We have investigated the role of autocrine/paracrine TGF-b secretion in the regulation of cell growth by androgens as demonstrated by its inhibition by two androgen response modifiers; the nonsteroidal antiandrogen hydroxyflutamide (OHF), believed to act by inhibiting androgen binding to androgen receptors, or finasteride, an inhibitor of 5a-reductase, the enzyme necessary for the conversion of testosterone to 5a-dihydrotestosterone (DHT), using the nontumorigenic rat prostatic epithelial cell line NRP-152. Growth of these cells was stimulated threeto sixfold over control by either testosterone or DHT under serum-free culture conditions. This was accompanied by a two-to threefold decrease in the secretion rate of TGF-b1, -b2, and -b3. Finasteride reversed the ability of testosterone but not DHT to stimulate growth and downregulate expression of TGF-b1, -b2, and -b3 in a dose-dependent fashion, suggesting that this activity of testosterone required its conversion to DHT. OHF antagonized the stimulatory effects of DHT on NRP-152 cell growth but could reverse the inhibitory effects of DHT only on TGF-b2 and TGF-b3 and not TGF-b1 secretion. This suggests that either TGF-b1 regulation by DHT or the androgen antagonism of OHF occurs independent of androgen receptor binding. Neutralizing antibodies to TGF-b (pantropic and isoform-specific) were able to block the ability of finasteride to antagonize the effects of testosterone nearly completely while only partially inhibiting the antiandrogenic effects of OHF. Thus, the ability of androgens to stimulate growth of NRP-152 cells involves the downregulation of the production of TGF-b1, -b2, and -b3 in addition to other growth-stimulatory mechanisms.