Insulin Affects Tissue Organization and the Kinetics of Epithelial Cell Death in the Rat Ventral Prostate After Castration

Prostate growth and physiology are regulated by steroid hormones and modulated by multiple endocrine factors We investigated the action of insulin on the tissue organization and kinetics of epithelial cells in the rat ventral prostate (VP) in response to castration up to 120 hours after surgery by using an acute protocol of alloxan induced diabetes Diabetes caused a reduction in volume density (Vv(o)/) and volume of the epithelium The effects of castration on the epithelium were accelerated in the diabetic animals as determined by changes in V(o)/, and volume The smooth muscle cells became atrophic and apparently relaxed in response to castration in contrast to the spinous aspect observed in nondiabetic castrated rats Counting of apoptotic nuclei in the epithelium showed the classical apoptosis peak at 72 hours in nondiabetic rats and an advance of the apoptosis peak to 48 hours after castration in diabetic rats Insulin restored the time of the peak to 72 hours These results were confirmed after immunostaining for cleaved caspase 3 and suggest a survival and antiapoptotic effect on VP epithelial cells in both the presence and absence of androgen stimulation This idea is supported by the observation that insulin also reduced the overall rate of apoptosis at all experimental points analyzed before and after castration

Early effects of estrogen on the rat ventral prostate

Complex interactions between androgen and estrogen (E2) regulate prostatic development and physiology. We analyzed the early effects of a high single dose of E2 (25 mg/kg body weight) and castration (separately or combined) on the adult 90-day-old male Wistar rat ventral prostate. Androgen levels, prostate weight, and the variation in the relative and absolute volume of tissue compartments and apoptotic indices were determined for 7 days. Castration and exogenous E2 markedly reduced ventral prostate weight (about 50% of the control), with a significant reduction in the epithelial compartment and increased stroma. The final volume of the epithelium was identical at day 7 for all treatments (58.5% of the control). However, E2 had an immediate effect, causing a reduction in epithelial volume as early as day 1. An increase in smooth muscle cell volume resulted from the concentration of these cells around the regressing epithelium. The treatments resulted in differential kinetics in epithelial cell apoptosis. Castration led to a peak in apoptosis at day 3, with 5% of the epithelial cells presenting signs of apoptosis, whereas E2 caused an immediate increase (observed on day 1) and a sustained (up to day 7) effect. E2 administration to castrated rats significantly increased the level of apoptosis by day 3, reaching 9% of the epithelial cells. The divergent kinetics between treatments resulted in the same levels of epithelial regression after 7 days (~30% of control). These results show that E2 has an immediate and possibly direct effect on the prostate, and anticipates epithelial cell death before reducing testosterone to levels as low as those of castrated rats. In addition, E2 and androgen deprivation apparently cause epithelial cell death by distinct and independent pathways.

Malignant lesions in the ventral prostate of alloxan-induced diabetic rats

The aim of this study was to evaluate the changes caused by chronic diabetes in the rat ventral prostate and to establish a correlation between diabetes and the development of prostatic lesions. Male rats received alloxan (42 mg/kg b.w.) to induce diabetes. Ninety days after diabetes diagnosis, animals were sacrificed and the ventral prostate was removed and prepared for general and immunohistochemical analyses. The total area showing different types of lesions was estimated. Diabetes led to a decrease in the body and prostatic weights, as well as in testosterone levels. The prostate morphology and stereology showed high variation in the diabetic group. Some animals had light changes; the great majority had an intense epithelial atrophy; and other rats showed premalignant and malignant lesions in the prostate. Such epithelial atrophy was, in some samples, combined with chronic inflammation, similar to proliferative inflammatory atrophy (PIA). The diabetic group also presented high incidence of prostatitis, adenocarcinoma and prostatic intra-epithelial neoplasia (PIN). Samples with adenocarcinoma had poorly differentiated acini with high levels of cellular proliferation and nuclear atypia. These lesions exhibited an invasive feature showing Bcl-2-positive cells and interruptions in the basement membrane. An association of PIA, PIN and adenocarcinoma was detected in one sample. Reduced androgen levels have a synergic effect to insulin dysfunction promoting negative effects in the rat prostate. Diabetic individuals had a high incidence of prostatitis, and this inflammation could stimulate the incidence of other forms of prostatic pathology.

Physical exercise on the rat ventral prostate: Steroid hormone receptors, apoptosis and cell proliferation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Repercussions of castration and vasectomy on the ductal system of the rat ventral prostate

Diseases. such as cancer and benign prostatic hyperplasia, are related to disruption of the mechanism regulating the balance between cell proliferation and apoptosis in prostatic cells. Since castration and vasectomy might alter that balance, this study evaluates the cell proliferation, apoptosis and height of the secretory epithelium of the ventral-prostate ductal system post-castration and vasectomy. Immunohistochemical (PCNA and Ki67), cytochemical (Fuelgen reaction) and morphometric investigation have been carried out. Cell proliferation indices decreased significantly in both regions of the ventral-prostate ductal system after castration compared to the sham-operated group. The apoptotic index increased significantly after 48 h, declining 7 days post-castration. The cell proliferation indices did not differ after 48 h significantly; however, they increased 7 days post-vasectomy in both regions. The apoptotic index did not differ significantly in either time post-vasectomy. Castration caused an imbalance in favor of apoptosis, whereas vasectomy caused an imbalance in favor of cell proliferation. (c) 2005 International Federation for Cell Biology. Published by Elsevier Ltd. All rights reserved.

Differential proliferative response of the ventral prostate and seminal vesicle to testosterone replacement

We have investigated epithelial cell proliferation and the rate of glandular recovery of the ventral prostate (VP) and seminal vesicle (SV) promoted by testosterone replacement (TR) in castration-induced regressed glands. Adult male Wistar rats were castrated and, after 21 days, they were treated with testosterone propionate (4 mg/kg/day). Intact (CT) and castrated rats without TR (CS) were also analysed. VP and SV were processed for histochemistry, morphometric-stereological analysis and immunocytochemistry to determine the PCNA index (PI). After 10 days of TR, the VP weight reached similar to 72% of the CT values, while the SV weight exceeded similar to 17% of the CT values. By the third day of TR, VP and SV presented a mean P1 of 34% and 94% for distal region and 14% and 22% for proximal region, respectively. SV also had more luminal cells PCNA-positive than VP, mainly in the distal region. The PI values fell on days 5, 7 and 10, but were still higher than CT. These findings indicate that epithelial cells from involuted SV are more responsive to TR than those from VP when Stimulated to proliferate and replace the luminal cell population, suggesting a different mechanism regulating cell proliferation in response to androgenic stimuli. (c) 2006 International Federation for Cell Biology. Published by Elsevier Ltd. All rights reserved.

Remodeling of rat ventral prostate after castration involves heparanase-1

Androgen deprivation causes the rat ventral prostate to reduce to 10% of its original size by 21 days after castration. The regressive changes result from the loss of epithelial cells by apoptosis and marked reorganization of the stroma. We have investigated whether these changes are accompanied by variations in heparanase expression. The ventral prostate of castrated rats was collected and processed for the quantification of heparan sulfate (HS), for the measurement of heparanase expression and its localization by reverse transcription/polymerase chain reaction, Western blotting, and immunohistochemistry, and for transmission electron microscopy (TEM). Absolute HS content decreased significantly as early as day 7 after surgery. Heparanase mRNA peaked 7 days after castration. The heparanase proenzyme (65 kDa) and the active form (50 kDa) were identified and peaked on day 7 after castration; this coincided with maximum HS-degrading activity. Heparanase was located to the basolateral surface of epithelial cells and in the adjacent stroma. After castration, staining for heparanase was reduced in the epithelium and increased in the stroma. TEM revealed that the peak of heparanase expression at day 7 after castration was associated with extensive changes in the basement membrane of the epithelium, endothelium and smooth muscle cells involving cell shrinkage and/or deletion by apoptosis. These results suggest that heparanase expression increases after castration and correlates with a decreased amount of HS. This variation in heparanase expression is involved in tissue remodeling and in the control of the regressive pattern after 1 week of androgen deprivation.

Chronic caffeine intake increases androgenic stimuli, epithelial cell proliferation and hyperplasia in rat ventral prostate

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Finasteride treatment alters MMP-2 and-9 gene expression and activity in the rat ventral prostate

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Combined effect of the finasteride and doxazosin on rat ventral prostate morphology and physiology

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Harmful effects of carbamazepine on the postnatal development of the rat ventral prostate

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Modulation of smooth muscle cell function: Morphological evidence for a contractile to synthetic transition in the rat ventral prostate after castration

In this study, we evaluated the involvement of rat ventral prostate smooth muscle cells (SMC) in secretory activity and whether this function is modulated after castration. Cell morphology was examined at both light and electron microscopy levels and the organelles involved in secretory function were labeled by the zinc-iodide-osmium (ZIO) method at the ultrastructural level and their volume density was determined by stereology. Castration resulted in marked changes of the SMC, which adopted a spinous aspect and abandoned the layered arrangement observed in the prostates of non-castrated rats. The volume density of ZIO reactive organelles increased progressively after castration, reaching significantly higher levels 21 days after castration, Since previous studies have demonstrated that SMC express SMC markers (even 21 days after castration) and are able to respond to adrenergic stimulation, we concluded that differentiated SMC are able to shift from a predominantly contractile to a more synthetic phenotype without changing their differentiation status. (c) 2005 International Federation for Cell Biology. Published by Elsevier Ltd. All rights reserved.

Biological behavior of the gerbil ventral prostate in three phases of postnatal development

In this study, we characterized the gerbil's ventral prostate histology ultrastructurally and quantitatively throughout three phases of postnatal development (young, adult, and old) in order to comprehend its biological behavior and propensity to developing spontaneous lesions with aging. The gerbil prostate is composed of alveoli and ducts immersed in a stroma composed of smooth muscle, fibroblasts, collagen and elastic fibers and vessels. The prostate tissue components present morphological and quantitative aspects that vary according to age. Young animals have an immature gland with modest secretory activity. Synthetic activity remained stable in adult and old gerbil. However, prostatic morphology was altered in the aging, showing an increased epithelium and stromal fibrosis. The nuclei of the secretory cells increased with aging, whereas nucleoli presented few alterations during postnatal development. The epithelial proliferation and stromal remodeling noted in this study indicate that the gerbil prostate may respond to the androgen declines typical of senescence through epithelial proliferation and stromal remodeling.

Postnatal growth of the ventral prostate in Wistar rats: A stereological and morphometrical study

Morphological and stereological analyses were used to characterize the growth kinetics of the Wistar rat ventral prostate (VP). Volume density and absolute volume of the epithelium, lumen, smooth muscle cells (SMCs), and nonmuscular stroma were determined by stereology and paired with plasma testosterone levels and different morphometric measurements. The VP shows an initial growth within the first 3 weeks, a resting phase, and the puberal growth. The puberal growth was coincident with the raise in plasma testosterone. Lumen formation occurred within the 3 postnatal weeks. After an expected increase during puberty, the lumen showed a further increase at the 12th week. The volume density of the nonmuscular stroma and of the SMCs decreased slowly postnatally. Absolute volume of the luminal compartment showed three phases of growth (weeks 1-3, 6-9, and 11-12). on the other hand, the increase in the absolute volume of the epithelium was steady up to the 8th week and then showed a marked increase up the 10th week. The increase in epithelial volume was characterized morphologically by the presence of epithelial infoldings and sprouts. The growth of the epithelium showed a 2-week delay as compared to the lumen and occurred only until the 10th week. The epithelial height was variable but could be related to the synthetic activity of the epithelium. In conclusion, the postnatal growth of the VP results from a combination of epithelial proliferation/differentiation and synthesis/accumulation of the secretory products in the lumen.

Cellular and extracellular behavior in the gerbil (Meriones unguiculatus) ventral prostate following different types of castration and the consequences of testosterone replacement

Mongolian gerbils (Meriones unguiculatus) were grouped into two experimental groups: GEx.01 suffered orchiectomy and after 30 days received doses of testosterone cipionate (T), while GEx.02 received weekly and alternated doses of the anti-androgens cyproterone acetate and flutamide for 30 days, and the animals were then euthanized. Structural evaluation reveals a more intense reduction in epithelial height in GEx.02. Smooth muscle cells (SMC) presented a star-shaped aspect after 30 days of hormonal ablation and basal membrane was shown to be more intensely grooved in GEx.01. In both groups, after hormonal replacement, recovery in epithelial height could be noted and the SMC presented its phenotypes, but an increase in RER was seen, characterizing a modulation from its contractile to secreting phenotype. In conclusion, the prostate presented involution capacity after androgen ablation and the ability to reorganize after hormonal replacement, but events resulting from orchiectomy and subsequent T replacement were shown to be more aggressive to the prostate. (c) 2006 International Federation for Cell Biology. Published by Elsevier Ltd. All rights reserved.