The present study took advantage of access to human prostate tissue collected during routine prostatectomy procedures to examine and contrast tissue and serum concentrations of isoflavones that had been administered by dietary supplementation for at least two weeks prior to surgery. There was a ~6-fold higher total isoflavone concentration in the tissue compared to serum levels sampled at the time of tissue harvesting. . Further examination of specific types of isoflavones indicated that the tissue vs. serum difference was smaller for genistein (4-fold) than for daidzein (10-fold).
The two primary soy isoflavones - genistein and daidzein - have been extensively investigated for their anticancer effects in vitro and in animal studies. In models pertaining to PCA, genistein inhibits receptor tyrosine kinases, nuclear factor kappa B (NF-kB) and vitamin D-24-hydroxylase thus induces apoptosis (10
) and enhances calcitriol action to inhibit proliferation of PCA cells (29
). Genistein activates tumor suppressor genes (12
), inhibits metastasis (13
), modulates androgen-responsive gene expression (14
), and down-regulates prostate-specific antigen (PSA) (9
) and the androgen receptor (7
Daidzein exhibits similar effects on apoptosis and cell cycle (17
), but has been reported to be less effective (16
). However, daidzein, unlike genistein, is metabolized to equol with a longer half-life than genistein and daidzein (8
) which has been shown to inhibit neoplastic transformation (11
The anti-carcinogenic effects of isoflavones are importantly dose dependent. In cell culture studies, concentrations of 10 μmol/L or higher were determined to be anti-proliferative (27
). A review of 19 bioavailability and 17 intervention studies with orally administered isoflavones ranging in dose from 37-128 mg/day reported peak serum levels of approximately 2 μmol/L that were achieved after ~6-8 hours. Many human studies examining serum concentrations have reported levels in the 1 μmol/L range (38
). The relatively high doses used in cell culture and animal model investigations raise questions as to whether biologically active isoflavone levels can be achieved in humans by oral ingestion. Perhaps more important is whether assessment of blood levels of isoflavones is a relevant surrogate measure of tissue levels, particularly in the prostate. Tissue levels were not determined in any of the studies cited above. In our study the administration of 82 mg total isoflavones per day resulted in a fasting total isoflavone serum level of 0.7 μmol/L with a corresponding tissue level of 2.3 μmol/L. The dose of 82 mg/day used in the study can be realistically achieved by natural dietary sources (42
Due to the greater accessibility to prostatic fluid relative to prostate tissue, and the less invasive sampling procedure, several studies have primarily observed the concentration of isoflavone within the prostatic fluid, with the assumption that this would correlate with tissue levels. Morton et al. observed that seminal fluid daidzein concentrations were twice that of serum (43
) and Hedlund et al., showed that prostate fluid taken from participants after isoflavone supplementation showed sufficient concentrations of genistein and daidzein to inhibit the growth of cultured prostatic epithelial cells (27
). However, the indirect assessment of the prostatic concentration by sampling the secreted glandular fluid may not reflect cellular levels and we are aware of no published work that has evaluated the strength of the correlation of isoflavone concentration between the prostatic tissue and seminal fluid. Direct measurement of prostate tissue levels of isoflavones, such as were obtained in our study, are more likely to be physiologically relevant than those obtained from prostatic fluid.
Limited data are available on isoflavone concentrations measured directly in prostate tissues. In agreement with our findings Farhan et al. reported a 10-fold increase in mouse prostate genistein concentrations compared to serum after only one oral dose of 250 mg of genistein (31
). Similarly, Hong et al. were the first to measure isoflavones in human prostatic tissue and reported consistently higher isoflavone concentrations in the prostate than in serum (34
). In that study, tissues were obtained from several sources including cystoprostatectomy and transurethral resection, all specimens were benign prostatic tissue, and subjects were not supplemented with isoflavones in their diet. Brössner et al. compared tissue concentrations of genistein in 63 men with benign prostatic hyperplasia (BPH) and 31 with PCA on a traditional Western diet (32
). The study found lower genistein concentrations in the PCA group than the BPH group, but neither assessed the serum level of the participants nor were subjects supplemented with isoflavones.
Ranniko et al. were the first to conduct a randomized placebo-controlled study investigating the effect of oral isoflavone supplementation on serum and tissue levels in a cohort of 40 men undergoing prostatectomy for cancer. After 2 weeks of 240 mg clover phytoestrogen supplementation, a two-fold higher tissue than serum concentration was reported (35
). In comparison to our study, despite the lower daily dosage of 82 mg for two weeks in our study, a slightly lower serum level was reached, but the tissue vs. serum ratio was ~6-fold. Among the limited number of studies in this area, only Guy et al. reported the contrary result with tissue concentrations observed to be lower than serum isoflavone concentration in 12 participants. The study population, however, consisted of men with BPH rather than PCA and used prostatic tissue chips. In our study, tissue levels were determined using sections from whole prostatic specimens from PCA patients.
The higher tissue/serum ratio of daidzein vs. genistein is noteworthy and indicates that despite the faster urinary excretion of daidzein vs. genistein(44
) the former is better concentrated into prostatic tissue than the latter. The predominant presence of the isoflavones as glucuronide and sulfate conjugates in prostate reflects the situation in the circulation but due to the low number of subjects investigated this needs to be confirmed in future larger studies.