Influence of hormone application by subcutaneous injections or steroid‐containing silastic implants on human benign hyperplastic prostate tissue transplanted into male nude mice

Abstract

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.

Characteristics of nonneoplastic human prostate tissue transplanted into nude mice

“…There have been several reports regarding transplantation of human prostate tissue into nude mice [8][9][10][11], with tiny pieces of BPH (e.g., 2-3 mm 3 ) maintained for 12 weeks under the influence of exogenous testosterone treatment. In our study, however, pieces of nonneoplastic tissue 5 × 5 × 5 mm were maintained without exogenous testosterone manipulation.…”

“…Preliminary studies on human BPH tissue xenografts in nude mice have indicated that successful preservation of tissue morphology is possible for up to 8 weeks [8][9][10]. However, this is not long enough for proliferation of prostate tissue in vivo.…”

Mitochondria-dependent apoptogenic activity of the aqueous root extract of Croton membranaceus against human BPH-1 cells

“…Although the normal stroma to epithelium ratio of the prostate is 2:1, in patients with BPH, this ratio is 5:1 (Prabhav and Bairy, 2009). A previous study showed that excessive proliferation of the stromal and epithelial cells (37-fold and 9-fold, respectively) was observed in some patients with BPH (Claus et al, 1993). This finding indicates that an imbalance of the molecular mechanisms of proliferation and apoptosis is involved in the development of BPH and prostate cancer.…”

Models for studying benign prostatic hyperplasia

“…42 The epithelial lining of the implants consistently expressed prostatic biomarkers PSA and prostate acid phosphatase. 38,42 However, additional stimuli may be required for sustained growth of these implants in long-term carcinogenesis studies. Equivocal data have been reported on the effect of dihydrotestosterone on the growth of tissue implants.…”

“…Equivocal data have been reported on the effect of dihydrotestosterone on the growth of tissue implants. 38,41,42 Transgenic mice Transgenic mice are used as a model to study the consequence of various transforming events on the prostate gland. Several prostate-speci®c regulatory elements have been evaluated for their ability to direct heterologous gene expression speci®cally and reproducibly to the prostate in transgenic mice.…”