title: Expression of 11 beta-hydroxysteroid dehydrogenase isoenzymes in the human pituitary: induction of the type 2 enzyme in corticotropinomas and other pituitary tumors.
abstract: One of the defining biochemical features of Cushing's disease is a relative insensitivity to glucocorticoid (GC) feedback, but an analysis of the GC receptor has failed to detect any major abnormalities. However, two isoenzymes of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD), either by converting cortisone (E) to cortisol (F) (type 1) or conversely by converting F to E (type 2), play an important prereceptor role in regulating corticosteroid hormone action at several sites. 11 beta HSD1 and -2 expression within the anterior pituitary gland itself may modulate GC feedback at an autocrine level, and we have speculated that this may be deranged in Cushing's disease. Detection of 11 beta HSD type 1 and 2 immunoreactive protein was performed using fluorescence immunohistochemistry. Double immunofluorescent studies were undertaken on normal pituitary to define the cellular localization of 11 beta HSD isoenzymes using antisera against GH, ACTH, LH, FSH, PRL, and S100, a nonhormonal marker of folliculo-stellate cells. In normal pituitary, positive staining for 11 beta HSD1-immunoreactive protein was observed in GH- and PRL-secreting cells and in folliculo-stellate cells; gonadotrophs, thyrotrophs, and ACTH-positive cells were negative. 11 beta HSD2 immunoreactivity was absent in all cell types. RT-PCR detected 11 beta HSD1 messenger 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 strongly positive in every case of corticotroph adenoma. 11 beta HSD1 immunoreactivity was also observed occasionally, but to a much lesser extent. In other pituitary tumors, both functional and nonfunctional, 11 beta HSD expression was variable in terms of isoenzyme mRNA and intensity of protein staining. The expression of 11 beta HSD1 (which generates F from E) in somatotrophs and lactotrophs suggests an autocrine role for this isoenzyme in the glucocorticoid regulation of pituitary GH and PRL secretion. 11 beta HSD2 expression is markedly induced in ACTH-secreting pituitary tumors and, by converting F to E, may explain the resetting of glucocorticoid feedback control in Cushing's disease.
authors.affiliation: Department of Endocrinology, St. Bartholomew's Hospital, London, United Kingdom EC1A 7BE.
authors.forename: M
authors.initials: M
authors.lastname: Korbonits
authors.forename: I
authors.initials: I
authors.lastname: Bujalska
authors.forename: M
authors.initials: M
authors.lastname: Shimojo
authors.forename: J
authors.initials: J
authors.lastname: Nobes
authors.forename: S
authors.initials: S
authors.lastname: Jordan
authors.forename: A B
authors.initials: AB
authors.lastname: Grossman
authors.forename: P M
authors.initials: PM
authors.lastname: Stewart
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases; D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010911:Pituitary Neoplasms / Q000201:enzymology* / Q000378:metabolism*; D012016:Reference Values; D014018:Tissue Distribution
chemical_list: D007527:Isoenzymes; D000324:Adrenocorticotropic Hormone; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases