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Centre for Urological Research (J.J.B., G.P.R.), Monash University, Clayton, Victoria, 3168, Australia; ANZAC Research Institute (D.J.H.), Concord Hospital and University of Sydney, Sydney, New South Wales, 2139, Australia; and Melbourne Pathology (J.S.P.), Collingwood, Victoria, 3066, Australia
Address all correspondence and requests for reprints to: Professor Gail P. Risbridger, Monash Institute of Reproduction and Development, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria, Australia, 3168. E-mail: gail.risbridger{at}med.monash.edu.au.
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Abstract |
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-reductase and aromatase enzymes, respectively. Exogenous estrogen inhibits prostate growth by indirect effects caused by suppression of pituitary gonadotropins and testicular testosterone output, but direct effects are less well known. Direct effects of estrogens were evaluated using the hypogonadal (hpg) mouse model, which has postnatal deficiency in gonadotropins and testosterone but remains hormone sensitive. Mature hpg mice were implanted sc with implants filled with E2. After 6 wk, prostate lobe [anterior prostate (AP) and ventral prostate (VP)] and seminal vesicle (SV) organ volumes were significantly increased (P < 0.05) but remained smaller than wild-type mice. Analysis of the relative volumes (the proportional composition) of each tissue compartment in these organs showed significant increases in cellular and luminal volumes (P < 0.05) in AP (but not VP) and in SVs. Stromal fibroblasts proliferated, whereas smooth muscle cells were reduced in the AP and SVs. In the epithelia, basal cells proliferated and became metaplastic in the AP and VP. In the AP, luminal debris accumulated, together with an inflammatory response, but there was no evidence of malignant changes. The current study unequivocally demonstrates direct proliferative responses to E2 in the hpg mouse AP and VP lobes and SVs, characterized by discrete lobe-specific changes, including smooth-muscle regression, fibroblast proliferation, inflammation, and basal epithelial cell proliferation and metaplasia. |
Introduction |
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In the prostate gland, blood testosterone entering the gland is converted to the more potent pure androgen dihydrotestosterone (DHT) by the 5-reductase enzyme (6, 7). The prostate gland also expresses endogenous aromatase enzyme (8, 9, 10, 11, 12, 13, 14), providing an alternative pathway for the metabolism of testosterone, to 17ß-estradiol (E2). A direct response to estrogen is mediated via estrogen receptors (ERs) that are located in the prostate stroma and epithelium: the ER subtype is found in the stroma (15, 16, 17, 18), whereas ERß has been identified in epithelial cells (15, 16, 19, 20, 21). However, the administration of estrogen to adult males suppresses pituitary gonadotropins, and testicular testosterone production is diminished. Using this therapeutic approach, estrogen treatment has long been used for palliative treatment of advanced prostate cancer. Androgen withdrawal results in involution and induction of apoptosis in the prostate (22, 23), and this may mask the direct effects of estrogens on the gland. However, there is considerable evidence for direct effects of estrogens on the prostate gland, including the induction of squamous metaplasia (24, 25, 26, 27, 28); imprinting during prostate development, resulting in altered hormonal sensitivity in later life (29, 30, 31, 32); and prostate hyperplasia and dysplasia upon aging (28, 30, 33, 34, 35, 36).
This study used the hypogonadal (hpg) mouse model, which features complete postnatal deficiency of pituitary gonadotropins and, subsequently, of sex steroids, to evaluate the direct effects of E2 in the absence of the confounding effects of the androgen withdrawal attributable to the indirect effects of estrogen. Using this model of androgen-deficiency, these findings have important implications by demonstrating that E2 has a direct effect on the prostate in addition to its well-known indirect effects producing a biochemical castration.
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Materials and Methods |
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Chemicals
SILASTIC implants filled with E2 were prepared from SILASTIC tubing (inside diameter, 1.47 mm; outside diameter, 1.95 mm; length, 1.00 cm; Dow Corning Corp., Midland, MI) and sealed at both ends with SILASTIC adhesive (Dow Corning Corp.).
Experimental design
E2-filled SILASTIC implants were administered sc to 6-wk-old hpg mice under local anesthetic. Age-matched untreated hpg mice and wild-type (wt) control littermates of the same strain were administered empty implants (n = 5–9/treatment group). At 12 wk of age, mice were weighed, then killed by cardiac exsanguination under anesthesia.
Anterior prostate (AP) and ventral prostate (VP) lobes and seminal vesicles (SVs) were excised and dissected free of extraneous fat using a dissecting microscope. The organs were immersion-fixed in Bouin’s fixative before processing. These organ weights could not be accurately determined because of their size; organ volumes were evaluated using stereological analysis. After dehydration, organs were embedded in paraffin wax, serially sectioned (5 µm), and stained with Mayer’s hematoxylin and eosin (H&E) before light microscopy for stereological analysis.
Hormone assays
Serum E2 levels were determined using a Delfia time-resolved fluoroimmunoassay (Perkin-Elmer Corp., Foster City, CA) using polyclonal antibodies. Mouse samples were first subjected to diethyl ether extraction before being analyzed. Cross-reactivity (at 50% inhibition) to estrone, estrone-sulfate, estriol (E3), 2-OH-E3, 16-OxoE2, 16OH-estrone, E2-SO4, and E2-glucuronide is less than 1%. Cross-reactivity to testosterone, progesterone, DHEA, and cortisol is less than 0.01%. The functional sensitivity is 12 pM (coefficient of variation < 15%).
Stereological analysis of prostatic and SV components
All assessments were performed using a BX-50 microscope (Olympus Corp., Tokyo, Japan). The images were captured by a PULNiX TMC-6 video camera (Pulnix America, Sunnyvale, CA) coupled to an IBM computer and projected directly onto a video screen using a Screen Machine II fast multimedia video adaptor (FAST Electronic, GmbH, Hamburg, Germany). CASTGRID V1.10 (Olympus Corp.) software was used to generate a set of counting frames and a point grid (grid properties were assessed individually for each organ and treatment group; sampling was conducted at predetermined intervals along x- and y-axes). Fields were selected by a systematic uniform random sampling scheme, and volumes of tissue compartments were determined based on protocols modified from those previously used in the testis (38) and prostate (39, 40).
Relative volume of tissue compartments.
Serial sections, 50 µm apart, were stained with Mayer’s H&E and were examined under x40 magnification. AP, VP, and SV tissues were classified into 3 compartments: stroma, epithelium, and lumen. The relative volume of stroma, epithelium, and lumen per organ was determined by the sum of the number of points that landed on each compartment divided by the sum of the number of points contacting the entire organ. At least 100 counts per tissue compartment were obtained.
Total organ volume and absolute volume of tissue compartments.
The organ volume was determined using the Cavalieri estimate (41). The absolute volume of each tissue compartment was determined by multiplying the organ volume and the relative volume.
Statistical analysis
All data were analyzed to determine normality, and significant differences were determined by one-way ANOVA followed by post hoc comparisons, with a significance threshold employed at a level of 5% (P < 0.05). Data analyses were conducted using Prism 2.01 software (GraphPad Software, Inc., San Diego, CA). Data are expressed as mean ± SEM.
Immunohistochemistry
Basal cell identification was made by immunolocalization of high-molecular-weight cytokeratins (CKHs) (CK 34ßE12; DAKO Corp., Carpinteria, CA). CK10 (DAKO Corp.) immunoreactivity was used to identify the presence of squamous metaplasia. Smooth muscle cells were examined by immunostaining for -actin (Sigma, St. Louis, MO). ER was detected with ER mouse monoclonal IgG antibody (1D5; DAKO Corp.). Progesterone receptor (PR) was immunolocalized with a specific polyclonal antibody (DAKO Corp.), as was androgen receptor (AR) (PG21, a kind gift from Gail Prins). Proliferating cells were identified by immunostaining with the proliferating cell nuclear antigen (PCNA) (DAKO Corp.), and apoptosis was examined using the Apoptag peroxidase in situ apoptosis detection kit (Intergen, Purchase, NY) as per instructions provided by the manufacturer. E-cadherin was detected using a mouse monoclonal IgG2A antibody (Transduction Laboratories, Inc., Lexington, KY).
Briefly, individual organs were sectioned longitudinally (5 µm), to reveal the proximal-distal orientation, and deparaffinized, rehydrated, and treated with 3% H2O2 in methanol for 30 min to block endogenous peroxidase. A number of pretreatment conditions were employed before inactivation of endogenous peroxidase, including trypsin digestion (0.4% trypsin at 37 C for 2 min; CKH) and antigen retrieval (0.01 M citrate buffer, pH6.0, for 15 min at 100 C; ER, PR, AR, PCNA, and E-cadherin). CK10 and -actin staining were detected immediately after endogenous peroxidase inactivation. Nonspecific binding was blocked using Super Block (Pierce Chemical Co., Rockford, IL) followed by incubation with primary antibodies for 1 h at room temperature. The primary antibodies were reacted with biotinylated rabbit antimouse IgG1 (Zymed Laboratories, Inc., San Francisco, CA), biotinylated goat antirabbit IgG (Zymed Laboratories, Inc.), or biotinylated rabbit antimouse IgG2A (Zymed Laboratories, Inc.), followed by incubation with an avidin-biotin peroxidase kit (ABC Elite; Vector Laboratories, Inc., Burlingame, CA) for 30 min, using diaminobenzidine tetrachloride as a chromogen. Finally, sections were counterstained with Mayer’s hematoxylin, gradually dehydrated with alcohol, cleared with Histolene, and coverslipped with DPX mountant.
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Results |
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).
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). Organ volumes were determined using stereological analysis. E2 treatment of hpg mice significantly increased AP, VP, and SV volumes (20-, 3-, and 16-fold increases; P < 0.05), compared with untreated hpg mice; however, they remained significantly smaller than organs from wt mice (Fig. 1).
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, A–C), VP (Fig. 2, D–F), and SV (Fig. 2, G–I) of wt mice comprised glandular ducts surrounded by stroma, lined by epithelial cells, and including a lumen. In contrast to wt (Fig. 2, A, D, and G), the AP, VP, and SV of hpg mice (Fig. 2, B, E, and H) were underdeveloped, and there was a lack of ductal branching and expansion; the stromal and epithelial cells were condensed, and luminal secretions were reduced. The effect of E2 treatment on hpg mice was assessed for each prostatic lobe and showed significant histological changes to the AP (Fig. 2C), VP (Fig. 2F), and SV (Fig. 2I) associated with an increase in organ size (Fig. 1).
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(A and B) confirm the rudimentary appearance of the AP of hpg mice, compared with wt littermate controls. After E2 treatment of hpg mice for 6 wk, the epithelium became multilayered and metaplastic, the stromal layer was more prominent, and the lumen was expanded (Fig. 2C). A significant increase in the calculated absolute volume of each cellular (stroma, epithelium) and luminal compartment was confirmed after E2 treatment (Fig. 3A) and was associated with an increase in organ size, compared with untreated hpg mice. The relative volumetric proportion of each compartment was determined and expressed as a relative volume, showing that, after E2 treatment, there was no proportional increase in the volume occupied by stromal tissue, a decrease in epithelial volume, and a significantly increased luminal volume, compared with untreated hpg AP (Fig. 3B; P < 0.05).
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-actin-positive stroma surrounded the ducts in wt and hpg mice (Fig. 4, A and B). After E2 treatment of hpg mice, the immunostaining pattern of -actin-positive cells was disrupted, and cells in this layer were interspersed with fibroblastic stroma (Fig. 4C), accompanied by an increase in peripheral and periductal fibroblasts (Fig. 4D). The normally elongate shape of the -actin-positive cells were altered, and the cells became more rounded and condensed in appearance (Fig. 4C).
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). The induction of squamous metaplasia was confirmed by immunostaining for CK10 (Fig. 4F).
The most significant changes to hpg mice treated with E2 occurred to the lumen. In wt mice, the luminal compartment harbors fluid secretions with minimal cellular material (Fig. 2A). In hpg mice, the luminal volume was negligible, presumably because of the lack of secretory activity in these hormone-deficient mice (Fig. 2B). Upon E2 stimulation, the epithelial cells became metaplastic and showed little evidence of secretory activity, but the lumen accumulated cellular debris that included epithelial cells, inflammatory cells (neutrophils), and deposits of keratin (Fig. 4G); in the more advanced inflammatory foci, anuclear keratinized whorls were detected in the lumen of E2-treated hpg AP (Fig. 4, G and J). The detection of neutrophils in the stroma (Fig. 4H) migrating through the epithelial layer (Fig. 4I) to the lumen, where the cellular debris and keratin were deposited (Fig. 4, I and J), was taken as evidence that these changes initiated an inflammatory response in the stroma.
VP.
The VP of hpg mice were underdeveloped and rudimentary, compared with that of wt mice (Fig. 2, D and E). In particular, the duct sizes were severely reduced, with negligible luminal volume (Fig. 2E). Stereological analysis of hpg mouse VP (untreated and E2-treated) showed a small (but significant) increase in the absolute volume of stroma, epithelium, and lumen after E2 treatment (Fig. 3C). When expressed as a change in the relative volume of each compartment, there was no significant change to stromal, epithelial, or luminal relative volume in E2-treated hpg VP, compared with untreated hpg VP (Fig. 3D).
Although the VP of hpg mice were rudimentary, stromal, epithelial, and luminal regions were clearly identified as in wt mice (Fig. 2, D and E). There were significant histological changes to VP of hpg mice after E2 treatment, including multilayering of the epithelium and expansion of the stroma (Fig. 2F), but they were less marked than changes to AP. The stroma of the VP included a continuous layer of -actin-positive smooth-muscle cells (Fig. 5, A–C) and a layer of periductal fibroblasts that was usually 1–2 cells thick (Fig. 5D). In contrast to the AP, the induction of fibroblasts in the VP did not result in disruption of the continuous layer of smooth-muscle cells (Fig. 5D, compared with 4D).
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). In addition, a differentiated layer of luminal secretory epithelial cells negative for CKH and CK10 was identified at the apical surface of the epithelium (Fig. 5, E and F) and was evidence of transitional metaplasia.
In the VP lumen, there was little evidence of inflammation or leukocytic infiltration after E2 treatment (Fig. 5, G and H). Cellular debris was infrequently observed (Fig. 5, E and H), and the lumen was usually unexpanded (Fig. 5G). The luminal changes were less severe in the VP of hpg mice in response to E2 treatment, compared with AP (Fig. 5G, compared with 4G).
SV.
A comparison of hpg SV with wt organs showed significant underdevelopment, characterized by a lack in ductal expansion and reduced luminal secretory activity (Fig. 2, G and H). Stereological analysis showed a significant increase in the absolute volume of lumen, epithelium, and (most notably) the stroma after E2 treatment (Fig. 3E). Analysis of the relative volume showed an increase in the stromal volume, a decrease in the epithelium, and no change to the lumen (Fig. 3F; P < 0.05).
As in the prostate, the stroma of the SV consisted of a thickened layer of -actin-positive smooth-muscle cells and a peripheral layer of undifferentiated fibroblasts that surrounded the vesicular duct (Fig. 6A). The thick smooth-muscle layer was maintained in the untreated hpg SV (Fig. 6B); but after E2 treatment, it was discontinuous and shown to be interspersed with fibroblastic cells (Fig. 6C) accompanied by an increase in peripheral and periductal fibroblastic stroma (Fig. 6D). Similar to AP, a more rounded and condensed appearance of smooth-muscle cells was noted (Figs. 4C and 6C).
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); small foci of multilayered cells were observed that were CKH-positive, indicating that these cells were of a basal cell phenotype (Fig. 6E). These foci demonstrated only weak transient expression of CK10 (Fig. 6F).
After E2 treatment of hpg mice, the SV demonstrated no evidence of an inflammatory response in the SV lumen, but neutrophils were identified in the stroma (Fig. 6, G and H).
Immunohistochemistry
E-cadherin.
In wt tissues, E-cadherin immunoreactivity was visualized on the cell surface of epithelial cells (Fig. 7, A–C), and staining persisted on the epithelia of untreated hpg tissues (Fig. 7, D–F). After treatment of hpg mice with E2, E-cadherin immunoexpression was strongly distributed throughout the multilayered basal epithelial cells of the AP (Fig. 7G), VP (Fig. 7H), and SV (Fig. 7I), including secretory cells of the VP and SV.
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immunoreactivity was not detected in the epithelium of wt AP, VP, or SV tissues; however, it did localize to the epithelium of the hpg AP and VP, with weak stromal immunostaining in the hpg AP and SV (data not shown). Weak immunoreactivity for ER was detected in the E2-treated hpg AP and VP, localizing to basal epithelial cells (Figs. 7, J and K). In the stroma, immunoexpression for ER was also weak, colocalizing to smooth-muscle cells and fibroblasts (data not shown). In the E2-treated hpg SV epithelium, strong immunoreactivity for ER was detected in basal and secretory epithelial cells (Fig. 7L) and in the stroma (smooth-muscle cells and fibroblasts; data not shown). Immunostaining for PR was detected in all E2-treated tissues, with moderate-to-strong expression localized to stromal and epithelial cells, including basal cells in the epithelium (data not shown). As expected, AR immunoreactivity was undetectable in the untreated or estrogen-treated hpg tissues (data not shown).
Proliferation and apoptosis.
Cellular proliferation, as shown by PCNA immunoreactivity, was detected in the epithelia of E2-treated tissues, immunolocalizing to basal epithelial cells lining the AP, VP, and SV epithelial ducts (Fig. 7, M–O). Weak immunoexpression for apoptosis was detected only in the stromal compartment of the E2-treated hpg tissues (data not shown).
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Discussion |
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Quantitative analyses, using stereological methods to measure the proliferative action of E2 on prostate and SV in hpg mice, confirmed the increase in organ size and showed a significant increase in absolute volume of all tissue compartments (stroma, epithelium, and lumen). The AP was most sensitive to E2 and showed the greatest increase in absolute volume, compared with untreated animals. However, the proportional changes to the volume of each tissue compartment of the AP, as shown by the relative volume, was altered after E2 treatment and was different in the epithelium and lumen. Therefore, E2-induced growth was not coordinated in this lobe. In the VP, the relative volumes of each tissue compartment were not altered by E2 treatment and, despite significant increases in absolute volume, this lobe showed a coordinated response to E2 different from that of the AP.
In the epithelium, the most severe changes were reported in the AP, compared with the VP, where squamous metaplasia was identified in the AP and transitional metaplasia in the VP. The more severe proliferative response in AP was also associated with an inflammatory response and subsequent disorganization of the epithelial cell layer. Inflammation of the AP was characterized by the identification of neutrophils in the stroma that seemed to migrate from resident blood vessels through the stroma to the epithelium, to reside adjacent to basal cells in the luminal epithelium. In the lumen itself, large volumes of necrotic debris and dense anuclear keratin deposits and whorls were present. These deposits significantly increased luminal volume after estrogen treatment. Transitional metaplasia, identified in the VP after estrogen treatment, is nonkeratinizing, and the absence of cellular debris is consistent with the low immunological response. The absence of inflammation suggests that the changes were not sufficient to elicit a similar inflammatory response, although prolonged duration of treatment may have resulted in similar observations to the AP.
The stroma is a target for estrogen action in the prostate and SV, causing peripheral and periductal fibroblast proliferation and smooth-muscle cell degradation. After E2 treatment, increased fibroblastic stroma was shown in AP and VP; however, the magnitude was notably greater in the AP. The loss and disorganization of smooth-muscle cells, as evident by the discontinuous -actin immunostaining, was shown in the AP, whereas the VP smooth-muscle layer remained intact. The low level of apoptosis in the stroma after E2 treatment supports the possibility of smooth-muscle dedifferentiation rather than cell death. The thickening of the periductal fibroblast layer caused peripheral displacement of smooth muscle and the separation of the normally homogenous muscle band by intermittent fibroblast invasion. The subsequent loss or dedifferentiation of normal smooth-muscle cell-cell contact may be responsible for the manifestation of the stromal aberrations. Additionally, the displacement of smooth-muscle cells, normally contiguous with the basement membrane, may also have negatively regulated epithelial behavior via disruption of normal paracrine communication (4, 50, 51, 52). It was previously shown that normal smooth-muscle cell morphology is dependent on androgens (4); however, this study confirms that estrogens may also contribute to this process. However, androgens may not be required for smooth-muscle cell homeostasis, and the preservation of a homogenous smooth-muscle layer in untreated hpg tissues is further support for this hypothesis.
In the prostate and SV, ER is normally expressed in the stroma (15, 16, 18); the stromal changes elicited by E2 on the hpg prostates were associated with the presence of ER immunoreactivity. However, the impact of ER in mediating the responses in the estrogen-treated hpg mouse prostates is not clear, given the low levels of staining observed in the prostatic epithelium (particularly the AP) and the absence of data for ERß; a role for ERß in the prostate is unknown, but it is not required for the initiation and progression of squamous metaplasia or neonatal imprinting (24, 36). The presence of ER immunostaining in the untreated hpg tissues is intriguing, considering the deficiency of E2 in these animals; however, this may be attributable to the absence of androgens in the hormonal system rather than stimulation by estrogenic ligands (53, 54 ; Stephen McPherson, personal communication). PR immunoreactivity was increased in these tissues, indicative of an ER-mediated response.
In the current study, E2 caused proliferative changes to the prostate lobes (AP and VP) and SV in vivo, whereas E2 was growth inhibitory in vitro (49). Estrogen-induced prostate growth is aberrant and not coordinated, as confirmed in aromatase-deficient mice with a lifelong elevation of serum androgen levels in the absence of estrogens (39). In the adult prostate, E-cadherin is associated with malignancy (55, 56, 57, 58, 59), as shown in mouse models for prostatic carcinoma (60, 61). In the current study, significant pathological responses were recorded in both prostate stromal and epithelial compartments; however, the absence of malignancy, in conjunction with the retention of normal E-cadherin immunoexpression, suggests that E2 alone may not induce prostatic carcinoma. The data from this study provide further evidence that hormonal carcinogenesis in mouse prostate requires the combined actions of androgens and estrogens (60, 62). The independent actions of androgens and estrogens have the potential to initiate changes to the prostate, including hyperplasia and dysplasia, but not malignancy; how these two hormones act in synergy to induce carcinogenesis is unknown.
It was previously suggested that the action of estrogen was dependent on the embryonic origin of the cell (36); the VP is endodermally derived, in contrast to the mesodermal origin of the SV, but the AP is composed of epithelium from the urogenital sinus (endoderm) that grows into and arborizes within the mesonephric duct (SV; mesoderm) mesenchyme. The embryology of these tissues may support the variability in the response of the prostate lobes (AP and VP) to E2 in the current study, because the AP and SV share common responses in the stroma, contrasting with the VP response.
This investigation uses the hpg mouse model to demonstrate the effects of E2 alone, in the absence of confounding effects of androgens. In contrast, a lifelong elevation of androgens, in the absence of estrogens, has been shown to elicit coordinated growth and proliferation of cellular (stroma and epithelium) and luminal compartments of the murine prostate in vivo (39). The current study also demonstrates that estrogens can stimulate growth and enlargement of prostatic and SV stroma, epithelium, and lumen; however, unlike the coordinated growth elicited by androgens, estrogen caused aberrant changes. The pathological significance of estrogen excess in pathogenesis of prostate disease requires further study. In conclusion, the action of estrogen in the hpg mouse prostate lobes (AP and VP) and SV were largely proliferative, associated with the presence of ER immunoreactivity, and were organ-specific, characterized by discrete lobe-specific responses in the smooth-muscle regression, fibroblast proliferation, inflammation, and basal epithelial cell proliferation and metaplasia.
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Acknowledgments |
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Footnotes |
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1 Current address: Alfred Hospital, Prahran, Victoria, 3181, Australia. 
Abbreviations: AP, Anterior prostate; AR, androgen receptor; CK, cytokeratin; CKH, high-molecular-weight CK; DHT, dihydrotestosterone; E2, 17ß-estradiol; ER, estrogen receptor; H&E, hematoxylin and eosin; hpg, hypogonadal; PCNA, proliferating cell nuclear antigen; PR, progesterone receptor; SV, seminal vesicle; VP, ventral prostate; wt, wild-type.
Received May 8, 2002.
Accepted for publication August 22, 2002.
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