Poster Presentation ESA-SRB Conference 2015

Bilateral macronodular adrenal hyperplasia and systematic testing for aberrant receptors: a bumpy journey (#261)

Yvonne Chow 1 2 , Alice Hong 2 , Christopher Yates 2 3 , Shane Hamblin 2 4
  1. Department of Endocrinology, Alfred Hospital, Prahran, VIC, Australia
  2. Department of Diabetes and Endocrinology, Western Health , St Albans, VIC, Australia
  3. University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, VIC, Australia
  4. University of Melbourne, Centre for Health, Research & Education, Sunshine Hospital, St Albans, VIC, Australia

Mrs SD is a 62-year-old Bosnian refugee, incidentally discovered to have bilateral nodular adrenal enlargement during investigation for haematuria. She had no specific examination features of Cushing’s syndrome but was centrally obese and had a history of type 2 diabetes, ischaemic heart disease, hypertension, stroke and osteopenia.  Cortisol failed to suppress after low and high dose dexamethasone and although incompletely suppressed, ACTH was low on repeated assessments, consistent with adrenal Cushing’s syndrome.

Bilateral macronodular adrenal hyperplasia (BMAH) is a rare cause of Cushing’s syndrome and usually presents around the fifth decade of life. In BMAH, there is emerging evidence that circulating hormones other than ACTH stimulate adrenal cortisol production via ectopic or deviant eutopic receptors for these hormones on adrenocortical cell membranes1. Blockade of these receptors has resulted in variable success as therapy for Cushing’s syndrome2,3.

Detection of aberrant receptor(s) can be achieved via targeted stimulation with potential candidate hormones. Using a protocol developed by Lacroix4, a strongly positive response to vasopressin was demonstrated; baseline cortisol rose by 119% without significant change in ACTH. A cortisol rise of 39% was also observed with Metoclopramide.

No cortisol rise was observed following subsequent testing with Desmopressin, a V2-selective agonist. The initial cortisol surge was thus thought due to aberrant V1 receptors. Aberrant V1 and 5HT-4 receptors are reported to be common causes of adrenal Cushing’s syndrome in BMAH.

Detectable bioactive ACTH was recently demonstrated in adrenal tissues of BMAH patients5. Hormones implicated with aberrant receptors also stimulated ACTH production by these adrenal explants. These in vitro findings raise the possibility that steroidogenesis in BMAH is not ACTH-independent, as previously supposed. This may explain why ACTH was incompletely suppressed.

This case raised our awareness of steroidogenesis by aberrant receptors in adrenal Cushing’s syndrome and challenged the paradigm of ACTH-independent Cushing’s syndrome.

  1. Lacroix et al; Aberrant G-protein coupled receptor expression in relation to adrenocortical overfunction; Clin Endocrinol (Oxf); 2010; 73(1); 1-15
  2. Lacroix et al; Propranolol therapy for ectopic beta-adrenergic receptors in adrenal Cushing’s syndrome; N Engl J Med; 1997; 13(33): 1429-34
  3. Preumont et al; Transient efficacy of octreotide and pasireotide (SOM230) treatment in GIP-dependent Cushing’s syndrome; Horm Metab Res; 2011; 43(4): 287-91
  4. Lacroix et al; Clinical evaluation of the presence of abnormal hormone receptors in adrenal Cushing’s syndrome; The Endocrinologist; 1999; 9(1): 9-15
  5. Louiset et al; Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia; N Engl J Med; 2013; 369(22): 2115-25