tuning of the cardiovascular response to mild stress.

References: 1. Bornstein SR, Ehrhart-Bornstein M, Scherbaum WA, Pfeiffer EF, Holst JJ. Effects of splanchnic nerve stimulation on the adrenal cortex may be mediated by chromaffin cells in a paracrine manner. Endocrinology. 1990;127:900–906. 2. Ehrhart-Bornstein M, Hinson JP, Bornstein SR, Scherbaum WA, Vinson GP. Intraadrenal interactions in the regulation of adrenocortical steroidogenesis. Endocr Rev. 1998;19:101–143. 3. Axelrod J, Reisine TD. Stress hormones: their interaction and regulation. Science. 1984; 224:452–459. 4. Doupe AJ, Landis SC, Patterson PH. Environmental influence in the development of neural crests derivatives: glucocorticoids, growth factors and chromaffin cells plasticity. J Neurosci. 1985; 5:2119–2142. 5. Wong DL, Siddall B, Wang W. Hormonal control of rat adrenal phenylethanolamine N-methyltransferase. Enzyme activity, the final critical pathway. Neuropsychopharmacology. 1995; 13:223–234. 6. Rudman D, Moffitt SD, Fernhoff PM, Blackston RD, Faraj BA. Epinephrine deficiency in hypocorticotropic hypopituitary children. J Clin Endocrinol Metab. 1981; 53:722–729.7 . Bornstein SR, Tajima T, Eisenhofer G, Haidan A, Aguilera G. Adrenomedullary function is severely impaired in 21-hydroxylase deficient mice. FASEB J. 1999; 13:1185–1194. 8. 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. New Engl J Med 2000; 343:1362–1368. 9. Tiosano D, Pannain S, Vassart G, Parma J, Gershoni-Baruch R, Mandel H, Lotan R, Zaharan Y, Pery M, Weiss RE, Refetoff S, Hochberg Z. The hypothyroidism in an inbred kindred with congenital thyroid hormone and glucocorticoid deficiency is due to a mutation producing a truncated thyrotropin receptor. Thyroid. 1999; 9:887–894. 10. Fallo F, Fanelli G, Cipolla A, Betterle C, Boscaro M, Sonino N. 24-hour blood pressure profile in Addison’s disease. Am J Hypertens. 1994; 7:1105–1109