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Cell Biology International (2005) 29, 778–784 (Printed in Great Britain)
Tissue remodeling in Guinea pig lateral prostate at different ages after estradiol treatment
Wellerson Rodrigo Scaranoa, Renato Simões Cordeiroa, Rejane Maira Góesb, Hernandes F. Carvalhoa and Sebastião Roberto Tabogab*
aDepartment of Cell Biology, UNICAMP, Campinas, São Paulo, Brazil
bSão Paulo State University – UNESP, Microscopy and Microanalysis Laboratory, Department of Biology, Rua Cristóvão Colombo, 2265, Jardim Nazareth, São José do Rio Preto, São Paulo, Brazil


Abstract

Estrogen seems to have an essential role in the fibromuscular growth characteristic of benign prostatic hyperplasia (BPH). This paper describes the effects of chronic estradiol treatment on Guinea pig prostatic stroma at different ages. Tissues from experimental animals were studied by histological and histochemical procedures, morphometric–stereological analysis and transmission electron microscopy (TEM). Marked fibromuscular hypertrophy was observed after estradiol treatment in animals of pre-pubertal and adult ages. Increases in the density and thickness of the collagen and elastic fibers were observed by histochemistry. TEM revealed wide distributions of collagen fibrils and large elastic fibers adjacent to the epithelial basal lamina and between the stromal cells, establishing contacts between them. These results indicate that the Guinea pig prostate simulates the stromal modifications observed in BPH in some aged animals after estrogen treatment at different ages, making it a good model for this disease.


Keywords: Estradiol, Prostate, Stroma, Collagen fibrils, Guinea pig, BPH.

*Corresponding author. Tel.: +55 17 3221 2386; fax: +55 17 3221 2390.


1 Introduction

Benign disease of the human prostate (benign prostatic hypertrophy/hyperplasia, BPH) is histologically complex, involving glandular and stromal hyperplasia, fibrosis and prostatitis (Horsfall et al., 1994). The stromal alterations are associated with smooth muscle cell hypertrophy/hyperplasia, increased synthetic capacity of the stromal cells and deposition of collagen fibrils (Rohr and Bartsch, 1980). Studies of BPH have been handicapped by the limited number of animal models that show these histological features (Karr et al., 1984), principally because such tissue alterations are associated with aging. Currently, the dog is regarded as the only non-primate to develop spontaneous prostatic hyperplasia with age, hence it has been widely used as a model for human BPH (Bartsch et al., 1979). Although BPH can be induced in young dogs by hormone manipulation (Moore et al., 1979; Rhodes et al., 2000), the resultant histological features differ from those that occur spontaneously in aged dogs.

Previous studies, however, have indicated that estrogen administration leads to increases in the size and number of smooth muscle cells in the rat prostate (Thompson et al., 1979). The Guinea pig prostate shows increased density and thickness of collagen fibrils in castrated adult animals after estradiol treatment (Neubauer and Mawhinney, 1981; Mariotti and Mawhinney, 1982); similar changes are observed in aged animals (Horsfall et al., 1994). These effects are directly associated with the presence of estrogen receptors (α-ER) in the prostatic stroma (Prins et al., 1998). Therefore, if BPH is essentially a stromal disease (Rohr and Bartsch, 1980), estrogen may be involved in its development (Tam and Wong, 1991).

In view of these considerations, the present work was undertaken to examine the effects of estradiol on the Guinea pig lateral prostate stroma at different ages in an attempt to evaluate the estrogenized Guinea pig as an experimental model for BPH.

2 Material and methods

2.1 Animals

Forty male Cavia porcellus Guinea pigs of the following ages were used: pre-pubescent (10 days after birth), pubescent (20 days after birth), post-pubescent (80 days after birth) and adult (120 days after birth) (Horsfall et al., 1994). The animals were housed under standard conditions (25°C, 40–70% relative humidity, 12h light/12h dark) and allowed access to chow and water ad libitum.

2.2 Experimental design

For each age group, the animals were divided in two groups of five (control and estrogen-treated). The treated groups received weekly subcutaneous injections of β-benzoate-3-estradiol (Sigma Chemical Co., St. Louis, Missouri) diluted in vegetable oil (25mg/ml) at a dose of 0.4ml/week/animal for four weeks, while the control groups received only vegetable oil (see Tam and Wong, 1991). In view of the weaning period and their experimental fragility as newborns, the pre-pubescent animals received only one dose of the hormone at 10 days of age.

At the 15 (pre-pubescent), 50 (pubescent), 110 (post-pubescent) and 150 (adult) days post-birth, the Guinea pigs of both groups were anesthetized lightly and killed by cervical displacement. The lateral prostate was removed and submitted to light microscopy and ultrastructural analysis. The lateral prostate was used in this work because it is highly responsive to hormonal modulation (Horsfall et al., 1994). As opposed to rats and mice, this animal has no ventral prostate.

2.3 Histochemistry

The excised lateral prostate was immediately fixed by immersion in modified Karnovsky solution (2% paraformaldehyde plus 2% glutaraldehyde in 0.1M phosphate buffer, pH 7.2) (Glauert, 1975), then washed with running tap water, dehydrated in an ethanol series, clarified in xylene, embedded in paraffin (Histosec, Merck) or glycol methacrylate resin (Leica historesin embedding kit), and sectioned (3μm) with a Leica automatic rotatory microtome. The sections were stained with hematoxylin–eosin (H&E) (Behmer et al., 1976). The distribution of stromal fibers was evaluated by the picrosirius–hematoxylin (Junqueira et al., 1979) and Masson's trichrome (Behmer et al., 1976) methods for collagen fibers; Gömöri's silver impregnation for reticular fibers (Behmer et al., 1976); and a modified Weigert's resorcin–fuchsin method for elastic fibers (Taboga et al., 2002).

2.4 Transmission electron microscopy

The lateral prostates of control and treated Guinea pigs were processed for transmission electron microscopy as described previously (Carvalho et al., 1994), employing the fixation procedure of Cotta-Pereira et al. (1976). Briefly, tissue fragments were fixed in 0.25% tannic acid plus 3% glutaraldehyde in Millonig's buffer, dehydrated in acetone and embedded in Araldite resin. Silver sections were cut with a diamond knife, stained with uranyl acetate and lead citrate and examined with a LEO-Zeiss 906 transmission electron microscope.

2.5 Stereological analysis

The volume densities of the tissue compartments were determined according to the procedure of Weibel (1978), using the 168 point grid test system, as applied to the prostate by Huttunen et al. (1981). Thirty microscopic fields for each experimental group at each age were chosen at random. Volume density was calculated from the number of points coinciding with each tissue compartment (epithelium, muscle stroma, lumen of acini and non-muscle stroma: connective tissue interacinar+connective tissue adjacent to the epithelium). The measurements were made on the distal portion of the prostate gland. The data were analyzed using Statistica 6.0 software (StarSoft©, Inc., 1984–1996). The proportions, expressed as percentages, were submitted to the Student's t test, and p0.05 was taken to indicate a significant difference.

3 Results

The Guinea pig lateral prostate consists of glandular acini and ducts lined by a single layer of simple cuboid to columnar epithelial cells. This epithelium delimits the lumen of the acinar units, where the epithelial cell secretions are stored. Adjacent to the epithelium there is fine vascularized connective tissue (Fig. 3). Each gland is surrounded by a well-defined layer of smooth muscle cells (Figs. 1a, 3, 5a) and the acinar units are separated from each other by delicate, loose fibrovascular connective tissue containing sparse fibroblasts.


Figs. 1–8

Fig. 1a–d: Pre-pubescent age: control group. (a) General view of an acinar unit shows the epithelium (e), the adjacent fine connective tissue (arrow head) and smooth muscle cells (m). Staining: H&E, 232×. (b) The arrow head points to the fine connective tissue adjacent to the epithelium. Staining: picrosirius–haematoxylin, 725×. (c) Disposition of sinuous reticular fibers (arrow head), which outline the smooth muscle cells and the base of the epithelium. Staining: Gomori's reticulin, 580×. (d) Detail of a prostatic acinus with rarely-observed fine elastic fibers (arrow head). Staining: Weigert's resorcin–fuchsin, 580×. Fig. 2a–d: Pre-pubescent age: treated group. (a) A general view of the prostatic acinus shows the epithelium (e), a well-defined connective tissue layer adjacent to the epithelium (arrow head) and a thick smooth muscle layer (m). Staining: H&E, 232×. (b) The arrow points to collagen fibrils around the epithelium. Staining: picrosirius–hematoxylin, 580×. (c) Detail of the epithelium–stroma transition showing thick and wavy reticular fibers (arrow head). Staining: Gomori's reticulin, 580×. (d) Detail of the connective tissue adjacent to the epithelium, where elastic fibers can be observed (arrow head). Staining: Weigert's resorcin–fuchsin, 580×.Figs. 3 and 4: Pubescent age: control and treated groups. General view of the prostatic acinus showing the epithelium (e), a well-defined connective tissue layer adjacent to the epithelium (arrow head) and the smooth muscle cells around them (m). Staining: H&E (Fig. 3), 232× and (Fig. 4), 116×. Fig. 5a–c: Post-pubescent age: control group. (a) Architecture of the prostatic gland showing the epithelium (e), some papillary folds and muscle cells (m). Note that the connective tissue is not visible. Staining: H&E, 91×. (b) The arrow head points to the fine collagen fibers adjacent to the epithelium. Staining: picrosirius–hematoxylin, 464×. (c) Distribution of the reticular fibers surrounding the epithelium and smooth muscle cells. Staining: Gomori's reticulin, 580×. Fig. 6a–c: Post-pubescent age: treated group. (a) General structure of the lateral prostate gland showing the epithelium (e) with many papillary folds, a well-delimited connective tissue layer adjacent to the epithelium (arrow head) and a hypertrophic smooth muscle layer (arrow). Staining: H&E, 91×. (b). The arrow points to the bundles of collagen fibrils adjacent to an epithelial fold. Staining: picrosirius–hematoxylin, 725×. (c) Thick reticular fibers can be observed adjacent to the basal membrane and surrounding the smooth muscle cells (arrow head). Staining: Gomori's reticulin, 725×. Fig. 7a–c: Adult age: control group. (a) Detail of the epithelium base showing fine collagen fibrils (arrow head). Staining: picrosirius–hematoxylin, 725×. (b) The arrow head shows the reticular fibers surrounding the epithelium. Staining: Gomori's reticulin, 290×. (c) Fine elastic fibers can be observed in the connective tissue adjacent to the epithelium (arrow head). Staining: Weigert's resorcin–fuchsin, 464×. Fig. 8a–c: Adult age: treated group. (a) The arrow points to bundles of collagen fibrils adjacent to an epithelial fold. Staining: picrosirius–hematoxylin, 580×. (b) Detail of the epithelium–stroma transition showing well-distributed elastic fibers (arrow head). Staining: Weigert's resorcin–fuchsin, 580×. (c) Distribution of reticular fibers (arrow head) surrounding the epithelium and smooth muscle. Staining: Gomori's reticulin, 725×.


The general structure of the control prostatic gland was similar at all the ages studied here, but the prostatic acinar diameter increased as aging progressed (Table 1). Papillary folds were occasionally present in the epithelium, principally at the post-pubescent and adult ages (Fig. 5a). The histochemical results showed that the stroma in control animals had sparse collagen fibrils and elastic fibers (Figs. 1b, d, 5b, c, 7a–c). Ultrastructurally, the collagen fibrils appeared adjacent to the basal lamina of the epithelium and among the stromal cells (Figs. 9 and 10). In some places they formed bundles, although they were mostly dispersed in the stroma. In contrast, elastic fibers were rarely observed in the stroma of control animals (Figs. 1d, 7c, 9 and 10).


Table 1.

Volume density of prostatic tissue compartments (%) shown by stereological analysis (mean ± standard deviation)a


Figs. 9–14

Fig. 9: Ultrastructure of the prostatic stroma in a pubescent control animal showing the smooth muscle cells (smc) and collagen fibrils (arrow head) dispersed below the basal lamina (bl), 7900×. Fig. 10: TEM of the prostatic stroma of an adult control animal indicating a basal cell of the epithelium (bc). The collagen fibrils (arrow head) are dispersed around the stroma and surrounding the smooth muscle cells (smc). In some places the collagen fibrils form bundles, 7900×. Fig. 11: Prostatic stroma of a pre-pubescent treated animal showing a basal cell of the epithelium (bc), bundles of collagen fibrils (arrow head) dispersed around the stromal compartment, and fibroblasts (f), 7900×. Fig. 12: Stromal compartment of an adult treated animal showing collagen fibrils dispersed and forming bundles (co), and elastic fibers (el) distributed below the epithelium (ep) and between the smooth muscle cells (smc) and fibroblasts (f) and in contact with the collagen fibrils and extracellular ground substance (*), 20,000×. Fig. 13: Epithelium–stroma transition in adult treated animal showing elastic fibers (el) and bundles of collagen fibrils (co) adjacent to the epithelium (ep) and inserted into the basal lamina folds (arrow head) and smooth muscle cell (smc) processes, 10,200×. Fig. 14: TEM of a post-pubescent treated animal showing bundles of collagen fibrils (co) adjacent to the epithelium (e) and between the smooth muscle cells (arrow), 12,930×.


EpitheliumNon-muscular stromaMuscular stromaLumen of the acini
Pre-pubertal ageControl23.3 ± 2.738.0 ± 2.725.3 ± 2.113.4 ± 3.8
Estrogen-treated21.2 ± 3.121.6 ± 3.840.4 ± 2.716.8 ± 4.3

Pubertal ageControl20.2 ± 1.926.4 ± 3.738.6 ± 2.814.8 ± 2.0
Estrogen-treated29.3 ± 3.627.6 ± 5.724.4 ± 3.518.8 ± 3.1

Post-pubertal ageControl17.4 ± 1.916.9 ± 1.925.3 ± 3.140.5 ± 4.0
Estrogen-treated30.4 ± 1.825.2 ± 2.217.2 ± 2.627.3 ± 4.2

Adult ageControl18.6 ± 2.322.3 ± 3.428.3 ± 3.030.9 ± 3.0
Estrogen-treated23.0 ± 2.726.3 ± 3.732.6 ± 2.618.2 ± 2.4
a Bolded values are statistically significantly different from the control, according to the Student's t test at p0.05.

Stromal fibromuscular hypertrophy was observed in the Guinea pig prostate after estradiol treatment at the pre-pubertal and adult ages. Both fibrillar and cellular components increased in number and thickness. Abundant collagen fibrils were detected in the stroma in the treated groups (Figs. 2b, 6b, 8a, 11–14). Collagen fibril aggregates occupied relatively large stromal areas; they were associated with the basal lamina of the epithelium, elastic fibers and stromal cells (Figs. 11–14). In some cases, the collagen fibrils and elastic fibers accompanied cytoplasmic processes of the smooth muscle cells and fibroblasts (Figs. 11–14). Elastic fibers in the stromal compartment were more abundant after estrogen treatment in treated groups than in the control groups (Figs. 2d, 8b, 13 and 14). They interconnected the collagen fibrils and were associated with the basal lamina of the epithelium and stromal cells (Figs. 12 and 13). The reticular fibers were disposed in fine layers adjacent to the epithelium and surrounding the smooth muscle cells in the control groups (Figs. 1c, 5c and 7b); in the treated groups, they were thicker and occupied a large area of the stroma (Figs.2c, 6c and 8c). Extracellular ground substance was apparent surrounding the fibrillar and cellular components of stroma in the treated groups (Fig. 12). Hypertrophy of the smooth muscle cells was also observed in the treated animals (Figs. 2a and 6a).

These modifications were contributed to increased volume densities on non-muscular and muscular stroma in adulthood (Table 1). At the pre-pubertal age, the increase of the muscular stroma balanced with the reduction of other stromal components. However, at the adult age, the increase of the stromal compartments was at the expense of the glandular lumen.

In addition, the increase in epithelial volume density showed marked increase at the post-pubertal and adult age (Table 1). This was not only due to the reduced profile of the lumen, but actually represented a development of the epithelium, which showed, however, less differentiated cells (Fig. 8a and b).

4 Discussion

Estrogen has been implicated in the pathogenesis of prostate hyperplasia and neoplasia and is thought to be of primary importance in influencing androgen metabolism and stimulating the prostatic stroma (Thompson et al., 1979). Furthermore, testosterone levels decline with aging but serum estrogen levels remain unaltered (Drafta et al., 1982), so estrogen may be involved in the development of BPH in aged humans.

Several studies have been conducted on rodents and dogs to evaluate the effect of estrogen on the prostatic stroma in vivo (Rhodes et al., 2000; Neubauer and Mawhinney, 1981; Tam and Wong, 1991). Recent data have demonstrated that the Guinea pig prostatic epithelial compartment and stroma are sensitive to estrogen treatment (Scarano et al., 2004), presenting marked intraepithelial dysplasia. In the present work, the epithelial dysplasia seems to have contributed to increased epithelial volume density in adulthood. Accordingly, it has been published before that estrogen treatment induces epithelial squamous hyperplasia (Cunha et al., 2001). Though it was not characterized in the present investigation, it correlates well with the reduction in the glandular lumen, observed at the estrogen-treated adult prostate, because it would result in reduced secretory activity and luminal accumulation.

Our results show that the thickness of the smooth muscle cell layer increased in the pre-pubescent, post-pubescent and adult Guinea pig groups after estradiol treatment, and the stromal fibrillar compartment was augmented. This would be enough to justify the increased volume density measured at these ages. However, the electron microscopy analysis allowed for the observation revealed that smooth muscle cells were hypertrophic.

The growth-promoting effects of estrogens and androgens in vivo may be mediated, at least in part, by local synthesis of growth factors (Huynh et al., 2001) that modulate cellular activity. Droller (1997) identified estrogen receptors in fibroblasts, basal epithelial and acinar epithelial human prostatic cells, indicating that estrogen could induce the expression of epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR) by stromal cells. According to Tilley et al. (1985), most of the estrogen receptors in the Guinea pig are present in the stroma rather than the epithelial portion, where androgen receptors are abundant. This difference in the distribution of estrogen receptors suggests that the fibromuscular stroma may be more responsive to estrogen.

The stromal modifications observed in the Guinea pig differ from that of reported for the rat, in which the fibroblasts are the most reactive cell, proliferating and forming a thick layer around the epithelium in response to neonatal estrogen administration (Chang et al., 1999). This may be attributed to lobe differences in the response to estrogen or are genuine species-specific characteristics.

During puberty the expression of estrogen receptors decreases as a function of the increase in serum testosterone (Tilley et al., 1985). This may explain why the pubescent Guinea pigs showed low sensitivity to estradiol treatment in our experiments, after showing high sensitivity post-natally, when estrogen receptor α is expressed by the stromal cells.

Moreover, the reduced response observed in post-pubertal and adult prostate may result from paracrine regulation by the epithelium, which express estrogen receptor β, or through an indirect effect of estrogen, downregulating the hypothalamus–pituitary axis.

Horsfall et al. (1994) established a relationship between the tissue alterations observed in human BPH and aged Guinea pig prostate: the synthetic capacity of the smooth muscle cells and the deposition of collagen fibrils increased in both cases. Zhao et al. (1992) demonstrated that the smooth muscle cells adopted a more synthetic phenotype; the myofibrillar volume fraction was lower in estrogenized rats. These findings may indicate a changing role for these cells during the development of BPH, in which they assume a synthetic phenotype, contributing to increased synthesis of extracellular matrix elements (Vilamaior et al., 2000). Similar effects were observed after finasteride treatment (Huynh et al., 2001) in castrated rats (Tilley et al., 1985) and in estrogenized intact and castrated Guinea pigs (Rohr and Bartsch, 1980; Bartsch et al., 1979, 1987). The stromal remodeling is similar in these experimental models and might be associated with changes in the synthetic machinery of the stromal cells after hormonal disorders.

After estradiol treatment, the pre-pubescent, post-pubescent and adult Guinea pig lateral prostate shows tissue modifications that are similar to the stromal changes associated with BPH. This indicates a probable role for estrogen in stromal hypertrophy. The estrogenized Guinea pig may provide a valuable adjunct to existing models for studying the various forms of BPH.

Acknowledgements

The authors are indebted to the Fundação de Amparo à Pesquisa do Estado de São Paulo – FAPESP for RSC and WRS fellowships and grants to SRT – Grant no. 00/06136-1 and CAPES. Special acknowledgments are due to Mr. Luiz Roberto Falleiros Junior and Ms. Rosana Silistino de Souza, MSc for technical assistance.

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Received 4 November 2004/18 March 2005; accepted 5 May 2005

doi:10.1016/j.cellbi.2005.05.003


ISSN Print: 1065-6995
ISSN Electronic: 1095-8355
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