Cortisol-secreting adrenal adenomas express 11 beta-hydroxysteroid dehydrogenase type-2 gene yet possess low 11 beta-HSD2 activity

Background: 11 beta -hydroxysteroid dehydrogenase Type-2 (11 beta -HSD2) is an unidirectional enzyme that catalyzes the conversion of glucocorticoid h ormones cortisol and corticosterone (B) into their corresponding inactive f orms, cortisone, and Il-dehydrocorticosterone (DH-B). We have provided evid ence that 11 beta -HSD2 is expressed as messenger RNA (mRNA) and protein in human adrenocortical cells, where its activity is inhibited in vitro by th e main glucocorticoid agonists, adrenocorticotropic hormone (ACTH) and angi otensin-II. It seemed worthwhile, therefore, to study the gene expression a nd activity of 11 beta -HSD2 in cortisol-secreting adrenocortical adenomas. Methods: Three adrenal adenomas that produced Gushing syndrome were recruit ed. Three normal adrenal glands were obtained from patients who underwent u nilateral nephrectomy with ipsilateral adrenalectomy for renal cancer. 11 b eta -HSD2 gene expression was studied by reverse transcription-polymerase c hain reaction (RT-PCR) in adenoma and normal adrenocortical tissue. Cortiso l, B, cortisone, and DH-B production by adenoma and adrenal slices in vitro was assayed by quantitative high-performance liquid chromatography (HPLC), and the activity of 11 beta -HSD2 was evaluated by measuring the conversio n of [H-3]-cortisol to [H-3]-cortisone. Results: RT-PCR allowed the detection of the 11 beta -HSD2 mRNA in the thre e adrenal adenomas and normal adrenal cortices examined. Under basal condit ions, adenoma slices secreted higher amounts of cortisol and B, but markedl y lower amounts of cortisone and DH-B than adrenal slices. ACTH raised cort isol and B production from both specimens, and it lowered cortisone and DH- B yield. The level basal conversion of [H-3]-cortisol to ra]-cortisone was notably less in adenomas than in adrenals, and ACTH decreased it in both ti ssues. Conclusions: Collectively, our findings indicate that cortisol-secreting ad renal adenomas express the 11 beta -HSD2 gene, but the activity of the enzy me is suppressed in adenomas when compared with the normal adrenal cortex. We advance the hypothesis that the elevated local concentration of steroid hormones that occur in adenomas down-regulates 11 beta -HSD2 activity, ther eby contributing to their abnormal steroidogenic function.