Expression of 11 beta-hydroxysteroid dehydrogenase isoenzymes in the humanpituitary: Induction of the type 2 enzyme in corticotropinomas and other pituitary tumors

One of the defining biochemical features of Gushing's disease is a relative insensitivity to glucocorticoid (GC) feedback, but an analysis of the GC r eceptor has failed to detect any major abnormalities. However, two isoenzym es of 11 beta -hydroxysteroid dehydrogenase (11 beta HSD), either by conver ting cortisone (E) to cortisol(F) (type 1) or conversely by converting F to E (type 2), play an important prereceptor role in regulating corticosteroi d hormone action at several sites. 11 beta HSD1 and -2 expression within th e anterior pituitary gland itself may modulate GC feedback at an autocrine level, and we have speculated that this may be deranged in Gushing's diseas e. Detection of 11 beta HSD type 1 and 2 immunoreactive protein was perform ed using fluorescence immunohistochemistry. Double immunofluorescent studie s were undertaken on normal pituitary to define the cellular localization o f 11 beta HSD isoenzymes using antisera against GH, ACTH, LH, FSH, PRL, and S100, a nonhormonal marker of folliculo-stellate:cells. In normal pituitar y, positive staining for 11 beta HSD1-immunoreactive protein was observed i n GH- and PRL-secreting cells and in folliculo-stellate cells; gonadotrophs , thyrotrophs, and ACTH-positive cells were negative. 11 beta HSD2 immunore activity was absent in all cell types. RT-PCR detected 11 beta HSD1 messeng er ribonucleic acid (mRNA) expression in the normal pituitary; 11 beta HSD2 mRNA expression was also seen in most normal tissue. By contrast, in ACTH-secreting adenomas 11 beta HSD2 immunostaining was str ongly positive in every case of corticotroph adenoma. 11 beta HSD1 immunore activity was also observed occasionally, but to a much lesser extent. In ot her pituitary tumors, both functional and nonfunctional, 11 beta HSD expres sion was variable in terms of isoenzyme mRNA and intensity of protein stain ing. The expression of 11 beta HSD1 (which generates F from E) in somatotro phs and lactotrophs suggests an autocrine role for this isoenzyme in the gl ucocorticoid regulation of pituitary GH and PRL secretion. 11 beta HSD2 exp ression is markedly induced in ACTH-secreting pituitary tumors and, by conv erting F to E, may explain the resetting of glucocorticoid feedback control in Gushing's disease.