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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 4 1340-1345
Copyright © 1999 by The Endocrine Society

Original Studies

17ß-Hydroxysteroid Dehydrogenase Type 1, 2, 3, and 4 Expression and Enzyme Activity in Human Anterior Pituitary Adenomas

V. L. Green, V. Speirs, A. M. Landolt, P. M. Foy and S. L. Atkin

Department of Medicine, University of Hull, and Neurosurgical Unit, Walton Hospital (P.M.F.), Liverpool, United Kingdom HU6 7RX; and Seestrusse 285 (A.M.L.), CH-8038 Zurich, Switzerland

Address all correspondence and requests for reprints to: Dr. V. L. Green, Department of Medicine, Wolfson Building, University of Hull, Cottingham Road, Hull, United Kingdom HU6 7RX.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
17ß-Hydroxysteroid dehydrogenase (17ßHSD) isoforms reversibly catalyze the final step in the formation of estradiol (E2) from estrone (E1) and the formation of testosterone from androstenedione. We have investigated 17ßHSD type 1, 2, 3, and 4 gene expression and 17ßHSD estrogenic activity in human anterior pituitary adenomas. 17ßHSD messenger ribonucleic acid (mRNA) expression was studied by RT-PCR in 42 pituitary tumors and 3 normal pituitaries, 17ßHSD activity was studied in 11 tumors and 17ßHSD type 1 was immunolocalized in vitro in 6 tumors. 17ßHSD type 1 gene expression was detected in 34 of 42 adenomas in all tumor subtypes; 17ßHSD type 2 mRNA was detected in 18 of 42 adenomas, but not in prolactinomas; 17ßHSD type 3 mRNA was detected in 12 of 42 adenomas, but not in corticotropinomas; 17ßHSD type 4 was expressed in 20 of 42 adenomas by all adenoma subtypes. Reversible 17ßHSD activity was found in 9 of 11 adenomas, and 17ßHSD type 1 immunopositivity was cytoplasmically distributed in all 6 adenomas in vitro. All 4 17ßHSD isoforms are variably expressed in human anterior pituitary adenomas, which also show 17ßHSD enzyme activity, suggesting that 17ßHSD may play an important role in regulating the local cellular levels of estradiol.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE CONTRIBUTION of estradiol (E2) to the growth of monoclonal human anterior pituitary adenomas remains unclear. E2 treatment is used as a model for prolactinoma formation and growth in the rat (1, 2), but there are only anecdotal reports implicating E2 in human prolactinoma growth and tumorigenesis (3, 4, 5, 6), although evidence for an in vitro effect has been reported (7). In addition, estrogen receptors are found in the normal human anterior pituitary (8) and pituitary adenomas, apart from pure somatotropinomas and corticotropinomas (9, 10).

E2 levels may be modulated at a local tissue level via the interconversion of inactive estrone (E1) and bioactive E2 by 17ß-hydroxysteroid dehydrogenases (17ßHSDs). Four human 17ßHSDs, all belonging to the short chain dehydrogenase/reductase protein family, have been fully characterized, each having different substrate specificities, activities, and cofactor dependence (11, 12, 13, 14). 17ßHSD type 1 is a soluble protein with a wide tissue distribution, which preferentially catalyzes the reductive conversion of E1 to E2 using NADPH (15), but can also reduce {Delta}4-androstenedione to testosterone to a lesser extent (16). The type 2 enzyme, first isolated from prostate (12), is most highly expressed in the liver, placenta, small intestine, and secretory endometrium (17). 17ßHSD type 2 is found in the microsomal fraction and preferentially catalyses the oxidative reaction using NAD+ and has equal affinity for both E2 and testosterone (12). However, the type 2 isoform is unique in that it also possesses 20{alpha}-hydroxylase activity by converting 20{alpha}-dihydroprogesterone to progesterone (17). 17ßHSD type 3 is found in the endoplasmic reticulum and shares approximately 23% sequence identity with types 1 and 2 (13); 17ßHSD type 3 preferentially catalyzes the reductive conversion of {Delta}4-androstenedione to testosterone and dehydroepiandrosterone to {Delta}5-androstenediol (16). The 17ßHSD type 3 (1.3-kb transcript) has been found to be principally expressed in the testis where gene mutations lead to male pseudohermaphroditism (13), it has also been found in human breast cancer (18), colonic carcinoma (19), and human adipose tissue (20). 17ßHSD type 4 is a 32-kDa protein and is covalently linked to 45-kDa ß-actin forming an 80-kDa heterodimer (14) that is found specifically in the peroxisomes of the cell (21). The type 4 enzyme has an oxidative preference for E2 and {Delta}5-androstenediol using NAD+ (22), and the 2.9-kb transcript of 17ßHSD type 4 has a wide tissue distribution. There is high sequence identity across species for a particular isoform, but there is less than 25% homology between the four 17ßHSD sequences in the same species (23).

17ßHSD activity has been described in the anterior pituitary gland of the rat and rhesus monkey (24, 25), but it is unknown whether 17ßHSD isoforms are present and active in the normal and adenomatous human anterior pituitary. Therefore, the aim of this study was to determine the expression of 17ßHSD type 1, 2, 3, and 4 isoforms and 17ßHSD estrogenic activity within human anterior pituitary adenomas and their relation to adenoma subtype.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Pituitary tissue

Forty-two human pituitary adenomas [preoperative diagnosis: 20 nonfunctional (NF) adenomas, 13 somatotropinomas (GH), 4 macro-prolactinomas, and 5 corticotropinomas (ACTH)] were removed by transsphenoidal surgery and received sequentially. The diagnosis of acromegaly was determined by standard criteria, and all of the patients with macroprolactinomas and nonfunctional tumors had presented to the neurosurgeons with visual impairment. Studies were performed initially without prior knowledge of the tumor type, and the diagnosis was determined retrospectively from clinical, biochemical, and immunohistochemical analyses. Normal pituitary tissue was obtained at autopsy within 6 h of death; three samples were ribonucleic acid (RNA) extracted for PCR analysis, and two were formalin fixed and paraffin embedded for immunohistochemistry.

RNA extraction and RT-PCR

RNA was extracted from all 42 tumors and 3 normal pituitaries using Trizol reagent according to the manufacturer’s protocol (Life Technologies, Paisley, UK). RNA (5 µg) was reverse transcribed for 1 h at 37 C using 800 U Moloney murine leukemia virus reverse transcriptase (Life Technologies) in the presence of RNA Guard (64.8 U; Pharmacia Biotech Ltd., St Albans, UK); first strand buffer (50 mmol/L Tris-HCl, 75 mmol/L KCl, 3 mmol/L MgCl2, pH 8.3, and dithiothreitol; 10 mmol/L; Life Technologies); oligo(deoxythymidine) (1.5 ng; Pharmacia Biotech); and 1 mmol/L each of deoxy (d)-ATP, dTTP, dGTP, and dCTP (Boehringer Mannheim UK Ltd., East Sussex, UK) in a total volume of 50 µL. The reaction was terminated by freezing at -20 C. Negative controls were also included in which the reverse transcriptase was omitted to assess genomic DNA contamination. Synthesized complementary DNA (cDNA; 1 µL), was used as a template in a PCR to amplify fragments of the 17ßHSD type 1, 2, 3, and 4 isoforms. The reaction consisted of 0.5 µg of each specific 17ßHSD oligonucleotide primer (Table 1Go; Cruachem, Glasgow, UK), reaction buffer [16 mmol/L (NH4)SO4, 67 mmol/L Tris-HCl (pH 8.8), 0.1% Tween-20]; 0.5–3.0 mmol/L MgCl2 optimized for each cDNA sample; (17ßHSD type 1) 1.5 mmol/L MgCl2 (17ßHSD type 2); 1.0 mmol/L MgCl2 (17ßHSD type 3); 2.0 mmol/L MgCl2 (17ßHSD type 4); (Bioline Ltd., London, UK); 200 µmol/L each of dATP, dGTP, dCTP, and dTTP (Pharmacia Biotech); and 1.5 U Biotaq (Bioline) made up to a final volume of 50 µL with dH2O. The mixture was overlaid with mineral oil, and amplification was achieved in a thermal cycler (Hybaid Omnigene, London, UK) using the following optimized program: 1) denaturation step of 94 C for 2 min; 2) 30 reaction cycles of 94 C for 30 s, 57.5 C (types 1 and 3) or 55 C (types 2 and 4) for 30 s, and 72 C for 30 s; and 3) a single primer extension step of 72 C for 5 min. PCR products were separated on a 1.8% agarose gel (Life Technologies) containing ethidium bromide (Sigma Chemical Co., Poole, UK; Fig. 1Go). cDNA from the breast cancer cell line BT-20 (American Type Culture Collection, Manassas, VA), provided a positive control for 17ßHSD types 1, 2, and 4, and RNA extracted from a human testicular biopsy provided a positive control for 17ßHSD type 3. The quality of the cDNA was confirmed using oligonucleotide primers designed to detect glyceraldehyde-3-phosphate dehydrogenase messenger RNA (mRNA) transcripts. Negative controls involved substituting the cDNA with distilled water. The primers for the 17ßHSD isoforms and the glyceraldehyde-3-phosphate dehydrogenase gene spanned introns within the genomic DNA of the gene. The spanning of introns ensured that the signal produced resulted from mRNA and not from possible contaminating DNA.


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  		Table 1. Primer sequences, product sizes, and restriction enzymes for 17ßHSD1, -2, -3, and -4

 


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  		Figure 1. A representative 1.8% agarose gel showing the products of PCR reactions using pituitary adenoma cDNA as template and primers designed to amplify fragments of the genes for 17ßHSD types 1, 2, 3, and 4 (a). In addition, the products following the restriction enzyme digestion are shown in the lane adjacent to the PCR product (b). 1) 17ßHSD type 1 (389 bp); 2) 17ßHSD type 2 (593 bp); 3) 17ßHSD type 3 (624 bp); 4) 17ßHSD type 4 (749 bp). s, 100-bp size standard.

 
Restriction enzyme digests

The identities of the 17ßHSD1, -2, -3, and -4 PCR products were confirmed by restriction enzyme digestion using the enzymes HinfI, PstI, DdeI, and EcoRI, respectively, which cleave the PCR products to yield fragments of distinct sizes (Life Technologies). PCR product was incubated with 10 U restriction enzyme and buffer in a total volume of 20 µL and incubated at 37 C for 2 h. The cleaved products were separated on an agarose gel (Fig. 1Go).

Radioactive enzyme conversion assay

Double isotope radioconversion assays were performed as previously described, with modifications (26), on 11 randomly selected tumors (1 GH, 9 NF, and 1 ACTH) to determine estrogenic 17ßHSD activity. Pituitary adenoma biopsies were dispersed to single cells as previously described (27). Selective culture was achieved by incubation in Iscove’s Modified Dulbecco’s Medium (Life Technologies) containing 0.2% BSA to minimize the growth of fibroblasts. Dispersed cells were plated at a density of 105/well in 8 wells of a 24-well plate and allowed to attach overnight in Iscove’s Modified Dulbecco’s Medium containing 0.2% BSA. Medium was replaced with serum-free, phenol red-free DMEM (Life Technologies), and either 4 x 105 cpm purified [3H]E1 or [3H]E2 (Amersham, Aylesbury, UK) was added to quadruplicate wells. Wells without cells were used as negative controls. The reaction was incubated for 4 h at 37 C, and medium was transferred to tubes containing 5 x 103 cpm of the opposite 14C-labelled E1 or E2 (NEN-DuPont, Boston, MA) to determine procedural losses and metabolism of product. After steroid extraction and separation by thin layer chromatography, the amount of labeled product was determined using liquid scintillation counting. The amount of steroid produced was determined using the equation: amount of product formed = [Ci product - (Ci recovery label x percent crossover of 14C)] x efficiency of machine x 100/2.22 x 1012 x specific activity of the substrate (Ci/mmol) x percent recovery. The value of the blank was subtracted from the samples, and average values were expressed per 105 cells, determined by whole cell counts. Statistical analysis of the difference between the reductive and oxidative directions was performed using the two-tailed Mann-Whitney test.

Immunochemistry

Immunochemistry was performed on both human anterior pituitary adenoma tissue sections (2 NF and 2 GH) and methanol-fixed pituitary adenoma cells selectively cultured in vitro (2 GH, 2 ACTH, and 2 NF). This was done using a rabbit antibody directed against human 17ßHSD type 1 (generated, characterized, and provided by Prof. R. Vihko, Oulu, Finland) (28). Microwave enhancement was employed on the paraffin-embedded tissue sections (29). After blocking of endogenous peroxidases with 3% H2O2 in methanol for 10 min and incubation with a 1:5 dilution of normal goat serum for 20 min (Sera-lab, West Sussex, UK), a 1:600 dilution of the primary antiserum was added followed by a biotinylated goat secondary antibody specific for the rabbit primary antibody (Dako Corp., High Wycombe, UK), both for 30 min. The streptavidin-biotin system linked to horseradish peroxidase (Dako Corp.) was used for detection (30), and resolution was achieved by reaction with diaminobenzidine and hydrogen peroxide provided in a Vector Laboratories, Inc., kit (Peterborough, UK). Paraffin-embedded sections of breast cancer tissue and BT-20 cells were used to optimize the antibody concentrations, and sections from two normal pituitaries obtained within 6 h of death were also immunostained.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The expression of 17ßHSD isoforms in individual pituitary adenoma subtypes is shown in Fig. 2Go. The 17ßHSD type 1 fragment obtained by RT-PCR was detected in 34 of the 42 (81%) pituitary adenoma biopsies, including 10 of 13 GH, 18 of 20 NF, 3 of 4 PRL, and 3 of 5 ACTH. 17ßHSD type 2 was expressed in 18 of 42 (43%) adenomas, which included 6 of 13 GH, 8 of 20 NF, and 4 of 5 ACTH. 17ßHSD type 2 was not expressed by any of the 4 prolactinomas investigated. 17ßHSD type 3 was expressed by 12 of 42 (29%) adenomas, including 6 of 13 GH, 5 of 20 NF, and 1 of 4 PRL. 17ßHSD type 3 was not expressed by any of the 5 corticotropinomas studied. 17ßHSD type 4 was found in 20 of 42 (48%) pituitary adenomas, which included 8 of 13 GH, 7 of 20 NF, 2 of 4 PRL, and 3 of 5 ACTH. Fisher’s exact test was used to determine any relationship between nonfunctional tumors/somatotropinomas and the expression of 17ßHSD types 1–4 (significant differences between prolactinomas and corticotropinomas could not be determined due to the small sample size); no significant associations were determined (P > 0.05 in all cases). In addition, no statistical differences were found between the expression of the 17ßHSD isoforms and the gender of the patient from which the pituitary adenoma was derived. Only 5 pituitary adenomas expressed all 4 of the 17ßHSD isoforms (2 GH and 3 NF), 5 adenomas expressed 3 isoforms, including 2 NF and 1 ACTH, which expressed types 1, 2, and 4, and 1 NF and 1 GH, which expressed types 2, 3, and 4. Nineteen adenomas expressed 2 isoforms; 17ßHSD types 1 and 4 were most frequently expressed (4 GH, 1 NF, and 1 PRL) followed by 17ßHSD types 1 and 2 (2 GH, 2 NF, and 1 ACTH). Of the adenomas expressing 2 isoforms, 2 of 19 expressed 17ßHSD types 2 and 4 only (oxidative), and 4 of 19 expressed types 1 and 3 only (reductive). One of 19 adenomas expressed both 17ßHSD types 2 and 3 only and 17ßHSD types 3 and 4 only. Eleven adenomas (8 NF, 1 PRL, 1 ACTH, and 1 GH) expressed the 17ßHSD type 1 isoform alone, and 1 PRL expressed 17ßHSD type 4 alone. Only 1 (NF) adenoma did not express any of the 4 17ßHSD isoforms. Of the 3 normal pituitary adenomas investigated, 1 expressed all 4 isoforms; 1 expressed types 2, 3, and 4; and the other expressed types 1 and 2 only.



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  		Figure 2. The percent expression of 17ßHSD types 1, 2, 3, and 4 in human pituitary adenomas: somatotropinomas (GH; n = 13), nonfunctional pituitary adenomas (NF; n = 20), prolactinomas (PRL; n = 4), and corticotropinomas (ACTH; n = 5).

 
Double isotope radioconversion assays showed that 9 of the 11 samples (1 GH, 7 NF, and 1 ACTH) had reversible activity within the intact monolayer (Table 2Go), and of these, 5 (4 NF and 1 GH) had a preferential catalytic activity in the oxidative (E2 to E1) direction; however, this was not significantly higher than the reductive (E1 to E2) value (Mann-Whitney test for significance, P > 0.05). Of those whose activity was not reversible, 1 NF had reductive and 1 NF had oxidative activity. The enzymatic activity was predicted in 3 of the 11 pituitary tumors investigated (3 NF); all 3 adenomas showed a preferential reductive activity forming E2, and all 3 tumors expressed 17ßHSD type 1 alone. In 7 of the pituitary adenomas, the expression of 17ßHSD isoforms was only partially reflected in the activity seen. Three of 4 adenomas expressing all 4 17ßHSD isoforms had preferential oxidative activity, and 1 had reductive activity; 2 adenomas expressed 17ßHSD types 1, 2, and 4, but 1 showed preferential oxidative and the other showed reductive activity; 1 adenoma expressed 17ßHSD types 1 and 4 and showed a preferential oxidative reaction forming E1; 1 adenoma showed no relationship between expression and activity of 17ßHSD with the expression of 17ßHSD types 1 and 3, but had oxidative activity.


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  		Table 2. Individual 17ßHSD oxidation and reduction activities and 17ßHSD 1, -2, -3, and -4 transcript expression

 
Immunohistochemistry using a 17ßHSD type 1 antiserum revealed that normal pituitary tissue was positive in specific individual cells (Fig. 3aGo) and was equivalent to the staining observed in the pituitary adenoma sections (Fig. 3bGo). BT-20 cells immunostained very strongly for the enzyme in all cells (Fig. 3cGo), and dispersed, selectively cultured, pituitary adenoma cells also showed an intense cytoplasmic staining for the 17ßHSD type 1 protein in all cells in vitro (Fig. 3dGo).



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  		Figure 3. Immunostaining of 17ßHSD type 1 using rabbit antiserum on formalin-fixed paraffin-embedded tissue. a, Normal pituitary; b, pituitary adenoma. Magnification, x1000. Arrows indicate the single positive cells in each section. 17ßHSD type 1 immunostaining of in vitro cultures of BT20 cells and dispersed pituitary adenoma cells is shown in c and d, respectively. Magnification, x400.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
These studies have shown that 17ßHSD isoforms 1, 2, 3, and 4 are expressed in human anterior pituitary adenomas and that the estrogenic enzyme activity is reversible. These data are in accord with the finding of 17ßHSD oxidative activity in the rat and rhesus monkey anterior pituitary gland (24, 25).

Unlike tissues such as prostate and meningioma, where there is specific isoform expression (31, 32), all four of the 17ßHSD isoforms were randomly detected in pituitary adenoma biopsies and normal pituitaries. The type 1 isoform was the most abundant form of the enzyme in the 42 pituitary tumors, followed by type 4, type 2, and type 3 17ßHSD. Many tumors expressed more than 1 isoform of 17ßHSD, but of those expressing 2 isoforms, few expressed reductive or oxidative enzymes alone. It may have been predicted that the reductive isoforms of 17ßHSD (types 1 and 3) may be present in prolactinomas, with the formation of E2 stimulating adenoma growth (1, 2, 3, 4, 5, 6). However, a limited number of prolactinomas was available to study, and only 2 of 4 expressed reductive 17ßHSD isoforms alone; a larger sample size would be required to test the significance of this. There was no relationship between tumor type and 17ßHSD expression in either nonfunctioning tumors or somatotropinomas. All four 17ßHSD isoforms were found variably expressed in the few normal pituitaries examined, although only 1 expressed all 4 isoforms. Whether the time between death and RNA extraction had caused loss of the message is unknown.

17ßHSD type 3 is mainly expressed in the testis (13), but it is also expressed in Sertoli-Leydig cell tumor of the ovary (33), breast cancer (18), colonic carcinoma (19), and human adipose tissue (20). In this study, 17ßHSD type 3 was expressed in pituitary adenomas, but no relationship was determined between the expression of 17ßHSD type 3 or the expression of the other 17ßHSD isoforms and the sex of the patient.

17ßHSD types 2 and 3 were not found in any of the prolactinomas or corticotropinomas, respectively, using RT-PCR. However, the sample number for these two subgroups of tumor was small and the frequency of expression of 17ßHSD types 2 and 3 in the other pituitary adenoma subtypes was in some cases below 50%. This suggests that a larger sample number of prolactinomas and corticotropinomas may have detected 17ßHSD type 2 and 3 expression.

Reversible estrogenic 17ßHSD activity was detected in all but two tumors investigated. Although the oxidative reaction leading to the inactivation of E2 occurred more frequently than the reductive direction, the difference between the oxidative and reductive directions in the same tumor was not significant. In cell homogenates, all four isoforms of 17ßHSD are reversible enzymes when the correct cofactor environment is provided (16), but in intact cells the enzymes become essentially unidirectional (15, 34, 35). Therefore, it is likely that the 17ßHSD activity observed in this report represents the sum of the different 17ßHSD isoforms present, and this composite activity may be modified by substrate and cofactor availability. This may explain the findings in two adenomas that expressed only unidirectional, rather than reversible, activity; one expressing all four isoforms showed reduction alone, whereas the other, expressing three isoforms (except isoform 3), showed oxidation alone. In addition, 17ßHSD activity may be modulated by cytokines (26, 36), of which there are a wide range in pituitary adenomas (37); both interleukin-6 and tumor necrosis factor-{alpha} have been shown to activate 17ßHSD reductive activity in cultured breast cancer cells (26, 36). Whether additional 17ßHSD isoforms are present in the pituitary contributing to the enzyme activity seen is unknown; 17ßHSD type 5, which converts androstenedione to testosterone, has been reported in human placenta, and 17ßHSD type 6 isolated from rat has now been identified (38, 39).

17ßHSD type 1 immunopositivity was localized to individual cells scattered throughout both normal pituitary sections and those of pituitary adenomas. However, most of the pituitary adenoma cells in vitro were strongly immunopositive, suggesting that culture conditions could stimulate 17ßHSD type 1 gene expression. Should this also be the case for the other 17ßHSD isoforms, then this may explain why the 17ßHSD enzyme activities measured in vitro may not correspond to the 17ßHSD isoform expression from the surgical biopsies. The cells immunopositive for 17ßHSD type 1 were localized to those with the morphological appearance of adenoma cells, but double immunostaining was not performed for confirmation. Antibodies to 17ßHSD isoforms 2, 3, and 4 were not available for study, and it is not known whether these are scattered in a similar distribution and whether a single pituitary adenoma cell may express more than one 17ßHSD isoform.

In conclusion, 17ßHSD type 1, 2, 3, and 4 mRNA were expressed variably in human anterior pituitary adenomas, reflecting the detection of reversible estrogenic activity within these tumors. These data suggest that a complex system of estrogen and androgen modulation through the different 17ßHSD isoforms exists within the pituitary adenoma, which may facilitate or protect against E2-induced tumor growth depending on the 17ßHSD isoforms present.

Received July 9, 1998.

Revised December 10, 1998.

Accepted December 15, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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