11β-Hydroxysteroid Dehydrogenase Types 1 and 2 are Up- and Downregulated in Cortisol-secreting Adrenal Adenomas

Abstract

Background

11β-Hydroxysteroid dehydrogenase types 1 and 2 (11βHSD1 and 11βHSD2) are two isoenzymes that convert inactive glucocorticoids (e.g., cortisone) to their active forms (e.g., Cortisol) and vice versa. Abundant evidence indicates that 11βHSD2 is expressed as mRNA and protein in both adrenal cortex and adrenal tumors. In contrast, 11βHSD1 has been investigated to a much lesser degree. We therefore studied and compared the expression and activity of the two isoenzymes in the human adrenal cortex (HAC) and cortisol-secreting adenomas (CSAs).

Methods

Six HAC and six CSA specimens were studied. 11βHSD1 and 11βHSD2 gene expression was studied by conventional and semiquantitative reverse transcription-polymer-ase chain reaction. 11βHSD1 and 11βHSD2 activity was assayed by measuring the capacity of both microsomal fraction and tissue fragments to convert [ ³ H]cortisone to [ ³ H]cortisol and vice versa. Steroid hormones were separated and purified by high-performance liquid chromatography, and Cortisol concentration was measured by radioimmunoassay.

Results

Semiquantitative reverse transcription-polymer-ase chain reaction and enzymatic assay demonstrated higher 11βHSD1 expression and activity and lower 11βHSD2 expression and activity in CSAs than in HACs. CSA slices secreted larger amounts of Cortisol than did HAC specimens, and the cholesterol side-chain-cleaving enzyme inhibitor ami-noglutethimide, by blocking the early step of steroid synthesis, reduced Cortisol secretion by approximately 70%. Ami-noglutethimide decreased [ ³ H]cortisol production from [ ³ H]cortisone and increased [ ³ H]cortisone production from [ ³ H]cortisol in both tissues, thereby annulling differences in 11βHSD1 and 11βHSD2 activity between HACs and CSAs.

Conclusion

Collectively, our findings indicate that 1) both 11βHSD isoenzymes are expressed as mRNA and proteins in the HAC and CSA, with 11βHSD1 upregulated and 11βHSD2 downregulated in CSAs; and 2) 11βHSD1 and 11βHSD2 activity is positively and negatively correlated with the intracellular concentration of steroid hormones. Hence, 11βHSD isoenzymes could act as amplifiers of the secreta-gogue effect of agonists and could contribute to the elevated hormonal secretion of CSAs.