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Center for Urological Research, Monash Institute of Reproduction and Development (S.J.M., H.W., G.P.R.), and Department of Anatomy (N.W.), Monash University, and Prince Henry’s Institute of Medical Research, Monash Medical Center (M.E.J., E.R.S.), Clayton, Victoria 3168; Melbourne Pathology (J.P.), Collingwood, Victoria 3066; and Garvan Institute of Medical Research (T.P.I.), Sydney, New South Wales 2010, Australia
Address all correspondence and requests for reprints to: Prof. G. P. Risbridger, Monash Institute of Reproduction and Development, 27–31 Wright Street, Clayton, Victoria 3168, Australia. E-mail: gail.risbridger{at}med.monash.edu.au
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-dihydrotestosterone as well as serum PRL
levels are significantly (P < 0.05) elevated in
mature male ArKO mice. Histological, stereological, and
immunohistochemical studies demonstrated enlargement of the ventral,
anterior, and dorsolateral lobes of the prostate in young and older
ArKO mice. Hyperplasia of the epithelial, interstitial, and luminal
compartments was identified and associated with up-regulation of
androgen receptors. There was no evidence of malignancy as the animals
aged (up to 56 weeks). The changes observed in the prostates of ArKO
mice were unaffected by maintaining mice on regular or soy-free diets.
It is concluded in ArKO mice that, despite the long-term elevation of
androgens and PRL, the absence of estrogen in these animals does not
result in induction of malignancy in the prostate gland. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Most of the studies associated with defining the effects of estrogen have relied upon the use of models in which exogenous estrogens [17ß-estradiol or diethylstilbestrol (DES)] are administered to rodents (2, 4, 7, 9, 10, 13, 14), from which opposite outcomes have been reported (4, 7, 8). The creation of knockout mice (ArKO), in which the cyp19 gene, encoding the aromatase enzyme, is disrupted (3), provides a means to study the long-term effects of endogenous estrogen withdrawal in the male in vivo and to examine the effects on prostatic growth. Thus, the aim of this study was to characterize the prostate gland in ArKO male mice; the endocrine status of the animals was determined together with histological and stereological analysis of the prostatic tissues. The influence of dietary substances with potential estrogen-like effects was examined by comparing mice maintained on a regular diet with those maintained on a soy-free diet.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Wild-type (Wt) and ArKO mice were killed at 8–14, 16–26, and 48–56 weeks of age. Blood was collected, and serum was stored at -20 C. Microdissected ventral (VP), anterior (AP), or dorsal and lateral (DLP) prostate lobes were removed in situ, weighed, and either fixed in Bouin’s fixative (4 h) or snap-frozen on dry ice.
Stereological analysis
After 4 h in Bouin’s fixative, VP, AP, and DLP lobes were
processed into paraffin and serially sectioned at 5-µm thickness for
histological and stereological analyses. Using a systematic uniform
random sampling scheme, approximately 20 sections each of VP, AP, and
DLP were chosen for stereological analysis. These sections were
subsequently stained with hematoxylin and eosin. Sections were examined
under a BH-2 microscope (Olympus Corp., Tokyo,
Japan); images were captured by a PULNiX TMC-6 video camera
coupled to an IBM computer and projected using a Screen Machine II fast
multimedia video adaptor (FAST Electronic, GmbH, Hamburg,
Germany). The computer program CASTGRID V1.10 (Olympus Corp., Albertslund, Denmark) was used to generate a point
grid, and absolute volumes of tissue compartments were determined based
on protocols modified from those previously used in the testis
(16). In brief, the 5-µm sections were examined under
x40 magnification. Tissue sections were mapped to define tissue
boundaries and were sampled at predetermined intervals along
x- and y-axes using a single point grid-counting
frame. At least 100 counts/tissue compartment were obtained, and these
were used to determine the relative volume of prostatic epithelium,
interstitium, or lumen. Point counts were combined to give a reference
volume for each tissue, and relative volumes of each compartment were
determined. Absolute volume estimates were obtained by multiplying the
relative volume of each compartment by the weight of the organ.
Immunohistochemistry
Androgen receptors (AR) were localized using an
affinity-purified polyclonal rabbit antibody, PG21–39 (batch 31;
provided by Dr. G. S. Prins, Chicago, IL). Keratinization of
DES-treated prostatic epithelium was detected by immunostaining for
cytokeratin 10 (CK10; DAKO Corp., Carpinteria, CA), and
progesterone receptor (PR) was detected using a specific polyclonal
antibody (DAKO Corp.). Various protocols of pretreatment,
with or without antigen retrieval, were employed. Briefly, tissue
blocks were sectioned longitudinally to reveal the proximal-distal
orientation of the organ. After mounting, sections were rehydrated,
then subjected to antigen retrieval (0.01 M citrate buffer,
pH 6.0; boiled 15 min; for AR and PR only) before being treated with
3% H2O2 diluted in
methanol for 30 min to quench endogenous peroxidases. A common
procedure for immunostaining was then used on all tissues. Nonspecific
binding was blocked using Superblock (Pierce Chemical Co.,
Rockford, IL) for 60 min before being incubated with primary antibody
[PG21–39 (no. 31), CK10 at 2 µg/ml; PR diluted 1:50] or
concentration-matched normal rabbit or mouse IgG (DAKO Corp., Glostrup, Denmark) for an additional hour at room
temperature. Primary antibody was reacted with a biotinylated goat
antirabbit IgG (Zymed Laboratories, Inc., San Francisco,
CA) or biotinylated rabbit antimouse IgG (DAKO Corp.,
Glostrup, Denmark) and then detected with an avidin-biotin peroxidase
kit (ABC-Elite, Vector Laboratories, Inc., Burlingame, CA)
using 3,3[prime-]diaminobenzidine tetrachloride as a chromogen.
Sections were counterstained with 0.1% Mayer’s hematoxylin,
dehydrated gradually with alcohol, cleared with histolene, and mounted
under DePeX (BDH Laboratory Supplies, Poole, UK), and
immunolocalization was examined using an Olympus Corp.
microscope at x40 times magnification.
The intensity of AR staining in prostate epithelium was estimated using a semiquantitative analysis, and numbers of cells staining positively and negatively for AR were counted in epithelium and interstitial tissue. Briefly, blocks of tissues from four ArKO and four Wt mice were selected randomly from animals in the age range 16–26 weeks and were sectioned longitudinally to reveal the proximal to distal orientation. The different regions of immunostained ducts were classed as proximal, intermediate, or distal, and the intensity of staining was scored blind by an independent observer as: 1 = weak, 2 = moderate, 3 = strong, or 4 = very strong staining. All tissues from Wt and ArKO mice were processed in the same immunohistochemical assay to minimize the discrepancies related to variability in staining intensity. For determination of AR-positive cell numbers, 5-µm sections stained for AR were subjected to systematic sampling, starting at a random point using an unbiased counting frame generated using CASTGRID V1.10 software. Under x40 magnification, cells were classified as AR positive or negative and as either epithelial or stromal. A minimum of 600 cells were counted per organ, cell numbers were combined, and percentages of AR-positive epithelial and stromal cells were determined.
Androgen and PRL measurements
Androgens, testosterone (T), and 5-dihydrotestosterone (DHT),
were extracted from prostatic tissue and serum, separated by HPLC, and
quantified by RIA as previously described (17). To follow
steroid recoveries throughout processing, 11,000–12,000 cpm
radiolabeled [1,2,6,7,16,17-3H]T
([3H]T; 121 Ci/mmol) and
[1,2,3,4,5,6-3H]DHT
([3H]DHT; 110 Ci/mmol; NEN Life Science Products, Boston, MA) were added to each tube after
homogenization. The specific activities of both tritiated tracers were
determined by RIA (17). Recoveries of added steroid
3H-labeled tracers at the final RIA stage were:
T, 53.6% (SD, 1.5%; n = 24); and DHT, 33.0%
(SD, 6.2%; n = 24). The within-assay variation was
assessed from the coefficient of variation for the measurement of five
samples from a single testis preparation (17% and 18% for T and DHT,
respectively). The between-assay variation in the respective assays was
based on the repeated assay of a steroid stock and was 12–15%. The
sensitivity of the combined extraction, HPLC, and RIA component of the
assay was calculated from the sensitivity of the RIA, the average
recoveries of tritiated steroid, and the average serum volume mass
extracted in the assay. These values were 0.37 ng/g prostate for T and
0.92 ng/g prostate for DHT.
Serum PRL levels were determined using a double antibody RIA as previously reported, with modifications (18). Mouse PRL (5 µg), dissolved in 10 µl 25 mM NH4HCO3, pH 9.0, was added to 10 µl 100 mM HEPES, pH 7.4, in a glass tube previously coated with Iodogen (Pierce Chemical Co., Rockford, IL). Na125I (0.5 mCi; Australian Radioisotopes, Inc., Lucas Heights, Australia) was added, and the reaction was allowed to proceed for 15 min at room temperature before the addition of 200 µl 0.2% (wt/vol) BSA in PBS (BSA/PBS). Iodinated PRL was purified from the reaction mixture using a prepacked D-Salt Excellulose column (40–100 µm; Pierce Chemical Co.), which has previously been equilibrated with 2% (wt/vol) BSA/PBS and washed with PBS. Fractions (0.5 ml) were collected into 0.5 ml 1% (wt/vol) BSA/PBS, and peak fractions (100-µl aliquots) were stored at -20 C. Before use, iodinated PRL was thawed and purified using Ultrogel AcA 54 (Sepraco, Pharmacia LKB Biotechnology, Uppsala, Sweden) chromatography to remove protein aggregates and degraded materials. The AcA 54 column was precoated with 0.2% BSA/PBS, and fractions (0.5 ml) were collected into 50 µl 2% RIA grade BSA (Sigma, St. Louis, MO) in PBS. Fractions containing monomeric PRL were diluted to 1000 cpm/50 µl in RIA buffer [150 mM NaCl, 10 mM EDTA, 10 mM sodium phosphate, 0.1% RIA grade BSA, and 0.1% (wt/vol) thimerosal (Sigma), pH 7.5] for use in RIA. Standards (0.1–100 ng/ml) and serum samples (50 µl diluted in RIA buffer) were incubated with primary antiserum [50 µl, 1:300,000, diluted in RIA buffer containing 3% (vol/vol) normal rabbit serum] and iodinated PRL (50 µl) overnight at 4 C. Secondary antiserum (50 µl goat antirabbit IgG diluted 1:16 in RIA buffer; Antibodies, Inc., Davis, CA; titer P-3) was added, and samples were incubated at room temperature for 30 min. After the addition of 50 µl 30% (wt/vol) polyethylene glycol (MW 6000, Sigma) in water, samples were centrifuged at 3660 x g for 15 min at 4 C, and pellets were counted (Wallac, Inc., Turku, Finland).
DES treatment of adult ArKO and Wt mice
Intact age-matched adult ArKO and Wt mice (n = 5/group)
were treated with sc implants of 20-mg pellets containing 2.5 mg DES
and 17.5 mg cholesterol. Groups of five Wt or ArKO animals were studied
after 3 weeks of DES treatment.
Data analysis
All data were analyzed to determine normality, then significance
was determined by one-way ANOVA or the appropriate t test,
which was applied using SigmaStat 2.02 statistical software (Jandel
Corp., San Rafael, CA). P < 0.05 was taken to indicate
statistical significance. Data are expressed as the mean ±
SEM unless otherwise indicated.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Serum DHT and PRL
levels were also significantly (P < 0.02) elevated in
ArKO mice, although they only showed 2- and 3-fold increases compared
with Wt mice, respectively (Table 1). In AP, the tissue levels of DHT
were significantly (P < 0.02) elevated in ArKO mice
compared with those in Wt mice, but levels of T in the AP
were not significantly different (Table 1).
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); however, there was no difference
between levels of AR expression in interstitial cells of ArKO or Wt
mice (Table 2). The intensity of AR labeling was consistently higher in
the ArKO compared with Wt tissues (Fig. 1
and Table 3), and visual assessment of
the levels of AR expression in prostatic epithelium was consistent with
an up-regulation of AR in the epithelium of ArKO mice in regions
proximal, intermediate, and distal to the urethra (Table 3). Similar
results were observed in the other prostatic lobes (data not
shown).
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), there were no significant differences
in body weights between ArKO and Wt mice of the same age (Fig. 2A). In
contrast, the weight of the VP in ArKO mice (Fig. 2B) was significantly
(P < 0.01) increased (at all ages) compared with that
in Wt mice. The relative increase in the weight of the VP in ArKO mice
(vs. Wt mice) was constant throughout the study (
60%,
46%, and 57% in each age group studied).
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.
AP weights were increased (P < 0.01) by 40%, 21%,
and 25% at 8–14, 16–26, and 48–56 weeks, respectively. Significant
changes were also observed in DLP (Fig. 2D), with percent increases
(P < 0.01) in the weight of the DLP of ArKO mice
compared with Wt of 54%, 55%, and 46%, respectively.
Change in volume of ArKO tissue compartments
The increase in weight of the prostate from ArKO mice is
associated with an increase in the actual size of the gland. To
determine whether the increased size is due to balanced growth through
the whole gland or is a consequence of localized dysplasia,
stereological techniques were used. In the VP of ArKO mice there was a
mean increase in lobular weight of approximately 50%, which was due to
a significant (P < 0.05) increase in epithelial and
luminal volume (Fig. 3, A and C,
respectively); the increase in interstitial volume was not significant
(Fig. 3B). Both AP (Fig. 3, D–F) and DLP (Fig. 3, G–I) of the ArKO
mouse showed significant (P < 0.05) increases in the
absolute volume of epithelial, interstitial, and luminal compartments,
consistent with hyperplasia of the cellular compartments. Consequently,
the increase in the absolute volume of individual tissue compartments
in the ArKO mouse prostate is the result of the increased volume of the
entire organ, rather than increased diameter of individual ducts or
localized dysplastic growth.
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, with low
columnar epithelial cells,surrounded by stroma. Hyperplasia,
characterized by increased infolding of the prostatic epithelium, was
observed in VPs from ArKO mice aged 8–14 weeks (Fig. 4B). In animals
aged 16–26 weeks, Wt tissue had normal histology (Fig. 4C), whereas
the ArKO mouse tissue showed limited areas of ductal hyperplasia (Figs. 4D). Prominent hyperplasia of ArKO VP tissue was observed (Fig. 4F) in
older animals, aged 48–56 weeks, in contrast to the mild hyperplasia
of Wt VP (Fig. 4E). There was no evidence of epithelial dysplasia in
ArKO or Wt VP at any of the ages examined.
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, G and H), lateral
lobes (Fig. 4, I and J), and AP lobes (not shown) are typical of those
previously described for normal organs (19), with no
evidence of dysplasia in either Wt or ArKO tissues at any age.
Dietary effects on ArKO prostate phenotype
Normal mouse chow consists of approximately 10% by weight of
soymeal, which contains isoflavones, such as daidzin and genistin. No
differences in weight of VP, AP, or DLP of Wt or ArKO mice were
observed in mice maintained on either a soy-free or a regular diet. The
results in Fig. 5 show that regardless of
diet, the DLPs of ArKO mice were significantly (P <
0.05) heavier than those in Wt (Fig. 5A), and this is due to a
significant (P < 0.05) increase in the absolute volume
of epithelium, interstitium, and lumen compartments (Figs. 5, B, C, and
D, respectively). Similarly, there was no significant effect of the
soy-free mouse chow compared with regular chow on VP or AP weights
(data not shown).
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) resulted in the induction of squamous
metaplasia in the AP of Wt and ArKO (Fig. 6, D and J, respectively)
compared with untreated animals (Fig. 6, A and G, respectively). The
action of DES was characterized by up-regulation of CK10 expression
within the basal and squamous cell layers in the DES-treated animals
(Fig. 6, E and K) compared with untreated controls (Fig. 6, B and H).
Further evidence of a response to DES was the induction of PR
immunostaining in the prostatic epithelium of ArKO and Wt mice (Fig. 6, F and L, respectively) compared with untreated controls (Fig. 6, C and
I).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In a previous report serum LH was elevated in ArKO mice, androgen levels were significantly different between ArKO and Wt animals, and PRL levels were not measured (3). Yet increases in T, DHT, and PRL levels might have been predicted as a consequence of a deficiency in estrogen synthesis, because androgens are the only precursors for the formation of estrogens, and estrogens normally exert negative feedback on pituitary secretion. Although Fisher and collaborators (3) demonstrate significantly elevated serum androgen levels in ArKO mice, there was a wide variation within the groups of mice. Our study measured T and DHT after chromatography of the serum samples and revealed a 10-fold increase in T and a 2-fold increase in DHT. These increased levels of total androgens in the peripheral circulation provide prostate tissue with androgens that can be further metabolized. In the prostate, T is converted to DHT, whose intraprostatic levels are significantly elevated in the AP of the ArKO. DHT is known to be a more potent stimulator of prostate epithelial cell proliferation than T (20), which remains at the same intraprostatic level as that in Wt tissue. These results are consistent with a role for DHT in causing prostatic enlargement, as observed in each lobe of the ArKO mouse prostate.
Serum levels of PRL were also elevated approximately 3-fold in ArKO
mice. Overexpression of PRL can result in prostatic enlargement and
dysplasia (21), indicating that PRL provides an additional
growth regulatory mechanism for the prostate. However, PRL can also
up-regulate 5-reductase activity (22, 23), resulting in
increased local levels of DHT and up-regulation of AR levels in the
prostate, leading to an increased response to androgens (24, 25), which is consistent with the data presented here showing
that AR levels were increased in the ArKO mouse. Androgens and PRL have
been shown to be involved in the growth of reproductive accessory
organs (26, 27, 28, 29), including the development of prostatic
hyperplasia (21). Therefore, it can be concluded that the
combined effects of elevated androgen and PRL levels in the absence of
estrogens resulted in prostate enlargement in the ArKO mouse, or at
least that PRL provides another growth stimulatory influence on the
prostate in addition to androgens.
Histological and stereological analyses demonstrated that increased growth occurred in the VP, AP, and DLP lobes of ArKO mice. In addition, there was an increase in the absolute volume of the epithelium, interstitium, and lumen, indicating that growth was coordinated, maintaining approximately normal ratios of these compartments in the glands, rather than being the result of increased diameter of individual ducts or localized hyperplasia or dysplasia in one individual cell type or tissue compartment.
The timing and duration of estrogen exposure that lead to dysplasia or malignancy are controversial. Most studies describing the effects of estrogens have relied upon the use of exogenously administered estradiol or DES to prenatal, neonatal, or mature animals (2, 4, 7, 8, 9, 10, 13, 30). In general, these reports demonstrate that the consequential effect of neonatal estrogen imprinting on the prostate results in altered size of the mature gland (4, 6, 7, 31), altered response to androgens (7, 8), and epithelial dysplasia (10) with aging. In the adult, administration of elevated levels of estrogen with androgen induces aberrant growth and malignant lesions (32, 33). In ArKO mice, the complete absence of endogenous estrogens and the consequent imbalance between androgens and estrogens may be important in prostatic neonatal imprinting and/or abnormalities in adulthood. In normal mice the balance between androgens and estrogens involves a combination of indirect actions of estrogen via the hypothalamic-pituitary axis and direct local actions on the prostate gland itself. Recent studies by Jarred and collaborators support the hypothesis that estrogen can directly affect prostate growth (12). A direct response could occur by alteration of AR signaling, thus regulating the response of the prostate to androgen itself, or by a specific effect of estrogen mediated by the estrogen receptor pathway. The question of whether intraprostatic estrogen regulates AR levels in the prostate needs to be determined directly, which may be resolved by investigating the effects of castration, estrogen replacement, and inhibition of PRL synthesis, alone or in combination, in ArKO mice.
The present study of estrogen-deficient mice failed to show malignancy by histological examination. This was a consistent finding in all animal groups, including the aged animals (up to 56 weeks), and suggests that a role may exist for estrogens, in combination with elevated androgens, in the induction of prostate malignancy. It is concluded that estrogens exert dual actions on the prostate gland, triggering aberrant growth and/or suppressing androgen-induced hyperplasia. The timing and mechanism of estrogen action in triggering prostate malignancy need further investigation. ArKO mice provide an animal model to determine a causal link between exposure to endogenous estrogens and abnormal growth of the prostate.
Dietary estrogens in the form of soymeal had no effect to reverse or enhance the observed changes in the prostate of ArKO mice. Dietary estrogens found in foods such as legumes and soya have been considered possible protective agents in the diet of Asian men, who have a lower incidence of prostate disease (34). In a single case report, a dietary preparation derived from red clover, containing concentrated levels of phytoestrogens such as genistein, was reported to induce apoptosis in human prostate tumor cells (35). The present study did not show any difference in prostate growth between animals kept on diets of regular or soy-free mouse chow. Soymeal is rich in isoflavones such as genistin and daidzin, which are converted in the gut to genistein and daidzein. The former, in particular, has been shown to have agonistic properties with the ß estrogen receptor (36). Despite this and the reported prostatic hyperplasia in the ß estrogen receptor knockout mouse (37), removal of soy from the diet of both ArKO and Wt mice had no effect on prostatic growth. Whether this reflects insufficient levels of phytoestrogens in the regular diet remains to be established.
Although the levels of phytoestrogens in the diet did not affect the ArKO prostate phenotype, short-term DES treatment of ArKO and Wt mice resulted in regression of the prostate lobes and induction of squamous metaplasia in the AP. The latter response was confirmed by the up-regulation of CK10 and PR in the squamous epithelial cell layer and was the same as that described in Wt mice (Risbridger, G. P., et al., unpublished data).
Based on these results we conclude that the ArKO mice, lacking estrogens, exhibit prostate hyperplasia, but not malignancy, in adult life. Together with other models of prostatic hyperplasia, such as transgenic mice overexpressing the PRL gene (21) or mice lacking the Nkx 3.1 homeobox gene (38), the ArKO mouse is a suitable model in which to investigate the hormonal regulation of prostate growth. Early and late life effects of estrogen replacement on prostate growth and the possible difference in the actions of endogenous vs. exogenous estrogens remain to be evaluated. The use of this animal model can also allow subsequent investigation of the influence that different types of estrogenic compounds, i.e. natural vs. synthetic, have on the growth and development of the prostate and the onset of growth abnormalities in later life.
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Acknowledgments |
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Footnotes |
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Received August 30, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-reductase activity impairs the
testosterone-dependent restoration of spermiogenesis in adult rats.
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hypophysectomized adult rats. Endocrinology 118:2268–2275-reductase, and arginase. Am J Physiol 229:1102–1109 and -ß, and progesterone receptor mRNA expression in
various prostatic lobes and microdissected normal and dysplastic
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J. J. Bianco, D. J. Handelsman, J. S. Pedersen, and G. P. Risbridger Direct Response of the Murine Prostate Gland and Seminal Vesicles to Estradiol Endocrinology, December 1, 2002; 143(12): 4922 - 4933. [Abstract] [Full Text] [PDF]
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) and ArKO (
)
mice at 8–14, 16–26, and 48–56 weeks of age. B, VP weight
(milligrams) in Wt and ArKO. C, AP weight (milligrams) of Wt and ArKO
mice in each group of animals. D, DLP weight (milligrams) of Wt and
ArKO mice in the three age groups. Each value represents the mean
± SEM of five or more animals. *, P <
0.01 compared with Wt mice.
