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Endocrinology, doi:10.1210/en.2003-0082
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Endocrinology Vol. 144, No. 7 3101-3106
Copyright © 2003 by The Endocrine Society

Localization of 11ß-Hydroxysteroid Dehydrogenase Types 1 and 2 in the Male Reproductive Tract

Brendan J. Waddell, Susan Hisheh, Zygmunt S. Krozowski and Peter J. Burton

School of Anatomy & Human Biology and the Western Australian Institute for Medical Research (B.J.W., S.H.), The University of Western Australia, Perth, Western Australia 6009, Australia; Baker Medical Research Institute (Z.S.K.), Melbourne, Victoria 3004, Australia; and Concept Fertility Centre (P.J.B.), King Edward Memorial Hospital, Subiaco, Western Australia 6008, Australia

Address all correspondence and requests for reprints to: Dr. Brendan Waddell, School of Anatomy and Human Biology, The University of Western Australia, 35 Stirling Highway, Crawley, Perth, Western Australia 6009, Australia. E-mail: bwaddell{at}anhb.uwa.edu.au


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The action of glucocorticoids in target tissues is dependent on the local expression of glucocorticoid receptors and two 11ß-hydroxysteroid dehydrogenase (11ß-HSD) enzymes, 11ß-HSD1 and 11ß-HSD2, which interconvert active and inactive glucocorticoids. This study examined expression of the 11ß-HSD enzymes in the male reproductive tract of the adult rat. 11ß-HSD1 was immunolocalized to the apical region of principal epithelial cells of the caput epididymis, with the less numerous clear cells devoid of signal. Epididymal 11ß-HSD1 expression was confirmed by Western blot analysis, with immunoreactive species identified at 34 kDa (the expected size for 11ß-HSD1) and at approximately 48 kDa. 11ß-HSD bioactivity was readily detectable in the epididymis, with 11-oxoreductase activity clearly the favored reaction (as observed in liver), consistent with 11ß-HSD1 expression. The epithelium of the vas deferens, seminal vesicle, and penile urethra were also immunopositive for 11ß-HSD1, as were smooth muscle cells of the vas deferens and penile blood vessels. 11ß-HSD2 was also immunolocalized to the epididymal epithelium, but its distribution was complementary to that of 11ß-HSD1 (i.e. clear cells showing intense 11ß-HSD2 staining but principal cells devoid of signal). 11ß-HSD2 was also present in the corpora cavernosa of the penis but not in other tissues. In conclusion, the differential expression of 11ß-HSD1 and 11ß-HSD2 throughout the male reproductive tract suggests that these enzymes locally modulate glucocorticoid and mineralocorticoid actions, particularly in the epididymis and penile vasculature.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
GLUCOCORTICOIDS AND mineralocorticoids exert a range of functions in the male reproductive tract, including regulation of ion and fluid transport across epithelia of the epididymis and vas deferens (1, 2, 3, 4), steroidogenesis in testicular Leydig cells (5, 6), and erectile function (7). Access of glucocorticoids and mineralocorticoids to the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) can be modulated locally by two 11ß-hydroxysteroid dehydrogenase enzymes (11ß-HSD1 and 11ß-HSD2) that interconvert active and inactive glucocorticoids (corticosterone and 11-dehydrocorticosterone, respectively, in rodents). The 11ß-HSD1 isoform predominantly catalyzes the reactivation of biologically inert 11-dehydrocorticosterone to corticosterone in vivo and thereby serves to amplify glucocorticoid action. This amplification is most notable in hepatocytes and adipocytes, and its physiological importance is highlighted by the compensatory adrenal hyperplasia observed in 11ß-HSD1-null mice (for review see Ref. 8). In contrast, 11ß-HSD2 exclusively catalyzes inactivation of corticosterone and is consistently coexpressed with the MR in aldosterone-responsive tissues (9). Because corticosterone has high affinity for the MR (10), coexpression of 11ß-HSD2 and the associated inactivation of corticosterone confers mineralocorticoid specificity on aldosterone target tissues (11, 12, 13).

We have previously shown that both 11ß-HSD enzymes are differentially expressed in an estrogen-dependent manner in the female reproductive tract, where they are likely to govern access to the GR (14, 15, 16). Both the GR and MR are also expressed in several tissues of the male reproductive tract including the epididymis (17, 18, 19), where specific aldosterone binding occurs in only a single population of epididymal epithelial cells, termed clear cells (18). Aldosterone binding in these cells suggests they are likely to express 11ß-HSD2 as in classical aldosterone-responsive tissues (9). Indeed, Moore et al. (20) recently reported 11ß-HSD1 and 11ß-HSD2 mRNA expression in the mouse epididymis, but their specific cellular localizations were not determined. Moreover, the recent identification of a role for glucocorticoids and mineralocorticoids in erectile function (7) raises the possibility that the 11ß-HSD enzymes are also expressed in penile vasculature. Indeed, the balance between 11ß-HSD1 and 11ß-HSD2 expression in vascular tissue has been proposed as a key determinant of local glucocorticoid action (21). Therefore, the present study examined 11ß-HSD1 and 11ß-HSD2 immunolocalization throughout the male reproductive tract of the adult rat. These analyses showed expression of both enzymes throughout the tract and, in particular, differential localization of 11ß-HSD1 and 11ß-HSD2 in epithelial cell subtypes and regions of the epididymis. Therefore, 11ß-HSD bioactivity and protein expression were also analyzed in the caput and cauda epididymis.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and chemicals
Male Albino Wistar rats, 3–5 months old and weighing 255 ± 33 g (mean ± SD), were obtained from the Animal Resources Centre (Murdoch, Western Australia, Australia). All rats were housed and managed as previously described (22), and procedures involving animals were conducted only after approval by the Animal Ethics Committee of The University of Western Australia. Steroids, biotinylated molecular weight standards, and nitrocellulose membranes were purchased from Sigma (St. Louis, MO). Thin-layer chromatography (TLC) plates precoated with silica gel 60 F254 were obtained from Merck (Darmstadt, Germany), and [1,2,6,7-3H]corticosterone from Amersham Australia (Sydney, Australia). Tritium-labeled 11-dehydrocorticosterone was prepared using rat liver microsomes as previously described (23), and the purity of both [3H]corticosterone and [3H]11-dehydrocorticosterone was maintained at more than 95% by TLC repurification.

Tissue collection
Rats were anesthetized with halothane/nitrous oxide and tissues obtained from the reproductive tract (caput, corpus, and cauda epididymis; vas deferens; seminal vesicle; prostate; penis; and testis) and kidney. Tissues were either fixed in Bouin’s solution and processed for routine paraffin histology as previously described (14) or snap-frozen on liquid nitrogen for subsequent Western blot analysis (n = 4). For estimation of 11ß-HSD bioactivity, samples of caput and cauda epididymis (n = 3) were placed immediately in ice-cold DMEM (Life Technologies, Inc., Glen Waverley, Australia) containing 26 mM NaHCO3, 25 mM HEPES, 5 mM L-glutamine, 50 mg/liter gentamicin sulfate, and 50,000 µg/liter streptomycin. Samples of testis and liver were also obtained to serve as positive controls for 11ß-HSD bioactivity.

Immunocytochemistry
Immunocytochemistry was performed on tissue sections from three rats using immunopurified polyclonal antibodies raised specifically against portions of the rat 11ß-HSD1 (24) and 11ß-HSD2 proteins (9). Positive immunoreactivity was visualized with a Vectastain Elite ABC kit (Vector Laboratories, Burlingame, CA) and diaminobenzidine as previously described for rat uterus (15). Omission of primary antibody resulted in no staining being evident in any of the tissues analyzed.

Western blot analysis
Tissue samples were homogenized in 4 vol 10 mM sodium phosphate buffer (pH 7.0) containing 0.25 M sucrose, 1 µM EDTA, 1 µM phenylmethylsulfonyl fluoride, 100 µg/ml trypsin inhibitor. Microsomes were recovered by sequential centrifugation and subjected to electrophoresis and Western blot analysis as previously described (16) using the same 11ß-HSD1 and 11ß-HSD2 antisera employed for immunocytochemistry (see above). The specificity of these antisera for the respective 11ß-HSD enzymes has been clearly demonstrated in previous reports (9, 24). Kidney was included as a positive control for 11ß-HSD2 and testis for 11ß-HSD1. Immunopositive signals were visualized using a Vectastain Elite ABC kit and chemiluminesence detection (SuperSignal Substrate, Western blotting; Pierce Chemical Co., Rockford, IL). Blots were placed against autoradiographic film (Kodak XAR film, Eastman Kodak Co., Rochester, NY), and the resultant images quantified by densitometry (16).

11ß-HSD bioactivity
Portions of caput and cauda epididymis, testis, and liver were cut into 1- to 2-mm3 fragments using fine scissors and rewashed in DMEM. 11ß-HSD bioactivity was then determined as previously described for whole rat placenta (23). Briefly, tissue fragments (100 mg) were incubated with 0.2 µCi of either [3H]corticosterone or [3H]11-dehydrocorticosterone in a final volume of 1 ml DMEM (with additives as described above) for 6 h. Thus, the final concentration of [3H]steroid substrate was 2.5 nM, but in addition the total substrate concentration included endogenous steroid already present in tissue fragments. All incubations were made in duplicate. Samples were extracted twice with diethyl ether and [3H]corticosterone and [3H]11-dehydrocorticosterone isolated by TLC (chloroform:ethanol, 96:4). Each was quantified using liquid scintillation spectrometry and the percentage conversion calculated from the relative amounts of substrate and product. Blank incubations (no tissue) were carried out to determine nonspecific interconversion, which was routinely less than 2%, and data from experimental incubations were adjusted accordingly.

Statistical analysis
Variation in 11ß-HSD1 immunoreactivity (Western analysis) was apportioned to band size and epididymal region by two-way ANOVA. Because there was a significant interaction term in this analysis, regional differences in 11ß-HSD1 immunoreactivity (caput vs. cauda epididymis) were assessed separately for each band size by paired t tests. Differences between 11ß-dehydrogenase and 11-oxoreductase bioactivities in caput and cauda epididymis, testis, and liver were assessed by paired t tests.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
11ß-HSD1 and 11ß-HSD2 immunolocalization
The most striking feature of 11ß-HSD1 distribution was its localization at the apical region of the principal epithelial cells of the caput epididymis, the most abundant epithelial cell of the epididymis (25); there was relatively little positive signal throughout the remainder of these cells (see Fig. 1AGo). The much less numerous clear cells of this epithelium, identified by their more centrally placed nuclei (25), were devoid of signal (Fig. 1AGo, arrows). Positive immunostaining for 11ß-HSD1 remained evident in principal cells in the corpus and caput regions of the epididymis, but the subcellular distribution changed from apical dominance to a more general cytoplasmic distribution (compare Fig. 1Go, A and B). The epithelium of the vas deferens, seminal vesicle, and penile urethra were also positive for 11ß-HSD1 (see Fig. 1Go, C–E). The signal in the vas deferens epithelium also appeared to be more prominent in the apical cytoplasm, although not to the same extent as in the caput epididymis. 11ß-HSD1 immunoreactivity was also localized to smooth muscle of the vas deferens and blood vessels of the penis (Fig. 1EGo), but the prostate and stromal portion of the vas deferens (Fig. 1CGo) were immunonegative. Compared with Leydig cells of the testis (Fig. 1FGo), the intensity of 11ß-HSD1 immunoreactivity throughout the tract was relatively low.



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  		Figure 1. Immunocytochemical localization of 11ß-HSD1 and 11ß-HSD2 in the male reproductive tract of the adult rat. Panels A–F, 11ß-HSD1. A, Caput epididymis showing intense immunolocalization of 11ß-HSD1 at the apical surface of principal epithelial cells and absence of staining in clear epithelial cells (arrowed); B, cauda epididymis; C, vas deferens; D, seminal vesicle; E, penile urethra and surrounding blood vessels; F, testis with intense staining in Leydig cells (positive control). Panels G–I, 11ß-HSD2. G, Caput epididymis showing intense immunolocalization of 11ß-HSD2 in clear epithelial cells (inset shows individual cell observed with x100 objective) and absence of staining in principal cells; H, corpus cavernosum of the penis (immunopositive staining on right side of image); I, kidney, showing intense staining in distal convoluted tubules (positive control). Immunolocalization of 11ß-HSD1 and 11ß-HSD2 was replicated three times in each of the tissues. Scale bars, 20 µm (inset of G); 50 µm (A–G); 100 µm (H and I).

 
11ß-HSD2 was also immunolocalized to the epididymal epithelium, but its distribution was far more restricted than that of 11ß-HSD1 and appeared complementary to it. Specifically, 11ß-HSD2 was localized to the cytoplasm of the clear cells of the epithelium (Fig. 1GGo), those cells that did not express 11ß-HSD1 (see above). The intensity of 11ß-HSD2 immunoreactivity in these cells appeared comparable to that in distal convoluted tubules of the kidney (included as a positive control; Fig. 1IGo). 11ß-HSD2 was also clearly evident in the corpora cavernosa of the penis (Fig. 1HGo) but not in any of the other tissues.

11ß-HSD1 and 11ß-HSD2 Western blot analyses
A 34-kDa immunoreactive signal was clearly evident for 11ß-HSD1 in the caput and cauda epididymis, but signal intensity was far less than that observed in testis (Fig. 2Go). The 34-kDa 11ß-HSD1 signal was more than 3-fold greater (P < 0.05) in the cauda relative to caput epididymis (Fig. 3Go). A higher molecular weight band of 11ß-HSD1 immunoreactivity (~48 kDa) was also present in both epididymal regions, and its intensity exceeded that of the 34-kDa species (P = 0.01, two-way ANOVA). Because the intensity of this 48-kDa band was similar in the two epididymal regions, the ratio of 48 kDa to 34 kDa decreased (P < 0.01, paired t test) from the caput (9.8 ± 1.6) to cauda (2.3 ± 0.2) epididymis. The 48-kDa band was also apparent in the testis but at a much lower intensity than the 34-kDa species (Fig. 2Go). Western analysis of 11ß-HSD2 showed a clear immunoreactive band at the expected size of 40 kDa in kidney (positive control), but no signal was detected in epididymis, consistent with its very limited distribution within the epithelium by immunocytochemistry.



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  		Figure 2. Western blot analysis of immunoreactive 11ß-HSD1 proteins in caput and cauda epididymis and testis. Note clear immunoreactive signal at the expected size of 34 kDa in all tissues and an additional band at approximately 48 kDa, particularly in the epididymis.

 


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  		Figure 3. Quantitative Western blot analysis of immunoreactive 11ß-HSD1 proteins in caput and cauda epididymis. Values are the mean ± SE (n = 4). Signal intensity varied significantly with band size (P < 0.0001; ANOVA) and there was significant interaction between band size and epididymal region. Therefore, paired t tests were used to compare differences in specific band intensities between epididymal regions. *, P < 0.05 compared with caput epididymis (paired t test).

 
11ß-HSD bioactivity
11ß-HSD bioactivity was readily detectable in fragments of both caput and cauda epididymis, and in both cases 11-oxoreductase clearly exceeded (P < 0.01) 11ß-dehydrogenase bioactivity, a pattern comparable to that observed in liver (see Fig. 4Go). In contrast, 11ß-dehydrogenase bioactivity in the testis clearly exceeded that of 11-oxoreductase (P < 0.05).



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  		Figure 4. 11ß-HSD bioactivity in fragments of caput and cauda epididymis, testis, and liver. Values are the mean ± SE (n = 3 per group) of the percentage conversion of 3H-corticosterone to 3H-11-dehydrocorticosterone (11ß-dehydrogenase activity) and 3H-11-dehydrocorticosterone to 3H-corticosterone (11-oxoreductase activity) during a 6-h incubation. *, P < 0.05; **, P < 0.01 compared with 11ß-dehydrogenase activity in same tissue (paired t test).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study investigated the cellular distribution of 11ß-HSD1 and 11ß-HSD2 in the male reproductive tract of the adult rat. The key findings were that both enzymes are expressed in various regions throughout the tract, and their differential expression between subtypes of the epididymal epithelium suggests glucocorticoid levels are exquisitely controlled among different parts of the epididymal environment. Specifically, the intense localization of 11ß-HSD1 at the apical region of principal epithelial cells in the caput epididymis suggests that this enzyme may amplify levels of active glucocorticoid within the epididymal lumen. This apical localization of 11ß-HSD1 in epididymis is similar to recent observations in the primate placenta (26). In contrast, expression of 11ß-HSD2, but not 11ß-HSD1, in the clear cells of the epithelium, suggests that this enzyme confers mineralocorticoid specificity as in other aldosterone-responsive cells, and thus accounts for the capacity of these cells to specifically bind aldosterone (17, 18). Expression of 11ß-HSD1 and 11ß-HSD2 within the penile vasculature suggests that both enzymes may modulate glucocorticoid and mineralocorticoid effects on erectile function.

Expression of 11ß-HSD1 in a range of glucocorticoid target tissues has been shown to amplify glucocorticoid action by locally enhancing active glucocorticoid levels (8, 27). The present work clearly shows that 11ß-HSD1 bioactivity in the epididymis favors 11-oxoreductase, similar to that in liver, and is therefore likely to amplify local glucocorticoid action in the epididymal epithelium as occurs in fat and liver (8, 27). The presence of 11ß-dehydrogenase bioactivity in epididymal fragments may reflect expression of 11ß-HSD2, although this expression was limited to only a very small number of epithelial cells and so may not have made a significant contribution to the measured bioactivity. Therefore, epididymal 11ß-dehydrogenase activity may be due to 11ß-HSD1 because this enzyme has a capacity for bidirectional activity. In contrast to epididymis, bioactivity in the testis clearly favored inactivation of corticosterone, consistent with previous reports on 11ß-HSD bioactivity in Leydig cells (5, 6). On the other hand, Leckie et al. (28) have shown that intact Leydig cells exhibit predominantly 11-oxoreductase bioactivity in culture, raising the possibility that 11ß-HSD in these cells could amplify glucocorticoid action in vivo. These differences among studies may partly reflect loss of 11-oxoreductase bioactivity associated with cellular damage as previously reported for placenta (23). Further studies on 11ß-HSD bioactivity in vivo, including estimates of trans-testicular interconversion of corticosterone and 11-dehydro-corticosterone, may resolve these uncertainties about the role of testicular 11ß-HSD1.

Amplification of glucocorticoid action within the epididymal epithelium may be important for a range of epididymal functions including carbohydrate and lipid metabolism (29, 30) and the expression of secretory proteins (31). These functions are likely to impact on sperm maturation and storage because sperm gain the capacity for motility and fertilization in the proximal region of the epididymis and are then stored in the distal region in a state of quiescence before ejaculation (for review, see Ref. 25). The different roles played by specific regions of the epididymis reflect precise variations in epididymal gene expression that emerge during development (32). The apical localization of 11ß-HSD1 in principal epithelial cells of the caput epididymis suggests that corticosterone levels may be enhanced within the epididymal lumen, with possible effects on sperm maturation or function. Indeed, glucocorticoids have been shown to enhance sperm motility in vitro (33) and influence acrosin activity in vivo (34). In addition, because 11ß-HSD1 can inactivate xenobiotic carbonyl compounds (35), its role in the epididymis may include metabolism of toxins that might otherwise gain access to the epididymal lumen and be detrimental to sperm. Interestingly, the fertility of the 11ß-HSD1-null mouse appears normal (8), suggesting that either the role/s played by this enzyme in the epididymis are not critical to sperm maturation, or the mouse and rat differ in this regard. In this context, it is noteworthy that, although the mouse epididymis expresses both 11ß-HSD1 and 11ß-HSD2 (20), the mouse testis does not express 11ß-HSD1 (36). Further studies are required to assess whether the distribution and function of 11ß-HSD1 in the mouse epididymis are similar to those in the rat.

While expression of 11ß-HSD2 was not observed in principal epithelial cells, it was clearly identified in a different subpopulation of the epididymal epithelium, namely the clear cells. This epithelial cell type has previously been shown to bind aldosterone (18) and thus is likely to account for mineralocorticoid binding activity measured in epididymal homogenates by classic binding assays (17). Because the MR has high affinity for glucocorticoids as well as mineralocorticoids (10), expression of 11ß-HSD2 is required to reduce active glucocorticoid levels locally and thereby confer mineralocorticoid specificity on cells expressing the MR (11, 12). It is likely, therefore, that 11ß-HSD2 plays a similar role in clear cells of the epididymal epithelium, thereby enabling aldosterone to activate the MR and regulate sodium and fluid flux. Accordingly, several previous studies have shown that aldosterone regulates ion and fluid transport in the epididymis and related structures (1, 2, 3, 4).

Expression of 11ß-HSD1 was also prevalent in smooth muscle cells of both the vas deferens and in blood vessels supplying the penis. In contrast, 11ß-HSD2, but not 11ß-HSD1, was identified within the corpora cavernosa of the penis. It is possible that glucocorticoid actions within the vascular microenvironment of the penis are dependent on the balance between their amplification via 11ß-HSD1 and dampening via 11ß-HSD2, as suggested for other vascular tissue (21). This balance may have direct relevance to normal erectile function because glucocorticoids have been shown to provide an important positive erectile stimulus (7). In contrast, excess glucocorticoids potentially interfere with erectile function because studies in other vascular beds show that cortisol inhibits cholinergic vasodilation (37), an integral component of normal erectile function (for review see Ref. 38). Further studies are required to assess how the differential expression of 11ß-HSD1 and 11ß-HSD2 within the penile vasculature impacts on erectile function.

A major band of immunoreactive 11ß-HSD1 was observed in the epididymis at the expected size of 34 kDa following Western analysis, and a corresponding band was observed in testis as previously reported (39, 40). The low epididymal expression of this 34-kDa band relative to the testis presumably reflects the more limited cellular distribution of 11ß-HSD1 in epididymis. The presence of an additional, major 11ß-HSD1 immunoreactive band at approximately 48 kDa is similar to our recent observations in the rat uterus with the same antibody (16), and the original studies of Monder (39) showing high molecular mass bands of immunoreactive 11ß-HSD1 in epididymis. It is possible that these immunoreactive species are glycosylated forms of 11ß-HSD1 but whether any possesses 11ß-HSD bioactivity is unclear. Interestingly, our observation that 11-oxoreductase activity was similar in the cauda and caput epididymis despite much lower expression of the 34-kDa band in the latter suggests that the 48-kDa species may indeed contribute to the measured bioactivity.

In conclusion, the present study has demonstrated extensive distribution of both 11ß-HSD1 and 11ß-HSD2 to specific cell types in several tissues of the male reproductive tract of the rat. The differential localization of the two enzymes among subpopulations of epididymal epithelial cells suggests they perform distinct roles within the epididymis, with likely effects on transepithelial ion and fluid passage and the concentration of active glucocorticoid within the epididymal lumen. Expression of 11ß-HSD1 and 11ß-HSD2 within the penile vasculature suggests that local metabolism of glucocorticoids within the penis may modulate their effects on erectile function.


   Footnotes
 
Abbreviations: GR, Glucocorticoid receptor; 11ß-HSD, 11ß-hydroxysteroid dehydrogenase; MR, mineralocorticoid receptor; TLC, thin-layer chromatography.

Received January 16, 2003.

Accepted for publication March 14, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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