Spontaneous Benign Prostatic Hyperplasia Research Articles

Correlation between Prostatic Atrophy and Apoptosis in the Canine Spontaneous Benign Prostatic Hyperplasia(BPH) Following Chlormadinone Acetate(CMA) Administration.

In order to confirm the relationship between benign prostatic hyperplasia (BPH) regression and atrophic effect of chlormadinone acetate (CMA), the prostates of spontaneous BPH dogs administered CMA for 6 months were investigated histopathologically and immunohistochemically. 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 0.68 ± 0.03 %. In groups 2 to 4, apoptotic indices were 10.32 ± 0.96 %, 2.05 ± 0.88 %, and 1.15 ± 0.75 %, 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.

Immunohistochemistry of the Canine Prostate.

In the canine prostate, 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. Immunoreactivity 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. After treatment with antiandrogen, chlormadinone acetate (CMA) on canine spontaneous benign prostatic hyperplasia (BPH), glandular atrophy was evident. The interacinar fibro-muscular stroma was prominent. The nuclear staining for AR in both epithelial 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.

Effects of a new steroidal aromatase inhibitor, TZA-2237, and/or chlormadinone acetate on hormone-induced and spontaneous canine benign prostatic hyperplasia.

It has been known for many years that human benign prostatic hyperplasia (BPH) is composed predominantly of hyperplastic stromal cells rather than epithelial cells. In the present study the effects of a new steroidal aromatase inhibitor on hormone-induced and spontaneous canine BPH were investigated. (1) Effects of TZA-2237 on hormone-induced canine BPH. Ten castrated beagles were administered testosterone and androstenedione 6 days/week for 8 months, and divided randomly into three groups after 2 months of treatment as follows. Group I served as controls, Group II was given 0.5 and Group III was given 2.5 mg/kg/day TZA-2237 5 days/week for 6 months. (2) Effects of TZA-2237 on spontaneous canine BPH. Twenty aged beagles with BPH were divided into five groups, Group IV was untreated, Group V was treated with 1 and Group VI with 5mg/kg/day TZA-2237 5 days/week for 31 weeks. Group VII was treated with 5mg/kg/day Atamestane and Group VIII was treated with 0.3 mg/kg/day chlormadinone acetate (CMA) 5 days/week. (3) Effects of TZA-2237 combined with CMA on spontaneous canine BPH. Three aged beagles with BPH were treated with 1mg/kg/day TZA-2237 and 0.03 mg/kg/day CMA 5 days/week for 20 weeks (Group IX) and a further three aged beagles with BPH were treated with 0.3 mg/kg/day CMA alone 5 days/week (Group X). Hormone-induced prostatic growth was significantly suppressed in group III compared with that in other groups. In Group III, the intraprostatic aromatase activity, estradiol level and androgen receptor content decreased significantly in comparison with the values in Group I. The prostatic weights in Groups V, VI and VII increased significantly in comparison with the weight in Group IV. Serum LH and testosterone levels in Groups V, VI, and VII increased significantly in comparison with the level in Group IV. The prostatic weight in Group IX was decreased only slightly, but the smooth muscle component was decreased significantly. TZA-2237 is a new, unique and effective aromatase inhibitor that causes inhibition of both epithelial and stromal compartments in hormone-induced canine BPH. Dual inhibition of androgen and estrogen resulted in inhibition of smooth muscle growth, and should prove effective as a new method of treatment given the atrophic effects on not only the epithelium but also the stroma in human BPH.

Spontaneous hyperplasia of the ventral lobe of the prostate in aging genetically hypertensive rats.

Recent studies have shown that the prostatic autonomic innervation takes part in its homeostasis and growth. Other works showed that spontaneously hypertensive rats (SHR) show excessive sympathetic activity, accompanied by lower urinary tract symptoms, increased growth capacity of prostatic stromal cells, and increased levels of androgens and their receptors. Furthermore, young SHR were reported to present incipient stages of benign prostatic hyperplasia (BPH). The aim of the present study was to examine whether this strain indeed develops spontaneous BPH with age, and can thus serve as a genuine natural model for this disorder. For this purpose, ventral lobes of prostates of one-year-old, male SHR and their normotensive counterparts, Wistar Kyoto (WKY) rats, were examined histopathologically, and the degree of hyperplasia was evaluated according to a score-chart protocol (histoscore). SHR exhibited severe adenomatous spontaneous BPH, characterized by piling-up of epithelial cells, with papillary formations, accompanied by a mild increase in the amount of fibrocytes and smooth muscle cells in the stroma. This was reflected by histoscore values of 38 +/-2. Thickening of prostatic arterioles also was noted, as well as mild chronic inflammatory exudate. WKY rats did not show any of these features of BPH despite their age (histoscore 17 +/- 3, significantly different from that of SHR). We conclude that SHR can serve as a rodent model for the spontaneous development of BPH with age, most probably due to the excessive neuroendocrine activity characteristic of this rat strain.

Atrophic effects of antiandrogen, chlormadinone acetate (CMA) on dog prostate with spontaneous benign prostatic hyperplasia.

The atrophic 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. 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. Immunoreactivity 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 epithelial 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. These results indicate that the uptake of testosterone and/or its androgenic effect on the prostate may be suppressed by CMA. The decreased AR-immunostaining may be explained by the decrease in the number of AR and/or antibody binding sites for AR. Therefore, the atrophy after treatment with CMA may be due to shrinkage of both glandular and stromal compartments in the prostate tissue.

Immunolocalization of Androgen Receptor (AR) and Steroid 5 Alpha-Reductase Type II (5 Alpha-Reductase Type II) in Canine Prostate. Effect of Antiandrogen, Chlornradinone Acetate (CMA).

The effect of a synthetic steroidal anti−androgen, 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 0.3mg/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. Immunolocalization of 5 alpha−reductase type II was clearly detected in the interacinar 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 intensity of the nuclear staining for AR in both epithelial and stromal cells was negative or very weak. Furthermore, the immunoreaction for 5 alpha−reductase type II in the interacinar 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 type II 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 CHIMPANZEE AS A MODEL OF HUMAN BENIGN PROSTATIC HYPERPLASIA

The etiology and natural history of benign prostatic hyperplasia (BPH), the most common benign disease in aging men, remain obscure. The canine BPH model has serious limitations but other animal BPH models have not been identified. We evaluated whether the chimpanzee, man's closest primate relative, developed spontaneous BPH. A cross-sectional analysis of a colony (White Sands Research Center) that contained 700 chimpanzees was undertaken by sampling 63 male and female (controls) chimpanzees 8 to 35 years old. The presence of spontaneous BPH was evaluated by assessing pathological and clinical variables, including prostate volume, serum prostate specific antigen, presence of histological BPH, serum androgens and estradiol, and urodynamics studies. The chimpanzee had evidence of spontaneous histological BPH, and incidence and grade increased with age. Spontaneous BPH was manifested by increased prostate volume, higher serum prostate specific antigen, higher stromal/epithelial ratio and decreased urinary flow rates. As in man, serum androgens did not correlate with BPH in the chimpanzee. Male chimpanzees developed spontaneous histological BPH at the same relative point in their life cycle as humans which resulted clinically in larger prostates and decreased urinary flow rates. Serum hormone levels did not appear to correlate with BPH. A better understanding of the chimpanzee BPH model may lead to new therapeutic strategies for BPH in man.

Histopathological Study of the Effect of Antiandrogen, Chlormadinone Acetate(CMA), 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. In addition, a histopathological study showed that CMA medication for 6 months exerted no effect on the testes except group 4 or on immunoreactive positive cells to LH antibody (pituitary LH cells). Therefore, it is suggested that CMA (0.03 and 0.1 mg/kg) causes regression of spontaneous canine BPH without any histopathological effects on the testes or pituitary LH cells. However, atrophy of seminiferous tubules in testes was found in CMA 0.3 mg/kg/day-treated animals, due apparently to a direct and/or indirect effect on the testes. It is suggested that a marginal antigonadotrophic effect can not be excluded.

Inhibitory influence of a new steroidal anti-androgen, TZP-4238, on prostatic hyperplasia in the beagle dog.

The effect of a synthetic steroidal anti-androgen, TZP-4238, on spontaneous benign prostatic hyperplasia (BPH) in dogs was investigated. Old male beagle dogs (5-9 years old) were divided into three experimental groups. Group 1 consisted of BPH controls. Groups 2 and 3 received TZP-4238 0.1 mg/kg/day and chlormadinone acetate (CMA) 0.3 mg/kg/day p.o., respectively, for 5 months. In group 1, glandular hyperplasia of the prostate was clearly detected. In contrast, TZP-4238 (Group 2) or CMA (Group 3) produced marked atrophy of the glandular epithelium. In addition, a histopathological study showed that TZP-4238 or CMA medication for 5 months exerted no effect on the testes and the pituitary luteinizing hormone (LH) cells. Therefore, it is suggested that TZP-4238 (0.1 mg/kg) or CMA (0.3 mg/kg) causes regression of spontaneous canine BPH without any histopathological effects on the testes and pituitary LH cells. However, slightly decreased serum testosterone levels were found in TZP-4238-treated animals, due apparently to a direct and/or indirect effect on the testes. Thus, it is suggested that a marginal antigonadotrophic effect cannot be excluded. It is concluded that TZP-4238 is a potent anti-androgen for the treatment of spontaneous canine BPH, without any negative influence on the function of the testes and the pituitary LH cells.

Magnetic resonance imaging of the efficacy of specific inhibition of 5α‐reductase in canine spontaneous benign prostatic hyperplasia

A leading role for prostatic levels of dihydrotestosterone (DHT) in the pathogenesis of benign prostatic hyperplasia is well established, if incompletely understood. The present study provides initial confirmation that 5 alpha-reductase inhibition alone is sufficient to prevent prostatic accumulation of DHT and to produce epithelial regression in the canine prostate. In dogs treated with the specific 5 alpha-reductase inhibitor finasteride, prostatic volume decreased to one-third of the baseline volume, while the prostatic concentration of DHT fell fivefold: both were constant in placebo control dogs. Demonstration that MR imaging can serve as accurate modality to assess prostatic volume was provided by serial measurements of the canine prostate and by correlation of the last imaging measurement with the weight of the excised prostate. Significant intensity changes were observed in T2-weighted images measured post-treatment; these changes correlated with the histopathology of the prostate. These results suggest that beyond quantifying regression, multiecho T2 measurements can be useful in probing accompanying changes occurring on the cellular level.

Dose‐dependent hormonal induction of benign prostatic hyperplasia (BPH) in castrated dogs

A model for the dose-dependent hormonal induction of benign prostatic hyperplasia (BPH) in castrated dogs has been established using subcutaneously implanted Silastic capsules containing 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol) and estradiol-17 beta. In vivo release rates per capsule approximated 122.0 +/- 4.2 micrograms 3 alpha-diol and 22.7 +/- 0.8 micrograms estradiol per day based on in vitro studies and resulted in dose-dependent increases in serum 3 alpha-diol and dihydrotestosterone concentrations. The implantation of castrated dogs with either 10 or 20 Silastic capsules containing 3 alpha-diol and one capsule containing estradiol or the intramuscular injection of 3 alpha-diol (75 mg/week) and estradiol (0.75 mg/week) for 99 days significantly increased (P less than .01) prostatic weights and total prostatic DNA over intact controls. These treatments also resulted in a histomorphological pattern similar to that observed in dogs with the glandular form of spontaneous BPH. In addition, normal prostatic secretory function as determined by semen volume was maintained in these dogs. Although subcutaneous implantation of five Silastic capsules containing 3 alpha-diol and one capsule containing estradiol into castrated dogs resulted in prostatic weights and total prostatic DNA that were similar (P less than .10) to intact controls, these prostates were characterized histomorphologically by glandular atrophy and squamous metaplasia. Furthermore, prostatic secretory function was decreased (P less than .05) in these animals compared with intact controls at 3 months of treatment. This study has led to the development of a model of steroid-induced BPH that will facilitate the evaluation of competitive androgen-receptor antagonists in the dog.

Immunocytochemical Localization of Estrogen Receptors in Spontaneous and Experimentally Induced Canine Benign Prostatic Hyperplasia

Estrogens are believed to play a critical role in the etiology of canine benign prostatic hyperplasia (BPH); however, the mechanism has not been elucidated. To gain insight into this problem, we investigated the immunocytochemical localization of estrogen receptors (ER) in normal prostates, spontaneous BPH, and experimentally induced BPH by using a monoclonal ER antibody (H222). In all canine prostates the majority of ER was localized in nuclei of the same histological components: (1) transitional epithelium and subjacent stroma of the prostatic urethra, (2) periurethral prostatic ductal epithelium, and (3) prostatic stroma. ER content in the stroma was highest in the periurethral region of the prostate. Among the different groups of dogs, differences in ER location were seen only in the glandular epithelium. No ER was found in the glandular epithelium of normal prostates of young untreated dogs. In striking contrast, glandular epithelium of spontaneous BPH contained specific nuclear ER staining, though this staining was heterogeneous and was observed in only a minority (less than 10%) of the acinar epithelial cells. ER-positive acini in BPH were located predominantly in the periurethral region. These data demonstrate anatomical and biochemical heterogeneity of prostatic components and indicate that the estrogen sensitivity of prostatic cells is heterogeneous. If estrogen does play a role in BPH, it appears to act selectively rather than uniformly throughout the prostate. We reasoned that if glandular epithelial ER are involved in the development of spontaneous BPH, one might expect to find the same location of ER in BPH that was induced experimentally by specific types of treatment with androgens +/- estradiol. However, among hormone-treated dogs the presence of ER-positive prostatic glandular epithelium varied with the type of hormonal treatment but did not correlate with the experimental induction of glandular BPH. Some treatment groups with induced BPH had ER-positive prostatic glandular epithelial nuclei (with the same extent and pattern of ER localization as in spontaneous BPH); however, other treatment groups with induced BPH had ER-negative glandular epithelium. These data indicate either that glandular epithelial ER may not be involved in the pathogenesis of canine BPH or that there may be different types of BPH that have different etiologies. Possible mechanisms by which estrogen may affect the canine prostate are discussed in light of these new data on ER location.

Aromatase Inhibition in the Dog. II. Effect on Growth, Function, and Pathology of the Prostate

To evaluate the role of aromatase inhibitors in the treatment of benign prostatic hyperplasia (BPH), the effects of a potent, oral, nonsteroidal aromatase inhibitor [4-(5,6,7,8-tetrahydroim-idazo[l,5a]pyridin-5yl)benzonitrile; CGS-16949A, CIBA-GEIGY] on canine BPH have been studied. Twelve mature beagles with enlarged prostates were divided into two groups of similar age, prostatic size, and prostatic histology. Dogs were given either CGS-16949A at a dosage of 2.5mg./kg./day p.o. (n = 6) or an oral placebo (n = 6) for 25 weeks.Treatment with aromatase inhibitor had no significant effect on prostatic weight nor on total DNA content when compared to controls (p >0.1). Semen volume did not change with treatment, and prostatic tissue concentrations of testosterone, dihydrotestosterone (DHT), and 5α-androstan-3α,17β-diol (3α-diol) were similar for the treated and control beagles (p >0.1). Protein concentration in the ejaculate, however, was significantly greater for the dogs receiving CGS-16949A (p <0.01). Histologically, there was no difference in the incidence or type of BPH between the two treatment groups. Beagles treated with aromatase inhibitor, however, did have a more severe inflammatory infiltrate of the prostatic parenchyma than the control dogs (p <0.01). The mean serum testosterone concentration for the beagles treated with aromatase inhibitor was 10 times greater than that for the control animals (p <0.01). The endocrine effect of this aromatase inhibitor in the male canine is presented in the preceding paper.Taken together, these results suggest that inhibition of endogenous aromatase activity is not an effective treatment for spontaneous BPH in the intact canine.

Light-Microscopic Stereologic Analysis of Spontaneous and Steroid-Induced Canine Prostatic Hyperplasia

A combined light-microscopic and stereologic analysis of the canine prostate was performed under the following experimental conditions: intact and castrated dogs, spontaneous benign prostatic hyperplasia, intact and castrated dogs after treatment with testosterone, 5α-dihydrotestosterone or 3α-androstanediol in combination with estradiol. Regarding the absolute amounts of the glandular and stromal parts of the prostate as well as the glandular cells, no difference was found among the testosterone, 3α-androstanediol and 5α-dihydrotestosterone treated castrated dogs. Treatment with 5α-dihydrotestosterone or 3α-androstanediol in combination with 17ß-estradiol induced a four-fold increase in glandular and a two-fold increase in stromal tissue. The glandular to stromal tissue ratio equals that found in spontaneous canine hyperplasia, which is indicative of the glandular type of spontaneous canine hyperplasia. Therefore, it can be stated that treatment with 5α-dihydrotestos-terone or 3α-androstanediol combined with 17β-estradiol not only induces prostatic overgrowth but also leads to prostatic hyperplasia of the glandular type. However, the stereologic analysis of canine prostates following steroid administration shows that canine hyperplasia is primarily a glandular disease, while human benign prostatic hyperplasia shows more stromal activation.

Immunocytochemical localization of estrogen receptors in spontaneous and experimentally induced canine benign prostatic hyperplasia

Estrogens are believed to play a critical role in the etiology of canine benign prostatic hyperplasia (BPH); however, the mechanism has not been elucidated. To gain insight into this problem, we investigated the immunocytochemical localization of estrogen receptors (ER) in normal prostates, spontaneous BPH, and experimentally induced BPH by using a monoclonal ER antibody (H222). In all canine prostates the majority of ER was localized in nuclei of the same histological components: (1) transitional epithelium and subjacent stroma of the prostatic urethra, (2) periurethral prostatic ductal epithelium, and (3) prostatic stroma. ER content in the stroma was highest in the periurethral region of the prostate. Among the different groups of dogs, differences in ER location were seen only in the glandular epithelium. No ER was found in the glandular epithelium of normal prostates of young untreated dogs. In striking contrast, glandular epithelium of spontaneous BPH contained specific nuclear ER staining, though this staining was heterogeneous and was observed in only a minority (less than 10%) of the acinar epithelial cells. ER-positive acini in BPH were located predominantly in the periurethral region. These data demonstrate anatomical and biochemical heterogeneity of prostatic components and indicate that the estrogen sensitivity of prostatic cells is heterogeneous. If estrogen does play a role in BPH, it appears to act selectively rather than uniformly throughout the prostate. We reasoned that if glandular epithelial ER are involved in the development of spontaneous BPH, one might expect to find the same location of ER in BPH that was induced experimentally by specific types of treatment with androgens +/- estradiol. However, among hormone-treated dogs the presence of ER-positive prostatic glandular epithelium varied with the type of hormonal treatment but did not correlate with the experimental induction of glandular BPH. Some treatment groups with induced BPH had ER-positive prostatic glandular epithelial nuclei (with the same extent and pattern of ER localization as in spontaneous BPH); however, other treatment groups with induced BPH had ER-negative glandular epithelium. These data indicate either that glandular epithelial ER may not be involved in the pathogenesis of canine BPH or that there may be different types of BPH that have different etiologies. Possible mechanisms by which estrogen may affect the canine prostate are discussed in light of these new data on ER location.

DNA synthesis in the canine prostate: Effects of androgen and estrogen treatment

Canine prostatic DNA synthesis was evaluated by measuring [3H]thymidine incorporation into DNA of tissue slices in vitro. Among untreated beagles, prostatic DNA synthesis rates in young dogs with normal prostates, young dogs with spontaneous benign prostatic hyperplasia (BPH), and old dogs with BPH were 676 +/- 186, 1,220 +/- 156, and 641 +/- 88 cpm/100 micrograms DNA/hr, respectively. Among 81 young beagles (intact or castrated) that had been treated for 4 months with various steroids, rates of DNA synthesis varied according to the type of hormonal treatment. Prostatic DNA synthesis (cpm/100 micrograms DNA/hr) was significantly different (P less than 0.001) for dogs treated with estradiol alone (1,658 +/- 221 cpm/100 micrograms DNA/hr; n = 10 dogs), androgen alone (testosterone, 5 alpha-dihydrotestosterone, or 5 alpha-androstane-3 alpha,17 beta-diol; 1,000 +/- 61 cpm/100 micrograms DNA/hr; n = 31 dogs). However, there was no correlation between prostate size and rate of DNA synthesis (cpm/100 micrograms DNA/hr). Although treatment with estrogen alone resulted in the highest rate of DNA synthesis, it produced squamous metaplasia and the smallest prostates; these results are indicative of a high rate of cell turnover. Comparing prostates that reached the same size following 4 months of treatment with androgen alone or androgen plus estrogen, the rate of prostatic cell turnover was lower in the androgen plus estrogen group. These results are interpreted to indicate an inhibitory effect of estradiol on the rate of cell death in the presence of androgens.

Involution of spontaneous benign prostatic hyperplasia in the dog under the influence of chronic treatment with a LHRH agonist.

Eight dogs with spontaneous benign prostatic hyperplasia were treated with daily subcutaneous injections of 25 micrograms of Buserelin, (D-Ser(TBU)6,des-Gly-NH2(10))ethylamide during 3 months. Prostate weight before treatment was estimated by tridimensional measurements during open surgery. After 3 months of treatment, prostate weight was decreased by 50-60% In two castrated control animals, prostate weight decreased about 70% after 3 months. Histological pattern in prostates from castrated or Buserelin-treated animals was similar and indicated considerable atrophy of glandular epithelium and predominance of stroma. At the same time, testes weight decreased with complete disappearance of spermatogenic activity. Acid phosphatase and arginine esterase activity levels, two markers of androgenic action in the prostate, were similar after Buserelin or castration. Steroid receptors for androgens, estrogens, and progesterone also behaved similarly under the influence of Buserelin and castration.

Dihydrotestosterone concentration of beagle prostatic tissue: effect of age and hyperplasia.

Dihydrotestosterone (DHT) concentration was measured in prostatic tissue obtained from castrate or intact beagles treated with androgens and/or estradiol-17 beta. Also DHT concentration was measured in prostatic tissue of beagles ranging from 0.7-9.2 yr; some with and others without spontaneously occurring benign prostatic hyperplasia (BPH). Three major results were forthcoming. First, a linear, positive correlation was observed between prostatic weight and DHT concentration in castrated or intact beagles treated with 11 of 15 steroid hormone regimens. Four additional treatments including intact or castrated beagles treated with either DHT or 5 alpha-androstan-3 alpha,17 beta-diol alone resulted in high concentrations of prostatic DHT but not equally high prostatic weight. Thus, prostatic DHT concentration is not always tightly coupled with prostate weight in the beagle. Second, there was no significant (P greater than 0.25) difference in prostatic DHT concentration between dogs with histologically normal prostates and those with spontaneous BPH. Thus, contrary to earlier reports, the tissue concentration of DHT in dog prostatic hyperplasia is not supranormal. Third, there was a dramatic change in prostatic DHT concentration which peaked at 3.8 yr. We conclude that steroid hormone treatment regimens which caused elevated prostatic DHT concentrations did not always result in equally high prostatic weight in the beagle. Also, if androgens like DHT are related causally to BPH in the dog, they probably play a permissive rather than an inductive role in the disease process.

Spontaneous benign prostatic hyperplasia in the beagle. Age-associated changes in serum hormone levels, and the morphology and secretory function of the canine prostate.

This paper is a cross-sectional study of spontaneous benign prostatic hyperplasia (BPH) in a single canine species. The effects of aging and hormonal changes on the growth, histology, and glandular secretory function of the canine prostate were studied in 42 male beagles ranging in age from 8 mo to 9 yr. The beagle prostate enlarges for at least 6 yr, whether normal or hyperplastic. In contrast, prostatic secretory function, determined by ejaculate volume and total ejaculate protein, declines markedly after 4 yr of age. These reciprocal growth and functional changes in the prostate are closely associated with a progressive increase in the incidence of BPH, which is already apparent in some dogs by age two. With age there is a modest decrease in serum androgen levels with no apparent change in serum 17 beta-estradiol levels. This suggests that the growth and functional changes that are associated with the development of BPH and are initiated very early in life reflect an altered sensitivity of the prostate to serum androgens or a response to the relative decrease in the serum androgen to estrogen ratio.