Increased androgen receptor expression correlates with development of age-dependent, lobe-specific spontaneous hyperplasia of the Brown Norway rat prostate

Androgens are essential for development and differentiated function, as wel l as proliferation and survival of cells within the prostate gland. Age-rel ated changes in the hormonal milieu, marked by a decrease in the serum andr ogen to estrogen ratio may contribute to the evolution of pathological chan ges, such as benign prostatic hyperplasia and carcinoma of the prostate gla nd, in older men. A similar phenomenon occurs in Brown Norway rats, in whic h the serum testosterone to estradiol ratio declines with age, and despite the lower serum testosterone level, age-dependent prostatic hyperplasia dev elops in the dorsal and lateral lobes, but not in the ventral lobe. To eval uate a role for changes in androgen action in the evolution of prostatic hy perplasia, we compared the immunostaining intensity of androgen receptor in the different prostate lobes from young (4 months of age) and old (24 mont hs of age) Brown Norway rats. Androgen receptor immunostaining was present in the nuclei of all epithelial cells and some stromal cells throughout the prostatic ducts of each lobe from both young and old rats. Whereas androge n receptor immunostaining intensity decreased in luminal epithelial cells o f the ventral prostate from old rats, it increased in luminal epithelial ce lls of the dorsal and lateral lobes from old rats, when compared with young rats. To validate immunocytochemical studies, Western blot analyses were p erformed. The total tissue level of androgen receptor decreased by 30% in t he ventral lobe of old rats, whereas tissue levels of androgen receptor inc reased 2.7-fold and 1.3-fold in the dorsal and lateral lobes, respectively, of old rats. Similarly, the percentage of epithelial cells staining positi ve for the proliferation marker, proliferating cell nuclear antigen, was in creased approximately 2-fold in the dorsal and lateral lobes as a function of older age. The presence of higher levels of androgen receptor and increa sed number of proliferating cell nuclear antigen-positive cells in the dors al and lateral lobes of old rats suggest that changes in androgen receptor levels may be related to the lobe-specific proliferation of cells that occu rs with increasing age. Additional evidence for lobe-specific regulation of androgen receptor expression was obtained from Western blots and by immuno cytochemistry following castration. Androgen receptor levels in the ventral and dorsal lobes, but not the lateral lobe, of young and old rats were dow n-regulated in the absence of testicular androgen. However, nuclear immunos taining of androgen receptor returned by 7-10 d after castration in the ven tral and dorsal lobes in the continued absence of androgen. Moreover, up-re gulation of the androgen receptor level occurred more rapidly in the ventra l and dorsal lobes of old, compared with young, castrated rats. Taken toget her, these results suggest that lobe-specific and age-dependent differences in the regulation of androgen receptor expression might lead to changes in tissue androgen responsiveness and the consequent development of lobe-spec ific hyperplasia in the Brown Norway rat prostate gland.