Dietary soy protein isoflavonoid effects on the reproductive tract of the nonhuman primate and neoplastic human prostate gland

Soy, a legume, contains polyphenolic, estrogen-like compounds termed isoflavonoids. Following the consumption of a soy-containing meal, isoflavonoids are absorbed in the gut, and can be detected in the serum in nanomolar concentrations. These polyphenolic compounds are structurally similar to the endogenous sex steroid hormone estradiol (17beta estradiol) and are able to bind to endogenous estrogen receptors (ER) with varying affinities. There are two ER receptor subtypes, ERalpha and ERbeta. Both ER subtypes are expressed in the prostate gland. Estrogen receptor alpha is preferentially expressed in the stroma and ERbeta is preferentially expressed in the epithelium. The effects of estrogen and estrogen-like compounds are mediated through these two receptors, although in the prostate gland they are thought to have opposing effects. Estrogen receptor beta expression is thought to have antiproliferative and anti-inflammatory effects, while ERalpha expression is thought to promote cell proliferation, squamous metaplasia, and inflammation or prostatitis. We conducted two parallel studies to investigate the effects of soy isoflavonoid consumption on the prostate gland. The purpose of our first study was to investigate the effects of isoflavonoids in the normal prostate gland. We used the cynomolgus macaque (Macaca fascicularis) model, a species sharing 97% genetic homology with humans for this placebo-controlled dietary study. We found no significant adverse effects of isoflavonoid consumption on the prostate gland in these 91 adult male macaques receiving: (1) a soy-free, casein-lactalbumin-based diet (n=30), (2) a low-soy isoflavonoid diet, approximating 75 mg human equivalents per day (n=30), or (3) a high-soy isoflavonoid diet, approximating 150 mg human equivalents per day (n=31) for 31 months. The purpose of our second study was to investigate the epigenetic effects of short-term isoflavonoid consumption on ERbeta in men with organ-localized prostate cancer. We hypothesized that ERbeta DNA promoter methylation would decrease in prostate cancer with soy isoflavonoid treatment and this would result in an increase in ERbeta expression. DNA promoter methylation density of a gene is inversely correlated with the gene's transcription and subsequent protein expression. During this 4 week, phase IIb, randomized, placebo-controlled clinical trial 62 men were randomized to receive 50 grams of protein/day composed of either (1) casein-lactalbumin protein (soy-free) or (2) soy protein containing a 100 mg/day dose of isoflavonoids. This dietary treatment resulted in an unexpected significant increase in promoter methylation of the ERalpha gene in the neoplastic epithelium and a 50% decrease in expression of the estrogen responsive gene, progesterone receptor, but no change in ERbeta DNA promoter methylation or expression. These findings demonstrate that dietary soy isoflavonoid treatment can result in significant epigenetic changes in the promoter regions of sex steroid receptor genes in prostate cancer, alter sex steroid hormone receptor expression, and may restore expression of the two ERs to a ratio that more closely resembles that found in normal prostate epithelium. (Abstract shortened by UMI.)...