Toxic Plant Estrogens

Also see:
20 Foods High In Estrogen (Phytoestrogens)
Plant Toxins in Response to Stress
Estrogen, Progesterone, and Fertility
Quotes: Thyroid, Estrogen, Menstrual Symptoms, PMS, and Infertility
Hormonal profiles in women with breast cancer
Alcohol Consumption – Estrogen and Progesterone In Women
Estrogen, Endotoxin, and Alcohol-Induced Liver Injury
Soy and Behavior
Baby Formula, Soy, and Immunosuppression
Estrogen Levels Increase with Age
Fat Tissue and Aging – Increased Estrogen
Estrogen Related to Loss of Fat Free Mass with Aging
PUFA Increases Estrogen
PUFA Inhibit Glucuronidation
PUFA Promote Cancer
Maternal PUFA Intake Increases Breast Cancer Risk in Female Offspring

“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.” -Ray Peat, PhD

“Twenty-five years ago I reviewed many of the issues of estrogen’s toxicity, and the ubiquity of estrogenic substances, and since then have regularly spoken about it, but I haven’t concentrated much attention on the phytoestrogens, because we can usually just choose foods that are relatively free of them. They are so often associated with other food toxins–antithyroid factors, inhibitors of digestive enzymes, immunosuppressants, etc.–that the avoidance of certain foods is desirable.” -Ray Peat, PhD

“Protein deficiency itself contributes to the harm done by toxins, since the liver’s ability to detoxify them depends on adequate nutrition, especially good protein. In the 1940s, Biskind’s experiments showed that protein deficiency leads to the accumulation of estrogen, because the liver normally inactivates all the estrogen in the blood as it passes through the liver. This applies to phytoestrogens and industrial estrogens as well as to the natural estrogens of the body. At a certain point, the increased estrogen and decreased thyroid and progesterone cause infertility, but before that point is reached, the hyperestrogenism causes a great variety of birth defects. Deformities of the male genitals, and later, testicular cancer in the sons and breast cancer in the daughters, are produced by the combination of toxins and nutritional deficiencies.” -Ray Peat, PhD

Nihon Naibunpi Gakkai Zasshi. 1991 May 20;67(5):622-9.
[The effects on the thyroid gland of soybeans administered experimentally in healthy subjects].
[Article in Japanese]
Ishizuki Y, Hirooka Y, Murata Y, Togashi K.
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.

Oncol Rep. 1998 May-Jun;5(3):609-16.
Maternal genistein exposure mimics the effects of estrogen on mammary gland development in female mouse offspring.
Hilakivi-Clarke L, Cho E, Clarke R.
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 that are the sites for malignant transformation, i.e., terminal end buds (TEBs), and a reduction in epithelial differentiation in the mammary gland. Some 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. 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, genistein, zearalenone, and tamoxifen all increased the density of TEBs in the mammary glands. Genistein reduced, and zearalenone increased, epithelial differentiation. Zearalenone also increased epithelial density, when compared with the vehicle-controls. None of the treatments had permanent effects on circulating E2 levels. 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. Zearalenone caused persistent cornification of the estrus smears. These findings indicate that 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. The estrogenic effects of zearalenone on the mammary gland, in contrast, are probably counteracted by the permanent changes in estrus cycling.

J Nutr. 1995 Mar;125(3 Suppl):771S-776S.
Potential adverse effects of phytoestrogens.
Whitten PL, Lewis C, Russell E, Naftolin F.
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 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. 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 persistent estrus state in coumestrol-treated females by 132 days of age. In contrast, the 10-day coumestrol treatments produced significant deficits in the sexual behavior of male offspring. 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.

J Clin Endocrinol Metab. 1995 May;80(5):1685-90.
Dietary intervention study to assess estrogenicity of dietary soy among postmenopausal women.
Baird DD, Umbach DM, Lansdell L, Hughes CL, Setchell KD, Weinberg CR, Haney AF, Wilcox AJ, Mclachlan JA.
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 that was provided with soy foods for 4 weeks or a control group that was instructed to eat as usual. 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. The percentage of vaginal superficial cells (indicative of estrogenicity) increased for 19% of those eating the diet compared with 8% of controls (P = 0.06 when tested by ordinal logistic regression). FSH and LH did not decrease significantly with dietary supplementation as hypothesized, nor did sex hormone binding globulin increase. Little change occurred in endogenous estradiol concentration or body weight during the diet. Women with large increases in urinary isoflavone concentrations were not more likely to show estrogenic responses than were women with more modest increases. On the basis of published estimates of phytoestrogen potency, a 4-week, soy-supplemented diet was expected to have estrogenic effects on the liver and pituitary in postmenopausal women, but estrogenic effects were not seen. At most, there was a small estrogenic effect on vaginal cytology.

Proc Soc Exp Biol Med. 1995 Jan;208(1):92-7.
Clinical changes in ovariectomized ewes exposed to phytoestrogens and 17 beta-estradiol implants.
Nwannenna AI, Lundh TJ, Madej A, Fredriksson G, Björnhag G.
Eight Swedish Finewool Landrace ewes, ovariectomized 5 months earlier and kept on nonestrogenic hay, were each fed 3.5 kg red clover silage, corresponding to 6.1 g phytoestrogens (of which 3.5 g was formononetin) per day, for 14 days in November (short days). In January (short days), two groups (3 each) of these ewes received one or two 17 beta-estradiol sc implants. In May (long days), one of two new groups (4 each) of these ewes was reexposed to phytoestrogens for another 14 days while the other served as a control. Physical examination of ewes for changes in reproductive organs was carried out two or three times per week during each feeding/treatment, and continued until observed changes disappeared. Clinically significant changes occurred in the reproductive organs of ewes fed red clover. Vulva color changed from pale to pink and red, and there were enlargements of the vulva, uterus, and udder. In addition, teat length and circumference increased, and secretion of milky fluid began. These changes were similar, but more pronounced during treatment with 17 beta-estradiol, particularly teat circumference. The changes in vulva were more dramatic in May than in November and resembled those observed in ewes treated with estradiol. Our data show that a daily intake of 3.5 g formononetin for 14 days caused the increase of teat size and changes in the color of the vulva and in uterus weight in ovariectomized ewes.

Proc Soc Exp Biol Med. 1995 Jan;208(1):6-12.
Chemical studies of phytoestrogens and related compounds in dietary supplements: flax and chaparral.
Obermeyer WR, Musser SM, Betz JM, Casey RE, Pohland AE, Page SW.
High-performance liquid chromatographic (HPLC) and mass spectrometric (MS) procedures were developed to determine lignans in flaxseed (Linum usitatissimum) and chaparral (Larrea tridentata). 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. 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 characterize the phenolic components, including lignans and flavonoids, of chaparral and to direct fractionation studies for the bioassays.

Proc Soc Exp Biol Med. 1995 Jan;208(1):98-102.
The phytoestrogen congeners of alcoholic beverages: current status.
Gavaler JS, Rosenblum ER, Deal SR, Bowie BT.
The idea that alcoholic beverages might contain biologically active phytoestrogenic congeners stemmed from findings of overt feminization observed in alcoholic men with alcohol-induced cirrhosis. Specifically, in addition to being hypogonadal, these chronically alcohol-abusing men with cirrhosis frequently manifest gynecomastia, palmar erythema, spider angiomata, and a female escutcheon. These physical signs of exposure to active estrogen occur in the presence of normal or only minimally elevated levels of endogenous steroid estrogens. Because levels of circulating steroid hormones failed to provide a satisfactory explanation for the feminization observed, alternate explanations were considered. If the estrogenization observed was not entirely a function of tissue expose to steroid estrogens produced endogenously, then perhaps tissues were being exposed to exogenous estrogenic substances from dietary sources. Given the degree of alcohol abuse in the population in which hypotheses for feminization were being formed, alcoholic beverages became a prime candidate as a dietary source of exogenous estrogenic substances.

Steroids. 1994 Jul;59(7):443-9.
Influence of phytoestrogen diets on estradiol action in the rat uterus.
Whitten PL, Russell E, Naftolin F.
The influence of coumestrol on the action of estradiol was examined in oral and parenteral tests. Coumestrol did not antagonize the uterotrophic action of estradiol when administered either prior to, or jointly with, E2 treatment, or when administered orally or parenterally. Additive effects on estradiol stimulation of uterine weight and reduction of cytosolic estrogen receptor binding were observed following oral, but not parenteral, administration of coumestrol. On the other hand, coumestrol pretreatment did appear to dampen estradiol’s induction of progestin receptors, uterine protein, and nuclear estrogen receptor binding. However, even at those endpoints where coumestrol pretreatment did dampen estradiol action, coumestrol itself produced an estrogenic response. These findings contradict the assumption that all phytoestrogens are necessarily antiproliferative agents and argue for specific identification of the actions of each chemical.

The estrogens in clover have been known for several decades to have a contraceptive action in sheep, and other phytoestrogens are known to cause deformities in the genitals, feminization of men, and anatomical changes in the brain as well as functional masculinization of the female brain. -Ray Peat, PhD

J Anim Sci. 1995 May;73(5):1509-15.
Detection of the effects of phytoestrogens on sheep and cattle.
Adams NR.
Cows and ewes fed estrogenic forage may suffer impaired ovarian function, often accompanied by reduced conception rates and increased embryonic loss. Males are relatively unaffected, but the mammary glands in females and castrate males may undergo hypertrophy of the duct epithelium, accompanied by secretion of clear or milky fluid. In cows, clinical signs resemble those associated with cystic ovaries. The infertility is temporary, normally resolving within 1 mo after removal from the estrogenic feed. However, ewes exposed to estrogen for prolonged periods may suffer a second form of infertility that is permanent, caused by developmental actions of estrogen during adult life. The cervix becomes defeminized and loses its ability to store spermatozoa, so conception rates are reduced, although ovarian function remains normal. Importantly, both temporary and permanent infertility in ewes often occur without observable signs and can be detected only by measurement of phytoestrogens in the diet, or measurement of their effects on the animal. Low background concentrations of dietary phytoestrogens are suggested to play an important role in prevention of disease in humans and laboratory rats, but subclinical effects of phytoestrogens in cattle have not yet been described. Effects of low concentrations of phytoestrogens on reproductive function in ruminants are likely to receive increasing attention.

Proc Soc Exp Biol Med. 1995 Jan;208(1):87-91.
Organizational and activational effects of phytoestrogens on the reproductive tract of the ewe.
Adams NR.
Ewes exposed to phytoestrogens may display two forms of infertility, categorized as temporary or permanent. Temporary infertility results from actions of estrogen that are similar to the activational effects of estrogen in most species of mammals. The permanent infertility results from changes to the cervix which are analogous to the organizational effects of estrogen reported in other species treated during organogenesis. However, in the ewe these effects may be produced after organogenesis by prolonged treatment during adult life. It has recently become apparent that the level of nutrition and metabolic hormones influence the degree of uterus-like histological change in the cervix produced by prolonged treatment with estrogen. It is hypothesized that, under some nutritional conditions, the hormonal milieu in adult ewes may simulate hormonal patterns that are normally experienced by fetal lambs in utero, thereby allowing the cervix of the adult ewe to give an organizational response to estrogen.

J Endocrinol. 1981 Jun;89(3):365-70.
Oestrogen receptors and metabolic activity in the genital tract after ovariectomy of ewes with permanent infertility caused by exposure to phytooestrogens.
Tang BY, Adams NR.
Characteristics of the uterus and cervix after ovariectomy of ewes with permanent phytooestrogen infertility (PPI) were compared with controls. Ewes with PPI had more oestrogen-binding sites in the cervix, but not in the uterus. There was no difference between the two groups of ewes in the binding affinity constant of receptors from the uterus or cervix. There were more keratinized cells in the vaginal epithelium of ewes with PPI, and the rates of protein and glycoprotein synthesis in the uterus and cervix were higher in ewes with PPI. These results offer further evidence that PPI in adult ewes is similar to the “persistent oestrus’ syndrome in rodents oestrogenized neonatally.

Acta Vet Scand. 1994;35(2):173-83.
Effects of oestrogenic silage on some clinical and endocrinological parameters in ovariectomized heifers.
Nwannenna AI, Madej A, Lundh TJ, Fredriksson G.
The influence of phytoestrogens was studied in 3 ovariectomized Swedish Friesian heifers fed 20 kg of 100% red clover silage per heifer/day for 14 days. Behaviour, reproductive organs and pituitary response to exogenous gonadotropin-releasing hormone (GnRH) injections were monitored. Clinical effects like oedema and mucous discharge in the vulva, presence of milky fluid in the mammae and increases in teat size and the cross-sectional distance of the uterus were observed in heifers fed red clover silage. Fluid accumulation in the uterus, visualized by means of ultrasonography, had still not disappeared 30 days after the red clover silage had been completely withdrawn. Red clover silage appeared to reduce the magnitude and duration of the pituitary response to GnRH injections.

J Reprod Fertil Suppl. 1981;30:223-30.
A changed responsiveness to oestrogen in ewes with clover disease.
Adams NR.
When clover-infertile ewes are subsequently exposed to non-oestrogenic pasture, they have a reduced fertilization rate, due to an inability to store spermatozoa in the cervix, and the cervical mucus has a reduced spinnbarkeit, caused by a slower response to oestrogenic stimulation. Vaginal cell keratinization and oestrous behaviour occurred more slowly after treatment of affected ewes with oestrogen. Other changes in affected ewes suggest that phyto-oestrogens have permanent mild differentiating effects on adults. Sexual behaviour is masculinized, the cervix takes on a uterine-like appearance and the genital tract becomes permanently oestrogenized. The manner in which these changes relate to the altered responsiveness to oestrogen remains to be clarified.

Ginecol Obstet Mex. 1998 Mar;66:111-8.
[Estrogens of vegetable origin].
[Article in Spanish]
Rubio Lotvin B.
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 vegetables include isoflavones, lignines and lactones. The review comprises their chemical structure, 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.

J Toxicol Environ Health. 1997 Jan;50(1):1-29.
Biochemical and molecular changes at the cellular level in response to exposure to environmental estrogen-like chemicals.
Roy D, Palangat M, Chen CW, Thomas RD, Colerangle J, Atkinson A, Yan ZJ.
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. 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. 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 produce multiple and multitype genetic and/or nongenetic hits. 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) DNA repair gene DNA polymerase beta transcripts are decreased and mutated. 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 alter cell cycle kinetics, produce telomeric associations, and produce chromosomal aberrations. 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.

Environ Health Perspect. 1997 Apr;105 Suppl 3:633-6.
Dietary estrogens stimulate human breast cells to enter the cell cycle.
Dees C, Foster JS, Ahamed S, Wimalasena J.
It has been suggested that dietary estrogens neutralize the effect of synthetic chemicals that mimic the effects of estrogen (i.e., xenoestrogens, environmental estrogens). Genistein, a dietary estrogen, inhibits the growth of breast cancer cells at high doses but additional studies have suggested that at low doses, genistein stimulates proliferation of breast cancer cells. Therefore, if dietary estrogens are estrogenic at low doses, one would predict that they stimulate estrogen-receptor positive breast cancer cells to enter the cell cycle. Genistein and the fungal toxin zearalenone were found to increase the activity of cyclin dependent kinase 2 (Cdk2) and cyclin D1 synthesis and stimulate the hyperphosphorylation of the retinoblastoma susceptibility gene product pRb105 in MCF-7 cells. The steroidal antiestrogen ICI 182,780 suppressed dietary estrogen-mediated activation of Cdk2. Dietary estrogens not only failed to suppress DDT-induced Cdk2 activity, but were found to slightly increase enzyme activity. Both zearalenone and genistein were found to stimulate the expression of a luciferase reporter gene under the control of an estrogen response element in MVLN cells. 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.

Nutr Cancer. 2006;54(2):184-201.
Phytoestrogen content of foods consumed in Canada, including isoflavones, lignans, and coumestan.
Thompson LU, Boucher BA, Liu Z, Cotterchio M, Kreiger N.
Phytoestrogens may play a role in hormone-related diseases such as cancer, but epidemiological and clinical data are conflicting in part due to inadequate databases used in intake estimation. A database of nine phytoestrogens in foods relevant to Western diets was developed to more accurately estimate intakes. Foods (N = 121) available in Ontario, Canada were prepared as commonly consumed and analyzed for isoflavones (genistein, daidzein, glycitein, formononetin), lignans (secoisolariciresinol, matairesinol, pinoresinol, lariciresinol), and coumestan (coumestrol) using gas chromatography-mass spectrometry methods. Data were presented on an as is (wet) basis per 100 g and per serving. Food groups with decreasing levels of total phytoestrogens per 100 g are nuts and oilseeds, soy products, cereals and breads, legumes, meat products, and other processed foods that may contain soy, vegetables, fruits, alcoholic, and nonalcoholic beverages. Soy products contain the highest amounts of isoflavone, followed by legumes, meat products and other processed foods, cereals and breads, nuts and oilseeds, vegetables, alcoholic beverages, fruits, and nonalcoholic beverages. Decreasing amounts of lignans are found in nuts and oilseeds, cereals and breads, legumes, fruits, vegetables, soy products, processed foods, alcoholic, and nonalcoholic beverages. The richest sources of specific phytoestrogens, including coumestrol, were identified. The database will improve phytoestrogen intake estimation in future epidemiological and clinical studies particularly in Western populations.

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