Restoring Adrenomedullary Function

One of the most neglected endocrine glands in the human body is the adrenal medulla. While major advances have been achieved in the treatment of adrenomedullary tumors including intraadrenal pheochromocytomas, little attention has been given to how the normal adrenal medulla functions.

That there are few cells in higher organisms that have been more extensively studied than chromaffin cell lines makes this even more astonishing. This may however be a part of the problem. Chromaffin cell lines - particularly PC 12 cells - have been used as a model for analyzing the basic principles of neurophysiology and molecular mechanism of secretion [1]. The development, regulation, functioning and regeneration of the chromaffin cell itself has however not been studied in detail.

The study by Mayumi Yoshida-Hiroi et al. in this issue is one of the first clinical investigations to provide therapeutic options for maintaining or restoring adrenomedullary function [2].

In vitro studies performed by Wurtman and Axelrod more than 30 years ago have conclusively demonstrated that the intact biosynthesis of catecholamines in chromaffin cells is dependent on adrenocortical glucocorticoids [3]. Glucocorticoids regulate chromaffin cell development, structure, and expression of enzymes involved in catecholamine biosynthesis and expression of neuropeptides [4].

However, this important functional relationship between the adrenal cortex and medulla derived from in vitro data has not been appreciated in the fields of physiology, in vivo endocrine regulation or clinical medicine for many years.

Over the last fifteen years, we and others have extensively analyzed the functional interdependence of the two endocrine systems in the adrenal gland [5]; we have demonstrated that defects in adrenocortical steroidogenesis due to deficiency in receptor and signaling molecules, transcription factors, enzymes or vitamins are always associated with a corresponding impairment in adrenomedullary function [6].

These data derived from gene knock-out studies in various animals models could be translated to human physiology and disease [7]. Patients with adrenocortical deficiency due to Addison’s disease have significantly lower epinephrine levels [8]. Patients with 21-OH deficiency present with an impaired adrenal structure and a significant decline in catecholamine and metanephrine levels. Furthermore, the decline in catecholamines seems to correlate with the rate of hospitalization due to hypoglycemia and hypotensive crisis in children with CAH [9]. Physical activity is also impaired in these patients.

However, replacement with glucocorticoids will further reduce intraadrenal glucocorticoid levels, which in turn will lead to a further reduction in catecholamine secretion. This pathophysiological concept may be extended to all patients receiving glucocorticoids such as patients with inflammatory bowel disease, tumors, connective tissue disorders or asthma.

A defect in catecholamine production is particularly undesirable in patients with asthma; thus, a therapeutic concept allowing a restoration of adrenomedullary function in patients with inborn, acquired or iatrogenic adrenocortical dysfunction would appear to be highly beneficial. Intranasal ACTH application may allow both adrenal cortical and chromaffin cells to maintain or restore their normal function.

In patients with ARDS or obstructive pulmonary disease ACTH applications may provide a novel mechanism for preserving endogenous epinephrine production. Similarly in patients receiving high doses of exogenous synthetic steroids during sepsis.

The study by Hiroi et al. is an excellent clinical basis to test this and other hypotheses in future clinical protocols.

References

• 1 Eaton M J, Duplan H. Useful cell lines derived from the adrenal medulla.  Mol Cell Endocrinol. 2004;  228 39-52
• 2 Yoshida-Hiroi M, Tsuchida Y, Higa M, Yosihino G, Hiroi N. Intranasal Administration of ACTH(1-24) Stimulates Catecholamine Secretion.  Horm Metab Res. 2005;  37 489-493
• 3 Wurtman R J, Axelrod J. Adrenaline synthesis: control by the pituitary gland and adrenal glucocorticoids.  Science. 1965;  150 1464-1465
• 4 Beaujean D, Rosenbaum C, Muller H W, Willemsen J J, Lenders J, Bornstein S R. Combinatorial code of growth factors and neuropeptides define neuroendocrine differentiation in PC12 cells.  Exp Neurol. 2003;  184 348-358
• 5 Bornstein S R, Chrousos G P. Clinical review 104: Adrenocorticotropin (ACTH)- and non-ACTH-mediated regulation of the adrenal cortex: neural and immune inputs.  J Clin Endocrinol Metab. 1999;  84 1729-1736
• 6 Bornstein S R, Yoshida-Hiroi M, Sotiriou S, Levine M, Hartwig H G, Nussbaum R L, Eisenhofer G. Impaired adrenal catecholamine system function in mice with deficiency of the ascorbic acid transporter (SVCT2).  FASEB J. 2003;  17 1928-1930
• 7 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
• 8 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
• 9 Merke D P, Bornstein S R. Congenital adrenal hyperplasia.  Lancet. 2005;  365 2125-2136