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Effects of soy phytoestrogens on the prostate

Abstract

Worldwide disparities exist between geographic regions with regard to prostate cancer incidence and mortality. Countries in East Asia have lower rates of prostate cancer compared with Western countries such as Canada and the US. Some suggest that dietary differences between the two geographic regions, particularly the higher amount of phytoestrogens consumed in East Asia, is responsible for the difference in prostate cancer incidence. The mechanism of action of the soy isoflavones is incompletely understood, but in regards to prostate carcinogenesis likely involves estrogenic effects, cell cycle inhibition, anti-angiogenesis and induction of apoptosis. Recent clinical studies have provided mixed results with regard to a clear association between prostate cancer and soy consumption. Further studies are needed to understand more clearly the relationship between soy consumption and prostatic diseases.

Introduction

Prostate cancer is the most common malignancy diagnosed in men in the US with an estimated 234 460 new cases in 2006.1 Worldwide, the US joins Australia and Canada as having the highest incidence rates for prostate cancer.2 These high incidence rates are in stark comparison to those in Singapore, Japan, China and Hong Kong, which have some of the lowest incidence rates of prostate cancer in the world. The death rate for prostate cancer in the US (15.8 per 100 000) is almost three times that in Japan (5.7 per 100 000) and almost 16 times that in China (1.0 per 100 000)1 (Table 1). This worldwide disparity in the incidence rates of prostate cancer suggests that environmental factors, such as certain dietary agents, might either increase or decrease the risk of developing the disease.

Table 1 Prostate Cancer Death Rates per 100 000 population, 2002

One class of dietary agents, the phytoestrogens, which are compounds found in plants such as soy, has received attention for its possible protective effect against certain cancers. In one recent study from Hong Kong, mortality from lung cancer, colorectal cancer, stomach cancer, and breast cancer was inversely associated with soy consumption.3 Some epidemiologic studies seem to suggest that the consumption of soy products is also associated with a reduced risk of prostate cancer. Hebert et al.4 studied predictive variables for prostate cancer mortality in 42 countries and found that soy products were significantly protective against prostate cancer death with an effect size per kilocalorie at least four times as large as that of any other dietary factor. Soy has been a major staple of diets in Asian countries for centuries and the average Asian diet consists of 10 times the amount of soy products consumed in the average American diet.5 Soy contains a relatively higher amount of isoflavones compared with other food sources.6 Many investigators believe that the isoflavones give soy its proposed anticancer benefit.7

Classification of compounds

Phytoestrogens are a group of biologically active plant compounds with a chemical structure that is similar to estradiol, an endogenous estrogen (Figure 1).8 There are three major classes of phytoestrogens: lignans, isoflavones and coumestans. The isoflavones are most important in regard to the prostate as they have been shown in vitro to inhibit significantly prostate cancer cell growth.9 The major isoflavone glycosides are genistin, daidzin and glycitin and their respective aglycones are genistein, daidzein and glycitein. Genistein and daidzein are found in high quantities in such food products as soybeans, tofu, kidney beans, chickpeas, lentils and peanuts.10 Overall, however, the richest source of isoflavonoids is the soybean, a large component of many Asian diets. Soybeans contain approximately 2 g of isoflavones per kilogram fresh weight.11

Figure 1
figure1

The chemical structures of genistein, daidzein and estradiol-17B. Reprinted with permission from Holzbeierlein JM, McIntosh J, Thrasher JB. The role of soy phytoestrogens in prostate cancer. Curr Opin Urol 2005; 15: 17–22.

Both genistein and daidzein have been extensively studied as cancer-protective agents. The chemical structure of these two isoflavones is very similar to that of estradiol, an endogenous estrogen. The chemical structures of the two isoflavones share a common diphenolic structure and differ by only one hydroxyl group. The isoflavones occur in plants as the inactive glycosides daidzin and genistin and their 4′-methyl ether derivates, formononetin and biochanin A.12 After being consumed, enzymes of the normal microflora in the digestive tract metabolize these precursors to the more active, unconjugated compounds; genistein and daidzein.13 After ingestion, the major serum peak level of the isoflavones occurs at 4–6 h and given its half-life of between 4 and 8 h, nearly all of the isoflavones are excreted after 24 h.14

Molecular effects of isoflavones

On a molecular level, the isoflavones are postulated to have an effect on prostate cancer cells owing to their estrogenic effects. Estrogen compounds have been used in the past to treat prostate cancer and some estrogen-based therapies are currently being tested in androgen-independent prostate cancer.15 Estrogens achieve castration by feedback inhibition on the hypothalamic–pituitary axis. This inhibition reduces luteinizing hormone (LH) release from the pituitary gland and thus subsequently reduces testicular production and secretion of testosterone. Given the chemical similarities of the isoflavones and the endogenous estrogen, the isoflavones have been shown to bind to estrogen receptors (ER) and exert estrogenic effects.8 In particular, the isoflavones have a higher affinity for a subset of ER, ER-β, which are strongly expressed in the prostate. Activation of ER-β has been shown in vitro and in animal models to suppress cellular proliferation and promote differentiation in the prostate.16

Genistein has been extensively studied at the molecular level to elucidate its effects on prostate cancer cells. Frequently, carcinogenesis involves defects in the regulation of the cell cycle. Cell-cycle progression is normally a structured and ordered set of events regulated by activation and subsequent inactivation of a series of cyclin-dependent kinases (CDKs).12 These CDKs cause the cell to move from G1 to S phase as well as from G2 to M phase. Shen et al.17 found that physiologic concentrations of genistein exerted a potent antiproliferative effect on LNCaP cells by inducing a G1 cell-cycle block. They found increased levels of p27(KIP1) and p21(WAF1), which are negative cell-cycle regulators that act as CDKs inhibitors. Genistein has also been shown to induce a G2/M cell-cycle arrest in both PC3 and LnCaP cell lines.18 Genistein, at very high concentrations, has been shown to inhibit protein-tyrosine kinase (PTK) and PTK has been shown to have a role in carcinogenesis, cell growth and apoptosis.19 PTK, which is also referred to as Akt, plays a critical role in controlling the balance between cell survival and apoptosis.20

Handayani et al. reported that the isoflavones altered the expression of 75 genes that are involved in metabolism, adhesion, metastasis, angiogenesis, cell growth and transcriptional regulation in PC-3 cells, a model of advanced prostate cancer.21 The authors reported that the isoflavones downregulated the expression of IL-8, a proinflammatory and potent angiogenic cytokine. In their study, Handayani found that the isoflavones decreased IL-8 mRNA by 81%. In another study, IL-8 has been shown to stimulate angiogenesis and the metastatic potential of prostate cancer cells.22 Looking further at aggressive models of prostate cancer, the isoflavones downregulated the expression of matrix metalloproteinase 13 (MMP-13). MMP-13 has been shown to be a marker of invasive prostate cancer and it was found that genistein decreased the expression of the protein in prostate cancer bone metastasis in mice.23 In these in vitro studies, the isoflavones inhibited the carcinogenesis of prostate cancer cells through a variety of mechanisms.

Much research has also focused on the in vitro effects of genistein on the androgen receptor (AR) and prostate-specific antigen (PSA). Bektic et al.24 showed that physiologic concentrations of genistein downregulated AR at both the mRNA and protein level in the androgen-sensitive LnCaP cell line. Due to this reduction in AR expression, these prostate cancer cells are postulated to have a muted response to hormonal stimuli. In another study, Yu et al. studies the effects of the isoflavones on the expression of another androgen-responsive gene, prostate androgen-regulated transcript-1 (PART-1). In androgen-sensitive LNCaP cells, genistein at 50 μmol/l completely inhibited expression of the PART-1 transcript in cells induced by dihydrotestosterone (DHT).25 These studies seem to add to the evidence that the isoflavones effect on prostate cancer cells is related to some type of hormonal effect.

Effects of soy in animal models

The study of the effects of isoflavones in vitro prompted research using animal models. Zhou et al. subcutaneously (s.c.) inoculated 8-week-old severe combined immune-deficient mice (SCID) with LNCaP cells (2 × 106) isolated from s.c. grown LNCaP tumors from donor SCID mice.26 All of the mice were inoculated in the right flank. The authors randomly assigned the mice to one of six experimental diets. The first was a control diet and the other five diets had two protein sources (20%, casein vs soy protein) and three levels of soy phytochemical concentrate (0, 0.2 and 1.0% of the diet). These diets had increasing levels of mg isoflavone equivalents/kg from 341 mg isoflavone equivalents/kg to 2120 mg isoflavone equivalents/kg.

The three diets which had the highest milligram isoflavone equivalents/kg (756, 1705 and 2120) significantly reduced tumor volume at 3 weeks by 28, 30 and 40% (P<0.05), respectively, compared with the mice fed the control diet. Histologic examination of tumor tissue showed that consumption of soy products significantly reduced tumor cell proliferation, increased tumor cell apoptosis and reduced tumor angiogenesis. As noted in prostate cancer cell lines, the isoflavones had a significant effect on sex steroid receptor expression, particularly on AR and the ER.

Fritz et al.27 investigated the effects of the isoflavone on sex steroid receptor expression in the rat prostate. Sprague–Dawley rats were fed genistein-containing diets from conception until day 70. Doses of genistein were 25, 250 and 1000 mg/kg and given to animals for their lifetime or for a 2-week period. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis demonstrated that AR mRNA expression in the rat prostate was reduced by 85% in the rats consuming the 250 mg genistein/kg diets as compared with controls. Prostate ER-α and ER-β mRNA was also significantly reduced for the animals fed the 250 mg genistein/kg diet as compared with controls. Even in the rats exposed to the genistein for only 2 weeks, mRNA expression of ER-α and ER-β was reduced. The authors noted that rats exposed to higher levels of genistein had higher concentrations of circulating testosterone, but there was no change in prostate weight. This was likely owing to a constant DHT concentration in these rats. This study provided further rationale for human clinical studies of soy products, because reduction in sex steroid hormone expression in rats was seen at concentrations of genistein (167 pmol/ml measured in the 25 mg genistein/kg rats), which are similar to those observed in humans (267 pmol total genistein/ml blood in Asian men consuming a traditional soy diet).

Clinical effects of soy in humans

The preceding information discussed the in vitro and animal studies evaluating the anti-carcinogenic effect of soy. Building on this research, investigators have investigated the use of soy in patients. Multiple studies have looked at the effects of soy on (PSA) in healthy men. Adams et al.28 performed a double-blind, randomized trial in which 81 healthy men with low PSA levels (mean 1.7 ng/ml) were assigned to consume a soy protein drink providing 83 mg/day isoflavones (45.6 mg genistein, 31.7 mg daidzein and 5.5 mg glycitein) or a similar drink with only a trace of isoflavones (3 mg/day). These men were a part of a larger soy isoflavone prevention trial which evaluated the effects of soy isoflavones on markers of colon cancer risk in colonic epithelium over a 12-month time period. PSA changed an average 0.5% more for a person consuming the soy drink compared with the control group, a number which was not statistically significant (P=0.97). The proportion of men with a clinically significant PSA velocity (>1 ng/ml/year) was not significantly different in comparing the groups (17.6% in the experimental arm vs 12.8% in the controls, P=0.54). This study was relatively short (12 months) and might have missed a true clinical effect of the isoflavones on PSA. The authors did not perform any biopsy results and thus any potential anti-neoplastic effect on prostate tissue by the isoflavone supplement would have been missed.

Jenkins et al.29 analyzed the PSA of 46 hyperlipidemic men, who had participated in a group of studies designed to assess the effects of soy protein on blood lipids. All studies involved a randomized crossover design in which subjects ate soy foods in the first phase and control foods in the other. The duration of these studies for all subjects ranged from 3–4 weeks, and one of the studies was extended for a total of 3 months for a small subset of 13 patients. On average the men consumed 44 g soy protein and 116 mg soy isoflavone measured as the aglycone daily in the experimental arm. The mean baseline PSA in both the control and experimental groups was 2.4 ng/ml and the majority of men had PSA values between one and four. The authors found no significant differences between soy and control treatments in terms of the difference between total and free PSA at baseline and at the end of the 3–4 week treatment period. There were similarly no effects of soy on PSA levels in small subset of men who consumed an additional 8 weeks of the predominant soy diet. This study is limited by the small number of subjects as well as the very limited study duration. Once again, any treatment effect of the isoflavones on prostate carcinogenesis might be missed in these studies with 12 months or less of therapy. In conclusion, these small clinical trials involving healthy men with normal PSA values suggest that over the short-term, a soy-rich diet does not affect PSA. As none of the subjects were required to undergo an end-of-study prostate biopsy, the true effect of soy on prostate carcinogenesis in healthy men, however, is not known.

In patients with a diagnosis of prostate cancer, multiple studies have evaluated the effect of soy compounds on PSA levels. DeVere White et al.30 offered high-dose supplemental soy isoflavones (genistein-rich extract providing 450 mg/day of genistein and 450 mg/day of other aglycone isoflavones) for 6 months to 52 men who had histologically proven prostate cancer and who either failed therapy (prostatectomy, radiation, combination prostatectomy and radiation, off cycle in hormonal-therapy) or chosen active surveillance. The supplement was well-tolerated and the only main side effect was diarrhea which occurred in three patients. Clinical chemistries including liver and renal function tests were unaltered. The study objective was to see if soy supplementation would lower PSA levels more than 50% in prostate cancer patients at 6 months. At the end of the study, only one patient had a reduction in PSA of greater than 50%. Seven patients had a reduction in PSA of less than 50%. They noticed that in men who chose active surveillance, eight of 13 men had either no rise or a decline in PSA levels of less than 50%. However, regression models showed an increase in the PSA level for all patients of about 5.5% per month with no overall difference after subjects began taking the soy supplement. The authors found no significant changes in the total testosterone and free testosterone levels in a subgroup of the study. Soy seemed to be only effective in patients in the surveillance group. As the authors note, however, the small sample size of patients undergoing active surveillance as well as the fact that lower Gleason scores were noted in the surveillance group, make it difficult from this study to conclude that soy has an effect on PSA levels even in patients undergoing watchful waiting.

Soy was also not effective in reducing PSA levels in a phase I clinical trial to determine the safety of high-dose oral isoflavones in 20 men with prostate cancer.31 Fischer et al.31 gave subjects with stage B, C or D prostate cancer a multiple-dose regimen of a soy isoflavone formulation (delivering approximately 300 or 600 mg/day genistein and half this much daidzein) for 84 days. Seven patients were excluded from the analysis of PSA values because the respective PSA was undetectable or <0.4 ng/ml. The PSA level for the other 13 patients rose during the trial at an estimated rate of increase of 0.28% per day and 0.70% per day during the 28 days following the study period. The authors reported no clinically significant adverse effects. The authors observed some minor estrogenic side effects (nipple tenderness, gynecomastia), however, men who reported these complaints were currently on or had a history of hormonal therapy for their prostate cancer. The authors found no significant changes in total and free testosterone, DHT and luteinizing hormone (LH) concentration after isoflavone treatment. They report 31.7% decrease in serum dehydroepiandrosterone concentration. This Phase I clinical study, designed to look at toxicity of a high-dose soy supplement, did not find that the supplement decreased PSA. This study however, because of its limited number of subjects, might not have been statistically powered to observe any significant effect of the soy supplement on PSA in prostate cancer patients.

In several studies, however, soy supplementation did have a favorable effect on PSA levels in some prostate cancer patients. Dalais et al.32 studied 28 men who were diagnosed with prostate cancer and scheduled for a radical prostatectomy. They randomized the men into three groups. The two high-phytoestrogen diets were achieved with bread composed of 50 g of heat-treated (HT) soy grits and bread composed of 50 g of HT soy grits and 20 g of linseed. The placebo group used pearled wheat bread. Each participant consumed four slices of the respective bread from the date of entry into the study until the date of surgery. The mean duration of each group's diet was between 22.2 and 27.4 days. The mean PSA in the soy grits group decreased from 7.16 ng/ml at baseline to 6.34 ng/ml at the end of the trial. The mean PSA in the control group increased from 5.81 to 7.11 ng/ml at the end of trial. This was a statistically significant difference for the percentage of change between the two groups (P=0.02). However, the PSA in the soy and linseed group, like the control group, increased as well from a mean baseline 6.31 to 6.99 ng/ml at the end of study. This increase in PSA seen in the soy and linseed group makes it difficult to conclude that a soy-rich diet has a clear beneficial effect. The HT soy grits and HT soy grits and linseed diets did not alter testosterone or DHT levels. Once again, this study enrolled a small group of patients and had a very short duration of 3–4 weeks.

Schroder et al.33 randomized 49 men with a history of prostate cancer and a rising PSA level after either radical prostatectomy or radiotherapy to receive a placebo or a primarily soy-based supplement. Subjects had to take a nutritional supplement containing soy isoflavones, lycopene, silymarin and antioxidants over a 10-week period. The research group designed the soy supplement used in the study. The authors reported that there were no adverse effects of the supplement on the patients in the trial. They used changes in the rate of increase of PSA (PSA slope and doubling time) as the primary parameters of efficacy. The authors reported that the median total PSA doubling time was 1150 days for the supplement and 445 days for the placebo. This translated into a 2.6-fold increase in the PSA doubling time for patients taking the supplement. Therefore, they concluded that the soy-based supplement significantly delayed PSA progression. The findings with regard to PSA deserve attention, but any effect of the soy supplement in this trial on residual tumor volume remains unclear.

Clearly, studies on the effect of the isoflavones on PSA in prostate cancer patients have given conflicting results and thus larger and longer-duration studies are needed to explore further this possible association. Furthermore, the content of isoflavones in the various supplements used in these trials is non-standardized and thus it is hard to make comparisons between dietary supplements of differing isoflavone composition. Despite the different composition of the isoflavone supplements, patients in these trials tolerated the respective experimental diet without significant adverse events.

Most of the evidence linking soy intake and prostate cancer risk has come from non-randomized, observational epidemiologic studies. Jacobsen et al.34 reviewed 225 new cases of prostate cancer in 12 395 California Seventh-Day Adventist men diagnosed from 1976 to 1992. This cohort of men filled out questionnaires in 1976 about how often they drank soy milk, a drink rich in isoflavones. Frequent consumption, which the authors defined as more than once a day, was associated with a 70% reduction of the risk of prostate cancer (RR=0.3). The authors found no relationship between soy milk consumption and prostate cancer incidence for 61 cases of advanced metastatic prostate cancer. In this study, the authors use the frequency of soy milk drinking and not the quantity of soy consumed and therefore it is hard to fully assess the proper dose of soy milk which would be protective against prostate cancer. Other studies have shown a trend, but have not reached statistical significance when describing an inverse relationship between soy intake and prostate cancer.35 In a meta-analysis, Yan36 examined eight epidemiologic studies examining the role of soy food in relation to prostate cancer risk and found that the consumption of soy food was related to an approximately 30% reduction in prostate cancer risk. The number of cases in these studies is small and the possibility of recall bias certainly exists in these dietary studies and thus larger, randomized clinical trials are clearly needed to fully address this issue. These studies also lack any consistency with regards to quantity of soy intake and therefore it is hard to figure out precisely the isoflavone dose, which might reduce prostate cancer risk.

A pilot study was recently completed at our institution to determine the dose effect of a soy supplement on serum hormone levels, ER-α, and AR expression in patients scheduled to undergo a radical prostatectomy.37 Thirteen patients over a 6-month period were enrolled and 11 of them went on to surgery. The first two patients were given two servings daily of a commercial soy protein powder (Ultra-Soy, Genisoy Products Co, Fairfield, CA, USA). However, a reformulation resulted in a product no longer consisting of pure soy and so all remaining patients received Flav-ein capsules (3B's Ltd, Lenexa, KS, USA), an all-natural, pure soy product in capsular form. Each capsule contains 560 mg of soy extract and 100 mg of legume powder. Each capsule contains 28 mg of total isoflavones (10–20% genistein, 50–70% daidzein, 20–40% glycitein). Three cohorts of patients received soy supplementation at increasing doses. The median time on supplementation before prostatectomy was 28 days (range 16–76). Serum testosterone levels decreased in nine of 11 patients and serum estrogen levels decreased in eight of 10 patients in a dose-dependent manner. The soy supplementation produced no consistent effect on serum PSA levels. Downregulation of ER-α expression was shown at the highest dose level, but there was no observed effect on AR expression. On the basis of results of the pilot study, enrollment is currently ongoing for a larger randomized, placebo-controlled clinical trial in which 86 patients with histologically confirmed adenocarcinoma of the prostate will be randomized (43 patients in each arm to placebo or four Flav-ein capsules twice daily (240 mg of total isoflavones)) before their scheduled prostatectomy. The goal is to assess the effect of soy supplementation on endogenous hormone levels and serum PSA. The effect of soy on ER-α expression, cell-cycle regulation and apoptosis will also be studied. The results of this study might further clarify the effect that the isoflavones have on prostate carcinogenesis.

Conclusion

With the recent publication of the Prostate Cancer Prevention Trial, much attention has been focused on the chemoprevention of prostate cancer.38 Prostate cancer chemoprevention involves the use of natural or synthetic agents that inhibit precancerous lesions from developing or delay the progression of these lesions.39 Clearly, multiple in vitro studies have shown an effect of the phytoestrogens on hormone-responsive cancers, particularly prostate cancer. Soy isoflavones, a class of phytoestrogens, have been shown to alter the expression of numerous genes associated with prostate cancer progression. This inhibitory effect on prostate cancer cell proliferation might be related to downregulation of proteins associated with cell signaling, interruption of the cell-cycle, inhibition of angiogenesis and induction of apoptosis. The findings in the laboratory also complement the epidemiologic findings that show that areas of the world, particularly in East Asia, which consume a great amount of soy in their diet have a lower incidence of prostate cancer.

Clinical trials, however, have failed to provide sufficient evidence for a chemopreventive effect of soy phytoestrogens on the development of prostate cancer or on delay in biochemical failure after definitive local therapy. These trials have failed to provide assistance with dosing of soy supplementation as well as characteristics of patients who would clearly benefit from the addition of dietary soy products. Yet, despite the conflicting evidence regarding soy and prostate cancer, published research has shown that the adverse effects associated with soy products are minimal. Furthermore, soy might have benefits outside the oncologic arena, particularly as it relates to coronary risk factors and bone health. Soy supplementation as noted in the clinical studies, even at high levels of isoflavone intake, is safe over the short term. There have been no studies in the literature which reported clinically relevant adverse events associated with isoflavone exposure.14 The possible oncologic and cardiac benefits, together with its low side effect profile, make soy an attractive nutritional supplement for aging men, who are more likely to suffer from a disease of the prostate. However, the urologic community has to await the results of more prospective, randomized trials (Table 2) before a clear recommendation can be made as to the benefit of soy supplementation on the prevention of prostate cancer or the prevention of prostate cancer recurrence.

Table 2 Recent clinical trials involving soy and prostate

Summary

Worldwide, a clear discrepancy exists between various geographic regions with regards to the incidence of prostate cancer. Countries in East Asia have a markedly reduced prostate cancer incidence and mortality compared with countries like the US. Many have theorized that dietary regimens, particularly the increased soy intake in East Asian countries, can account for this geographic discrepancy. Multiple studies in the laboratory have attempted to clarify on a molecular level the effects of the isoflavones on prostate cancer cells. Studies on humans with regards to prostate cancer risk and soy intake to date have been inconclusive Yet, soy remains a nutritional supplement of interest because it might have both oncologic and cardiac benefits and it poses minimal risk to prostate cancer patients. In the future, larger, randomized trials are needed to fully assess the effect of soy phytoestrogens on prostate diseases.

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Correspondence to J B Thrasher.

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Goetzl, M., VanVeldhuizen, P. & Thrasher, J. Effects of soy phytoestrogens on the prostate. Prostate Cancer Prostatic Dis 10, 216–223 (2007). https://doi.org/10.1038/sj.pcan.4500953

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Keywords

  • soy
  • isoflavones
  • prostate
  • prostate cancer
  • phytoestrogens

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