Castration-induced apoptotic cell death in the Brown Norway rat prostate decreases as a function of age

Growth and differentiation of the prostate gland depends upon androgens, ye t overgrowth of the human prostate occurs later in life when serum levels o f testosterone are declining. We have reported a similar phenomenon in the Brown Norway rat, but the age-dependent overgrowth of the prostate is confi ned to the dorsal and lateral lobes and, hence, is lobe specific. Because t issue growth depends upon the balance between proliferation and death of ce lls, the present study was designed to investigate whether cell death diffe red in the various prostatic lobes of Brown Norway rats as a function of ag e. Apoptosis of cells in the ventral, dorsal,lateral, and anterior lobes of the prostate was examined in young (4-month-old) and old (24-month-old) Br own Norway rats after castration. Whereas castration caused tissue weights of all four prostatic lobes to decrease over the course of 10 days, this oc curred more rapidly and to a greater magnitude in the ventral than in the d orsal, lateral, and anterior lobes. Tissue DNA content, a measure of cell n umber, decreased only in the ventral lobe after castration. DNA fragmentati on, indicative of apoptotic cell death, was detected by in situ labeling us ing the terminal deoxynucleotidyltransferase-mediated dUTP nick end-labelin g method and as intranucleosomal cleavage of genomic DNA analyzed by agaros e gel electrophoresis. Both methods demonstrated the correlation between lo ss of DNA content and apoptotic cell death in the ventral lobe, whereas onl y the highly sensitive terminal deoxynucleotidyltransferase-mediated dUTP n ick end-labeling (TUNEL) method revealed relatively few dying cells in the dorsal, lateral, and anterior lobes after castration. Moreover, when examin ed as a function of age, less cell death occurred in all four lobes of old rats compared with young rats. In both young and old rat prostates, cell de ath was observed in epithelial and stromal cells within the ventral lobe wh ere apoptotic cells were detected throughout the branched ductal network an d were not restricted to a particular region. Taken together, these studies demonstrate the marked differences in cell death and survival between the different rat prostatic lobes in response to castration and further suggest that the androgen-sensitive apoptotic response is age dependent. Hence, th e lower rates of cell death observed for the dorsal and lateral lobes, acco mpanied by the further decline that occurs with increasing age, are importa nt components of the age-dependent and lobe-specific overgrowth observed fo r these lobes. Moreover, the age-dependent decline in apoptotic cell death observed in the prostates of old rats suggests that prostatic cells develop androgen independence as a function of age, and survival of these cells do es not require androgen.