Jessica Tolman and Dr. Merrill J Christensen, Department of Nutrition
The intent of the following research was to fulfill the thesis requirements for the BYU Honors Program, the following report is complied from excerpts from my Honors Thesis. The results were presented at the 8th International Symposium on Selenium in Biology and Medicine. At the beginning of this project I focused my interests on the effect of isoflavone and selenium on body composition. I later used these findings and the effect of isoflavone and selenium on hormone serum levels to determine the effect of isoflavone and selenium on prostate cancer risk.
Among American men prostate cancer is the most commonly diagnosed cancer, and the third leading cause of cancer deaths (1). Selenium (Se) and isoflavones have individually been shown to produce a chemopreventive effect against prostate cancer.
During 2006 the American Cancer Society (ACS) estimates 234,460 new cases of prostate cancer will be diagnosed in the United States. American men have a 1 in 6 probability of developing prostate cancer, while 1 in 33 men will die from prostate cancer (1). Prostate cancer is a good candidate for chemoprevention by dietary means because of its long latency period. Although prostate cancer is a big concern for men in most western countries, Asian countries have the lowest incidence and mortality rates of prostate cancer in the world. This low incidence is believed to be associated with their high isoflavone intake due to their diets which are rich in soy products consumed in these countries (4). Although incidence is much lower than in western countries, prostate cancer is becoming one of the leading male cancers in many Asian countries. The most recognized explanation for this increase is the westernization of their lifestyle, with increasing obesity and increased consumption of fat (5,6). This finding is relevant to prostate cancer as it has been noted that obesity and prostate cancer are linked. Although the exact relationship between obesity and prostate cancer remains unclear, evidence has shown that excess fat centered around the abdomen may increase insulin and insulin-like growth factors (e.g. IgF-1). IgF-1 is an important regulator of growth hormone actions on somatic cell growth. IgF-1 is also an important regulator of cell metabolism, differentiation and survival. High levels of IgF-1 is related to increased prostate cancer risk (1,7,8).
Another connection between obesity and prostate cancer is leptin. Leptin is a protein produced by the ob gene, which regulates appetite and energy expenditure. The regulation of appetite and energy expenditure allows leptin to control body weight homeostasis. Obese patients show significantly higher leptin levels than patients who maintain healthy weight. Intermediate leptin levels have been shown to stimulate prostate growth and angiogenesis (9).
Testosterone is another hormone known to promote prostate cancer. Androgens have been associated with the pathogenesis of prostate cancer, and circulating hormone levels have been suggested as having an effect on prostate cancer risk (10). In the past, the primary treatment for prostate cancer was orchectomy, surgical excision of a testis or of both testes, in order to decrease testosterone in the body. Once an orchectomy has taken place, testosterone levels decrease and prostate cancer can regress. Previous studies have shown that men with total serum testosterone in the highest quartile of the population are 2.34 times more likely to develop prostate cancer (10,11). The same studies tested the effect of dihydrotestosterone (DHT) and estradiol serum levels. Neither hormone showed significant effects on the risk of prostate cancer. We measured serum levels of all of these hormones (IgF-1, leptin, and testosterone) to determine the effect of isoflavones and Se.
The primary purpose of this study is to determine how Se and isoflavones interact in reducing the risk of prostate cancer. To determine this, we divided 35-42 day old male and female Noble rats into 6 groups. Each group was fed a different stock diet. The diets provided 10, 200, or 600 ppm isoflavones. In addition, half the animals received diets that were supplemented with 0.33-0.37 ppm Se, or 3.0 ppm Se in a 3×2 factorial design. After 30 days males and females were bred. Females continued consuming their respective diets and their pups were weaned to the same diets. Male pups in each dietary group were sacrificed at 35 (pre-pubertal), 100 (early adulthood), or 200 (mature) days of age. Breeders were sacrificed at 321-330 days. Final body weights and total body fat were measured on day of sacrifice. ELISA kits were used to measure hormone (testosterone, estradiol, IgF-1, and leptin) serum levels.
Consistent with previous studies, a high phytoestrogen intake in this work significantly decreased body fat and body weight in male pups, independent of Se intake (8). However, the same effect was not seen in male breeders whose exposure to the diet began after puberty. This suggests that the timing and duration of exposure to isoflavones determine their effect on body weight and composition (see Figure 1). Our studies are consistent with previous observation by Klein (30), which suggested that early exposure to isoflavones have effects on various body systems.
Body fat (adipose tissue) correlates with leptin concentration, and leptin circulates at levels proportional to adipose tissue. High leptin concentration is associated with increased prostate cancer cell growth (37). High isoflavone intake was associated with lower leptin levels in the 200 day old pups and the female breeders. Both 35 day old pups and 100 day old pups showed significantly lower leptin levels with high Se intake. It is likely that both isoflavones and Se can lower leptin levels, however more research is needed. Previous studies have shown that high isoflavone intake can lower serum leptin concentrations (8). Our research is consistent with these previous findings. High isoflavone intake may decrease prostate cancer risk by decreasing body fat and serum leptin levels, which are associated with increased prostate cancer risk.
Increased IgF-1 concentrations have also been correlated with increased prostate cancer cell growth (7). Although high Se and high isoflavone intake showed a significant effect in decreasing IgF-1 concentration, the effect of Se was seen throughout four of the age groups, whereas the effect of isoflavone was only present in the 35 and 100 day pups. The combination of high isoflavone and high dietary Se intake had a significant effect in both 100 and 200 days (see Figure 2). The combination of high isoflavone and high Se intake resulted in lower IgF-1 serum concentration levels.
In male pups, high phytoestrogen increased serum testosterone while high Se decreased it. Previous studies have concluded that high testosterone serum levels have a pronounced effect in increasing prostate cancer risk (10,11). Se’s protective effects against prostate cancer may be mediated in part by its effects on IgF-1 axis and testosterone.
In conclusion, time and length of exposure to isoflavones are critical for isoflavones to have an effect on body weight and body fat. Isoflavone’s protective effects against prostate cancer may be associated with it decreasing body weight, body fat, and leptin concentrations. Se may decrease prostate cancer risk by decreasing IgF-1 and testosterone concentrations. Isoflavone may enhance Se ability to decrease IgF-1 serum concentration and thus decreasing the risk of prostate cancer development.