Abnormal expression of 11β-hydroxysteroid dehydrogenase type 2 in human pituitary adenomas:: a prereceptor determinant of pituitary cell proliferation

The physiological effects of glucocorticoids (GCs) are, at least in part, mediated by inhibition of cell proliferation. Two isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) interconvert cortisol (F) and inactive cortisone (E), and are thus able to modulate GC action at an autocrine level. Previously, we have demonstrated absent expression of 11beta-HSD2 in normal pituitaries; however, in a small number of pituitary tumors analysed, 11beta-HSD2 was readily demonstrable. Here we have used real-time RT-PCR to quantify expression of mRNA for 11beta-HSD1 and 2 in 105 human pituitary tumors and have performed enzyme expression and activity studies in primary pituitary cultures. Overall, pituitary tumors expressed lower levels of 11beta-HSD1 mRNA compared with normals (0.2-fold, P<0.05). In contrast, expression of 11beta-HSD2 mRNA was 9.8-fold greater in tumors than in normals (P < 0.001). Enzyme assays showed significant 11beta-HSD2 activity (71.9+/-22.3pmol/h/mg protein (mean+/-s.d.)) but no detectable 11beta-HSD1 activity. Proliferation assays showed that addition of glycyrrhetinic acid (an 11beta-HSD2 inhibitor) resulted in a 30.3+/-7.7% inhibition of cell proliferation. In summary, we describe a switch in expression from 11beta-HSD1 to 11beta-HSD2 in neoplastic pituitary tissue. We propose that abnormal expression of 11beta-HSD2 acts as a proproliferative prereceptor determinant of pituitary cell growth, and may provide a novel target for future tumor therapy.