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    <head><title>Natural Estrogens</title></head>
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        <h1>
            Natural Estrogens
        </h1>

        <p>
            The fact that an extremely large number of naturally occurring compounds, and an unlimited number of
            synthetic compounds, have an estrogen-like activity has been exploited by the drug companies to produce
            patented proprietary drugs, especially the contraceptives.
        </p>
        <p>
            The promotion of "natural estrogens" is a new marketing strategy that capitalizes on the immense promotional
            investment of the drug companies in the concept of estrogen replacement as "therapy."
        </p>
        <p>
            <hr />
        </p>
        <p>
            <strong>"Whether weak or strong, the estrogenic response of a chemical, if not overcome, will add extra
                estrogenic burden to the system. At elevated doses, natural estrogens and environmental estrogen-like
                chemicals are known to produce adverse effects. The source of extra or elevated concentration of
                estrogen could be either endogenous or exogenous.</strong> The potential of exposure for humans and
            animals to environmental estrogen-like chemicals is high."
        </p>

        <p>D. Roy, et al., 1997</p>
        <p>
            <hr />
            <hr />
        </p>
        <p>
            Estrogen marketing has entered a new phase, based on the idea of "specific estrogen-receptor modulators,"
            the idea that a molecule can be designed which has estrogen's "good qualities without its bad qualities."
            This specific molecule will be "good for the bones, the heart, and the brain," without causing cancer of the
            breast and uterus, according to the estrogen industry. Meanwhile, soybeans are said to contain estrogens
            that meet that goal, and it is often said that "natural estrogens" are better than "synthetic estrogens"
            because they are "balanced."
        </p>
        <p>
            Estrogen's effects on cells are immediate and profound, independent of the "estrogen receptors."
        </p>

        <p>
            Japanese women's relative freedom from breast cancer is independent of soy products<strong>:</strong>
            traditional soy foods aren't the same as those so widely used in the US, for example, soy sauce doesn't
            contain the so-called soy estrogens, and tea is used much more commonly in Japan than in the US, and
            contains health protective ingredients. The "estrogenic" and "antioxidant" polyphenolic compounds of tea are
            not the protective agents (they raise the level of estrogen), but tea's <em>caffeine</em> is a very powerful
            and general anti-cancer protectant. The influential article in <em>
                Lancet</em> (D. Ingram, <em>Lancet</em> 1997;<em>350</em>:990-994. "Phytoestrogens and their role in
            breast cancer,"<em>
                Breast NEWS: Newsletter of the NHMRC National Breast Cancer Centre, Vol. 3,</em> No. 2, Winter 1997)
            used a method known to produce false results, namely, comparing the phytoestrogens (found in large amounts
            in soybeans) in the urine of women with or without breast cancer. For over fifty years, it has been known
            that the liver excretes estrogens and other toxins from the body, and that when (because of liver inertia)
            estrogen isn't excreted by the liver and kidneys, it is retained in the body. This process was observed in
            both animals and humans decades ago, and it is <em>also well established that estrogen itself suppresses the
                detoxifying systems, causing fewer carcinogens to be excreted</em> in the urine. Ingram's evidence
            logically would suggest that the women who have cancer are failing to eliminate estrogens, including
            phytoestrogens, at a normal rate, and so are retaining a higher percentage of the chemicals consumed in
            their diets. Flavonoids and polyphenols, like our own estrogens, suppress the detoxifying systems of the
            body.
        </p>

        <p>
            Our bodies produce estrogen in a great variety of tissues, not just in the ovaries. Fat cells are a major
            source of it. The tendency to gain weight after puberty is one of the reasons that women's estrogen levels
            rise with aging throughout the reproductive years, though this isn't the basic reason for estrogen's
            lifelong growing influence, even in men.
        </p>
        <p>
            Our diets provide very significant, if not always dangerous, amounts of estrogen. "Weak estrogens" generally
            have the full range of harmful estrogenic effects, and often have additional toxic effects. American women
            who eat soy products undergo changes that appear to predispose them to cancer, making their tissues even
            more unlike those of the relatively breast-cancer resistant Japanese than they were before eating the soy
            foods.
        </p>
        <p>
            People under stress, or who have a thyroid deficiency, or who don't eat enough protein, typically have
            elevated estrogen levels. The accumulation of the "essential fatty acids," the polyunsaturated oils, in the
            tissues promotes the action of estrogen in a variety of ways, and this effect of diet tends to be
            cumulative, and to be self-accelerating.
        </p>

        <p>
            Science is a method that helps us to avoid believing things that are wrong, but there is a distinct herd
            instinct among people who "work in science," which makes it easy to believe whatever sounds plausible, if a
            lot of other people are saying it is true. This is just as evident in physics as it is in medicine.
            Sometimes powerful economic interests help people to change their beliefs, for example as the insurance
            industry helped to convince the public of the dangers of smoking. Two of the biggest industries in the
            world, the estrogen industry and the soy bean industry, spend vast amounts of money helping people to
            believe certain plausible-sounding things that help them sell their products. Sometimes they can achieve
            great things just by naming the substance.
        </p>
        <p>
            Estrogenicity can be defined most simply as "acting the way estrogen does," (originally, the term "estrogen"
            meant "producing estrus," the female readiness to mate) and since our natural estrogen does many things, the
            definition is often, for practicality, based on the rapid changes produced in certain female organs by
            estradiol, specifically, the enlargement of the uterus by first taking up a large amount of water, and
            secondarily by the multiplication of cells and the production of specific proteins. A similar process
            occurring in the breast is also recognized as an important feature of the estrogen reaction, but as we try
            to define just what "estrogenicity" is, we see that there is something deeply wrong with this method of
            defining a hormone, because we are constantly learning more about the actions of estrogen, or of a specific
            form of the molecule. Calling it "the female hormone" distracted attention from its many functions in the
            male, and led to great confusion about its antifertility actions and its other toxicities. Many biologists
            called it "folliculin," because of the ovarian follicle's significant role in its production, but the
            pharmaceutical industry succeeded in naming it in relation to <strong><em>
                    one</em></strong> of its functions, and then in extending that idea of it as "the producer of female
            receptivity" to the even more misleading idea that it is "the female hormone." But when people speak about
            the "estrogenicity" of a substance, they mean that it has properties that parallel those of "folliculin,"
            the particular group of ovarian hormones that includes estradiol, estrone, and estriol.
        </p>
        <p>
            Over the last 100 years, thousands of publications about estrogen's toxicity have created a slight
            resistance to the consumption of the major estrogen products. One ploy to overcoming this resistance is to
            call certain products "natural estrogen," as distinguished from "synthetic estrogens." The <strong
            >three</strong>
            <strong>main estrogens in our bodies are estradiol, estrone, and estriol, though there are many other minor
                variants on the basic molecule.</strong> These three estrogens, singly or in combinations, are being
            sold as natural estrogens, with their virtues explained in various ways. Implicit in many of these
            explanations, is the idea that these are safer than synthetics. They are sometimes contrasted to the "horse
            estrogen" in Premarin, as if they are better because they are like the estrogens that people produce. But it
            was exactly the normal human estrogens, produced by the ovaries, that led to the basic discoveries about the
            toxicity of estrogen, its ability to produce cancer in any organ, to cause seizures, blood clots, birth
            defects, accelerated aging, etc.
        </p>

        <p>
            Although I would suppose that a hormone from a horse might be "more natural" for a person's body than a
            hormone from a plant, the word "natural" as used in the phrases "natural food store," or "natural medicine,"
            has come to be associated strongly with things derived from plants. The health food industry, now largely
            taken over by giant corporations to sell products that weren't producing as much revenue when sold in
            supermarkets and drugstores, has helped to create a culture in which botanical products are thought to be
            especially good and safe. Naturally grown free-range chickens used to be favored, because they could eat
            anything they wanted, but now eggs laid by factory chickens, eating an industrial corn-and-soy diet, are
            from "vegetarian chickens," because the marketers know the public will favor eggs that have the vegetarian
            mystique.
        </p>
        <p>
            Biologically active molecules have both general and specific properties. Estrogenicity is a general
            property, but all molecules which have that property also have some other specific properties. Estriol is a
            little more water soluble than estrone, so it interacts with every body system in a slightly different way,
            entering oily environments with slightly less ease, etc.
        </p>
        <p>
            The estrogen which occurs in yeasts, estradiol, is identical to the major human estrogen, and it is thought
            to have a reproductive function in yeasts, though this isn't really understood. A feature of this molecule,
            and of all other molecules that "act like estrogen," is the phenolic function, an oxygen and hydrogen group
            attached to a resonant benzene ring. Phenol itself is estrogenic, and the phenolic group is so extremely
            common in nature that the number of existing estrogenic substances is great, and the number of potential
            molecules with estrogen-function is practically infinite.
        </p>
        <p>
            The phenolic group has many biological functions. For example, it commonly functions as an "antioxidant,"
            though something which functions as an antioxidant in one situation is often a pro-oxidant in another
            situation. The molecule can have catalytic, germicidal, aromatic, neurotropic, and other functions. But it
            also always has, to some degree, the "estrogenic" function. This overlap of functions probably accounts for
            why so many plants have significant estrogenic activity. (Natural estrogens, like other phenolics, including
            the flavonoids, are also mutagenic.)
        </p>

        <p>
            The estrogenic properties of legumes were studied when sheep farmers found that their sheep miscarried when
            they ate clover. (I think it's interesting how this terribly toxic effect has been neglected in recent
            decades.) All legumes have this property, and all parts of the plant seem to contain some of the active
            chemicals. In beans, several substances have been found to contribute to the effect. The estrogenic effects
            of the seed oils and the isoflavones have been studied the most, but the well-known antithyroid actions
            (again, involving the oils, the isoflavones, and other molecules found in legumes) have an indirect
            estrogen-promoting action, since hypothyroidism leads to hyperestrogenism. (Estrogens are known to be
            thyroid suppressors, so the problem tends to be self-accelerating.)
        </p>
        <p>
            The various specific actions of the many estrogenic substances in beans and other legumes haven't been
            throughly studied, but there is evidence that they are also--like estrogen itself--both mutagenic and
            carcinogenic.
        </p>
        <p>
            The estrogen-promoting actions of soy oil apply to <strong>all of the commonly used polyunsaturated fatty
                acids. The same fatty acids that suppress thyroid function, have estrogenic effects.</strong>
        </p>

        <p>
            The isoflavones (many of which are now being promoted as "antioxidants" and "cancer preventives") are toxic
            to many organs, but they have clear estrogenic effects, and are active not only immediately in the mature
            individual, but when they are present prenatally, they cause feminization of the male genitalia and
            behavior, and early maturation of the female offspring, with the tissue changes that are known to be
            associated with increased incidence of cancer.
        </p>
        <p>
            There are interesting associations between vegetable "fiber" and estrogens. Because of my own experience in
            finding that eating a raw carrot daily prevented my migraines, I began to suspect that the carrot fiber was
            having both a bowel-protective and an antiestrogen effect. Several women who suffered from premenstrual
            symptoms, including migraine, had their serum estrogen measured before and after the "carrot diet," and they
            found that the carrot lowered their estrogen within a few days, as it relieved their symptoms.
        </p>
        <p>
            Undigestible fiber, if it isn't broken down by bowel bacteria, increases fecal bulk, and tends to speed the
            transit of material through the intestine, just as laxatives do. But some of these "fiber" materials, e.g.,
            lignin, are themselves estrogenic, and other fibers, by promoting bacterial growth, can promote the
            conversion of harmless substances into toxins and carcinogens. When there is a clear "antiestrogen" effect
            from dietary fiber, it seems to be the result of accelerated transit through the intestine, speeding
            elimination and preventing reabsorption of the estrogen which has been excreted in the bile. Laxatives have
            this same effect on the excretion of estradiol.
        </p>
        <p>
            Some of the isoflavones, lignins, and other phytoestrogens are said to prevent bowel cancer, but some of
            them, e.g., lignin, appear to sometimes increase its likelihood.
        </p>

        <p>
            The phytoestrogens appear to pose a risk to organs besides the breast and uterus, for example the liver,
            colon, and pancreas, which isn't surprising, since estrogen is known to be carcinogenic for every tissue.
            And carcinogenesis, like precancerous changes, mutations, and reduced repair of DNA, is probably just an
            incidental process in the more general toxic effect of acceleration of aging.
        </p>
        <p><strong><h3>REFERENCES &amp; ABSTRACTS</h3></strong></p>
        <p>
            <strong>"Stimulatory influence of soy protein isolate on breast secretion in pre- and postmenopausal
                women,"</strong> Petrakis NL; Barnes S; King EB; Lowenstein J; Wiencke J; Lee MM; Miike R; Kirk M;
            Coward L Department of Epidemiology and Biostatistics, University of California, San Francisco 94143-0560,
            USA. Cancer Epidemiol Biomarkers Prev, 1996 Oct, 5:10, 785-94 "Soy foods have been reported to have
            protective effects against premenopausal breast cancer in Asian women. No studies have been reported on
            potential physiological effects of dietary soy consumption on breast gland function. We evaluated the
            influence of the long-term ingestion of a commercial soy protein isolate on breast secretory activity. We
            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. At monthly intervals for 1 year, 24 normal pre- and
            postmenopausal white women, ages 30 to 58, underwent nipple aspiration of breast fluid and gave blood and
            24-h urine samples for biochemical studies. No soy was administered in months 1-3 and 10-12. Between months
            4-9 the women ingested daily 38 g of soy protein isolate containing 38 mg of genistein. NAF volume, <strong
            >gross cystic disease fluid protein (GCDFP-15) concentration</strong>, and NAF cytology were used as
            biomarkers of possible effects of soy protein isolate on the breast. In addition, plasma concentrations of
            estradiol, progesterone, sex hormone binding globulin, prolactin, cholesterol, high density
            lipoprotein-cholesterol, and triglycerides were measured. Compliance was assessed by measurements of
            genistein and daidzein and their metabolites in 24-h urine samples. Excellent compliance with the study
            protocol was obtained. Compared with NAF volumes obtained in months 1-3, <strong>a 2-6-fold increase in NAF
                volume ensued during months 4-9 in all premenopausal women.</strong> A minimal increase or no response
            was found in postmenopausal women. No changes were found in plasma prolactin, sex hormone binding globulin,
            cholesterol, high density lipoprotein cholesterol, and triglyceride concentrations. Compared with
            concentrations found in months 1-3 (no soy), <strong>plasma estradiol concentrations were elevated
                erratically throughout
            </strong>

            a "composite" menstrual cycle during the months of soy consumption. No significant changes were seen in
            plasma progesterone concentrations. No significant changes were found in plasma estrogen levels in
            postmenopausal women. A moderate decrease occurred in the mean concentration of GCDFP-15 in NAF in
            premenopausal women<u> during the months of soy ingestion. </u>
            <strong><u>Of potential concern was the cytological detection of epithelial hyperplasia in 7 of 24 women
                    (29.2%) during the months they were consuming soy protein isolate. The findings did not support our
                    a priori hypothesis. Instead, this pilot study indicates that prolonged consumption of soy protein
                    isolate has a stimulatory effect on the premenopausal female breast, characterized by increased
                    secretion of breast fluid, the appearance of hyperplastic epithelial cells,</u> and elevated levels
                of plasma estradiol.
            </strong>These findings are suggestive of an estrogenic stimulus from the isoflavones genistein and daidzein
            contained in soy protein isolate.
        </p>
        <p>
            J Clin Endocrinol Metab 1995 May;80(5):1685-1690 <strong>Dietary intervention study to assess estrogenicity
                of dietary soy among postmenopausal women.</strong> Baird DD, Umbach DM, Lansdell L, Hughes CL, Setchell
            KD, Weinberg CR, Haney AF, Wilcox AJ, Mclachlan JA. National Institute of Environmental Health Sciences,
            Research Triangle Park, North Carolina 27709, USA. We tested the hypothesis that postmenopausal women on a
            soy-supplemented diet show estrogenic responses. Ninety-seven postmenopausal women were randomized to either
            a group <strong>that was provided with soy foods for 4 weeks or a control group that was instructed to eat
                as usual.</strong> Changes in urinary isoflavone concentrations served as a measure of compliance and
            phytoestrogen dose. Changes in serum FSH, LH, sex hormone binding globulin, and vaginal cytology were
            measured to assess estrogenic response. <strong>The percentage of vaginal superficial cells (indicative of
                estrogenicity) increased for 19% of those eating the diet compared with 8% of controls</strong>
            <hr />
        </p>

        <p>
            Oncol Rep 1998 May-Jun;5(3):609-16 <strong>
                "Maternal genistein exposure mimics the effects of estrogen on mammary gland development in female mouse
                offspring."</strong> Hilakivi-Clarke L, Cho E, Clarke R Lombardi Cancer Center, Research Bldg., Room
            W405, Georgetown University, 3970 Reservoir Road, NW, Washington, DC, 20007-2197, USA. <strong>Human and
                animal data indicate that a high maternal estrogen exposure during pregnancy increases breast cancer
                risk among daughters. This may reflect an increase in the epithelial structures</strong> that are the
            sites for malignant transformation, i.e., terminal end buds (TEBs), and a reduction in epithelial
            differentiation in the mammary gland. Some <strong>phytoestrogens, such as genistein which is a major
                component in soy-based foods, and zearalenone, a mycotoxin found in agricultural products, have
                estrogenic effects on the reproductive system, breast and brain.
            </strong>The present study examined whether in utero exposure to genistein or zearalenone influences mammary
            gland development. Pregnant mice were injected daily with i) 20 ng estradiol (E2); ii) 20 microg genistein;
            iii) 2 microg zearalenone; iv) 2 microg tamoxifen (TAM), a partial estrogen receptor agonist; or v)
            oil-vehicle between days 15 and 20 of gestation. E2, <strong>genistein, zearalenone, and tamoxifen all
                increased the density of TEBs in the mammary glands. Genistein reduced, and zearalenone increased,
                epithelial differentiation.</strong> Zearalenone also increased epithelial density, when compared with
            the vehicle-controls. None of the treatments had permanent effects on circulating E2 levels. <strong>
                Maternal exposure to E2 accelerated body weight gain, physical maturation (eyelid opening), and puberty
                onset (vaginal opening) in the female offspring. Genistein and tamoxifen had similar effects on puberty
                onset than E2.</strong> Zearalenone caused persistent cornification of the estrus smears. These findings
            indicate that <strong>maternal exposure to physiological doses of genistein mimics the effects of E2 on the
                mammary gland and reproductive systems in the offspring. Thus, our results suggest that genistein acts
                as an estrogen in utero, and may increase the incidence of mammary tumors if given through a pregnant
                mother.
            </strong>

            The estrogenic effects of zearalenone on the mammary gland, in contrast, are probably counteracted by the
            permanent changes in estrus cycling.
        </p>
        <p>
            <strong>[The effects on the thyroid gland of soybeans administered experimentally in healthy
                subjects]</strong>
            Ishizuki Y; Hirooka Y; Murata Y; Togashi K Nippon Naibunpi Gakkai Zasshi, 1991 May 20, 67:5, 622-9 To
            elucidate whether soybeans would suppress the thyroid function in healthy adults, we selected 37 subjects
            who had never had goiters or serum antithyroid antibodies. They were given 30g of soybeans everyday and were
            divided into 3 groups subject to age and duration of soybean administration. In group 1, 20 subjects were
            given soybeans for 1 month. Groups 2 and 3 were composed of 7 younger subjects (mean 29 y.o.) and 10 elder
            subjects (mean 61 y.o.) respectively, and the subjects belonging to these groups received soybeans for 3
            months. The Wilcoxon-test and t-test were used in the statistical analyses. In all groups, the various
            parameters of serum thyroid hormones remained unchanged by taking soybeans, however TSH levels rose
            significantly although they stayed within normal ranges. The TSH response after TRH stimulation in group 3
            revealed a more significant increase than that in group 2, although inorganic iodide levels were lowered
            during the administration of the soybeans. We have not obtained any significant correlation between serum
            inorganic iodide and TSH. Hypometabolic symptoms (malaise, constipation, sleepiness) and goiters appeared in
            half the subjects in groups 2 and 3 after taking soybeans for 3 months, but they disappeared 1 month after
            the cessation of soybean ingestion. These findings suggested that excessive soybean ingestion for a certain
            duration might suppress thyroid function and cause goiters in healthy people, especially elderly subjects.
        </p>
        <p>
            Exp Clin Endocrinol Diabetes 1996;104 Suppl 4:41-5 <strong>Iodolactones and iodoaldehydes--mediators of
                iodine in thyroid autoregulation.</strong> Dugrillon A Central Clinical Laboratory, University of
            Heidelberg, Germany. "Within the last decades multiple iodolipid-classes have been identified in thyroid
            tissue. For a long time they have been supposed to be involved in thyroid autoregulation, but for the time
            being no specific compounds could be isolated. A new approach was stimulated by the finding that <strong
            >thyroid cells were able to iodinate polyunsaturated fatty acids</strong> to form iodolactones and by the
            identification of alpha-iodohexadecanal (alpha-IHDA) as the major compound of an iodolipid fraction."
        </p>

        <p>
            <strong>Plasma free fatty acids, inhibitor of extrathyroidal conversion of T4 to T3 and thyroid hormone
                binding inhibitor in patients with various nonthyroidal illnesses.</strong>
            Suzuki Y; Nanno M; Gemma R; Yoshimi T Endocrinol Jpn, 1992 Oct, 39:5, 445-53.
        </p>
        <p>
            <strong>[Endemic goiter in Austria. Is iodine deficiency the primary cause of goiter?]</strong>
            Grubeck-Loebenstein B; Kletter K; Kiss A; Vierhapper H; Waldh"usl W Schweiz Med Wochenschr, 1982 Oct 30,
            112:44, 1526-30 <strong>
                In spite of government-regulated iodide admixture to table salt, the incidence of goiter is still high
                in Austria.</strong>
            Iodine excretion and thyroid function were therefore investigated in 80 patients suffering from ordinary
            goiter in whom thyroid size and resulting symptoms had increased lately. 25 euthyroid non-goitrous subjects
            served as controls. 48% of the goitrous patients investigated presented with iodine excretion of less than
            70 micrograms/24 h, suggesting an insufficient iodine supply. Thyroid I131 uptake, basal and TRH-stimulated
            plasma TSH concentrations, and serum T3 levels were higher, whereas serum T4 levels were lower in these
            patients than in goitrous patients with higher iodine excretion and non-goitrous controls. Iodine deficiency
            thus appears to be of pathogenetic relevance in about half of the goitrous Austrian population. <strong
            >Other factors enhancing goiter development seem to assume particular importance in goitrous patients with a
                sufficient iodine supply.</strong>
        </p>
        <p>
            <strong>Biochemical and molecular changes at the cellular level in response to exposure to environmental
                estrogen-like chemicals.</strong> Roy D; Palangat M; Chen CW; Thomas RD; Colerangle J; Atkinson A; Yan
            ZJ Environmental Toxicology Program, University of Alabama, Birmingham 35294, USA. J Toxicol Environ Health,
            1997 Jan, 50:1, 1-29. Estrogen-like chemicals are unique compared to nonestrogenic xenobiotics, because in
            addition to their chemical properties, the estrogenic property of these compounds allows them to act like
            sex hormones. <strong>
                Whether weak or strong, the estrogenic response of a chemical, if not overcome, will add extra
                estrogenic burden to the system. At elevated doses, natural estrogens and environmental estrogen-like
                chemicals are known to produce adverse effects. The source of extra or elevated concentration of
                estrogen could be either endogenous or exogenous.</strong> The potential of exposure for humans and
            animals to environmental estrogen-like chemicals is high. Only a limited number of estrogen-like compounds,
            such as diethylstilbestrol (DES), bisphenol A, nonylphenol, polychlorinated biphenyls (PCBs), and
            dichlorodiphenyltrichloroethane (DDT), have been used to assess the biochemical and molecular changes at the
            cellular level. Among them, DES is the most extensively studied estrogen-like chemical, and therefore this
            article is focused mainly on DES-related observations. In addition to estrogenic effects, environmental
            estrogen-like chemicals <strong>produce multiple and multitype genetic and/or nongenetic hits.</strong>
            Exposure of Syrian hamsters to stilbene estrogen (DES) produces several changes in the nuclei of target
            organ for carcinogenesis (kidney): (1) Products of nuclear redox reactions of DES modify transcription
            regulating proteins and DNA; (2) transcription is inhibited; (3) tyrosine phosphorylation of nuclear
            proteins, including RNA polymerase II, p53, and nuclear insulin-like growth factor-1 receptor, is altered;
            and (4<strong>) DNA repair gene DNA polymerase beta transcripts are decreased and mutated.</strong> Exposure
            of Noble rats to DES also produces several changes in the mammary gland: proliferative activity is
            drastically altered; the cell cycle of mammary epithelial cells is perturbed; telomeric length is
            attenuated; etc. It appears that some other estrogenic compounds, such as bisphenol A and nonylphenol, may
            also follow a similar pattern of effects to DES, because we have recently shown that these compounds <strong
            >alter cell cycle kinetics, produce telomeric associations, and produce chromosomal aberrations.
            </strong>

            Like DES, bisphenol A after metabolic activation is capable of binding to DNA. However, it should be noted
            that a particular or multitype hit(s) will depend upon the nature of the environmental estrogen-like
            chemical. The role of individual attack leading to a particular change is not clear at this stage.
            Consequences of these multitypes of attack on the nuclei of cells could be (1) nuclear toxicity/cell death;
            (2) repair of all the hits and then acting as normal cells; or (3) sustaining most of the hits and acting as
            unstable cells. Proliferation of the last type of cell is expected to result in transformed cells.
        </p>
        <p>
            <strong>Potential adverse effects of phytoestrogens.</strong> Whitten PL; Lewis C; Russell E; Naftolin F
            Department of Anthropology, Emory University, Atlanta, GA 30322. J Nutr, 1995 Mar, 125:3 Suppl, 771S-776S
            Evaluation of the potential benefits and risks offered by naturally occurring plant estrogens requires
            investigation of their potency and sites of action when consumed at natural dietary concentrations. Our
            investigations have examined the effects of a range of natural dietary concentrations of the most potent
            plant isoflavonoid, coumestrol, using a rat model and a variety of estrogen-dependent tissues and endpoints.
            Treatments of immature<strong>
                females demonstrated agonistic action in the reproductive tract, brain, and pituitary at natural dietary
                concentrations. Experiments designed to test for estrogen antagonism demonstrated that coumestrol did
                not conform to the picture of a classic antiestrogen.
            </strong>
            However, coumestrol did suppress estrous cycles in adult females. Developmental actions were examined by
            neonatal exposure of pups through milk of rat dams fed a coumestrol, control, or commercial soy-based diet
            during the critical period of the first 10 postnatal days or throughout the 21 days of lactation. The 10-day
            treatment did not significantly alter adult estrous cyclicity, but the 21-day treatment produced in a
            <strong>persistent estrus state in coumestrol-treated females by 132 days of age.</strong> In contrast, the
            10-day coumestrol treatments produced <strong>significant deficits in the sexual behavior of male
                offspring.</strong> These findings illustrate the broad range of actions of these natural estrogens and
            the variability in potency across endpoints. This variability argues for the importance of fully
            characterizing each phytoestrogen in terms of its sites of action, balance of agonistic and antagonistic
            properties, natural potency, and short-term and long-term effects.
        </p>

        <p>
            Am J Obstet Gynecol 1987 Aug;157(2):312-317 <strong>
                Age-related changes in the female hormonal environment during reproductive life.</strong> Musey VC,
            Collins DC, Musey PI, Martino-Saltzman D, Preedy JR. Previous studies have indicated that serum levels of
            follicle-stimulating hormone rise with age during the female reproductive life, but the effect on other
            hormones is not clear. We studied the effects of age, independent of pregnancy, by comparing serum hormone
            levels in two groups of nulliparous,<strong>
                premenopausal women aged 18 to 23 and 29 to 40 years. We found that increased age during reproductive
                life is accompanied by a significant rise in both basal and stimulated serum follicle-stimulating
                hormone levels. This was accompanied by an increase in the serum level of estradiol-17 beta and the
                urine levels of estradiol-17 beta and 17 beta-estradiol-17-glucosiduronate.</strong> The serum level of
            estrone sulfate decreased with age. Serum and urine levels of other estrogens were unchanged. The basal and
            stimulated levels of luteinizing hormone were also unchanged. There was a significant decrease in basal and
            stimulated serum prolactin levels. Serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate
            decreased with age, but serum testosterone was unchanged. It is concluded that significant age-related
            changes in the female hormonal environment occur during the reproductive years.
        </p>
        <p>
            Rodriguez, P; Fernandez-Galaz, C; Tejero, A. <strong>Controlled neonatal exposure to estrogens: A suitable
                tool for reproductive aging studies in the female rat.</strong>
            Biology of Reproduction, v.49, n.2, (1993): 387-392. The present study was designed to determine whether the
            modification of exposure time to large doses of estrogens provided a reliable model for early changes in
            reproductive aging. Silastic implants containing estradiol benzoate (EB) in solution were placed into
            5-day-old female Wistar rats and removed 1 day (Ei1 group) or 5 days (Ei5) later. In addition, 100 mu-g EB
            dissolved in 100 mu-l corn oil was administered s.c. to another group (EI). Control rats received either
            vehicle implants or 100 mu-l corn oil. Premature occurrence of vaginal opening was observed in all three
            estrogenized groups independently of EB exposure. However, females bearing implants for 24 h had first
            estrus at the same age as their controls and cycled regularly, and neither histological nor gonadal
            alterations could be observed at 75 days.. Interestingly, they failed to cycle regularly at 5 mo whereas
            controls continued to cycle. On the other hand, the increase of EB exposure (Ei5, EI) resulted in a gradual
            and significant delay in the onset of first estrus and in a high number of estrous phases, as frequently
            observed during reproductive decline. At 75 days, the ovaries of these last two groups showed a reduced
            number of corpora lutea and an increased number of large follicles. According to this histological pattern,
            ovarian weight and <strong>progesterone (P) content gradually decreased whereas both groups showed higher
                estradiol (E-2) content</strong> than controls. This resulted in <strong>a higher E-2:P ratio,
                comparable to that observed in normal aging rats.</strong> The results allow us to conclude that the
            exposure time to large doses of estrogens is critical to the gradual enhancement of reproductive decline.
            Furthermore, exposures as brief as 24 h led to a potential early model for aging studies that will be useful
            to verify whether neuroendocrine changes precede gonadal impairment.
        </p>

        <p>
            Cancer Lett 1992 Oct 30;67(1):55-59 <strong>
                Evidence of hypothalamic involvement in the mechanism of transplacental carcinogenesis by
                diethylstilbestrol.</strong> Smith DA, Walker BE Anatomy Department, Michigan State University, East
            Lansing 48824-1316. Disruption of hypothalamic sex differentiation in the fetus is one hypothesis to explain
            female reproductive system anomalies and cancer arising from prenatal exposure to diethylstilbestrol (DES).
            To further test this hypothesis, breeding performance and behavior were monitored in a colony of mice
            exposed prenatally to DES, using a schedule previously shown to produce anomalies and cancer of the female
            reproductive system. <strong>
                Fertility decreased with age more rapidly in DES-exposed females than in control females.</strong>
            DES-exposed females were less accepting of the male than control females. These observations support the
            hypothesis of abnormal hypothalamic sex differentiation as a basic mechanism in DES transplacental
            carcinogenesis.
        </p>
        <p>
            Int J Cancer 1980 Aug;26(2):241-6 <strong>
                The influence of the lipid composition of the feed given to mice on the immunocompetence and tumour
                resistance of the progeny.</strong>
            Boeryd B, Hallgren B. In inbred CBA mice, the immunocompetence of adult progeny from breeding pairs fed
            three different diets was compared.<strong>
                Substitution of soy oil for animal fat in the feed of the mice during gestation or lactation
                significantly decreased the PFC response to SRBC in the adult offspring.</strong> Addition of
            2-methoxy-substituted glycerol ethers to the feed of mothers deprived of animal fat during lactation partly
            restored the PFC response of the male offspring. In the adult mice fed differently pre- and perinatally the
            resistance to a transplanted syngeneic sarcoma was similar. The growth of offspring from mice fed the three
            diets was similar. In mice deprived of animal fat at weaning and for the following 21 days the immune
            reactivity to SRBC, tested about 3 months after stopping the diet, was not influenced. However, the
            resistance to a transplanted tumour in similarly fed mice was increased and this resistance was brought
            approximately to the control level by methoxy-substituted glycerol ethers.
        </p>

        <p>
            Cancer Res 1987 Mar 1;47(5):1333-8. <strong>
                Effects of dietary fats and soybean protein on azaserine-induced pancreatic carcinogenesis and plasma
                cholecystokinin in the rat.</strong> Roebuck BD, Kaplita PV, Edwards BR, Praissman M<strong>
                Both dietary unsaturated fat and raw soybean products are known to enhance pancreatic carcinogenesis
                when fed during the postinitiation phase. A comparison of these two dietary components was made
                to</strong> evaluate the relative potency of each ingredient for enhancing pancreatic carcinogenesis and
            to determine if this enhancement was correlated with an increase in plasma cholecystokinin (CCK) levels.
            Male Wistar rats were initiated with a single dose of azaserine (30 mg/kg body weight) at 14 days of age.
            The rats were weaned to test diets formulated from purified ingredients. Dietary protein at 20% by weight
            was either casein or soy protein isolate (heat treated or raw).. Corn oil was the unsaturated fat of major
            interest and it was fed at either 5 or 20% by weight. Pancreases were quantitatively evaluated for
            carcinogen-induced lesions at 2- and 4-month postinitiation. In a second experiment designed to closely
            mimic the above experiment, rats were implanted with cannulae which allowed plasma to be repetitively
            sampled over a 2.5-week period during which the test diets were fed. Plasma was collected both prior to
            introduction of the test diets and afterwards. Plasma CCK was measured by a specific radioimmunoassay. Both
            the 20% corn oil diet and the raw soy protein isolate diet enhanced pancreatic carcinogenesis. The effects
            of the raw soy protein isolate on the growth of the carcinogen-induced lesions were significantly greater
            than the effects of the 20% corn oil diet. Plasma CCK values were not elevated in the rats fed the 20% corn
            oil diet, but they were significantly elevated in the rats fed the raw soy protein isolate. Heat-treated soy
            protein isolate neither enhanced carcinogenesis nor elevated the plasma CCK level. This<strong>
                study demonstrates that certain plant proteins enhance the growth of carcinogen-induced pancreatic foci
                and that this effect is considerably greater than the enhancement by high levels of dietary unsaturated
                fat. Furthermore, the enhancement by the raw soy protein isolate may be mediated by CCK; but this does
                not appear to be the mechanism by which the unsaturated fat, corn oil, enhances pancreatic
                carcinogenesis.</strong>
        </p>
        <p>
            J Biol Chem 1988 Mar 15;263(8):3639-3645 <strong>
                Dynamic pattern of estradiol binding to uterine receptors of the rat.</strong>
            <strong>
                Inhibition and stimulation by unsaturated fatty acids.</strong> Vallette G, Christeff N, Bogard C,
            Benassayag C, Nunez E
        </p>
        <p>
            J Biol Chem 1986 Feb 25;261(6):2954-2959 <strong>
                Modifications of the properties of human sex steroid-binding protein by nonesterified fatty
                acids.</strong> Martin ME, Vranckx R, Benassayag C, Nunez EA The effect of unsaturated and saturated
            nonesterified fatty acids (NEFAs) on the electrophoretic, immunological, and steroid-binding properties of
            human sex hormone-binding protein (SBP) were investigated. Tests were carried out on whole serum from
            pregnant women and on purified SBP using polyacrylamide gel electrophoresis, crossed immunoelectrophoresis
            with autoradiography, and equilibrium dialysis. All three methods showed that NEFAs influence the binding of
            sex steroids to SBP both in whole serum and with the purified protein. Saturated NEFAs caused a 1.5-2-fold
            increase in binding of<strong>
                dehydrotestosterone, testosterone, and estradiol to SBP, while unsaturated NEFAs, such as oleic (18:1)
                and docosahexaenoic (22:6) acids inhibited the binding of these steroids to SBP. Thus, unsaturated
                NEFAs</strong> in the concentration range 1-100 microM are more inhibitory for estradiol binding than
            for testosterone or dehydrotestosterone binding. In addition to these binding changes, polyacrylamide gel
            electrophoresis and immunoelectrophoretic studies revealed a shift in SBP from the slow-moving active native
            form to a fast-moving inactive one. There was also a reduction in the apparent SBP concentration by Laurell
            immunoelectrophoresis in the presence of unsaturated NEFA (5.5 nmol of NEFA/pmol of protein). These studies
            indicate that unsaturated NEFAs induce conformational changes in human SBP which are reflected in its
            electrophoretic, immunological, and steroid-binding properties. They suggest that the fatty acid content of
            the SBP environment may result in lower steroid hormone binding and thus increased free hormone levels.
        </p>
        <p>
            J Biol Chem 1986 Feb 25;261(6):2954-2959 <strong>
                Modifications of the properties of human sex steroid-binding protein by nonesterified fatty
                acids.</strong> Martin ME, Vranckx R, Benassayag C, Nunez EA The effect of unsaturated and saturated
            nonesterified fatty acids (NEFAs) on the electrophoretic, immunological, and steroid-binding properties of
            human sex hormone-binding protein (SBP) were investigated. Tests were carried out on whole serum from
            pregnant women and on purified SBP using polyacrylamide gel electrophoresis, crossed immunoelectrophoresis
            with autoradiography, and equilibrium dialysis. All three methods showed that NEFAs influence the binding of
            sex steroids to SBP both in whole serum and with the purified protein. Saturated NEFAs caused a 1.5-2-fold
            increase in binding of<strong>
                dehydrotestosterone, testosterone, and estradiol to SBP, while unsaturated NEFAs, such as oleic (18:1)
                and docosahexaenoic (22:6) acids inhibited the binding of these steroids to SBP.
            </strong>

            Thus, unsaturated NEFAs in the concentration range 1-100 microM are more inhibitory for estradiol binding
            than for testosterone or dehydrotestosterone binding. In addition to these binding changes, polyacrylamide
            gel electrophoresis and immunoelectrophoretic studies revealed a shift in SBP from the slow-moving active
            native form to a fast-moving inactive one. There was also a reduction in the apparent SBP concentration by
            Laurell immunoelectrophoresis in the presence of unsaturated NEFA (5.5 nmol of NEFA/pmol of protein). These
            studies indicate that unsaturated NEFAs induce conformational changes in human SBP which are reflected in
            its electrophoretic, immunological, and steroid-binding properties. They suggest that the fatty acid content
            of the SBP environment may result in lower steroid hormone binding and <strong>
                thus increased free hormone levels.
            </strong>
        </p>
        <p>
            J Steroid Biochem 1986 Feb;24(2):657-659 <strong>
                Free fatty acids: a possible regulator of the available oestradiol fractions in plasma.</strong> Reed
            MJ, Beranek PA, Cheng RW, James VH Consumption of dietary fats has been linked to the high incidence of
            breast cancer found in Western women. In vitro studies we have carried out show that <strong>
                unsaturated free fatty acids can increase the biologically available oestradiol fractions in
                plasma.</strong> It is possible therefore that the increased risk for breast cancer associated with a
            diet high in fats may be related to an elevation in the biologically available oestradiol fractions in
            plasma.
        </p>
        <p>
            Endocrinology 1986 Jan;118(1):1-7 <strong>
                Potentiation of estradiol binding to human tissue proteins by unsaturated nonesterified fatty
                acids.</strong> Benassayag C, Vallette G, Hassid J, Raymond JP, Nunez EA Nonesterified fatty acids
            (NEFAs) have been recently shown in the rat to be involved in steroid hormone expression, having effects on
            plasma transport and <strong>intracellular activity. </strong>

            This study examines the influence of saturated and unsaturated NEFAs on estradiol (E2) binding to cytosol
            from human uterus, breast, and melanoma. Binding was analyzed after separation with dextran-coated charcoal
            or hydroxylapatite and by sucrose density gradient centrifugation. <strong>
                Unsaturated NEFAs induced a 2- to 10-fold increase (P less than 0.001) in E2 binding to cytosol
            </strong>from normal, fibromatous, and neoplastic uteri, while saturated NEFAs<strong>
                had a slight inhibitory effect</strong> (P less than 0.05). Similar effects were seen with cytosol from
            metastatic melanoma lymph nodes and neoplastic breast tissues. By contrast, unsaturated NEFAs did not
            increase E2 binding to serum from these patients. Density gradient centrifugation indicated that the
            increased binding was associated with the proteins present in the 2- to 4 S region. Analysis of E2
            metabolites in the presence of unsaturated NEFAs showed the formation of water-soluble derivatives. Seventy
            percent of these E2 derivatives were trichloracetic acid precipitable, suggesting a covalent link between
            the steroid and a protein. The existence of such water-soluble metabolites could be erroneously interpreted
            as a true binding to soluble cytoplasmic receptors.
        </p>
        <p>
            Ann N Y Acad Sci 1988;538:257-264 <strong>
                Possible relevance of steroid availability and breast cancer.</strong> Bruning PF, Bonfrer JM
            Netherlands Cancer Institute (Antoni van Leeuwenhoekhuis), Amsterdam. "The as yet circumstantial evidence
            for a central role of estrogens in the promotion of human breast cancer is supported by many data. However,
            it has not been possible to identify breast cancer patients or women at risk by abnormally elevated estrogen
            levels in plasma. <strong>The concept of available, i.e., non-SHBG bound sex steroid seems to offer a better
                understanding than total serum steroid levels do. We demonstrated that sex steroid protein binding is
                decreased by free fatty acids."</strong>
        </p>
        <p>
            J Surg Oncol 1993 Feb;52(2):77-82. <strong>
                The effect of the fiber components cellulose and lignin on experimental colon neoplasia.</strong> Sloan
            DA, Fleiszer DM, Richards GK, Murray D, Brown RA Department of Surgery, University of Kentucky College of
            Medicine, Lexington. Sixty Sprague-Dawley rats were pair-fed one of three nutritionally identical diets. One
            diet contained "low-fiber" (3.8% crude fiber); the others contained "high fiber" (28.7% crude fiber)
            composed of either cellulose or lignin. Although both "high fiber" diets had similar stool bulking effects,
            <strong> only the cellulose diet</strong>
            was associated with a reduction in 1,2-dimethylhydrazine (DMH)-induced colon neoplasms. The cellulose diet
            was also associated with distinct changes in the gut bacterial profile and with a lowered serum cholesterol.
        </p>

        <p>
            Nutr Cancer 1984;6(2):77-85 <strong>
                Enhancement of 1,2-dimethylhydrazine-induced large bowel tumorigenesis in Balb/c mice by corn, soybean,
                and wheat brans.</strong> Clapp NK, Henke MA, London JF, Shock TL This study was designed to determine
            the effects of four well-characterized dietary brans on large bowel tumorigenesis induced in mice with
            1,2-dimethylhydrazine (DMH). Eight-week-old barrier-derived male Balb/c mice were fed a semisynthetic diet
            with 20% bran added (either corn, soybean, soft winter wheat, or hard spring wheat) or a no-fiber-added
            control diet. Half of each group was given DMH (20 mg/kg body weight/week, subcutaneously for 10 weeks)
            beginning at 11 weeks of age. Surviving mice were killed 40 weeks after the first DMH injection. Tumors were
            not found in mice not subjected to DMH. In DMH-treated mice, tumors were found almost exclusively in the
            distal colon. Tumor incidences were as follows: <strong>controls, 11%; soybean group, 44%; soft winter wheat
                group, 48%; hard spring wheat group, 58%; and corn group, 72%.
            </strong>
            Tumors per tumor-bearing mouse ranged from 1.4 to 1.6, except in the corn group, which had 2.1. <strong>A
                positive correlation was found between percentage of neutral detergent fiber in the brans and tumor
                incidences</strong>
            but not between the individual components of cellulose, hemicellulose, or lignin. The <strong>enhancement of
                DMH-induced large bowel tumorigenesis by all four bran types may reflect a species and/or mouse strain
                effect that is bran-source related. These data emphasize the importance of using well-defined bran in
                all "fiber" studies.
            </strong>
        </p>
        <p>
            Prev Med 1987 Jul;16(4):540-4 <strong>
                Fiber, stool bulk, and bile acid output: implications for colon cancer risk.</strong> McPherson-Kay R
            Dietary fiber has direct effects on stool bulk and bile acid output that may be of relevance in the etiology
            of colon cancer. Most types of fiber increase the total volume of stool and reduce the concentration of
            specific substances, including bile acids, that are in contact with the bowel wall. However, fibers differ
            in their effect on stool bulk, with wheat fiber being a more effective stool bulking agent than fruit and
            vegetable fibers. In addition, the extent to which a specific fiber reduces bile acid concentration will be
            modified by its concomitant effects on total fecal sterol excretion. Whereas wheat bran reduces fecal bile
            acid concentration, <strong>pectin, lignin, and oat bran do not. These three fibers significantly increase
                total bile acid output. Bile acids act as promoters of colonic tumors in mutagenesis assay systems and
                in various animal models.</strong> Human epidemiological studies show a relationship between various
            dietary variables, including fat and fiber intake, fecal concentration of bile acids, and colon cancer risk.
        </p>
        <p>
            Eur J Gastroenterol Hepatol 1998 Jan;10(1):33-9 <strong>Intestinal absorption of oestrogen: the effect of
                altering transit-time.</strong> Lewis SJ, Oakey RE, Heaton KW University Department of Medicine, Bristol
            Royal Infirmary, UK. OBJECTIVE: The mechanism by which a high fibre diet may reduce serum oestrogens is
            unknown. We hypothesized that time is a rate-limiting factor in oestrogen absorption from the colon so that
            changes in colonic transit-rate affect the proportion of oestrogen that is deconjugated and/or absorbed.
            AIM: To determine if alteration of intestinal transit rate would influence the absorption of an oral dose of
            oestradiol glucuronide. PARTICIPANTS: Twenty healthy postmenopausal women recruited by advertisement.
            SETTING: Department of Medicine, Bristol Royal Infirmary. METHODS: Volunteers consumed, in turn, wheat bran,
            senna, loperamide and bran shaped plastic flakes, each for 10 days with a minimum 2 week washout period
            between study periods, dietary intake being unchanged. Before and in the last 4 days of each intervention
            whole-gut transit-time, defecation frequency, stool form, stool beta-glucuronidase activity, stool pH and
            the absorption of a 1.5 mg dose of oestradiol glucuronide were measured. RESULTS: Wheat bran, senna and
            plastic flakes led to the intended reduction in whole-gut transit-time, increase in defecatory frequency and
            increase in stool form score. Loperamide caused the opposite effect. <strong>The length of time the absorbed
                oestrogen was detectable in the serum fell with wheat bran and senna, although this was only significant
                for oestradiol.</strong>
            Oestrone, but not oestradiol, was detectable for a longer time with loperamide. Plastic flakes had no effect
            on either oestrogen. Areas under the curve did not change significantly but tended to fall with the three
            transit-accelerating agents and to rise with loperamide. CONCLUSION: Our data indicate there is likely to be
            an effect of intestinal transit on the absorption of oestrogens but more refined techniques are needed to
            characterize this properly.
        </p>
        <p>
            Br J Cancer 1997;76(3):395-400. <strong>
                Lower serum oestrogen concentrations associated with faster intestinal transit.</strong> Lewis SJ,
            Heaton KW, Oakey RE, McGarrigle HH University Department of Medicine, Bristol Royal Infirmary, UK. Increased
            fibre intake has been shown to reduce serum oestrogen concentrations. We hypothesized that fibre exerts this
            effect by decreasing the time available for reabsorption of oestrogens in the colon. We tested this in
            volunteers by measuring changes in serum oestrogen levels in response to manipulation of intestinal transit
            times with senna and loperamide, then comparing the results with changes caused by wheat bran. Forty healthy
            premenopausal volunteers were placed at random into one of three groups. The first group took senna for two
            menstrual cycles then, after a washout period, took wheat bran, again for two menstrual cycles. The second
            group did the reverse. The third group took loperamide for two menstrual cycles. At the beginning and end of
            each intervention a 4-day dietary record was kept and whole-gut transit time was measured; stools were taken
            for measurement of pH and beta-glucuronidase activity and blood for measurement of oestrone and oestradiol
            and their non-protein-bound fractions and of oestrone sulphate. <strong>
                Senna and loperamide caused the intended alterations in intestinal transit, whereas on wheat bran
                supplements there was a trend towards faster transit. Serum oestrone sulphate fell with wheat bran (mean
                intake 19.8 g day(-1)) and with senna; total- and non-protein-bound oestrone fell with senna.</strong>
            No significant changes in serum oestrogens were seen with loperamide. No significant changes were seen in
            faecal beta-glucuronidase activity. Stool pH changed only with senna, in which case it fell. In conclusion,
            speeding up intestinal transit can lower serum oestrogen concentrations.
        </p>
        <p>
            J Steroid Biochem Mol Biol 1991 Aug;39(2):193-202 <strong>Influence of wheat bran on NMU-induced mammary
                tumor development, plasma estrogen levels and estrogen excretion in female rats.</strong> Arts CJ, de
            Bie AT, van den Berg H, van 't Veer P, Bunnik GS, Thijssen JH TNO Toxicology and Nutrition Institute, The
            Netherlands. In our animal experiments the hypothesis was tested that a high-fiber (HF) diet reduces tumor
            promotion<strong>
                by interruption of the enterohepatic circulation resulting in lowered estrogen exposure of the
                estrogen-sensitive tissue.
            </strong>

            In the first experiment the development of N-nitrosomethylurea (NMU) induced mammary tumors was
            investigated. One group of rats (HF) was fed a HF diet (11% fiber, based on wheat bran), the other group
            (LF) fed a low-fiber diet (0.5% fiber, based on white wheat flour). Tumor incidence (90 and 80%,
            respectively) and latency (121 and 128 days, respectively) were similar in the HF and LF groups. Compared to
            the LF group, HF rats had lower tumor weights (0.16 vs 0.55 g; P less than 0.01) and a slightly lower tumor
            multiplicity (1.8 vs 2.8 tumors per tumor-bearing rat). These differences were reduced after adjustment for
            body weight. In a second experiment rats, not treated with the carcinogen, were kept on the same HF and LF
            diets. From these rats 24-h urine and feces and orbital blood samples were<strong>
                collected for analysis of (un)conjugated estrogens. The excretion of both free and conjugated estrogens
                in fecal samples was about 3-fold higher in HF rats than in LF rats. During the basal period of the
                cycle urinary excretion of estrone was lower in HF rats (mean 9.7 ng/day) than in LF rats (mean 13.0
                ng/day; P less than 0.05). It is concluded that wheat bran interrupts the enterohepatic circulation of
                estrogens, but plasma levels are not affected. Whether the development of mammary tumors is reduced by
                the introduction of specific components of wheat bran, or by a reduced body weight due to a lower
                (effective) energy intake remains to be determined.
            </strong>
        </p>
        <p>
            Nutr Cancer 1998;31(1):24-30 <strong>
                Dietary lignin, and insoluble fiber, enhance uterine cancer but did not influence mammary cancer induced
                by N-methyl-N-nitrosourea in rats.</strong>
            Birt DF, Markin RS, Blackwood D, Harvell DM, Shull JD, Pennington KL Eppley Institute for Research in Cancer
            and Allied Disease, University of Nebraska Medical Center, Omaha 69198, USA. Previous investigations
            suggested potential breast cancer-preventive properties of dietary fiber from cabbage. The purpose of the
            present investigation was to determine whether lignin, a component of cabbage fiber, would protect against
            mammary carcinogenesis by N-methyl-N-nitrosourea (MNU) in Sprague-Dawley rats. A six-week study was
            conducted using diets containing 0.5-5% dietary wood lignin (a readily available, purified source). These
            diets were well tolerated by the rats, and a carcinogenesis study using 5 mg MNU/100 g body wt i.v. at 50
            days of age was conducted, with the 2.5% lignin diet fed from 6 through 8 weeks of age followed by 5% lignin
            diet until 20 weeks after MNU. Dietary lignin and MNU treatment increased food consumption (p &lt; 0.05),
            and body weight was slightly reduced at 10 and 20 weeks after MNU in the MNU-5% lignin diet group (p &lt;
            0.05). Serum estradiol was not altered by dietary lignin or MNU treatment, but uterine weights were highest
            in the MNU-control diet group 4 and 12 weeks after MNU. Expression of creatine kinase B, an
            estrogen-responsive gene, was lower in the uteri of the MNU-lignin diet group than in other groups at 20
            weeks. Mammary carcinogenesis was not altered by dietary lignin.<strong>
                However, uterine endometrial adenocarcinoma was observed only in the MNU-lignin diet group (4
                carcinomas/40 effective rats) (p &lt; 0.05).
            </strong>
        </p>

        <p>
            Ginecol Obstet Mex 1998 Mar;66:111-8 <strong>
                [Estrogens of vegetable origin].</strong> [Article in Spanish] Rubio Lotvin B Reproduccion y de
            Ginecologia y Obstetricia Facultad de Medicina, UNAM Depto. de Ginecologia y Obstetricia Hospital Americano,
            Britanico Cowdray. Mexico, D.F. In recent years, estrogens of vegetable origin have acquired some importance
            that justify the presentation of the available data. The compounds that have estrogenic effect when ingested
            as food through<strong>
                vegetables include isoflavones, lignines and lactones. The review comprises their chemical
                structure,</strong> metabolism and excretion as well as their effect on plasmatic levels of estrogens
            FSH, LH and SHBG as well as their activity over lipoproteins and, naturally, their action on menopause
            symptoms and breast cancer.
        </p>
        <p>
            Proc Soc Exp Biol Med 1995 Jan;208(1):6-12 <strong>Chemical studies of phytoestrogens and related compounds
                in dietary supplements: flax and chaparral.</strong> Obermeyer WR, Musser SM, Betz JM, Casey RE, Pohland
            AE, Page SW Division of Natural Products, Food and Drug Administration, Washington, District of Columbia
            20204. High-performance liquid chromatographic (HPLC) and mass spectrometric (MS) procedures were developed
            to determine lignans in flaxseed (Linum usitatissimum) and chaparral (Larrea tridentata).<strong>
                Flaxseed contains high levels of phytoestrogens. Chaparral has been associated with acute nonviral toxic
                hepatitis and contains lignans that are structurally similar to known estrogenic compounds.
            </strong>

            Both flaxseed and chaparral products have been marketed as dietary supplements. A mild enzyme hydrolysis
            procedure to prevent the formation of artifacts in the isolation step was used in the determination of
            secoisolariciresinol in flaxseed products. HPLC with ultraviolet spectral (UV) or MS detection was used as
            the determinative steps. HPLC procedures with UV detection and mass spectrometry were developed to<strong>
                characterize the phenolic components, including lignans and flavonoids,</strong> of chaparral and to
            direct fractionation studies for the bioassays.
        </p>
        <p>
            Brain Res 1994 Jul 25;652(1):161-3 <strong>
                The 21-aminosteroid antioxidant, U74389F, prevents estradiol-induced depletion of hypothalamic
                beta-endorphin in adult female rats.</strong>
            Schipper HM, Desjardins GC, Beaudet A, Brawer JR Department of Anatomy and Cell Biology, Bloomfield Centre
            for Research in Aging, Jewish General Hospital, McGill University, Montreal, Que., Canada.<strong>
                A single intramuscular injection of 2 mg estradiol valerate (EV) results in neuronal degeneration
            </strong>and beta-endorphin depletion in the hypothalamic arcuate nucleus of adult female rats. We have
            hypothesized that peroxidase-positive astrocytes in this brain region oxidize estrogens and
            catecholestrogens to semiquinone radicals which mediate oxidative neuronal injury. In the present study,
            dietary administration of the potent antioxidant 21-aminosteroid, U-74389F, completely blocked EV-induced
            beta-endorphin depletion in the hypothalami of adult female rats. Neither EV nor 21-aminosteroid treatment
            had any effect on hypothalamic concentrations of neuropeptide Y and Met-enkephalin, <strong>confirming that
                the estradiol lesion is fairly selective for the beta-endorphin cell population.
            </strong>
            The present findings support the hypothesis that the toxic effect of estradiol on hypothalamic
            beta-endorphin neurons is mediated by free radicals.
        </p>
        <p>
            J Steroid Biochem Mol Biol 1998 Feb;64(3-4):207-15, <strong>"Effects of tea polyphenols and flavonoids on
                liver microsomal glucuronidation of estradiol and estrone."</strong>
            Zhu BT, Taneja N, Loder DP, Balentine DA, Conney AH "Administration of 0.5 or 1% lyophilized green tea (5 or
            10 mg tea solids per ml, respectively) as the sole source of drinking fluid to female Long-Evans rats for 18
            days stimulated liver microsomal glucuronidation of estrone, estradiol and 4-nitrophenol by 30-37%, 15-27%
            and 26-60%, respectively. Oral administration of 0.5% lyophilized green tea to female CD-1 mice for 18 days
            stimulated liver microsomal glucuronidation of estrone, estradiol and 4-nitrophenol by 33-37%, 12-22% and
            172-191%, respectively. The in vitro addition of a green tea polyphenol mixture, a black tea polyphenol
            mixture or (-)-epigallocatechin gallate inhibited rat liver microsomal glucuronidation of estrone and
            estradiol in a concentration-dependent manner and their IC50 values for inhibition of estrogen metabolism
            were approximately 12.5, 50 and 10 microg/ml, respectively. Enzyme kinetic analysis indicates that the
            inhibition of estrone glucuronidation by 10 microM (-)-epigallocatechin gallate was competitive while
            inhibition by 50 microM (-)-epigallocatechin gallate was noncompetitive. Similarly, several flavonoids
            (naringenin, hesperetin, kaempferol, quercetin, rutin, flavone, alpha-naphthoflavone and
            beta-naphthoflavone) also inhibited rat liver microsomal glucuronidation of estrone and estradiol to varying
            degrees. Naringenin and hesperetin displayed the strongest inhibitory effects (IC50 value of approximately
            25 microM). These two hydroxylated flavonoids had a competitive mechanism of enzyme inhibition for estrone
            glucuronidation at a 10 microM inhibitor concentration and a predominantly noncompetitive mechanism of
            inhibition at a 50 microM inhibitor concentration."
        </p>

        <p>
            Toxicology 1997 Sep 26;122(1-2):61-72, <strong>
                "Effects of co-administration of butylated hydroxytoluene, butylated hydroxyanisole and flavonoids on
                the activation of mutagens and drug-metabolizing enzymes in mice.</strong>" Sun B, Fukuhara M Effects of
            co-administration of food additives and naturally occurring food components were studied on the activation
            of mutagens. Male mice (ddY) were given diets containing butylated hydroxytoluene (BHT) or butylated
            hydroxyanisole (BHA) and flavone or flavanone (2,3-dihydroflavone) for two weeks and the ability of hepatic
            microsomes to activate aflatoxin B1, benzo[a]pyrene and N-nitrosodimethylamine was determined by the
            mutagenicity test. Co-administration of an antioxidant (0.1% BHT or 0.2% BHA in diet) and a flavonoid (0.1%
            flavone or 0.1% flavanone) <strong>resulted in additive effects on the activation of aflatoxin B1 and
                benzo[a]pyrene,</strong> while the activation of N-nitrosodimethylamine was not elevated significantly
            by the co-administration. To understand the mechanism for the additive effects, induction of specific
            isozymes of cytochrome P450 involved in the activation of the mutagens was studied. Co-administration of BHT
            (0.1%) and flavone (0.1%) increased markedly the levels of proteins and the activities of the enzymes
            related to the isozymes of CYP2A and CYP2B, while co-administration of BHA (0.2%) and flavanone (0.1%)
            elevated those related to CYP1A. Further, the activation of aflatoxin B1 and benzo[a]pyrene in hepatic
            microsomes was inhibited by the antibodies against these isozymes, which suggested that the enhanced
            activation of the mutagens by the co-administration might be mediated by the induction of these isozymes.
        </p>
        <p>
            Biochem Soc Trans 1977;5(5):1489-92. <strong>Frameshift mutagenicity of certain naturally occurring phenolic
                compounds in the 'Salmonella/microsome' test: activation of anthraquinone and flavonol glycosides by gut
                bacterial enzymes.</strong> Brown JP, Dietrich PS, Brown RJ
        </p>

        <p>
            Mutagenesis 1997 Sep;12(5):383-90 <strong>
                "Involvement of rat cytochrome 1A1 in the biotransformation of kaempferol to quercetin: relevance to the
                genotoxicity of kaempferol.</strong>" Silva ID, Rodrigues AS, Gaspar J, Maia R, Laires A, Rueff J.
            "Kaempferol is a flavonoid widely distributed in edible plants and has been shown to be genotoxic to V79
            cells in the absence of external metabolizing systems. The presence of an external metabolizing system, such
            as rat liver homogenates (S9 mix), leads to an increase in its genotoxicity, which is attributed to its
            biotransformation to <strong>the more genotoxic flavonoid quercetin</strong>, via the cytochrome P450 (CYP)
            mono-oxygenase system."
        </p>
        <p>
            Environ Health Perspect 1997 Apr;105 Suppl 3:633-6 <strong>Dietary estrogens stimulate human breast cells to
                enter the cell cycle.</strong> Dees C, Foster JS, Ahamed S, Wimalasena J.<strong>
                "Our findings are consistent with a conclusion that dietary estrogens at low concentrations do not act
                as antiestrogens, but act like DDT and estradiol to stimulate human breast cancer cells to enter the
                cell cycle."</strong>
        </p>

        <p>
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