Concern has been expressed that some phytoestrogens may disrupt the developing endocrine system similarly to the effects of other endogenous estrogens [264,265]. Much of this concern has stemmed from animal research. There are well-described examples of phytoestrogen-containing plants inhibiting fertility via estrogenic activity in animals. For instance, sheep grazing on Australian pastures containing a particular type of clover rich in formononetin, which is converted to daidzein in the rumen during fermentation, developed a widespread infertility in the 1940s [248, 266]. Other examples are the "moldy corn syndrome" in pigs and cattle fed corn contaminated by Fusarium sp., which produces the estrogenic b-resorcyclic acid lactone, zearalenone , and the inhibition of reproduction of California quail by phytoestrogens produced by plants growing in dry conditions . The use of soybean in captive cheetah in Cincinnati zoo was also shown to be responsible for an infertility syndrome, reversed by its removal from the feed . The phytoestrogen, coumestrol, which is ~30 times more effective than genistein in mice, is known to cause estrogen-related disorders in animals which seem to have a cumulative effect. Whitten et al.  demonstrated the effect of phytoestrogens on the sexual differentiation of gonadotropin function by examining neonatal exposure of pups through milk of rat dams fed coumestrol (100 |ig-g-1) during the critical period of the first 10 postnatal days or throughout the 21 days of lactation. In females, exposure to coumestrol throughout the period of lactation produced growth suppression and an acyclic condition in early adulthood resembling the premature anovulatory syndrome.When the period of treatment was restricted to the first 10 postnatal days, however, no effects on vaginal cyclicity were seen. The 10-day exposure period produced more marked effects in males, resulting in transitory reductions in body weight in weaning males and reductions in mount and ejaculation frequency and prolongation of the latencies to mount and ejaculate. Testicular weights and plasma testosterone levels did not differ among treatment groups suggesting that the deficits in male sexual behavior were not due to deficits in adult gonadal function. These data provide evidence that lactational exposure to phytoestrogen diets can alter neuroendocrine development in both female and male rats. In addition, feeding flaxseed, the richest source of the mammalian lignan precursor secoisolariciresinol digly-coside, to rats during a hormone-sensitive period has demonstrated reproductive effects . The female offspring had shortened anogenital distance, greater uterine and ovarian relative weights, earlier age and lighter body weight at puberty, lengthened estrous cycle, and persistent estrus, whereas the males had reduced postnatal weight gain and greater sex gland and prostate relative weights, suggesting estrogenic effects. These examples in animals suggest that the phytoestrogen content of soy products and other dietary products may induce unintended adverse effects on reproduction and development in humans. A general argument can be made that the long history of apparent safe use of soy argues that it is not toxic. To date, there are no long-term studies in humans in which a possible association between soy exposure and toxicity has been systematically and rigorously explored. Given the prevalence of soy exposure and the possible health benefits, it is appropriate to include adverse effects in any future large-scale, long-term epidemiological studies. Because reproductive and developmental toxicity have been demonstrated in animals and humans with a wide variety of estrogens, and phytoestrogen exposure has been shown to induce reproductive and developmental toxicity in experimental animals and livestock, these endpoints should receive particular attention.
Despite the hypothesized beneficial effects of phytoestrogens in human cancer, two reports suggest that caution may be necessary at this stage. In one study, 29 women took 60 g soybean (containing 45 mg isoflavones) for 14 days and demonstrated a significant increase in the proliferation rate of breast lobular epithelium . In an earlier study, Petrakis et al.  evaluated the influence of the long-term ingestion of commercial soy protein isolate on breast secretory activity. It was hypothesized that the features of nipple aspirate fluid (NAF) of non-Asian women would be altered so as to resemble those previously found in Asian women. Both pre- and post-menopausal white women ingested 38 g of soy protein isolate containing 38 mg of genistein daily. Unfortunately, the findings did not support their hypothesis. Compared to baseline values, a 2- to 6-fold increase in NAF volume ensued during ingestion of soy protein isolate in all premenopausal women. This 6-months pilot study indicates that prolonged consumption of soy protein isolate has a stimulatory effect on premenopausal female breast, characterized by increased secretion of breast fluid, the appearance of hyperplastic epithelial cells and elevated levels of plasma E2. Compared with white and African-American women, hyperplastic, atypical epithelial cells and apocrine metaplasia were less frequently found in NAF from Chinese and Japanese women [63,272-275].
Safety concerns regarding soy-based formulas have been raised despite no apparent deleterious effects. Unfortunately, there is very little known in regard to the toxicity of estrogens in human infants. Longer-term studies to assess the potential benefits or adverse effects of phytoestrogen exposure early in life are needed. Soy formula feedings in early life have been associated with the devel opment of auto-immune thyroid disorders . The soybean and its products have been considered goitrogenic in humans and animals. Goiter and hypothyroidism were reported in infants receiving soy-containing formula [277-279] although iodine supplementation of the formula has reversed this problem . Several investigators have reported induction of goiter in iodine-deficient rats maintained on a soybean diet [281-284]. Furthermore, Kimura et al.  reported the induction of thyroid carcinoma in rats fed an iodine-deficient diet containing 40 % defatted soybean diet. Genistein and daidzein were found to inhibit the thyroid peroxidase-catalyzed iodination of tyrosine at concentrations that approach the total isoflavone levels previously measured in plasma from humans consuming soy products . Because inhibition of thyroid hormone synthesis can induce goiter and thyroid neoplasia in rodents, delineation of anti-thyroid mechanisms for soy isoflavones may be important for extrapolating goitrogenic hazards identified in chronic rodent bioassays to humans consuming soy products. It is difficult for humans to consume the amounts of isoflavones from natural soy foods to reach the toxicological levels that induce pathological effects recorded in animals. However, a trend towards isoflavone supplements (e.g., in pill form) will facilitate patient intake and the potential dangerous effects of mega-dosing are a concern. Careful studies of the soy infant formula-exposed population should be undertaken, as it is a well-identified group and phytoestrogen doses can be estimated with some accuracy. Such studies should include not only infants currently consuming soy infant formulas, but older children, adolescents and adults previously exposed. They should incorporate estrogenic and thyroid hormone related endpoints, as well as a wide variety of other endpoints of toxicity.
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