Pathophysiological Significance of Steroid Hormone–synthesizing Enzyme Genes in Pheochromocytoma

Objective: We have encountered cases of pheochromocytoma (Pheo) accompanied by excessive cortisol (F) production as well as a case of Pheo associated with excessive aldosterone (aldo) production. In this study, we investigated the gene expression and methylation status of the cortisol-synthesizing enzyme gene CYP11B1 and the aldosterone-synthesizing enzyme gene CYP11B2 in Pheo tissues. Design and method: The study included two cases of Pheo with excessive F production, one case of Pheo with excessive aldo production, five cases of Pheo without excessive production of F or aldo, and four autopsy-derived adrenal medullary tissue samples. Gene expression of CYP11B1 and CYP11B2 was analyzed by quantitative PCR (qPCR). Methylation analyses were performed using bisulfite sequencing and/or pyrosequencing. Results: Pheochromocytomas with excessive F production showed high CYP11B1 gene expression and a hypomethylated state. The Pheo with excessive aldo production demonstrated high CYP11B2 gene expression and hypomethylation. Conclusions: In general, pheochromocytoma is known to enhance adrenal cortical production of F and aldo through excessive catecholamine secretion. However, our findings suggest that in a subset of cases, steroid hormones may be produced directly by the tumor itself, potentially contributing to the pathophysiology of the disease.