The role of estrogens and estrogen receptors (ER) in the human prostate remains unresolved. In this study we have used the monoclonal ER antibody H222 to investigate the histological localization of ER in normal and diseased human prostates by immunocytochemistry. Prostate tissue was obtained from 3 young organ donors (Group I-normal prostate), from 14 prostates removed by radical prostatectomy or radical cystoprostatectomy, which had caused no or only mild obstructive symptoms (Group II-non-obstructive prostate), and from 11 prostates removed by suprapubic prostatectomy, which had caused severe obstructive symptoms due to a large benign prostatic hyperplasia (BPH) (Group III-obstructive prostate). In prostates of all groups ER were found to be in nuclei of the prostatic urethra and of the periurethral prostatic duct. In striking contrast, ER in the interglandular prostatic stroma was not as homogeneous among the different groups. We observed a low concentration of ER in the stroma of normal prostates, the highest concentration in non-malignant stroma of non-obstructive prostates, and no ER at all in stroma of obstructive prostates. Based on the immunocytochemical localization of ER in normal and diseased human prostate, our results indicate that stromal growth in obstructive BPH may not be mediated via ER. However, we cannot exclude that an increase of stromal ER concentration (as observed in non-obstructive prostates) is directly involved in induction of BPH, leading further prostate growth thereafter into an estrogen independent state.
The induction of benign prostatic hyperplasia (BPH) from normal prostate is obviously associated with a distinct increase in epithelial and stromal proliferation. We have shown previously that the further increase of BPH volume in aging men is not associated with a further increase in proliferation. We studied whether an imbalance between programmed cell death (apoptosis) and cell proliferation may explain continuing growth in aging men. In prostates of 17 men with BPH removed by open prostatectomy proliferating cells were localized immunohistochemically with the Ki-67 antibody. Apoptotic cells were detected with the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method. Proliferation and apoptotic index was calculated with a computer assisted image analysis system. Mean proliferation index +/- standard deviation in epithelium (0.142 +/- 0.097) and stroma (0.121 +/- 0.082) was nearly identical. Mean apoptotic index in epithelium (0.172 +/- 0.156) was negligibly higher than the corresponding proliferation index. In stroma, however, no apoptotic cells were detectable. Proliferation index and apoptotic index in epithelium and proliferation index in stroma showed no correlation to patient age or prostate volume. In the epithelium of BPH, obviously the cell kinetic is balanced. On the other hand, our results indicate stromal growth due to cell proliferation in the absence of cell death. This may explain the continuous increase of BPH volume in aging men.
To study whether benign prostatic growth in aging men correlates with an increase in proliferation, proliferation rates were determined immunohistochemically using the antibody Ki-67 in 20 benign hyperplastic prostates (BPH) and in four normal prostates (NPR). There was no significant correlation between age and proliferation rate in epithelium or stroma in BPH. In addition, no significant correlation between prostate weight and proliferation rate could be demonstrated in either compartment. In NPR the proliferation rate in epithelium and stroma was 9 times and 37 times lower, respectively, than in BPH. Obviously the induction of BPH from NPR may be associated with a distinct increase in proliferation. The further increase in BPH volume, however, is not correlated with a further increase in proliferation rate.
To study the influence of androgens and estrogens on human benign prostatic hyperplasia (BPH) tissue, BPH fragments were grafted subcutaneously (s.c.) into male nude mice. Testosterone alone (group I) or in combination with 17 beta-estradiol (group III) were administered either by s.c. injections as oil suspensions or continuously by s.c. implanted steroid-containing Silastic implants (groups II and IV). Intact mice without transplants and treatment served as a control (group V). After 4 weeks of treatment, animals were exsanguinated, transplants were removed, and serum was obtained. Ninety-six percent of the BPH fragments were located; they displayed histologically typical BPH acini and stroma. In transplants of all treatment groups, the majority of secretory, as well as basal, cells displayed a proliferation comparable to the original tissue. In glandular cells of all transplants, prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) could be demonstrated immunohistochemically. Specimens removed from animals bearing testosterone implants displayed a very well preserved ultrastructure that was found less frequently in samples from injection-treated animals. Acini-bearing metaplastic epithelium were more often present in transplants treated by steroid injections and seemed to be due to lower androgen or higher estrogen serum levels. Endogenous serum testosterone levels (ng/ml +/- SD; n) were lower and more variable (i.e., higher standard deviation) in groups treated by injections (group I: 3.68 +/- 2.12; n = 5 and group III: 3.86 +/- 1.13; n = 5) and were similar to those seen in intact controls (3.93 +/- 1.62; n = 6) compared with groups treated by Silastic implants (group II: 5.11 +/- 1.14; n = 10 and group IV: 10.20 +/- 0.52; n = 4). These results indicate that by application of steroids via Silastic implants, reproducible hormone effects can be obtained on BPH tissue transplanted into male nude mice, thus providing a reliable new model system for study.
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