Phytoestrogens: soy ploy

Int J Vitam Nutr Res 2003 Mar;73(2):120-6
Potential risks and benefits of phytoestrogen-rich diets.
Cassidy A. Biosciences Division, Unilever Research, Colworth House, Sharnbrook, Bedfordshire, UK, MK 44 ILQ.

  Interest in the physiological role of bioactive compounds present in plants has increased dramatically over the last decade. Of particular interest in relation to human health are the class of compounds known as the phytoestrogens, which embody several groups of non-steroidal oestrogens including isoflavones & lignans that are widely distributed within the plant kingdom. Data from animal and in vitro studies provide plausible mechanisms to explain how phytoestrogens may influence hormone dependent states, but although the clinical application of diets rich in these oestrogen mimics is in its infancy, data from preliminary studies suggest potential beneficial effects of importance to health. Phytoestrogens are strikingly similar in chemical structure to the mammalian oestrogen, oestradiol, and bind to oestrogen receptors (ER) with a preference for the more recently described ER beta. This suggests that these compounds may exert tissue specific effects. Numerous other biological effects independent of the ER (e.g. antioxidant capacity, antiproliferative and antiangiogenic effects) have been ascribed to these compounds. Whether phytoestrogens have any biological activity in humans, either hormonal or non hormonal is a contentious issue and there is currently a paucity of data on human exposure. Much of the available data on the absorption and metabolism of dietary phytoestrogens is of a qualitative nature; it is known that dietary phytoestrogens are metabolised by intestinal bacteria, absorbed, conjugated in the liver, circulated in plasma and excreted in urine. Recent studies have addressed quantitatively what happens to isoflavones following ingestion--with pure compound and stable isotope data to compliment recent pharmacokinetic data for soy foods. The limited studies conducted so far in humans clearly confirm that soya isoflavones can exert hormonal effects. These effects may be of benefit in the prevention of many of the common diseases observed in Western populations (such as breast cancer, prostate cancer, menopausal symptoms, osteoporosis) where the diet is typically devoid of these biologically active naturally occurring compounds. However since biological effects are dependent on many factors including dose, duration of use, protein binding affinity, individual metabolism and intrinsic oestrogenic state, further clinical studies are necessary to determine the potential health effects of these compounds in specific population groups. However we currently know little about age related differences in exposure to these compounds and there are few guidelines on optimal dose for specific health outcomes.

PMID: 12747219

J Steroid Biochem Mol Biol 2002 Dec;83(1-5):133-47
Phytoestrogens for hormone replacement therapy?
Wuttke W, Jarry H, Westphalen S, Christoffel V, Seidlova-Wuttke D. Department of Clinical and Experimental Endocrinology, University of Goettingen, Robert-Koch-Strasse 40, 37075 Goettingen, Germany.

  Due to some severe side effects "classical" hormone replacement therapy (HRT) is currently being challenged by a therapy with phytoestrogens. Particularly soy and red clover derived isoflavones are advertised as selective estrogen receptor modulators (SERMs) with only desired and no undesired estrogenic effects. Evidence that this is the case however is scarce. Most studies investigating climacteric complaints did not find beneficial effects. A proposed beneficial effect on mammary cancer is unproven. The majority of studies however indicate an antiosteoporotic effect of isoflavones, while putative beneficial effects in the cardiovascular system are questionable due to the fact that estradiol which--like isoflavones--increase HDL and decrease LDL concentrations appear not to prevent arteriosclerosis in the human. In the urogenital tract, including the vagina, soy and red clover derived isoflavones are without effects. Cimicifuga racemosa extracts are traditionally used for the treatment of climacteric complaints. Evidence is now available that the yet unknown compounds in Cimicifuga racemosa extracts prevent climacteric complaints and may also have antiosteoporotic effects.

PMID: 12650710

J Steroid Biochem Mol Biol 2002 Dec;83(1-5):113-8
Phytoestrogens and breast cancer.
Adlercreutz H. Institute for Preventive Medicine, Nutrition, and Cancer, Folkhalsan Research Center, and Division of Clinical Chemistry, University of Helsinki, PL 60, Helsinki FIN-00014, Finland.

  The role of phytoestrogens and consumption of phytoestrogen-rich foods such as soy containing isoflavones and whole grain products with lignans for the prevention of breast cancer is reviewed. It is concluded that soy-containing diet in adult women is not or only slightly protective with regard to breast cancer, but that it may be beneficial if consumed in early life before puberty or during adolescence supporting results of immigrant and epidemiological studies. No negative effects of soy on breast cancer have been observed. On the other hand, a diet low in lignans, resulting in a low plasma enterolactone concentration, increases risk both in a case-control and a prospective study, but some controversial results have also been obtained. Some of these results may be explained by the fact that the determinants of plasma or urinary enterolactone concentration are very different in different countries. In Scandinavia, the main determinants are whole grain cereal food, vegetables and berries. Whether the protective effect is caused by the phytoestrogens in the diet or whether they are only biomarkers of a healthy diet has not been established.

PMID: 12650707

J Nutr 1995 Mar;125(3 Suppl):771S-776S
Potential adverse effects of phytoestrogens.
Whitten PL, Lewis C, Russell E, Naftolin F Department of Anthropology, Emory University, Atlanta, GA 30322.

  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.

PMID: 7884563

Proc Soc Exp Biol Med 1995 Jan;208(1):13-7
Phytoestrogen content and estrogenic effect of legume fodder.
Saloniemi H, Wahala K, Nykanen-Kurki P, Kallela K, Saastamoinen I Department of Basic Veterinary Medicine, College of Veterinary Medicine, Helsinki, Finland.

  This study is a summary of Finnish investigations of the phytoestrogen content of legume plants, red clover, white clover, alfalfa, and goat's rue. In addition to the chemical analyses, biological studies were performed. Uterine weight of immature rats was used as an indicator of the estrogenic effect of the fodder used. All red clover varieties studied contained estrogenic isoflavones, especially formononetin and biochanin-A. The phytoestrogen content varied from 1.0% to 2.5% of dry matter. The biological study of white clover showed a clear estrogenic effect not visible through chemical analysis. Alfalfa contains small quantities of formononetin and biochanin-A, but 25-65 ppm coumestrol in dry matter. The estrogenic effect of alfalfa was obvious in the biological study. Goat's rue did not contain any known phytoestrogens, and the biological study was completely negative.

PMID: 7892287

Gastroenterology 1987 Aug;93(2):225-33
Dietary estrogens--a probable cause of infertility and liver disease in captive cheetahs.
Setchell KD, Gosselin SJ, Welsh MB, Johnston JO, Balistreri WF, Kramer LW, Dresser BL, Tarr MJ

  The cheetah in the wild is "racing towards extinction" mostly due to habitat destruction. Its survival will probably depend on accelerated captive breeding. At this time, however, reproductive failure and liver disease threaten the future of the captive cheetah population. Histopathological evaluation of more than 100 cheetah livers identified venocclusive disease as the main hepatic lesion responsible for liver disease in this species. Analysis of the commercial feline diet by high-performance liquid chromatography and gas-liquid chromatography-mass spectrometry revealed large amounts of two phytoestrogens identified as daidzein and genistein. These compounds were found to be derived from a soybean product that was a component of the cheetah diet, and their concentrations both ranged from 18 to 35 micrograms/g diet. The adult cheetah consequently consumes approximately 50 mg/day of these weak estrogens. When extracts of the diet were tested for estrogenicity using a bioassay, a dose-related increase in uterine weight was observed. In 4 cheetahs studied, withdrawal of this feline diet by substitution with a chicken diet resulted in an improvement in conventional liver function tests and a normalization in the appearance of hepatic mitochondria. We conclude that the relatively high concentrations of phytoestrogens from soybean protein present in the commercial diet fed to captive cheetahs in North American zoos may be one of the major factors in the decline of fertility and in the etiology of liver disease in this species. The survival of the captive cheetah population could depend upon a simple change of diet by excluding exogenous estrogen.

PMID: 3297906

J Anim Sci 1995 May;73(5):1509-15
Detection of the effects of phytoestrogens on sheep and cattle.
Adams NR CSIRO Division of Animal Production, Australia.

  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.

PMID: 7665383

Med Hypotheses 1982 Apr;8(4):349-54
The possible connection between phytoestrogens, milk and coronary heart disease.
Seely S

  Phytoestrogens are estrogen mimics produced mainly by leguminous plants, like clover, lucerne and soya beans, but also by some grasses and other plants. They are isoflavones and other plant phenols, bearing no resemblance to natural estrogens, but somewhat similar to non-steroidal synthetic estrogens, like diethylstilbestrol. Normally they have little ill effect on herbivores, but in large doses they can result in prolonged periods of estrus. It is suggested that when consumed by lactating cows, the estrogenic substance appears in their milk and transferred to the human consumer, on whom the effect could be similar to that of diethylstilbestrol - a substance with well substantiated atherogenic properties. This could be the explanation of the strong positive correlation between the consumption of milk and mortality from coronary disease reported in previous papers of the writer and other authors, and also of the differences between male and female mortality from coronary disease. When phytoestrogens are consumed directly in plants like soya beans, they appear to be correlated with cerebrovascular disease.

PMID: 7099059

J Clin Endocrinol Metab 1999 Jun;84(6):2249-52
Identification of a potent phytoestrogen in hops (Humulus lupulus L.) and beer.
Milligan SR, Kalita JC, Heyerick A, Rong H, De Cooman L, De Keukeleire D Physiology Division, School of Biomedical Sciences, King's College, Strand, London, UK.

  The female flowers of the hop plant are used as a preservative and as a flavoring agent in beer. However, a recurring suggestion has been that hops have a powerful estrogenic activity and that beer may also be estrogenic. In this study, sensitive and specific in vitro bioassays for estrogens were used for an activity-guided fractionation of hops via selective solvent extraction and appropriate HPLC separation. We have identified a potent phytoestrogen in hops, 8-prenylnaringenin, which has an activity greater than other established plant estrogens. The estrogenic activity of this compound was reflected in its relative binding affinity to estrogen receptors from rat uteri. The presence of 8-prenylnaringenin in hops may provide an explanation for the accounts of menstrual disturbances in female hop workers. This phytoestrogen can also be detected in beer, but the levels are low and should not pose any cause for concern.

PMID: 10372741

Baillieres Clin Endocrinol Metab 1998 Dec;12(4):667-90
Reproductive actions of phytoestrogens.
Whitten PL, Naftolin F Department of Anthropology, Emory University, Atlanta, GA 30322, USA.

  This chapter reviews the reproductive actions of phytoestrogens, comparing mechanisms of action, dose-response relationships, and human exposures. Although a wide range of biochemical actions have been reported for phytoestrogens, in vitro tests suggest that phytoestrogens may be more likely to act through receptor-mediated mechanisms than through enzyme inhibition. Epithelial cell proliferation in the reproductive tract and anestrus are well-documented actions of isoflavonoids in experimental studies of animals. However, thus far, soy-based diets have generally failed to produce epithelial proliferation in ovariectomized rats and monkeys or menopausal women, and clinical studies have produced mixed evidence for effects of soy isoflavones on the human menstrual cycle or post-menopausal gonadotropin secretion. There has been considerable interest in the use of phytoestrogens as oestrogen replacement therapy in menopausal women. Reported results of initial clinical trials have been mixed, and it is unclear whether isoflavones in presently advised doses can substantially reduce menopausal symptoms. Some recent trials with oral isoflavone supplements report reductions in hot flushes, vaginal dryness, and breast pain. There is also limited clinical evidence for protective actions of isoflavones in mammary cancer. Like other oestrogenic substances, the isoflavonoids are effective differentiating agents in rodent models of development. The consequences of these actions for humans is of interest due to the high concentrations of isoflavonoids in some infant formulae. Thus, it is likely that some humans may experience greater exposure to phytoestrogens in infancy than in any other lifestage. At the time of writing, no ill effects of such exposure have been reported.

PMID: 10384819

J Paediatr Child Health 1998 Apr;34(2):135-8
Isoflavone content of infant foods and formulas.
Knight DC, Eden JA, Huang JL, Waring MA School of Obstetrics and Gynaecology, Royal Hospital for Women, Randwick, New South Wales, Australia.

  OBJECTIVE: The purpose of this study was to investigate the phytoestrogen content of different foods, formulas and drinks that may be consumed by infants during their first year of life in an attempt to define levels of exposure on different feeding regimens. METHODOLOGY: High performance liquid chromatography (HPLC) was used to determine the levels of genistein, daidzein, biochanin A, formononetin and equol in samples purchased from Australian supermarkets. Single lots of duplicate or triplicate samples of soy beverages, cow's milks, infant formulas and infant yoghurts were analysed. RESULTS: All foods tested contained isoflavones, at varying levels, suggesting that exposure to these compounds is almost ubiquitous. Casein-based infant formulas contained between 0.001 and 0.03 mg L(-1). Soy-based infant formulas ranged from 17.2 to 21.9 mg L(-1) with the values detected in yoghurt at similar levels to that of cow's milk. For comparison, the soy-based beverages (which are not recommended for use under 12 months of age) contained levels of isoflavones from 22.9 to 71.5 mg L(-1). CONCLUSIONS: Given the relatively broad choice of infant foods becoming available, exposure to dietary isoflavones during the first year of life is virtually ubiquitous. The exposure may be higher if soy infant formulas are consumed, however, the levels attained appear to fall within normal physiological boundaries.

PMID: 9588635

Proc Soc Exp Biol Med 1998 Mar;217(3):379-85
Herbal medicines, phytoestrogens and toxicity: risk:benefit considerations.
Sheehan DM National Center for Toxicological Research, U.S. Food and Drug Administration, DHHS, Jefferson, Arkansas 72079, USA.

  There are several suggested health benefits of phytoestrogens, particularly those found in soy products. Herbal medicines are also widely thought to confer health benefits. Additionally, drugs are prescribed to improve human health, but unlike phytoestrogens and herbal medicines, toxicities are defined in experimental animals and monitored in humans before and after marketing. Knowledge of toxicity is crucial to decrease the risk:benefit ratio; this knowledge defines appropriate conditions for use and strategies for development of safer products. However, our awareness of the toxicity of herbal medicines and phytoestrogen-containing foods is dramatically limited compared to drugs. Some aspects of the toxicity of herbal medicines are briefly reviewed; it is concluded that virtually all of our knowledge is derived from human exposures leading to acute toxicities. Importantly, detection of toxicity is sporadic, and little information is available from prior animal experimentation. Additionally, well-organized monitoring of human populations (as occurs for drugs) is virtually nonexistent. Important toxicities with long latencies are particularly difficult to associate with a causative agent during or even after large scale exposures, as exemplified by tobacco smoking and lung cancer; estrogen replacement therapy and endometrial cancer; diethylstilbestrol and reproductive tract cancers; and fetal alcohol exposure and birth defects. These considerations suggest that much closer study in experimental animals and human populations exposed to phytoestrogen-containing products, and particularly soy-based foods, is necessary. Among human exposures, infant soy formula exposure appears to provide the highest of all phytoestrogen doses, and this occurs during development, often the most sensitive life-stage for induction of toxicity. Large, carefully controlled studies in this exposed infant population are a high priority.

PMID: 9492351

Proc Soc Exp Biol Med 1998 Mar;217(3):247-53
Phytoestrogens in soy-based infant foods: concentrations, daily intake, and possible biological effects.
Irvine CH, Fitzpatrick MG, Alexander SL Animal and Veterinary Sciences Group, Lincoln University, Canterbury, New Zealand.

  Exposure to estrogenic compounds may pose a developmental hazard to infants. Soy products, which contain the phytoestrogens, genistein and daidzein, are becoming increasingly popular as infant foods. To begin to evaluate the potential of the phytoestrogens in these products to affect infants, we measured total genistein and daidzein contents of commercially available soy-based infant formulas, infant cereals, dinners, and rusks. We also assayed phytoestrogens in dairy-based formulas and in breast milk from omnivorous or vegetarian mothers. In most cases, the glucoside forms of the phytoestrogens were hydrolyzed before separation by HPLC. Mean (+/-SEM) total genistein and daidzein contents in four soy infant formulas were 87+/-3 and 49+/-2 microg/g, respectively. The phytoestrogen content of cereals varied with brand, with genistein ranging from 3-287 microg/g and daidzein from 2-276 microg/g. By contrast, no phytoestrogens were detected in dairy-based infant formulas or in human breast milk, irrespective of the mother's diet (detection limit = 0.05 microg/ml). When fed according to the manufacturer's instruction, soy formulas provide the infant with a daily dose rate of total isoflavones (i.e., genistein + daidzein) of approximately 3 mg/kg body weight, which is maintained at a fairly constant level between 0-4 months of age. Supplementing the diet of 4-month-old infants with a single daily serving of cereal can increase their isoflavone intake by over 25%, depending on the brand chosen. This rate of isoflavone intake is much greater than that shown in adult humans to alter reproductive hormones. Since the available evidence suggests that infants can digest and absorb dietary phytoestrogens in active forms and since neonates are generally more susceptible than adults to perturbations of the sex steroid milieu, we suggest that it would be highly desirable to study the effects of soy isoflavones on steroid-dependent developmental processes in human babies.

PMID: 9492332

Am J Obstet Gynecol 1999 Mar;180(3 Pt 1):737-43
Maternal and neonatal phytoestrogens in Japanese women during birth.
Adlercreutz H, Yamada T, Wahala K, Watanabe S Department of Clinical Chemistry, University of Helsinki, Finland.

  OBJECTIVE: High levels of soy isoflavonoids among adult Japanese persons are associated with a low incidence of hormone-dependent cancers, but nothing is known about isoflavonoids in pregnancy.Study Design: We studied 7 young healthy Japanese women at delivery by measuring 6 phytoestrogen metabolites in maternal and cord plasma and in amniotic fluid. RESULTS: Total maternal plasma isoflavonoid concentrations ranged from 19 to 744 nmol/L (mean 232 nmol/L), cord plasma values ranged from 58 to 831 nmol/L (mean 299 nmol/L), and amniotic fluid values ranged from 52 to 779 nmol/L (mean 223 nmol/L). Maternal and cord plasma and amniotic fluid lignan values were low. CONCLUSIONS: The high levels of isoflavonoid phytoestrogens found in healthy neonatal Japanese infants indicate transfer of isoflavonoids from the maternal to the fetal compartment. These compounds may modify estrogen metabolism and action during fetal life and perhaps affect cancer risk.

Environ Health Perspect 1988 Jun;78:171-4
Phytochemical mimicry of reproductive hormones and modulation of herbivore fertility by phytoestrogens.
Hughes CL Jr Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27710.

  Plants have physical and chemical mechanisms for defense from attack by animals. Phytochemical defenses that protect plants from attack by insects include antifeedants, insecticides, and insect growth regulators. Phytochemical options exist by which plants can modulate the fertility of the other major group of plant predators, vertebrate herbivores, and thereby reduce cumulative attacks by those herbivores. The success of such a defense depends upon phytochemical mimicry of vertebrate reproductive hormones. Phytoestrogens do mimic reproductive hormones and are proposed to be defensive substances produced by plants to modulate the fertility of herbivores.

PMID: 3203635

Am J Clin Nutr 1998 Dec;68(6 Suppl):1333S-1346S
Phytoestrogens: the biochemistry, physiology, and implications for human health of soy isoflavones.
Setchell KD Clinical Mass Spectrometry Center, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

  The importance of estrogens in homeostatic regulation of many cellular and biochemical events is well illustrated by the pathophysiologic changes that occur with estrogen deficiency. Many of the major diseases of Western populations are hormone dependent and epidemiologic data have shown a strong association between their incidence and diet. In particular, the importance of a plant-based diet is evident from the current dietary recommendations that emphasize an increase in the proportion and amount of fruit and vegetables that should be consumed. Although interpretation of the role of individual components of the diet is difficult from epidemiologic and dietary studies, it is recognized that there are many plant-derived bioactive nonnutrients that can confer significant health benefits. Among these phytochemicals is the broad class of nonsteroidal estrogens called phytoestrogens, and in the past decade there has been considerable interest in the role of isoflavones because of their relatively high concentrations in soy protein. The isoflavones in modest amounts of ingested soy protein are biotransformed by intestinal microflora, are absorbed, undergo enterohepatic recycling, and reach circulating concentrations that exceed by several orders of magnitude the amounts of endogenous estrogens. These phytoestrogens and their metabolites have many potent hormonal and nonhormonal activities that may explain some of the biological effects of diets rich in phytoestrogens.

Toxicol Lett 1998 Dec 28;102-103:349-54
Dietary phytoestrogens and their role in hormonally dependent disease.
Strauss L, Santti R, Saarinen N, Streng T, Joshi S, Makela S Institute of Biomedicine and Medicity Research Laboratory, University of Turku, Finland.

  Epidemiological studies suggest that diets rich in phytoestrogens (plant estrogens), particularly soy and unrefined grain products, may be associated with low risk of breast and prostate cancer. It has also been proposed that dietary phytoestrogens could play a role in the prevention of other estrogen-related conditions, namely cardiovascular disease, menopausal symptoms and post-menopausal osteoporosis. However, there is no direct evidence for the beneficial effects of phytoestrogens in humans. All information is based on consumption of phytoestrogen-rich diets, and the causal relationship and the mechanisms of phytoestrogen action in humans still remain to be demonstrated. In addition, the possible adverse effects of phytoestrogens have not been evaluated. It is plausible that phytoestrogens, as any exogenous hormonally active agent, might also cause adverse effects in the endocrine system, i.e. act as endocrine disrupters.

Am J Clin Nutr 1998 Dec;68(6 Suppl):1453S-1461S
Isoflavone content of infant formulas and the metabolic fate of these phytoestrogens in early life.
Setchell KD, Zimmer-Nechemias L, Cai J, Heubi JE Clinical Mass Spectrometry Center, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

  Soy-based infant formulas have been in use for >30 y. These formulas are manufactured from soy protein isolates and contain significant amounts of phytoestrogens of the isoflavone class. As determined by HPLC, the isoflavone compositions of commercially available formulas are similar qualitatively and quantitatively and are consistent with the isoflavone composition of soy protein isolates. Genistein, found predominantly in the form of glycosidic conjugates, accounts for >65% of the isoflavones in soy-based formulas. Total isoflavone concentrations of soy-based formulas prepared for infant feeding range from 32 to 47 mg/L, whereas isoflavone concentrations in human breast milk are only 5.6 +/- 4.4 microg/L (mean +/- SD, n = 9). Infants fed soy-based formulas are therefore exposed to 22-45 mg isoflavones/d (6-11 mg x kg body wt(-1) x d(-1)), whereas the intake of these phytoestrogens from human milk is negligible (<0.01 mg/d). The metabolic fate of isoflavones from soy-based infant formula is described. Plasma isoflavone concentrations reported previously for 4-mo-old infants fed soy-based formula were 654-1775 microg/L (mean: 979.7 microg/L: Lancet 1997:350;23-7), significantly higher than plasma concentrations of infants fed either cow-milk formula (mean +/- SD: 9.4 +/- 1.2 microg/L) or human breast milk (4.7 +/- 1.3 microg/L). The high steady state plasma concentration of isoflavones in infants fed soy-based formula is explained by reduced intestinal biotransformation, as evidenced by low or undetectable concentrations of equol and other metabolites, and is maintained by constant daily exposure from frequent feeding. Isoflavones circulate at concentrations that are 13,000-22,000-fold higher than plasma estradiol concentrations in early life. Exposure to these phytoestrogens early in life may have long-term health benefits for hormone-dependent diseases. [or long-term deleterious effects LF]

Am J Clin Nutr 1998 Dec;68(6 Suppl):1431S-1435S
Effects of soy-protein supplementation on epithelial proliferation in the histologically normal human breast.
McMichael-Phillips DF, Harding C, Morton M, Roberts SA, Howell A, Potten CS, Bundred NJ Department of Epithelial Biology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, United Kingdom.

  A high dietary intake of soy products (eg, as in Japan and Singapore) has been associated with a reduction in the incidence of breast cancer in premenopausal women. Phytoestrogens present in soybeans inhibit human breast cancer cell proliferation in vitro and breast cancer development in animal models, but no data exist on the effects of phytoestrogens on histologically normal human breasts. This study examines the effects of dietary soy supplementation on the proliferation rate of premenopausal, histologically normal breast epithelium and the expression of progesterone receptor. Women (n = 48) with benign or malignant breast disease were randomly assigned to receive their normal diet either alone or with a 60-g soy supplement (containing 45 mg isoflavones) taken daily for 14 d. Biopsy samples of normal breasts were labeled with [3H]thymidine to detect the number of cells in S phase and were immunocytochemically stained for the proliferation antigen Ki67. The phytoestrogens genistein, daidzein, equol, enterolactone, and enterodiol were measured in serum samples obtained before and after supplementation. Serum concentrations of the isoflavones genistein and daidzein increased in the soy group at 14 d. Results showed a strong correlation between Ki67 and the thymidine labeling index (r = 0.868, P < or = 0.001). The proliferation rate of breast lobular epithelium significantly increased after 14 d of soy supplementation when both the day of menstrual cycle and the age of patient were accounted for. Progesterone receptor expression increased significantly in the soy group. Short-term dietary soy stimulates breast proliferation; further studies are required to determine whether this is due to estrogen agonist activity and to examine the long-term effects of soy supplementation on the pituitary gland and breast.

[Is it wise to dose the infant with soy? LF]

J Am Diet Assoc 1995 May;95(5):545-51
Urinary isoflavonoid phytoestrogen and lignan excretion after consumption of fermented and unfermented soy products.
Hutchins AM, Slavin JL, Lampe JW Department of Food Science and Nutrition, University of Minnesota, St. Paul, USA.

  OBJECTIVE: To compare the effects of consumption of fermented and unfermented soy products on excretion of urinary isoflavonoid phytoestrogens and lignans in healthy men. DESIGN: A randomized, crossover trial consisting of two 9-day feeding periods following 5 days of baseline data collection. SUBJECTS: Healthy men, aged 20 to 40 years, were recruited from the University of Minnesota Twin Cities community. Of the 22 subjects who began the study, 17 completed all feeding periods. INTERVENTIONS: Fermented soy product (112 g tempeh) or unfermented soy (125 g soybean pieces) was consumed during each controlled feeding period. MAIN OUTCOME MEASURE: Urine samples collected while subjects consumed their habitual diets and on the last 3 days of each feeding period were analyzed for isoflavonoid and lignan content by isotope dilution gas chromatography-mass spectrometry. STATISTICAL ANALYSIS PERFORMED: Comparisons of isoflavonoid and lignan excretion were analyzed using the general linear model procedure. Orthogonal contrasts were used to determine treatment differences of interest. RESULTS: Urinary excretion of isoflavonoids (equol, O-desmethylangolensin [O-DMA], daidzein, genistein) was higher and excretion of lignans (enterodiol, enterolactone) was lower when subjects consumed soy-supplemented diets than when they consumed their habitual diets (P < .05). Urinary isoflavonoid excretion and lignan excretion were similar when subjects consumed tempeh and soybean pieces diets; however, recovery of daidzein and genistein was significantly higher when subjects consumed the tempeh diet than when they consumed the soybean pieces diet (P < .002). When fed soy, 5 of 17 subjects excreted high amounts of equol. These five subjects tended to excrete less O-DMA and daidzein than the 12 subjects who excreted low amounts of equol (P < .06). CONCLUSIONS: Fermentation of soy decreased the isoflavone content of the product fed but increased the urinary isoflavonoid recovery. This finding suggests that fermentation increases availability of isoflavones in soy.

PMID: 7722188

Lancet 1993 May 29;341(8857):1392-5
Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract?
Sharpe RM, Skakkebaek NE MRC Reproductive Biology Unit, Centre for Reproductive Biology, Edinburgh, UK.

  The incidence of disorders of development of the male reproductive tract has more than doubled in the past 30-50 years while sperm counts have declined by about half. Similar abnormalities occur in the sons of women exposed to diethylstilbestrol (DES) during pregnancy and can be induced in animals by brief exposure to exogenous oestrogen/DES during pregnancy. We argue that the increasing incidence of reproductive abnormalities in the human male may be related to increased oestrogen exposure in utero, and identify mechanisms by which this exposure could occur. Comments: Comment in: Lancet 1993 Jul 10;342(8863):123-4 Comment in: Lancet 1993 Jul 10;342(8863):124 Comment in: Lancet 1993 Jul 10;342(8863):124-5 Comment in: Lancet 1993 Jul 10;342(8863):125 Comment in: Lancet 1993 Jul 10;342(8863):125-6 Comment in: Lancet 1995 Oct 14;346(8981):1040-1 Comment in: Lancet 1996 Feb 24;347(9000):553-4

PMID: 8098802

J Am Diet Assoc 1994 Jul;94(7):739-43
Tofu and soy drinks contain phytoestrogens.
Dwyer JT, Goldin BR, Saul N, Gualtieri L, Barakat S, Adlercreutz H Tufts University School of Medicine, Boston, Mass. 02111.

  OBJECTIVE: As the intakes of soy foods rise in the American diet, the weak estrogenic activity of plant phytoestrogens may reach biologically effective levels. We determined the content of phytoestrogens (plant compounds with weak estrogenic activity in human beings) in tofu, a commercially produced soy drink, and three soy-based formulas. DESIGN: A modified isotope dilution gas chromatography-mass spectrometry method was used to analyze samples obtained from supermarkets or manufacturers. SAMPLES: Two or three lots of duplicate samples of four brands of tofu, one commercially produced soy drink, and three soy-based specialty formulas were analyzed. Means and standard deviations were calculated for the isoflavones daidzein, Biochanin A, genistein, coumestrol, and formononetin. RESULTS: Tofu soy products were highest in isoflavone content; means of brands ranged from 73.0 to 97.5 micrograms/g daidzein per g wet weight and 187.4 to 215.9 micrograms genistein per g wet weight. The commercial soy drink followed with 7.0 micrograms daidzein per g wet weight and 21.0 micrograms genistein per g wet weight; the soy-based formulas were nearly devoid of these two isoflavones. Mean levels of Biochanin A, formononetin, and coumestrol were very low or nil (eg, 0 to 1.0 microgram/g) in all products. CONCLUSIONS: Tofu contained the highest amounts of isoflavones among the products tested, and there was some variability from brand to brand. The soy drink contained lesser amounts, and soy-based formulas were devoid of isoflavones.

Comment in: J Am Diet Assoc 1994 Nov;94(11):1253-4

PMID: 8021414

Drugs Exp Clin Res 1999;25(2-3):111-4
Nonalcoholic compounds of wine: the phytoestrogen resveratrol and moderate red wine consumption during menopause.
Calabrese G Department of Human Nutrition, Universita Cattolica S. Cuore, Piacenza, Italy.

   The literature on the natural sources of resveratrol, a phytochemical substance found in grapes and wine, is reviewed herein. Its structure is similar to that of diethylstilbestrol and, like other authors, we consider that resveratrol might be a phytoestrogen. We analyzed the populations who ingest this substance, as well as the known biological effects of phytoestrogens in humans. The literature on the effects of resveratrol on female reproduction, osteoporosis and cancer was assessed using relevant case reports and cohort studies, as well as randomized trials and review articles. We conclude that phytoestrogens exhibit physiological effects in humans and that these estrogenic actions increase the biological reactions produced by moderate red wine consumption with meals.

PMID: 10370872

Rev Reprod 1997 May;2(2):69-73
Environmental oestrogens--present understanding.
Turner KJ, Sharpe RM MRC Reproductive Biology Unit, Centre for Reproductive Biology, Edinburgh, UK.

  Three years ago it was hypothesized that the reported adverse changes in male reproductive health could be explained by exposure to compounds with oestrogenic (or other hormone disruptive) activity. Although this issue has been highly publicized, there has been little progress towards a realistic assessment of whether environmental oestrogens pose a health risk to humans. This article attempts to give a brief overview of the current status of knowledge concerning environmental oestrogens and highlights some of the difficulties associated with risk assessment. Compounds within several major groups of chemicals, including organochlorine pesticides, polychlorinated biphenyls, phenolic compounds and phthalate esters, have been identified as being weakly oestrogenic by in vitro and in vivo screening methods. Many of these compounds are widespread and persistent in the environment. They are likely to be present in the food chain, drinking water, plastics, household products and food packaging, although which is the most important route of human exposure is unclear. In addition to exposure to man-made chemicals, the consumption of plant-derived oestrogens in foodstuffs poses a potential risk to human health as phytoestrogens are more potent oestrogens and their intake by some infants is likely to be considerable.

PMID: 9414467


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