The physiological effects of glucocorticoids (GCs) are, at least in part, mediated by an inhibition of cell proliferation. More contentious is their anti-proliferative action and possible tumour modifying effects in neoplastic tissues. Central to the action of GCs in target tissues is the expression and function of two isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) that serve to interconvert active cortisol (F) and inactive cortisone (E). 11beta-HSD type 1 (11beta-HSD1) predominantly converts E to F; the type 2 enzyme (11beta-HSD2) serves to inactivate F to E. Our previous studies of 11beta-HSD expression in pituitary adenomas have demonstrated a dramatic switch in isozyme expression from 11beta-HSD1 in normal pituitaries to 11beta-HSD2 in pituitary adenomas. We have assessed the functional consequences of this observed change in isozyme expression in primary human pituitary cultures (n=6). Cultured cells were assayed after 3 days for 11beta-HSD activity and cell proliferation was assessed by 3H-thymidine incorporation in the basal state and following treatment with glycyrrhetinic acid (GE), an inhibitor of 11beta-HSD. All primary pituitary cultures showed significant 11beta-HSD2 activity (F to E conversion, 71.9 pmol/hr/mg protein +/- 22.3) but none exhibited measurable activity for 11beta-HSD1. Proliferation measured by 3H-thymidine incorporation (n=3) showed that in the basal state, pituitary-derived cells were proliferating in culture. Addition of GE to the culture medium resulted in a 65.5% (+/-15) reduction in cell proliferation. We propose that the combination of significant 11beta-HSD2 activity and undetectable 11beta-HSD1 activity in pituitary adenomas will metabolise active F to inactive E, thereby removing the anti-proliferative effect of F. Addition of GE inhibits 11beta-HSD2, restoring local concentrations of F, which imposes an anti-proliferative influence. Our current data continue to support a central role for 11beta-HSDs and GC metabolism in neoplastic growth.
08 - 11 Apr 2002
British Endocrine Societies