Expression of 11ß-Hydroxysteroid Dehydrogenase Isoenzymes in the Human Pituitary: Induction of the Type 2 Enzyme in Corticotropinomas and Other Pituitary Tumors
Márta Korbonits,
Iwona Bujalska,
Masako Shimojo,
Jenny Nobes,
Suzanne Jordan,
Ashley B. Grossman and
Paul M. Stewart
Departments of Endocrinology (M.K., J.N., A.B.G.) and
Histopathology (S.J.), St. Bartholomew’s Hospital, London, United
Kingdom EC1A 7BE; Division of Medical Sciences, University of
Birmingham, Queen Elizabeth Hospital (I.B., P.M.S.), Birmingham, United
Kingdom B15 2TH UK; and Department of Internal Medicine, Toho
University (M.S.), Tokyo, Japan 143-8541
Address all correspondence and requests for reprints to: Dr. Ashley Grossman, Department of Endocrinology, St. Bartholomew’s Hospital, West Smithfield, London, United Kingdom EC1A 7BE. E-mail:
a.b.grossman{at}mds.qmw.ac.uk
Abstract
One of the defining biochemical features of Cushing’sdisease is a
relative insensitivity to glucocorticoid (GC) feedback,but an analysis
of the GC receptor has failed to detect anymajor abnormalities.
However, two isoenzymes of 11ß-hydroxysteroiddehydrogenase
(11ßHSD), either by converting cortisone(E) to cortisol (F) (type 1)
or conversely by converting F toE (type 2), play an important
prereceptor role in regulatingcorticosteroid hormone action at several
sites. 11ßHSD1and -2 expression within the anterior pituitary gland
itselfmay modulate GC feedback at an autocrine level, and we have
speculatedthat this may be deranged in Cushing’s disease. Detection
of11ßHSD type 1 and 2 immunoreactive protein was performedusing
fluorescence immunohistochemistry. Double immunofluorescentstudies
were undertaken on normal pituitary to define the cellularlocalization
of 11ßHSD isoenzymes using antisera againstGH, ACTH, LH, FSH, PRL,
and S100, a nonhormonal marker of folliculo-stellatecells. In normal
pituitary, positive staining for 11ßHSD1-immunoreactiveprotein was
observed in GH- and PRL-secreting cells and in folliculo-stellate
cells;gonadotrophs, thyrotrophs, and ACTH-positive cells were
negative.11ßHSD2 immunoreactivity was absent in all cell types.
RT-PCRdetected 11ßHSD1 messenger ribonucleic acid (mRNA)expression
in the normal pituitary; 11ßHSD2 mRNA expressionwas also seen in
most normal tissue.
By contrast, in ACTH-secreting adenomas 11ßHSD2 immunostainingwas
strongly positive in every case of corticotroph adenoma.11ßHSD1
immunoreactivity was also observed occasionally,but to a much lesser
extent. In other pituitary tumors, bothfunctional and nonfunctional,
11ßHSD expression wasvariable in terms of isoenzyme mRNA and
intensity of proteinstaining. The expression of 11ßHSD1 (which
generatesF from E) in somatotrophs and lactotrophs suggests an
autocrinerole for this isoenzyme in the glucocorticoid regulation of
pituitaryGH and PRL secretion. 11ßHSD2 expression is markedly
inducedin ACTH-secreting pituitary tumors and, by converting F to E,
mayexplain the resetting of glucocorticoid feedback control in
Cushing’sdisease.
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