The role of the melanocortin receptors in adrenal growth, development and stem cell maintenance

Abstract

The adrenal gland is a highly dynamic organ with the ability to respond to changes in its environment with rapid changes in hormone production, and dramatic remodelling of its structure. Our understanding of the role of the melanocortin peptides in this process has been mostly restricted to the anterior pituitary hormone ACTH, via the melanocortin 2 receptor MC2R. The presence of additional melanocortin receptors and their antagonists has been demonstrated in rat and bovine adrenals, but the role of these in humans has not been well explored. An intensive clinical and biochemical work-up of a single patient with ACTH-independent Cushing’s syndrome and a gastrointestinal stromal tumour (GIST) was performed. The data presented are consistent with the possibility that her disease was caused by release of some bioactive molecule released from the GIST. We propose that alpha-MSH is a possible candidate for this molecule, on the basis that the GIST immuno-stained for alpha- MSH but not ACTH, that alpha-MSH but not ACTH was present in supernatant from a primary culture, and that alpha-MSH has the potential to stimulate cortisol production from adrenal cells. The precise mechanism for alpha-MSH secretion from the tumour is not fully elucidated, and further work is required to corroborate this hypothesis. The patient had both pigmented skin and pigmented adrenal nodules, and we further demonstrated the presence of the alpha-MSH receptor MC1R was demonstrated with her excised adrenal gland. The pigment was identified as melanin, and we went on to show that same pattern in primary pigmented nodular adrenal disease, and to demonstrate that the zona reticularis in normal adrenal gland contains melanin, and has additional features in common with melanocytic tissues elsewhere in the body. The role of alpha-MSH in normal adrenal function, and the possibility that melanin is also playing an important role, perhaps for its antioxidant properties, is an exciting area for future study.