Growth of the prostate is a hormone-mediated phenomenon regulated by both androgens and estrogens [
1‐
4]. Within the prostate, ERβ has been shown to be an important player [
2,
4] in regulating hormone-dependent morphological alterations. Moreover, the DHT metabolite 3βAdiol, is the predominant endogenous estrogen in rodent prostate [
2,
3]. 3βAdiol, via binding to ERβ, regulates prostate AR gene expression and serves as an anti-proliferative agent [
2‐
4] by decreasing the influence of androgen action. Recent finding demonstrate that neonatal exposure to estrogens interrupts normal prostate development [
19]. Down-regulation of AR protein was found to occur immediately following neonatal exposure to estradiol benzoate and then persist through adulthood indicating a permanent imprint on the ability of the prostate to express normal AR levels [
19]. Furthermore, this exposure to estrogen and subsequent down-regulation of AR protein levels, identified in the ventral prostate gland, looks to be via an acceleration of AR degradation, which is mediated through the proteosome pathway [
19].
In the studies presented here, we have identified that dietary soy-derived phytoestrogens, perhaps in a manner similar to 3βAdiol, decreased prostate weight and down-regulated AR expression in the prostate. Previous research by Fritz et al. [
20] identified a similar reduction in AR in rats fed genistein. Furthermore, in these studies exposure to genistein in the diet, starting at conception resulted in not only down-regulated AR, but also ERα and -β mRNA expression in the dorsolateral prostate in a dose-dependent manner [
20] a finding they also identified in genistein fed adults [
20]. Since phytoestrogens bind ERβ with a high RBA [
5‐
7] and because ERβ regulates prostate growth by down regulating AR expression, it is possible that the reduction in prostate weight (and AR expression) seen in the present study are a result of high circulating phytoestrogens from diet and subsequently high steady state levels of phytoestrogens in prostate tissue. Since the changes in prostate weight was only present following the initiation of puberty our data suggest that the differences in prostate weight are the result of the reduction in AR expression and resulting decrease in androgenic stimulation. It is interesting to note that previous research from our lab has shown that dietary phytoestrogens have no effect of circulating testosterone or estrogen levels [
13]. The effect of phytoestrogens on prostate growth may be direct via binding ERβ [
20]. However, there may be an indirect consequence of this binding and subsequent reduction in AR expression in the prostate that may involve other metabolites of phytoestrogens that are not completely understood or alternative pathways. For example, dietary soy products have been shown to inhibit experimental prostate tumor growth through a combination of direct effects on tumor cells such as blocking cell cycle progression at the G2-M phases and enhancing DNA fragmentation [
21]. Furthermore, genistein's action as a tyrosine kinase inhibitor cannot be ruled out as a possible means by which the phytoestrogens in diet are affecting prostate weight and AR expression [
22]. However, no matter the mechanism of action these data help to more firmly establish the broad implications for prostate health in the dietary applications of phytoestrogens, as reported by other investigators [
8‐
10,
12,
13,
15,
20‐
22].