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Expression of 11ß-Hydroxysteroid Dehydrogenase Isoenzymes in the Human Pituitary: Induction of the Type 2 Enzyme in Corticotropinomas and Other Pituitary Tumors

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’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 11ß-hydroxysteroid dehydrogenase (11ßHSD), 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. 11ßHSD1 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 11ßHSD 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 11ßHSD isoenzymes using antisera against GH, ACTH, LH, FSH, PRL, and S100, a nonhormonal marker of folliculo-stellate cells. In normal pituitary, positive staining for 11ßHSD1-immunoreactive protein 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-PCR detected 11ßHSD1 messenger ribonucleic acid (mRNA) expression in the normal pituitary; 11ßHSD2 mRNA expression was also seen in most normal tissue.

By contrast, in ACTH-secreting adenomas 11ßHSD2 immunostaining was strongly positive in every case of corticotroph adenoma. 11ßHSD1 immunoreactivity was also observed occasionally, but to a much lesser extent. In other pituitary tumors, both functional and nonfunctional, 11ßHSD expression was variable in terms of isoenzyme mRNA and intensity of protein staining. The expression of 11ßHSD1 (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. 11ßHSD2 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.

CUSHING’S DISEASE, pituitary-dependent Cushing’s syndrome, is due to excessive secretion of ACTH by the pituitary. Pathologically, this is usually caused by small pituitary tumors only a few millimeters in diameter. One of the most characteristic biochemical features of Cushing’s disease is the relative resistance to corticosteroid feedback, the level of ACTH being reset to a new higher level of circulating cortisol (F); this relative resistance can also be used diagnostically, as demonstrated by dexamethasone suppression studies (1).

The effects of circulating corticosteroids on corticotrophs are mediated by an interaction with glucocorticoid and/or mineralocorticoid receptors, principally the type II glucocorticoid receptor (GR) in the pituitary. The glucocorticoid feedback resistance in Cushing’s disease is only partial, as most patients show suppression when high doses of dexamethasone are used, suggesting that the cardinal feature of their deranged biochemistry is a resetting of F feedback (2). It has been speculated that a change in the number or function of the corticotroph GRs might decrease the activity of corticosteroid feedback and thus allow selective clonal expansion of a mutated phenotype, but, in general, there is little evidence that the GR is abnormal in structure or function in the majority of corticotropinomas (3, 4). However, it is now recognized that 11ß-hydroxysteroid dehydrogenases (11ßHSD), either by activating F from cortisone (E; type 1 isoenzyme) or conversely by inactivating F to E (type 2 isoenzyme), may play an important prereceptor role in regulating corticosteroid hormone action at some sites (5, 6, 7, 8). If 11ßHSD1 and/or -2 were to be expressed within the anterior pituitary gland itself, they could, in theory, modulate glucocorticoid feedback: we have speculated that this might be deranged in Cushing’s disease. Furthermore, corticosteroids are also known to modify the secretion of other pituitary hormones such as GH, TSH, the gonadotropins and PRL (9, 10, 11, 12). We have therefore investigated the expression and localization of 11ßHSD types 1 and 2 in normal and tumorous pituitary tissue to explore their possible roles in pituitary tumorigenesis and specifically in Cushing’s disease.

Materials and Methods

Tissues studied

Pituitary adenomas were obtained at the time of transsphenoidal surgery with the approval of the local ethics committee. Patients were routinely treated with hydrocortisone (100 mg, im) with their premedication before surgery. The tumor type was determined on the basis of clinical and biochemical findings before surgery and morphological and immunohistochemical data. All patients with Cushing’s disease were pretreated with F-lowering drugs (metyrapone and/or ketoconazole) for 6–8 weeks before surgery to produce mean serum F levels within the normal range (150–300 nmol/L) (13). Patients studied by immunohistochemistry (n = 20; 7 women and 13 men; mean age, 49 yr; range, 16–82 yr) included 4 prolactinomas, 4 nonfunctioning pituitary adenomas (NFPAs), 4 FSH-secreting tumors (FSHomas), one TSH-secreting tumor (TSHoma), 4 somatotroph adenomas, and 3 corticotroph adenomas. Patients studied by RT-PCR (n = 35; 16 women and 19 men; mean age, 46 yr; range, 19–82 yr) included 4 prolactinomas, 8 NFPAs, 2 FSHomas, 1 TSHoma, 11 somatotroph adenomas, and 9 corticotroph adenomas; 11 of 35 of these patients were also included in the immunohistochemical studies. Normal human pituitaries were collected at autopsy (24 h postmortem) for RT-PCR (n = 8) and immunohistochemistry (n = 4). In each case, there was no evidence of any underlying endocrine abnormality.

RT-PCR

Total ribonucleic acid (RNA) was obtained and reverse transcribed into complementary DNA (cDNA) by a standardized technique, as previously described (14). The integrity of messenger RNA (mRNA) from each specimen was verified by RT-PCR for the housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH; GenBank accession no. M33197). RT-PCR with omission of reverse transcriptase and RT-PCR with water replacing template were used as negative controls. The PCR was performed using primers spanning one or more introns of the genes studied to allow for exclusion of genomic DNA contamination. Previously published primers for the 11ßHSD type 1 cDNA (GenBank accession no. M76661-M76665; sense, 5'-GTCGGATGGCTTTTATG-3'; antisense 5'-CTTGCTTGCAGAATAGG-3') and type 2 (GenBank accession no. U26726; sense, 5'-ACCGTATTGGAGTTGACAGC-3'; antisense, 5'-TCACTGACTCTGTCTTGAAGC-3') gave rise to products of 571 and 478 bp, respectively (15). A PCR reaction for the Pit-1 cDNA (GenBank accession no. D10216; sense, 5'-AGTGCTGCCGAGTGTCTACCA-3'; antisense, 5'-TTTCTTTTCCTTTCATTTGCT-3'), which is only expressed in somato-, lacto-, and thyrotroph cells, was also performed on ACTH- and FSH-secreting tumors and on nonfunctioning pituitary adenomas. We used previously published primers that gave rise to a product of 560 bp (16).

Gene expression was determined by duplex PCR using the 11ßHSD1 or -2 primers and the GAPDH primers (17, 18). All of the PCRs were performed before the plateau phase of the synthesis curve. cDNA (2.5 µL; 250 ng RNA equivalent) template was incubated with 0.5 µL 20 µmol/L deoxynucleotides (Promega Corp., Southampton, UK), 0.5 µmol 11ßHSD primers, 0.1 µmol GAPDH primers, 0.125 U Hotstart enzyme (QIAGEN, Crawley, UK), QiaBuffer containing 1.5 mmol/L MgCl₂, and 5 µL Q solution according to the manufacturers’ guidelines in a 25-µL PCR reaction. For 11ßHSD type 1 and 2 duplex PCR reactions, 30 cycles were performed at 94 C for 1 min, 52 C (type 1) or 55 C (type 2) for 1 min, and 72 C for 1 min after a denaturing cycle of 95 C for 15 min. For the Pit-1 gene reaction (16), we used a 0.2-µmol primer concentration and 30 cycles were performed at 94 C for 30 s, 55 C for 30 s, and 72 C for 45 s after a denaturing cycle of 95 C for 3 min. A final extension cycle of 10 min at 72 C was used. The PCR products were visualized on ethidium bromide-stained 2% agarose gels.

Contamination of ACTH- and FSH-secreting tumors and NFPAs by somato-, lacto-, or thyrotroph cells of nontumorous tissue was excluded by confirming undetectable expression of the Pit-1 gene. In normal pituitary tissue cDNA we were still able to detect Pit-1 expression at a 1:50 dilution, suggesting that contamination of tumor samples with normal pituitary would be detected at this level.

Fluorescence immunohistochemistry

Detection of 11ßHSD1 and -2 immunoreactivity in formalin-fixed, paraffin-embedded normal and tumorous human pituitary sections was performed by immunohistochemical staining. Antihuman 11ßHSD type 1 and type 2 antibodies were raised in sheep (The Binding Site, Birmingham, UK) as previously reported (19, 20) and were used at 1:800 dilution followed by alkaline phosphate-conjugated secondary antibody (donkey, antisheep, The Binding Site) at 1:200 dilution. Antigens were localized with the Vector Red Substrate System according to the suppliers’ protocols (Vector Laboratories, Inc., Burlingame, CA) producing an intense stable fluorescent reaction product. Blue 4,6-diaminodo-2-phenylindole (Sigma, Poole, UK) counterstain was used for cell nuclei.

Double-fluorescent immunohistochemical localization of 11ßHSD type 1 and pituitary hormone antigens involved sequential staining for the 11ßHSD type 1 enzyme and pituitary hormones. Detection of 11ßHSD1 antigen was carried out as described above, followed by pituitary hormone localization with a primary antibody at a given dilution (GH, 1:500; ACTH, 1:400; LH, 1:100; FSH, 1:100; PRL, 1:100, DAKO Corp., Cambridge, UK) and fluorescein isothiocyanate-conjugated secondary antibody (1:400 dilution). Nucleic acids in the cell nuclei were counterstained with 4,6-diaminodo-2-phenylindole. Folliculo-stellate cells were identified with the S-100 nonhormonal marker (21) using polyclonal antibody at 1:2000 concentration (DAKO Corp.).

Results

Normal pituitary, 11ßHSD type 1

In normal pituitary, both 11ßHSD type 1 mRNA (Fig. 1A) and 11ßHSD type 1 immunoreactivity were detected in each of the samples studied. Double antigen labeling of the pituitary sections revealed colocalization of 11ßHSD type 1 enzyme with GH- and PRL-secreting cells, whereas no colocalization was observed with ACTH, TSH, or LH (Fig. 2). The presence of 11ßHSD1 in folliculo-stellate cells, identified by the specific nonhormonal marker S-100, was also detected.

View larger version (56K): [in this window] [in a new window]   Figure 1. Duplex RT-PCR reaction shown for 11ßHSD1 (A, upper band) or 11ßHSD2 (B, upper band) and the housekeeping gene GAPDH (lower band). Np, Normal pituitary; C, corticotroph adenoma; A, somatotroph adenoma; P, prolactinoma; N, nonfunctioning adenoma; F, FSHoma; Pd, plasmid control containing 11ßHSD type 1 cDNA; Pl, placenta, as positive control for 11ßHSD type 2.

View larger version (70K): [in this window] [in a new window]   Figure 2. Immunohistochemistry of normal pituitary. Pituitary hormones and S-100 are shown in green (left panels), 11ßHSD type 1 is shown in red (middle panels), and if colocalization is present, yellow cytoplasmic stain is visible (right panels). Nuclei are counterstained with blue. Magnification: GH, PRL, TSH, and S100, x100; LH and ACTH, x60.

Seven of the eight normal pituitaries showed a detectable level of expression of 11ßHSD type 2 mRNA (Fig. 1B). However, no 11ßHSD type 2 immunoreactivity was detected by immunohistochemistry despite the positive immunofluorescence seen in the kidney control tissue (Fig. 3).

View larger version (53K): [in this window] [in a new window]   Figure 3. Immunocytochemistry for GH (green, left panel), 11ßHSD2 (red, middle panel), and the two together (right panel) in normal pituitary. Positive 11ßHSD2 staining (red) is shown in normal human kidney (bottom panel). Nuclei are counterstained with blue. Magnification, x60.

mRNA expression was present for both 11ßHSD1 and 11ßHSD2 (Figs. 1, A and B) in all of the prolactinomas and somatotroph tumors and the single TSHoma studied; both isoenzymes were expressed in one, whereas only the type 2 isoenzyme was present in the other FSHoma. RNA expression in the NFPAs was variable; one was negative for both enzymes, four were positive for both, and three were positive only for type 2. Seven of the nine corticotropinomas studied were strongly positive for 11ßHSD2, whereas two were negative. For 11ßHSD1, seven of the corticotropinomas showed no expression, and two showed only a low level of expression at the mRNA level (Fig. 1, A and B). The data for 11ßHSD1 or 11ßHSD2 expression did not correlate with the patient’s response to a dexamethasone suppression test.

At the protein level, prolactinomas showed more type 2 11ßHSD immunoreactivity than type 1, whereas somatotropinomas and FSHomas showed equally strong staining for both enzymes. The TSHoma studied showed scattered, but strong, staining for both enzymes. All NFPAs showed the presence of both enzymes. Figure 4 shows the data in the corticotroph adenomas. Immunoreactivity for both 11ßHSD isoforms was variably present, but, in general, there was no or only slight type 1 immunoreactivity, whereas strong positive immunostaining for 11ßHSD type 2 was observed in all tumors.

View larger version (65K): [in this window] [in a new window]   Figure 4. Immunohistochemistry for 11ßHSD1 (left panel) and 11ßHSD2 (right panel), both in green, in a corticotroph tumor. There is negative staining for 11ßHSD1 and positive staining for 11ßHSD2. Nuclei are counterstained with blue. Magnification, x100.

We have localized 11ßHSD1 to specific cells in the normal human pituitary. Our data suggest that 11ßHSD1 protein is expressed in GH- and PRL-secreting cells, whereas it is very low or absent from ACTH- and TSH-secreting and gonadotroph cells. It is also present in folliculo-stellate cells. The enzyme was expressed in tumors derived from the relevant cell lineage and thus was present in somatotroph and lactotroph tumors. However, we also found RNA and enzyme expression in some FSHomas and, albeit variably, in some NFPAs. As we were unable to colocalize the type 1 enzyme to gonadotroph or thyrotroph cells in the normal pituitary, it seems that there may be a change in expression of the enzyme in certain tumors derived from or related to these cell types. The significance of this is presently unclear. In corticotropinomas, 11ßHSD1 mRNA was usually absent, whereas its protein staining was also absent or slight. The expression of 11ßHSD1 is thus not a common characteristic of either normal or abnormal ACTH-secreting cells.

In relation to the type 2 enzyme, this was absent from the normal pituitary using immunohistochemistry, although we were able to detect an mRNA signal in some normal tissue. This suggests that either the enzyme is transcribed at a low level, but not translated, or it is translated to an extent that was not detectable by our immunofluorescent technique. In either case it is unlikely to be of major significance in the normal pituitary. By contrast, both RNA and protein expressions for the type 2 enzyme were seen in many of the pituitary adenomas studied, particularly in the corticotropinomas. 11ßHSD2 has not previously been demonstrated in normal or abnormal human pituitary tissue (22, 23). In the case of the corticotropinomas, it is unlikely to be a consequence of the corticosteroid excess rather than its cause, as all patients routinely had their mean serum F levels normalized for some weeks before operation, although it cannot be entirely excluded that the changes we report are consequential to elevated corticosteroid levels. Patients with all types of pituitary tumors were given a single bolus dose of hydrocortisone some hours before the operation.

The presence of functional 11ßHSD1 activity has been documented in the central nervous system, especially in the hypothalamus and the hippocampus of the rat, on the assumption that this enzyme was a dehydrogenase (24, 25). Only some years later was it appreciated that 11ßHSD1 acts as a reductase in intact cells (26), suggesting that this view needed to be revised. 11ßHSD1 acts predominantly as a reductase in the brain (27), whereas 11ßHSD2 is exclusively a dehydrogenase (15, 27). The presence of 11ßHSD1 in ovine pituitary was previously reported (28), whereas no human data were available. The expression of 11ßHSD2 in either animal or human pituitary has not previously been reported. The presence of 11ßHSD2 in the adenomatous pituitary may clearly be of major importance in the regulation of corticotroph function; in particular, it would act to decrease F levels in the region of the GR, thus diminishing functional feedback, and would allow selective secretion of the tumorous corticotrophs vis à vis the surrounding untransformed ACTH-secreting cells. Reduced local 11ßHSD1 activity would have similar F-reducing action in the tissue. The cause and the consequence of the up-regulation of the type 2 enzyme in relation to other cell lineages are less obvious, but equally intriguing. Glucocorticoids have been shown to have a direct effect on other pituitary hormones; they inhibit PRL and TSH release while acutely stimulating gonadotropin and GH secretion (10, 11, 12). It has recently been demonstrated that glucocorticoids act in part to inhibit ACTH, PRL, and TSH release via the stimulation of lipocortin 1, an antiinflammatory protein that belongs to the annexin family (29); this protein is principally synthesized by folliculo-stellate and corticotroph cells in the normal anterior pituitary (30) and acts on specific receptors present on hormone-secreting pituitary cells (31). As our data suggest that folliculo-stellate cells also express 11ßHSD1 protein, the control of local glucocorticoid action could be further modulated by the activity of this enzyme in normal pituitary. Folliculo-stellate cells are present in pituitary adenomas in low numbers (32), and according to preliminary data (33), these cells contain lipocortin 1. The influence of 11ßHSD isoenzymes on lipocortin-mediated glucocorticoid feedback in pituitary tumors needs further investigation.

Several abnormalities have previously been reported in corticotroph tumors, but none has been clearly shown to relate to the principal biochemical abnormality of deranged corticosteroid feedback (4). The increased expression of 11ßHSD2 in parallel with a low level or absent 11ßHSD1 expression could at least in part explain this finding. Clonal expansion of such a cell would lead to suppression of nontumorous corticotrophs and would also have the effect of suppressing the hypothalamic drive to ACTH-secreting cells. Thus, exogenous dexamethasone would act only on the pituitary, rather than on both the hypothalamus and pituitary, which may account for its decreased efficacy in patients with Cushing’s disease. In addition, there is some evidence that dexamethasone itself may be subject to metabolism by 11ßHSD2 (8).

In summary, the expression of 11ßHSD1 in normal somatotrophs and lactotrophs indicates a possible role for this isoenzyme in the glucocorticoid regulation of pituitary GH and PRL secretion. 11ßHSD2 protein expression is essentially absent from the normal pituitary, but is markedly induced in several tumor types, including ACTH-secreting pituitary tumors; in this latter case it may, by converting F to E, explain at least in part the re-setting of glucocorticoid feedback control in Cushing’s disease.

Received July 5, 2000.

Revised December 1, 2000.

Revised February 7, 2001.

Accepted February 14, 2001.

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