Michael S. Morton

Diet and its preventive role in prostatic disease.

Asian men have much lower incidences of prostate cancer and possibly of benign prostatic hyperplasia (BPH) than their Western counterparts. Vegetarian men also have a lower incidence of prostate cancer than omnivorous males. Both Asian and vegetarian men consume low-fat, high-fibre diets which provide a rich supply of weak dietary oestrogens. These plant or phyto-oestrogens have been proposed as chemopreventive agents, particularly for Asian men and to a lesser extent, for vegetarian men also. The three principal classes of phyto-oestrogens are the isoflavonoids, flavonoids and lignans. Many foods of plant origin contain varying amounts of these compounds and hundreds of plants manifest some degree of oestrogenic activity. Soya, a dietary staple in many parts of Asia, is a major source of the isoflavonoids, daidzein and genistein. Flavonoids are present in high concentration in many fruits, vegetables and crop species. In particular, apigenin and kaempferol are regarded as major flavonoids because of their common occurrence in plants, and their significant concentrations when present. Apples, onions and tea-leaves are excellent sources of flavonoids. Plant lignans are present in many cereals, grains, fruits and vegetables, and give rise to the mammalian lignans, enterodiol and enterolactone; however, the richest source is linseed (flaxseed) and other oilseeds. In addition to their oestrogenic activity, many of these plant compounds can interfere with steroid metabolism and bioavailability, and also inhibit enzymes, such as tyrosine kinase and topoisomerase, which are crucial to cellular proliferation.

6Phytoestrogens and diseases of the prostate gland

Abstract Both benign hyperplasia (BPH) and cancer of the prostate are manifest in men beyond the age of 50. Approximately 50% of men greater than 50 years of age will suffer from the symptoms associated with BPH, especially from bladder outlet obstruction. With the ever-increasing proportion of the population over 65 years of age worldwide, BPH is becoming an important medical problem as the world moves into the next millennium. Cancer of the prostate is the second most commonly diagnosed cancer after skin cancer in the male population of the United States, and the second most common cause of death from cancer after that of the lung. Overall, around the world the incidence of carcinoma of the prostate is increasing annually by 2–3%. Both race and geographical location have a profound influence of the prevalence of prostate cancer worldwide. Black men in the USA have the highest incidence, while the incidence is much lower in Asian men from China, Japan and Thailand. Although the prostate gland is androgen-dependent, it is now recognized that the biological actions of endocrine-related factors, such as androgens, oestrogens, glucocorticoids and certain dietary and environmental factors, are mediated within the gland by various growth regulatory factors. The growth regulatory factors such as epidermal growth factor (EGF), keratinocyte growth factors (KGF), fibroblast growth factors (FGFs) and insulin-like growth factors II and I are mitogenic and directly stimulate cell proliferation under the modulating influence of steroid hormones. Steroids are therefore essential but not directly responsible for cell proliferation. Certain plant compounds such as isoflavonoids, flavonoids and lignans have been proposed as cancer protective compounds in populations with low incidences of prostate diseases. In particular, soya contains the isoflavone genistein, a compound with many properties which could influence both endocrine and growth factor signalling pathways.

Certain aspects of molecular endocrinology that relate to the influence of dietary factors on the pathogenesis of prostate cancer

Isoflavonoids, flavonoids and lignans are natural oestrogenic compounds derived from soya, tea, fruits and vegetables and they have been proposed as chemopreventive agents in Asian men, in whom the incidence of prostate cancer is much lower than in men from the West. In addition to their weak oestrogenic activity, oestrogen antagonistic activity has also been described for some of these compounds. Furthermore, the lignan, enterolactone and the soya-derived isoflavone genistein are inhibitors of several steroid metabolising enzymes, such as aromatase, 5α-reductase and 17β-hydroxysteroid dehydrogenase. Genistein is a potent inhibitor of tyrosine kinases and along with flavonoids such as kaempferol and apigenin is also an inhibitor of topoisomerases I and II, enzymes which are crucial to cellular proliferation. Genistein is also an inhibitor of angiogenesis and many experimental in vivo and in vitro models, including those for prostate cancer, are growth inhibited by isoflavonoids, flavonoids and lignans. It is estimated that the traditionally eating Japanese male consumes approximately 20 mg of isoflavones per day, whereas for Western men, the daily consumption would be less than 1 mg/day. This is reflected in a high mean plasma concentration of genistein (180 ng/ml, n = 72) in Japanese men, compared to a level of <10 ng/ml for Western males.

Plasma and urinary phyto-oestrogens as biomarkers of intake: validation by duplicate diet analysis

Estimating intake of phyto-oestrogens (PO) is difficult because there is inadequate information on the PO content of foods. Development of a biomarker of intake is therefore necessary for carrying out epidemiological studies. We aimed to validate a newly constructed PO database, containing more than 600 values assigned to foods by using duplicate diet analysis, and to investigate the relationships between measured PO intake, urinary excretion and plasma concentrations of PO. Fourteen subjects with estimated dietary intakes of PO ranging from 0 to 44 mg/d, measured by 7 d weighed intake, completed a duplicate diet collection over 24 h. Concurrently, a 24 h urine collection, validated using p-aminobenzoic acid, was obtained and one timed spot plasma sample taken. Duplicate diets, complete urine collections and plasma samples were analysed for total genistein and daidzein using liquid chromatography-MS to determine PO intake. The potential for 24 h urinary excretion and plasma PO concentrations to reflect dietary intake was investigated. Mean estimated and measured dietary PO intakes were 12.3 and 11.0 mg/d respectively. The correlation between estimated intake and measured intake of PO was highly significant (r 0.98, P<0.001). Urinary excretion (24 h) and plasma concentrations of PO were significantly related to measured dietary PO intake (r 0.97, P<0.001 and r 0.92, P<0.001 respectively). The relationship between 24 h urinary PO excretion and timed plasma concentrations was also significant (r 0.99, P<0.001). These findings validate the PO database and indicate that 24 h urinary excretion and timed plasma concentrations can be used as biomarkers of PO intake.

Effect of red clover-derived isoflavone supplementation on insulin-like growth factor, lipid and antioxidant status in healthy female volunteers: a pilot study

Background: Isoflavones are estrogen-like plant compounds that may protect against cardiovascular disease and endocrine-responsive cancer. Isoflavones may, because of their ability to act as selective estrogen receptor modulators, alter insulin-like growth factor (IGF) status.Objective: The aim of this study was to assess the effect of 1-month isoflavone supplementation (86 mg/day red clover-derived isoflavones) on IGF status.Design and subjects: Healthy pre- (n=16) and postmenopausal (n=7) women were invited to take part in a randomised, placebo-controlled crossover study with a minimum 2-month washout period.Results: For premenopausal subjects, the change in IGF-1, IGF-BP1 and IGF-BP3 assessed at different points of the menstrual cycle did not differ between isoflavone and placebo phase. However, the change in IGF-1, when examined pre- and post-supplementation, was nonsignificantly reduced (P=0.06) on the isoflavone supplement compared to placebo. For postmenopausal subjects, the change in IGF-1, IGF-BP1 and IGFBP-3 concentrations over the supplementation period did not differ between isoflavone or placebo phase. Isoflavones increased HDL in postmenopausal women compared to placebo (P=0.02) but did not alter either cholesterol or triacylglycerol concentrations, and had no effect on antioxidant status.Conclusions: This study shows that 1-month supplementation with red clover isoflavones has a positive effect on HDL cholesterol, but at most a small effect on IGF status in premenopausal and no effect in postmenopausal subjects. Further studies are required to ascertain the role these dietary compounds may have to play in breast cancer prevention.Sponsorship: The isoflavone and placebo supplements were kindly supplied by Novogen (North Ryde, Sydney, Australia). This study was supported by Action Against Breast Cancer registered charity number 1020967.

Possible relationship between dietary factors and pathogenesis of prostate cancer.

Our knowledge and understanding of the endocrine, biochemical and molecular processes implicated in the pathogenesis of prostatic disease is rapidly growing. Although it is recognized that symptomatic clinical benign prostatic hyperplasia (BPH) associated with bladder outlet obstruction is not a premalignant condition that leads to the development of prostatic cancer, current views’ suggest that the earlier stages in the natural history of BPH related to epithelial cell hyperplasia and microscopic BPH may give rise to cancer in the transition zone. Prostatic enlargement associated with bladder outlet obstruction is generally the end result of dysfunctional growth regulatory mechanisms within the gland that can result in the development of a benign stromal adenoma (Fig. 1). It is also clear from our understanding ofthe natural history of BPH2>’ that similar risk factors are associated with both BPH and the pathogenesis of prostatic cancer. 1-4 Both clinical conditions generally present in men beyond 50 years of age,4 indicating that an age factor is associated with risk, both are promoted by androgen in that functional testes are required, since neither disease develops in their absence and, moreover, both conditions clinically respond to androgen ablative therapy. It is also well accepted that the early phases in the pathogenesis of cancer can be identified a number of years prior to clinical evidence of the disease. Certain bothersome symptoms are now being recognized in men in their ~ O ’ S , ~ , ~ and histologic BPH, epithelial cell hyperplasia and nodular hyperplasia, can be seen in the prostate glands ofmen in their early 20’s. Moreover, the classical studies of Coffey and his colleague^^^^ identified an increasing prevalence of foci of epithelial hyperplasia with increasing age in men from various parts of the world. The molecular biology associated with these

Investigation of the reliability of 24 h urine excretion as a biomarker of isoflavone exposure over time and over a wide range of isoflavone intakes

Objective: To study the variation in genistein+daidzein intake over a 6-month period and test the reliability of 24 h urinary isoflavones as a biomarker of exposure over time.Design: Dietary genistein+daidzein intake was assessed at various time points throughout six months in 15 healthy subjects. Group 1 (n=8) followed nonsupplemented diets and Group 2 (n=7) took a 35 mg/d isoflavone supplement for 3 months and each subject provided a 24 h urine collection, validated with para-aminobenzoic acid, during weeks 7, 15 and 19. Urine was analysed for genistein and daidzein using LC-MS.Results: Isoflavone intake in Groups 1 and 2 ranged from 0.00 to 1.1 mg/d and 0.1 to 53.1 mg/d, respectively. Urine excretion for both groups ranged from 0.20 to 9.56 mg/d. The relationship between 24 h excretion and isoflavone intake is y=0.44 × ±0.03(standard deviation) + 1.57; r=0.89, P<0.001.Conclusion: The 24 h urinary isoflavones can be used as biomarkers of isoflavone exposure over time.

Plasma and urine concentrations of isoflavones as biomarkers of phyto-oestrogen intake following dietary soy supplementation

AbstractBackgroundThe current study assessed the value of spot urine and plasma samples as biomarkers of phyto-oestrogen exposure. DesignTwenty-one subjects, aged 21–76 (9 males and 12 females) completed the five-week intervention study. They provided spot urine and plasma samples at the start of the study, weekly samples for four weeks while eating a daily cereal bar containing 28 mg total genistein and daidzein, and samples one week after discontinuation of the supplement. Dietary phyto-oestrogen intake was estimated using food diaries. ResultsPhyto-oestrogen intake ranged from 0.05 to 77.3 mg and correlated with urine and plasma concentrations; r = 0.86, p<0.001 and r = 0.88, p<0.001, respectively. The relationship between phyto-oestrogen intake and plasma and urine concentrations is y= 1.34(standard deviation (SD) 0.09)x+1.23 and y = 0.88(SD 0.05)x + 1.02, respectively. ConclusionsPhyto-oestrogen concentrations in spot urine and plasma samples can be used as biomarkers of phyto-oestrogen intake.

Dietary Phyto-Estrogens and the Menopause

Acute menopausal symptoms are commonly reported in Caucasian women [1,2], but have been found to be less common in Asians [3,4]. While hot flushes tend to occur in at least 60% of Caucasians [5], Japanese women suffer fewer symptoms with hot flushes recorded in only 10.8% in one study [6]. Chinese women also experience fewer symptoms [7,8]. Whether the low incidence of vasomotor symptoms in Asian women reflects cultural, psychological, or physiological differences requires further study. However, as vasomotor symptoms are related to the decline in ovarian function and hence declining estrogen influence [9], the low incidence of menopausal symptoms in Asian women may also reflect their high intake of weakly estrogenic compounds in their traditional diets.