Spontaneous Benign Prostatic Hyperplasia Research Articles

Decreased mitophagy aggravates benign prostatic hyperplasia in aged mice through DRP1 and estrogen receptor α

Benign prostatic hyperplasia (BPH) is an age-related disease, whose etiology largely remains unclear. The regulation of mitophagy plays a key role in aging and associated diseases, however, its function in BPH has not been studied. Although the expression of the androgen receptor is primarily implicated in BPH, the estrogen receptor (ER) has been reported to be involved in the development of BPH by mediating the proliferation of prostate cells. Here, we studied the involvement of mitophagy and ERs in spontaneous BPH in aging mice and investigated their functions. To identify the activation of mitophagy and expression of ERs, 8-week, 12-month, and 24-month-old mice were used. Mice were treated with mitochondrial division inhibitor mdivi-1, a dynamin-related protein 1 (Drp1) inhibitor, to examine the expression of mitophagy-related proteins and the development of BPH. In addition, prostate stromal cells were treated with an ER antagonist to investigate the regulation of mitophagy following the expression of ERs. With aging, the Drp1 and phosphorylation of parkin reduce. Electron microscopy revealed reduced mitochondrial fission and mitophagy. In addition, the expression of androgen receptor was decreased and that of ERα was increased in aged mice with BPH. Treatment with mdivi-1 exacerbated BPH and increased cell proliferation. In addition, blockade of ERα increased mitophagy and decreased cell proliferation. In conclusion, mitophagy is reduced with aging during the development of BPH. We speculate that spontaneous BPH progresses through the reduction in the expression of ERα in aged mice by downregulating mitophagy.

Prostatic artery embolization: magnetic resonance image (MRI) findings in the early detection of prostate infarction in a canine spontaneous benign prostatic hyperplasia model.

BackgroundThe purpose was to assess the association between prostate infarction and prostate volume (PV) reduction after prostatic artery embolization (PAE) and define the best time point in detection of prostate infarction.MethodsTen male beagles (3.5–6.4 years) with spontaneous benign prostatic hyperplasia (BPH) underwent PAE. Magnetic resonance image (MRI) was conducted immediately before and 1 week, 2 weeks and 1 month after PAE to document prostate infarcts and measure PV. The sum of infarct areas (SUMIA) was measured and calculated using OsiriX software. Spearman’s rank correlation was used to estimate the relationship of PV reduction rate with infarction percentage and SUMIA reduction.ResultsIn comparison with baseline data, significant PV reduction (P<0.001) occurred at 2 weeks and continued to decrease substantially (P=0.004) from 2 weeks to 1 month after PAE. In the same fashion, significant decrease in both SUMIA and infarction percentage was observed from 1 to 2 weeks (P=0.002), and subsequently to 1 month (P=0.039 and P=0.016, respectively). Spearman’s rank correlation test demonstrated infarction percentage at 1 week had a stronger correlation (r=0.880, P=0.001) with PV reduction rate at 1 month than infarction percentage at 2 weeks (r=0.733, P=0.016). PV reduction rate had a significant correlation with decrease in SUMIA (r=0.854, P=0.002) at 1 month after PAE.ConclusionsOne week after PAE is an ideal time point to evaluate prostate infarction. Prostate infarction percentage at 1 week is a good predictor for prostate shrinkage at 1 month after PAE.

Prostatic artery embolization with polyethylene glycol microspheres: evaluation in a canine spontaneous benign prostatic hyperplasia model

BackgroundProstatic artery embolization (PAE) is a minimally invasive technique for the management of symptomatic benign prostatic hyperplasia (BPH) relieving the lower urinary tract symptoms in patients. Various embolic agents have been tested in animal models and subsequently used in human patients. The purpose of this study was to evaluate the technical feasibility, effectiveness, and safety of PAE with polyethylene glycol microspheres in a canine spontaneous BPH model.ResultsFive adult male Beagle dogs (4.78 ± 1.11 years) were diagnosed by tranrectal ultrasonography of spontaneous BPH (prostate volume > 18 ml) and underwent PAE with polyethylene glycol microspheres (400 ± 75 μm). PAE procedures were performed successfully in all dogs. After PAE, all dogs were inspected for potential procedure-related complications during 1 month of follow-up. No major complications were observed any animal. Follow-up angiography was performed in each animal at 1 month of follow-up. Recanalization was demonstrated in all the embolized prostatic arteries or main branches at the end of the study. Magnetic Resonance Imaging (MRI) evaluations were performed immediately before PAE as baseline data, and 1 week, 2 weeks and 1 month after PAE. MRI study showed that the prostate shrank substantially with ischemic necrosis in each dog. There was a significant reduction in the mean prostate volume at 2 weeks and 1 month compared with the baseline data, from 19.95 ± 1.89 mL to 13.14 ± 2.33 and 9.35 ± 2.69 mL (p < 0.001), respectively. Histopathological study was conducted after 1-month follow-up angiography and confirmed the therapeutic responses with diffuse glandular atrophy and interstitial fibrosis.ConclusionsThe findings of the present study support that PAE with the use of polyethylene glycol microspheres is a safe and feasible procedure that may induce a significant shrinkage of prostate due to the local ischemia and secondary glandular atrophy. Early recanalization of target arteries remains to be further addressed in both laboratory investigation and clinical practice.

Specific expression pattern of tissue cytokines analyzed through the Surface Acoustic Wave technique is associated with age-related spontaneous benign prostatic hyperplasia in rats

The aim of the study reported herein was to evaluate the suitability of the Surface Acoustic Wave (SAW) technique as a possible diagnostic tool in benign prostatic hyperplasia (BPH). Moreover, for the first time, the BPH model was a totally physiological using naturally aged rats with spontaneous, age-related BPH instead of the pharmacologically induced models usually used. Eighteen male Wistar rats were distributed according to their age: 6 weeks (young), 12 weeks (adult) and 12 months (old) old. Prostate gland was removed and analyzed by mini-arrays, Western blotting (WB) and SAW techniques. Mini-arrays indicated that there were significant differences in the expression of 29/34 inflammation-related cytokines. WB was carried out to confirm the results after selection of 4 cytokines from which one showed no changes, namely PDGF-AA, and the other three, which significantly increase in older animals, were CD86, β-NGF and VEGF. Notwithstanding, WB of old rats yielded confusing results due to an anomalous migration of proteins, dismissing this technique as an useful tool in these animals. Accurate results in old rats were uniquely obtained by using the SAW technique. Thus, SAW analysis showed that there were not differences among groups in the amount of PDGF-AA. On the contrary, SAW analysis showed that amounts of CD86, β-NGF and VEGF in old rats were 2.0, 1.9 and 5.7-fold higher than that from young ones, respectively. These results indicate that SAW is a highly accurate technique for determining changes in the cytokines expression in BPH.

Testosterone-induced benign prostatic hyperplasia rat and dog as facile models to assess drugs targeting lower urinary tract symptoms

Benign prostatic hyperplasia (BPH) is an age-related disease, affecting a majority of elderly men worldwide. Medical management of BPH is an alternative to surgical treatment of this disease. Currently, α1-adrenergic receptor (α1-AR) antagonists are among the first line drugs to treat BPH by reducing the tension of urinary track and thus the obstructive symptoms in voiding. In drug development, old male dogs with spontaneous BPH are considered the golden standard of the animal models. However, old dogs (>6 years) are expensive and not all old dogs develop BPH. So it is necessary to develop more accessible animal models for drug efficacy evaluation. Here we describe the development of testosterone-induced BPH models in both rats and young adult dogs and their applications in the in vivo evaluation of α1-AR antagonist. The BPH rats and dogs induced by chronic testosterone treatment have significantly increased micturition frequency and reduced mean voided volume, very similar to the clinical symptoms of BPH patients. Silodosin, an α1-AR antagonist, significantly reduces the urinary frequency and increases the voided volume in BPH model animals in a dose-dependent manner. The results demonstrate that testosterone-induced BPH rat and dog models might provide a more efficient way to evaluate micturition behavior in anti-BPH drug studies.

Correlation between Cholinergic Innervation, Autophagy, and Etiopathology of Benign Prostatic Hyperplasia.

Background:Whether cholinergic innervations and/or autophagy have a role in the etiopathology of benign prostatic hyperplasia (BPH) is still unknown. This study aimed to investigate the role of cholinergic innervation and autophagy in the etiopathology of BPH.Methods:Male, 13-week-old spontaneous hypertension rats (spontaneous BPH animal model) were divided into three groups: an experimental group (EG, n = 24), a control group (CG, n = 24), and a normal control group (NC, n = 10). The EG animals were intragastrically injected with tolterodine (3.5 mg/kg, twice a day), CG animals were intragastrically injected with physiological saline, and the NC animals did not receive any treatment. Rats were sacrificed every 4 weeks, and the prostatic gross morphological changes, wet weight/body weight (ww/bw), dry weight/wet weight (dw/ww), histological changes, ultrastructural changes, and LC3 immunohistochemistry were continuously observed and compared.Results:The gross morphological and ww/bw changes in the three groups were similar at every stage. The dw/ww (mg/mg) values of the EG at week 17, 21, 25, and 29 were 0.1478 ± 0.0034, 0.1653 ± 0.0036, 0.1668 ± 0.0045, and 0.1755 ± 0.0034, respectively, and the CG values were 0.1511 ± 0.0029, 0.1734 ± 0.0020, 0.1837 ± 0.0052, and 0.1968 ± 0.0045, respectively. The difference between EG and CG for dw/ww showed statistical significance after 21 weeks of age (week 21: P = 0.016, week 25: P = 0.008, and week 29: P = 0.001). Both EG and CG, prostatic glandular epithelial cell proliferation, and secretory function improved with age, but in EG, these improvements were slower than those in CG, and all the differences were statistically significant after 21 weeks. An increasing number of autophagosomes in the prostatic glandular cell cytoplasm, attenuation of LC3-I immunohistochemical staining, enhancement of LC3-II staining, and the ratio of LC3-II/LC3-I staining were all progressive in both groups, but the rate of change in EG was faster than that in CG, and these differences gained statistical significance after 25 weeks. Comparisons with regard to the above indexes between CG and NC showed no statistical significance at any stage.Conclusions:Cholinergic innervations and activation of autophagy appear to have important functions in the etiopathology of BPH. Drug-mediated blockade of cholinergic innervations could delay the physiopathology processes. Moreover, overactivation of autophagy may also play an important role in this delay.

Canine prostate models in preclinical studies of minimally invasive interventions: part II, benign prostatic hyperplasia models.

Canine prostate is widely used as animal model in the preclinical evaluation of emerging therapeutic interventions. Spontaneous benign prostatic hyperplasia (BPH) is common in adult intact male dogs with two distinct pathological types: glandular and complex form of prostatic hyperplasia. The complex form of prostatic hyperplasia, usually occurring in older dogs, represents an ideal model because of its unique pathologic feature, including not only glandular hyperplasia but also an increase in prostate stromal components. The limited commercial availability of adult dogs with spontaneous BPH motivates experimentally induced BPH in young dogs. Hormone-induced canine BPH model has been well established with various hormonal treatment regimens and administration approaches. The goal of this review is to provide the veterinary background in spontaneous BPH in dogs, summarize the techniques in hormonal induction of canine BPH, and highlight the pathological and clinical limitations of the canine models that may lead to distinct therapeutic responses compared to clinical trials in humans.

Effects of competitive and noncompetitive 5f-reductase inhibitors on serum and intra-prostatic androgens in beagle dogs

Background 5α-Reductase inhibitors (5α-RI) act by inhibiting the conversion of testosterone to dihydrotestosterone (DHT), thereby preventing DHT induced benign prostatic hyperplasia. The existing 5α-RIs can be classified into two types: competitive and noncompetitive. Currently, limited evidence is available concerning the effect differences between the two types of 5α-RI on androgens. The purpose of this study was to assess the effects of competitive and noncompetitive 5α-RIs on serum and intra-prostatic androgens in beagle dogs. Methods Twenty beagles with spontaneous benign prostatic hyperplasia were randomly allocated into two groups: epristeride group (n=10) in which beagles were treated with epristeride at 1 mg/kg once a day for 3 months, and finasteride group (n=10) in which beagles were treated with finasteride at 1 mg/kg once a day for 3 months. The levels of intra-prostatic testosterone and DHT were measured before treatment and on day one after three months medication. Serum levels of testosterone and DHT were measured at the same time points. Changes in androgen levels before and after treatment were analyzed, and comparisons were made within each treatment group and between treatment groups. Results After 3-month treatment, serum and intra-prostatic DHT levels all decreased significantly in both the epristeride and finasteride groups. The change of DHT in serum was significantly higher in the finasteride group (-14% and -43% in epristeride and finasteride groups respectively, with P&lt;0.001); however there was no significant difference in the changes of intra-prostatic DHT between the two groups (-47% and -51% in epristeride and finasteride groups, respectively, P=0.304). The decreases in DHT levels were accompanied by reciprocal increases in serum and intra-prostatic testosterone levels. Changes of testosterone were significantly higher in finasteride group both in serum (20% and 42% in epristeride and finasteride groups, respectively, P&lt;0.001) and in prostate tissue (18% and 29% in epristeride and finasteride groups, respectively, P=0.004). Conclusions Two types of 5T-RI have similar effects in reducing DHT in prostate tissue in beagles. Competitive 5α-RI may reduce serum DHT to a greater scale, and significantly increase testosterone in beagle serum and prostate.

Intra-prostatic injection of botulinum toxin type A in treatment of dogs with spontaneous benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is a common, naturally developing, age-related condition in dogs. The pathogenesis of BPH is not completely known; however, DHT is a hormone involved in enlargement of the prostate. Recently, the effect of botulinum toxin A (BT-A) was investigated in the rat and human prostate and has shown to induce atrophy of the gland on the canine prostate. This study investigated the effect of BT-A in the canine prostate and on the semen. Eight sexually intact male dogs with BPH (detected radiographically and ultrasonographically), and with clinical signs of BPH (e.g. hematuria or tenesmus) were used. Each lobe of the prostate received an injection of 125U of BT-A with one-needle pass under transabdominal ultrasound guidance. The clinical results were evaluated at baseline and after treatment. No local complications or systemic adverse effects were reported. At 4weeks, the mean prostate volume (PV) was not significantly changed after BT-A (from 17.70±6.34 to 16.48±5.98cm3). At 8 weeks the PV had further decreased to 16.04±5.80cm3, reaching its maximum effect, but that change was not significant. The results were maintained at 16 weeks. All dogs had normal libido, erection, and ejaculation during semen collection. No significant difference was observed in all seminal parameters. Results suggest that the administration of 250U of BT-A do not contribute to PV reduction and do not adversely affect the semen quality of dogs with BPH.

Three-Dimensional Conformal Radiation Therapy of Spontaneous Benign Prostatic Hyperplasia in Canines

The purpose of this study was to determine the effect and possible mechanism of three-dimensional conformal stereotactic radiation therapy (3D-CRT) for the treatment of spontaneous benign prostatic hyperplasia (BPH) in a canine model. Eight canines (7-15 years old) with spontaneous benign prostatic hyperplasia (prostate volume >18 cm3) were used as experimental models. The prostates were directly exposed to 3D-CRT at a total dose of 14 Gy. Serum prostate-specific antigen (PSA) and prostate acid phosphatase (PAP), prostate volume (measured by transrectal ultrasound), apoptosis index [AI, measured by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)], proliferation index [PI, measured by proliferating cell nuclear antigen (PCNA) expression], alpha-SMA, Bax, and bFGF were measured before and after radiation therapy. Histopathology of the prostate, rectum, and bladder tissue was also examined before and after irradiation. 3D-CRT treatment significantly decreased prostate volume, and the PI, PSA, and alpha-SMA, but significantly increased the AI, and had no effect on PAP. There was no evidence of Bax expression before or after irradiation. Irradiation led to no detectable symptoms of diarrhea or changes in stool, but did lead to minor bladder injury, based on light microscopy, scanning electron microscopy, and transmission electron microscopy. In our canine model, 3D-CRT is an effective, noninvasive treatment of BPH that is associated with minimal side effects. Our treatment appeared to reduce prostate size by treatment of the underlying pathological processes.

A novel nonsecosteroidal VDR agonist (CH5036249) exhibits efficacy in a spontaneous benign prostatic hyperplasia beagle model

To date, there have been no reports showing the efficacy of nonsecosteroidal vitamin D receptor (VDR) agonists in a benign prostatic hyperplasia (BPH) animal model. To examine the efficacy of CH5036249, a novel nonsecosteroidal VDR agonist, we orally administered the compound at 0.03 μg/kg to a beagle model with spontaneous BPH. Prostate volume was checked by rectal ultrasonic probe periodically during 11 months of administration and the prostate tissues histologically examined. CH5036249 inhibited prostate growth in two out of three dogs compared with vehicle-treated dogs. In the prostate specimens, substantial atrophy of the epithelium was observed in all dogs administered CH5036249. At the dose given, serum calcium levels slightly increased in the CH5036249-treated dogs but stayed within a normal range. We next examined the cell growth inhibition of CH5036249 using human prostate stromal cells and found the cell growth inhibitory activity of CH5036249 to be comparable to that of 1α,25(OH) 2D 3. The bioavailability from oral administration in rats was 95.1% with a t 1/2 of 17.6 h. Both micro-AMES and micronucleus tests were negative. Although the results are still preliminary, we consider the novel nonsecosteroidal VDR agonist CH5036249 to be a possible new drug candidate for the treatment of BPH in humans.

Human benign prostatic hyperplasia heterotransplants as an experimental model

Benign prostatic hyperplasia is a nonmalignant adenomatous enlargement of the periurethral prostate gland. It is a common disease in older men. In addition to man, spontaneous benign prostatic hyperplasia occurs in chimpanzee and the dog. Alternatives to these spontaneous models are induced benign prostatic hyperplasia, xenografts and in vitro models. Xenografts may be induced by cells cultured in vitro or by the heterotransplantation of primary surgical specimens into immunosuppressed mice. The purpose of this review is to integrate data from more than 30 years of heterotransplantation research in the study of benign hyperplasia of the prostate. Heterotransplantation has provided data regarding the histopathology, morphology, tissue markers, androgen receptor expression, tissue kinetics, take rate and tissue vasculature for this prostate disease. There are advantages, as well as limitations, that have been identified for human prostate disease heterotransplants versus xenotransplantation of cultured cells. Overall, heterotransplanted tissue is better at retaining tissue morphology, pathology, secretory activity, expression of tissue markers and human vasculature of the patient's original specimen. Furthermore, heterotransplanted tissue preserves the three-dimensional tissular architecture of the prostate to maintain critical stromal-epithelial cell interactions.

Dynamic Contrast Enhanced Magnetic Resonance Imaging as a Biological Marker to Noninvasively Assess the Effect of Finasteride on Prostatic Suburethral Microcirculation

We assessed dynamic contrast enhanced magnetic resonance imaging as a biological marker of in vivo changes in microcirculation in the prostatic suburethral region. A total of 12 male beagle dogs with spontaneous benign prostatic hyperplasia were randomly allocated to 1 control group and 1 finasteride (Merck and Co., Whitehouse Station, New Jersey) treated group. Two baseline dynamic contrast enhanced magnetic resonance imaging examinations and 3 followups were performed to assess prostate microcirculation. Treatment duration was 3 months. The pharmacokinetic parameters evaluated in prostatic suburethral areas were the maximum enhancement ratio in AU, time to maximum signal enhancement in minutes, amplitude in AU and the exchange rate constant in minutes(-1). After completion of the therapeutic regimen time to maximum signal enhancement was significantly longer in the finasteride group than in controls (p < 0.01). Amplitude and the exchange rate constant decreased 39% and 34%, respectively, in the finasteride group at the end of treatment, which significantly differed from results in the control group (p < 0.05). Dynamic contrast enhanced magnetic resonance imaging is capable of noninvasively assessing the prostatic microcirculation changes induced by finasteride. Pharmacokinetic parameters show considerable promise to be biomarkers for the development of benign prostatic hyperplasia drugs such as 5alpha-reductase inhibitors by the in vivo monitoring of microvascular changes. A relevant clinical application could be the pretreatment assessment of finasteride effectiveness to decrease perioperative bleeding at transurethral prostate resection and in treatment for hematuria.

Effect of Silodosin on Intraurethral Pressure Increase Induced by Hypogastric Nerve Stimulation in Dogs with Benign Prostatic Hyperplasia

We compared the urethral and cardiovascular effects of silodosin (selective alpha(1A)-adrenoceptor antagonist), a novel medication for benign prostatic hyperplasia (BPH), with those of tamsulosin (selective alpha(1A)/alpha(1D)-adrenoceptor antagonist) and naftopidil (selective alpha(1D)-adrenoceptor antagonist). We evaluated the effects of these three drugs on the increase in intraurethral pressure (IUP) induced by electrical stimulation of the hypogastric nerve in anesthetized dogs with spontaneous BPH. All three drugs dose-dependently reduced both the increase in IUP and the mean blood pressure (MBP). The rank order of potencies was tamsulosin>silodosin>naftopidil for the reductions in both IUP and MBP. However, the uroselectivity (ED(15) value for hypotensive effect/ID(50) value for reduction in IUP) of silodosin (uroselectivity, 19.8) was about 21 and 4 times higher than that of tamsulosin (0.939) and naftopidil (4.94), respectively. These data suggest that silodosin might be one of the most useful medications for dysuria in BPH patients.

Two for the price of one?

British Journal of Pharmacology (2005) 144, 1–2. doi:10.1038/sj.bjp.0706038

Effect of tamoxifen citrate on reproductive parameters of male dogs

Tamoxifen is a synthetic, nonsteroidal Type I antiestrogenic compound that competitively blocks estrogen receptors with a mixed antagonist–agonist effect. The manifestation of these different actions depends on each species, organ, tissue and cell type considered. Very little is known about the effect of antiestrogens in dogs. The objectives of this study were to determine the effects of tamoxifen citrate on some testis, prostate, hormone, and semen parameters in seven Beagle dogs with uncomplicated spontaneous benign prostatic hyperplasia. Two dogs were normospermic, four were oligozoospermic, and one was azoospermic. The dogs were allocated to a control pre-treatment period, followed by a treatment period, and five post-treatment periods (the duration of each period was 4 weeks). During the treatment period, 2.5 mg tamoxifen citrate was given p.o. daily for 28 days to all the dogs. Maximum scrotal width, testicular consistency, libido semen parameters, prostatic volume, serum testosterone concentrations, and side effects were assessed. Tamoxifen negatively affected testis size and libido ( P<0.01), and decreased prostatic volume ( P<0.02) and testosterone concentrations during treatment. Semen quality deteriorated to nadir values ( P<0.01) approximately one spermatic cycle after treatment and returned to pre-treatment values on the second cycle after treatment in all the dogs, except one young oligoazoospermic dog, in which the sperm count was higher ( P<0.01) at that time. No side effects were observed and fertility was conserved at the end of the study. Tamoxifen acted more like an agonist than antagonist on the gonadal axis and, therefore, upon both the prostate and testis. Therefore, tamoxifen may have therapeutic applications in dogs.

Evidence that chlormadinone acetate exhibits antiandrogenic activity in androgen-dependent cell line

Chlormadinone acetate (CMA), like other 17-hydroxyprogesterone derivatives, is thought to be a potential antiandrogen on the basis of its effect on spontaneous benign prostatic hyperplasia (BPH) in dogs. This work was undertaken to find out whether CMA presents antiandrogen activity in human androgen-dependent cell line. For this purpose, we used PALM cells, the PC-3 cell line stably transfected with human androgen receptor and a luciferase gene under transcriptional control of MMTV. Potential antiandrogenic activity was compared with that of cyproterone acetate (CPA), a standard steroidal antiandrogen. Both compounds were tested in competitive binding assays at 37 °C in the presence of 1 nM of [ 3H] R1881, a synthetic and non-metabolizable androgen. Their impact on AR transcriptional activity was evaluated by the measure of luciferase activity in the presence of R1881 with increasing concentrations of CMA or CPA (10 −8–10 −6 M). In whole cell binding assays, competitive studies revealed that the Ki for CMA was 3.3±1.5×10 −8 M (versus 7.2±1.3×10 −8 M for CPA). Inhibition of AR transcriptional activity was 40±5% for CMA (3×10 −7 M) versus 59±6% for CPA at the same concentration. Moreover, CMA caused a slower import of green fluorescent protein (GFP)-AR to the nuclei of COS-7 cells than R1881. These data show that CMA exerted a competitive binding for AR and significantly decreased the AR transcriptional activity. In conclusion, this synthetic progestin presents simultaneous antiandrogenic activity that could be helpful as a new therapeutic option in women with luteal defect along with clinical signs of hyperandrogenism.

Immunohistochemical Studies of the Effect of Chlormadinone Acetate (CMA) on Prostatic Hyperplasia.

The atrophic effect of a synthetic steroidal antiandrogen, chlormadinone acetate (CMA), on spontaneous benign prostatic hyperplasia (BPH) was investigated. Male beagle dogs (5-8 years old) were divided into four experimental groups. Group 1 consisted of untreated controls. Groups 2 to 4 received CMA 0.03, 0.1 and 0.3 mg/kg/day, p.o., respectively, for 6 months. In group 1, glandular hyperplasia of the prostate was clearly detected. The glandular epithelial cells showed uniformly intense nuclear staining for androgen receptor (AR). AR was also localized in the nuclei of the fibro-muscular stromal cells. Immunoreactively of 5 alpha-reductase type I was positive in most glandular epithelial cells. No fibro-muscular stromal cells were stained. Immunolocalization of 5 alpha-reductase type II was clearly detected in the interacinar fibro-muscular stromal cells, but not in the glandular epithelial cells. In groups 2 to 4, CMA produced marked atrophy of the glandular epithelium. The interacinar fibro-muscular stroma was prominent. The nuclear staining for AR in both epitheial and stromal cells was remarkably decreased. Furthermore, the immunoreaction for 5 alpha-reductase type I in most glandular epithelial cells was negative or very weak. The immunoreaction of 5 alpha-reductase type II in the interacinar fibro-muscular stromal cells was negative or very weak. The decreased AR-immunostaining may be explained by the decrease in the number of AR and it may play a key role in the down-regulation of 5 alpha-reductase gene expression by CMA. The atrophy after treatment with CMA may be due to shrinkage of both glandular and stromal compartments in the prostate tissue.

The effects of chlormadinone acetate (CMA), antiandrogen, on the pituitary, testis, prostate and adrenal gland of the dog with spontaneous benign prostatic hyperplasia.

The effect of chlormadinone acetate (CMA), a synthetic steroidal antiandrogen, on spontaneous benign prostatic hyperplasia (BPH) in dogs was investigated. Male beagle dogs (5-8 years old) were divided into four experimental group. Group 1 consisted of untreated controls. Groups 2 and 3 received CMA 0.03 and 0.1 mg/kg/day, p.o., respectively, for 6 months. In group 1, glandular hyperplasia of the prostate was clearly detected. The glandular epithelial cells showed uniformly intense nuclear staining for androgen receptor (AR). AR was also localized in the nuclei of the fibro-muscular stromal cells. In groups 2 and 3, CMA produced marked atrophy of the glandular epithelium. The interacinar fibro-muscular stroma was prominent. The nuclear staining for AR in both epithelial and stromal cells was remarkably decreased. In addition, a histopathological study showed that CMA medication for 6 months exerted no effect on the testes and adrenal glands or on immunoreactive positive cells to LH- and ACTH-antibody (pituitary LH- and ACTH-cells). Therefore, it is concluded that CMA (0.03 and 0.1 mg/kg) causes regression of spontaneous canine BPH without any histopathological effects on the testes, adrenal glands or pituitary LH- and ACTH-cells.

Chlormadinone Acetate (CMA) Induces Apoptosis on Canine Spontaneous Benign Prostatic Hyperplasia (BPH).

The effect of a synthetic steroidal antiandrogen, chlormadinone acetate (CMA), on spontaneous benign prostatic hyperplasia (BPH) in dogs was investigated. Male beagle dogs (5-8 years old) were divided into four experimental groups. Group 1 consisted of untreated controls. Groups 2 to 4 received CMA 0.03, 0.1, and 0.3 mg/kg/day, p.o., respectively, for 6 months. In group 1, glandular hyperplasia of the prostate was clearly detected. In groups 2 to 4, CMA produced marked atrophy of the glandular epithelium. The interacinar fibro-muscular stroma was prominent. To evaluate the frequency of apoptosis, we counted the positive cells stained by the nick end labeling method. In group 1, the apoptotic index was 0.76±0.03%. In groups 2 to 4, apoptotic indices were 15.41±1.26%, 2.63±0.98% and 1.45±0.85%, respectively. Apoptotic cell death was mainly observed in the glandular epithelial cells. Based on our data, regression of BPH after treatment with CMA may be apoptotic cell death.