Clinical, biochemical, and molecular characterization of macronodular adrenocortical hyperplasia of the zona reticularis: A new syndrome

Hans K. Ghayee, Juilee Rege, Lori M. Watumull, Fiemu E. Nwariaku, Kelley S. Carrick, William E. Rainey, Walter L. Miller, Richard J. Auchus

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Context: Macronodular adrenocortical hyperplasia classically presents with progressive hypercortisolemia and Cushing syndrome. We describe a 29-yr-old man with massive macronodular adrenocortical hyperplasia without hypercortisolemia but rather markedly elevated and nonsuppressible production of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). Objective: To characterize the clinical and molecular features of this caseandto determine whether the tissue biochemically resembles the zona reticularis or fetal adrenal. Setting: University clinic, hospital, and laboratories. Design: Static and dynamic blood and urine testing were performed preoperatively. Tissue was studied by light microscopy, immunoblot, RNA microarray, and enzyme assay. Participant: A 29-yr-old man with incidentally discovered bilateral adrenal enlargement. Intervention: Bilateral adrenalectomy. Main Outcome Measures: Molecular studies compared with control samples. Results: Hypercortisolism and 21-hydroxylase deficiency were excluded. DHEA, DHEAS, and 17-hydroxypregnenolone were markedly elevated and did not suppress with dexamethasone 2 mg/d for 4 d. Homogenates of the adrenals demonstrated high 17-hydroxylase, good 17,20-lyase, and low or absent 21-hydroxylase and 3β-hydroxysteroid dehydrogenase activities. Immunoblots confirmed robust expression of cytochrome P450c17 and AKR1C3 but not P450c21. Microarray analysis demonstrated high CYP11A1 and CYP17A1 expression but low or absent HSD3B1, HSD3B2, and CYP21A2 expression. Expression of mRNA for cytochrome b5 (CYB5A) and AKR1C3, markers of the zona reticularis, were markedly elevated. Conclusion: This is the first case of macronodular hyperplasia of the adrenal zona reticularis confirmed with studies of enzyme activity, mRNA expression, and protein identification. We speculate that this condition can be clinically silent in men but might cause severe hyperandrogenemia in women.

Original languageEnglish (US)
Pages (from-to)E243-E250
JournalJournal of Clinical Endocrinology and Metabolism
Issue number2
StatePublished - Feb 2011

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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