Article

Effects of dietary soy isoflovones on health, steroidogenesis, and thyroid gland function in dogs

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Abstract

To evaluate the effect of a soy-based diet on general health and adrenocortical and thyroid gland function in dogs. Animals-20 healthy privately owned adult dogs. In a randomized controlled clinical trial, dogs were fed a soy-based diet with high (HID; n = 10) or low (LID; 10) isoflavones content. General health of dogs, clinicopathologic variables, and serum concentrations of adrenal gland and thyroid gland hormones were assessed before treatment was initiated and up to 1 year later. Differences between groups with respect to changes in the values of variables after treatment were assessed by means of a Student t test (2 time points) and repeated-measures ANOVA (3 time points). No differences were detected between the 2 groups with respect to body condition and results of hematologic, serum biochemical, and urine analyses. Most serum concentrations of hormones did not change significantly after treatment, nor were they affected by diet. However, the mean change in serum concentration of total thyroxine was higher in the HID group (15.7 pmol/L) than that in the LID group (-1.9 pmol/L). The mean change in estradiol concentration after ACTH stimulation at 1 year after diets began was also higher in the HID group (19.0 pg/mL) than that in the LID group (-5.6 pg/mL). Phytoestrogens may influence endocrine function in dogs. Feeding soy to dogs on a long-term basis may influence results of studies in which endocrine function is evaluated, although larger studies are needed to confirm this supposition.

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... They found that most of the diets that included soybean ingredients had detectable concentrations of phytoestrogens, which could have biological effects when ingested by dogs long-term. To explore that possibility, Cerundolo et al. (2009) evaluated the effect of dietary soybean isoflavones on general health and adrenocortical and thyroid gland function in dogs [55]. They were fed a hydrolyzed soybean-isolate-based diet or the same diet without isoflavones, and most serum concentrations of hormones were not affected by diet. ...
... They found that most of the diets that included soybean ingredients had detectable concentrations of phytoestrogens, which could have biological effects when ingested by dogs long-term. To explore that possibility, Cerundolo et al. (2009) evaluated the effect of dietary soybean isoflavones on general health and adrenocortical and thyroid gland function in dogs [55]. They were fed a hydrolyzed soybean-isolate-based diet or the same diet without isoflavones, and most serum concentrations of hormones were not affected by diet. ...
... Further research is needed to find out the right enzymes and enzyme supplementation timing for dogs to increase the nutrient utilization of soybeans. In addition, microbially fermented soybean ingredients and phytoestrogens, such as isoflavones, were suggested to have additional potential health benefits (prevention of certain types of cancers or control of obesity), but there are also concerns about the estrogenic effect when dogs receive high amounts of isoflavones on a long-term basis [53,55]. More detailed research on the optimal dose and health effects from long-term consumption of these functional soybean-based ingredients may provide more opportunities to expand soybean utilization in pet food. ...
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Simple Summary Soybean is a dominant oilseed in the U.S. Although soybeans are valuable ingredients for dogs and cats, soybean use in current pet foods has been low. The research was conducted to answer this question: What effects, if any, do soybean ingredients in dog or cat diets have on animal health and nutrition, palatability, feeding behavior, allergenicity, and extrusion processing? We summarized the most current research on soybeans in pet foods published since 2000. We discussed the strengths, weaknesses, opportunities, and threats of soybean in pet food applications. We concluded that various food processing technologies and the versatility of soybean ingredients have been demonstrated to offer considerable potential for inclusion as oil, protein, fiber, or functional ingredients in pet foods. Our work will be valuable, providing research status and gaps. Abstract Soybean use has been low in pet foods, even though they are an excellent source of protein, polyunsaturated fatty acids, and gut fermentable fibers. The purpose of this evaluation was to conduct a systematic review of the public literature to explore how soybeans have been researched for pet food applications since 2000 and to provide strengths, weaknesses, opportunities, and threats for soybeans in the pet food industry. The review covered a total of 44 articles related to soybean ingredients and their potential value in the pet food arena. The articles were categorized by their research contents and narratively summarized to demonstrate useful information to both the pet and soybean industries. When soybean-based products have been adequately processed to reduce the antinutritive factors, they are comparable to processed animal proteins in nutritional value, palatability, and functionality in pet food processing. We conclude that various food processing technologies and the versatility of soybean ingredients allow soybean to have considerable inclusion potential in pet foods. More research on dietary soybean ingredients regarding pet food processing, fermentation benefits on health, and consumer acceptance will be needed to understand soybean’s position in the future pet food industry.
... Skin and coat health: • An in vitro study using a nutrient combination that included curcumin demonstrated promise in helping to maintain the canine skin barrier (Fray et al., 2004). • Healthy dogs fed high-or low-isoflavone soy-based diets, had no detectable differences in skin and coat health, indicating soy as a safe ingredient for dogs with skin and hair issues (previously thought to have negative impact) (Cerundolo et al., 2009). • Both healthy dogs supplemented with flax or sunflower seeds showed improvements in their skin and coat condition scores after 1 month (Rees et al., 2001). ...
... Soy was historically a common ingredient in dog food. Due to their oestrogenic activity at high doses, soy isoflavones were suspected to impact the hormonal status of dogs and cause negative impacts to skin quality, along with hair loss and thinning (Cerundolo et al., 2009). However, in a prospective controlled randomized trial, 30 normal dogs were either fed a high-or a low-isoflavone soy-based diet for 12 months. ...
... However, in a prospective controlled randomized trial, 30 normal dogs were either fed a high-or a low-isoflavone soy-based diet for 12 months. Upon conclusion of the study, no detectable differences were found in skin and coat quality, and the authors concluded that inclusion of soy isoflavones appears to have no positive or negative impact on skin health (Cerundolo et al., 2009). ...
Article
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Dogs possess the ability to obtain essential nutrients, established by the Association of American Feed Control Officials (AAFCO), from both animal- and plant-based ingredients. There has been a recent increase in the popularity of diets that limit or completely exclude certain plant-based ingredients. Examples of these diets include ‘ancestral’ or ‘evolutionary’ diets, raw meat-based diets and grain-free diets. As compared to animal sources, plant-derived ingredients (including vegetables, fruits, grains, legumes, nuts and seeds) provide many non-essential phytonutrients with some data suggesting they confer health benefits. This review aims to assess the strength of current evidence on the relationship between the consumption of plant-based foods and phytonutrients (such as plant-derived carotenoids, polyphenols and phytosterols) and biomarkers of health and diseases (such as body weight/condition, gastrointestinal health, immune health, cardiovascular health, visual function and cognitive function) from clinical trials and epidemiological studies. This review highlights the potential nutritional and health benefits of including plant-based ingredients as a part of balanced canine diets. We also highlight current research gaps in existing studies and provide future research directions to inform the impact of incorporating plant-based ingredients in commercial or home-prepared diets.
... In prior work we found a marked effect on thyroid function in cats administered a soy diet for 3 months that resulted in significant elevations in thyroxine (T 4 ) concentrations relative to triiodothyronine (T 3 ) concentrations (White et al. 2004). Conversely, we conducted a similar study in dogs and found no effect of a soy-based diet on T 4 concentrations (Cerundolo et al. 2009). One of the proposed mechanisms for this increase in T 4 relative to T 3 is inhibition by soy isoflavones of thyroid peroxidase the enzyme that converts T 4 to T 3 , (Divi et al. 1997;Divi and Doerge 1996;White et al. 2004). ...
... In this study, we quantified and compared the soy isoflavone metabolite profiles in urine samples collected from cats and dogs that were fed a soybean-based diet daily for 3 months or 12 months (respectively). These diets had been shown in previous studies to cause detectable effects on endocrine function, including elevated free T 4 concentrations in the cats (White et al. 2004) and elevated estradiol concentrations without thyroid hormone effects in the dogs (Cerundolo et al. 2009). Since we found evidence for much lower (or no) concentrations of glucuronidated metabolites in urine from cats versus dogs, we also attempted to replicate these findings by in vitro glucuronidation assays using livers from cats and dogs, and also extend the findings to an additional 11 other mammalian species. ...
... Urine samples from 10 healthy dogs, owned by students and staff at the University of Pennsylvania Veterinary Teaching Hospital, and 18 healthy cats, owned by students and staff at Tufts University, were used for this study as reported in detail previously (Cerundolo et al. 2009;White et al. 2004). These studies were conducted to determine the effect of dietary soy on endocrine function. ...
Article
1. Soybean is a common source of protein in many pet foods. Slow glucuronidation of soy-derived isoflavones in cats has been hypothesized to result in accumulation with adverse health consequences. Here, we evaluated species’ differences in soy isoflavone glucuronidation using urine samples from cats and dogs fed a soy-based diet and liver microsomes from cats compared with microsomes from 12 other species. 2. Significant concentrations of conjugated (but not unconjugated) genistein, daidzein and glycitein, and the gut microbiome metabolites, dihydrogenistein and dihydrodaidzein, were found in cat and dog urine samples. Substantial amounts of conjugated equol were also found in cat urine but not in dog urine. 3. β-Glucuronidase treatment showed that all these compounds were significantly glucuronidated in dog urine while only daidzein (11%) and glycitein (37%) showed any glucuronidation in cat urine suggesting that alternate metabolic pathways including sulfation predominate in cats. 4. Glucuronidation rates of genistein, daidzein and equol by cat livers were consistently ranked within the lowest 3 out of 13 species’ livers evaluated. Ferret and mongoose livers were also ranked in the lowest four species. 5. Our results demonstrate that glucuronidation is a minor pathway for soy isoflavone metabolism in cats compared with most other species.
... 23 There was also a report evaluating the effect of a soy-based diet on adrenocortical and thyroid gland function in adult dogs. 24 In the study, dogs were fed one of two diets, either a "high isoflavone diet" or a "low isoflavone diet", and estrogen levels were measured after adrenocorticotropic hormone (ACTH) stimulation at 0, 6, and 12 months. Significant differences in estrogen values existed between the two groups after ACTH stimulation testing at 1 year. ...
... According to the authors, findings from these studies suggest that phytoestrogens may affect endocrine function in dogs and can be associated with increases in serum concentrations of endogenous estrogens. 24 Whether these findings are valid for tofu remains to be elucidated. The objective of this study was to investigate whether tofu supplementation would raise endogenous estrogen levels in spayed incontinent female dogs and recapitulate study findings described by Cerundolo. ...
Article
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The objective of this randomized controlled study was to determine whether supplementing a spayed female dog’s diet with tofu can raise levels of endogenous estrogen (EE), which could be beneficial for estrogen-responsive incontinence. A total of 23 client-owned spayed female dogs diagnosed with urinary incontinence but no other known health conditions participated in the study. Enrolled subjects were randomly assigned to 2 groups: Control Group (n=10) who received normal diet with a placebo supplement or Test Group (n=13) who received tofu supplementation. Supplements were given twice daily for 14 days. Blood samples were collected on Day 0 and Day 14 to assess pre-treatment and post-treatment EE levels. Effects of tofu supplementation were assessed based on group comparison of EE level improvement. The EE level within the Control Group had a nonsignificant decrease from days 0 to 14 (56.9±22.8 → 54.6±25.3 pg/mL, p=0.54). Test Group EE level significantly increased after 14 days (37.1±17.2 → 58.5±28.9 pg/mL, p=0.013). For intergroup comparison, the change of EE levels in the Test Group was significantly greater than the Control Group (Control: -2.3±11.5 versus Test: 21.4±27.5 pg/mL, p=0.0002). The study also found that Test Group owner impression of urinary incontinence improvement (11/13) was significantly greater (p=0.0001) than that in the Control Group (0/10). The results of this study suggest the potential for developing a holistic, natural food therapy for urinary incontinence in spayed female dogs. Future prospective studies, with larger enrollment, that also consider factors such as treatment dose and duration are warranted.
... In addition to TBG, FT4 levels were also affected by the activity of peripheral deiodinase, which is responsible for converting FT4 to FT3. Animal study had shown that after 12 months of consumption of soy phytoestrogens in dogs, serum T4 level increased but T3 level did not change, which may be related to inhibition of 50-deiodinase activity [14]. de Souza Dos Santos MC et al [15] found that phytoestrogens have a broad inhibitory effect on 1deiodinase, and the inhibitory effect of different phytoestrogens varies. ...
Preprint
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Background Estrogen and thyroid hormone interact extensively in vivo, but the relationship between phytoestrogens and thyroid function and thyroid hormone sensitivity remains unclear. Methods Using 2007–2010 NHANES data of United States, we analysed the association of 6 types of urinary phytoestrogens with thyroid function and thyroid hormone sensitivity using a multivariate linear regression model. Results A total of 2,521 participants were included in the final analysis. After adjustment for multiple factors, we found that urinary phytoestrogens were associated with thyroid function and thyroid hormone sensitivity, and the associations were sex and type specific. For thyroid function: Phytoestrogens were negatively associated with FT4 and TT4 in overall analysis. After sex stratification, Equol, Enterodiol and TT4 were negatively associated in men. In women, Daidzein, O-Desmethylangolensin (O-DMA) and Genistein were positively associated with FT4, while Enterodiol was negatively associated with FT4. In addition, Enterolactone was negatively associated with TT4. For thyroid hormone sensitivity: Phytoestrogens were associated with Thyroid feedback quantile-based index (TFQI) in overall analysis. After sex stratification, Genistein was positively associated with FT3/FT4 ratio and Enterolactone was positively associated with TFQI in men. In women, Daidzein and O-DMA were negatively associated with FT3/FT4 ratio and positively associated with TFQI. Conclusion Urinary phytoestrogens were associated with FT4 and TT4 levels and may adversely affect the central thyroid hormone sensitivity. Given the risk of hypothyroidism and SCH associated with reduced thyroid hormone sensitivity, more health monitoring of people with high phytoestrogens intake is warranted.
... In contrast, less well known are the effects on thyroid function tests in dogs related to the administration of a prolonged diet of soybeans high in phytoestrogens that can inhibit 5'-iodothyronineadeiodinase responsible for the conversion of T 4 to T 3 . It has, in fact, been documented that dogs fed for more than a year on soybeans high in phytoestrogens can have increased T 4 concentrations (Cerundolo et al. 2009). ...
Article
The purpose of this study was to measure circulating TSH, T4 and fT4 concentrations in dogs submitted to a clinical visit for general symptoms (weight gain, polyuria and polydipsia, changes in hair coat). Twenty-eight dogs, 14 cross-breed and 14 purebreds (Golden Retriever, Labrador, Doberman), of both sexes (14 males and 14 females), aged 8 to 14 years, were assessed. No significant differences of circulating TSH, T4 , fT4 concentrations between the baseline and after therapeutic treatment nor between intact and neutered females were observed. Compared to baseline values, intact males showed higher TSH concentrations (p⟨0.01), and castrated males lower TSH concentrations (p⟨0.01) after therapeutic treatment. Compared to intact males, castrated males showed baseline TSH concentrations higher (p⟨0.01), but lower (p⟨0.01) after therapeutic treatment. No significant differences of T4 and fT4 concentrations between baseline conditions and after therapeutic treatment, nor between intact and castrated males, were observed. The experimental sample considered in this study falls within that casuistry involving elevated TSH concentrations but low serum T4 and fT4 concentrations or close to the minimum physiological cut-off, in which the common clinical signs suggestive of hypothyroidism was, essentially, overweight and neglected appearance of the hair.
... Diet is also the most important route of exposure to xenoestrogens in pets. Soy, which is rich in phytoestrogens, is a common pet food ingredient [102,121], and cereals and grains are a major source of mycotoxin contamination. It is commonly known that dry dog food contains larger amounts of cereals than wet dog food, and some studies, in fact, proved that dry dog food is contaminated with mycotoxins, including ZEA, at higher levels and frequency than wet dog food [122,123]. ...
Article
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Over the past few decades, several pollutants classified as environmental endocrine-disrupting chemicals (EDCs) have become a matter of significant public health concern. Companion animals play a major role in human society, and pet ownership is substantially increasing worldwide. These intimate human–pet relationships imply sharing much of the same environment, thus including exposure to similar levels of EDCs in daily routine. Here, we review the current knowledge on the sources and routes of exposure to EDCs in domestic indoor and outdoor environments and discuss whether endocrine disruption is a health concern in pets. We summarize the phenomenon of endocrine disruption, providing examples of EDCs with a known impact on dog and cat health. Then, we propose an overview of the literature on the adverse effects of EDCs in domestic pets, with a special focus on the health of reproductive and thyroid systems. Finally, we explore the potential role of companion animals as unintentional sentinels of environmental exposure to EDCs and the implications for public health risk assessment in a “shared risk” scenario. Overall, this review supports the need for an integrated approach considering humans, animals, and the environment as a whole for a comprehensive assessment of the impact of EDCs on human and animal health.
... In addition, phytoestrogens are structurally and functionally similar to 17β-E 2 and have the ability to bind to the 17β-E 2 receptors (ER), interacting more with ER-α than with ER-β 17 . Phytoestrogens may compete for the active binding site of 17β-E 2 and can contribute to maintain the profile of the hormone 17 . Furthermore; these molecules can contribute to the regulation of the expression of certain antioxidant enzymes through NrF2 18 . ...
Article
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There are few studies evaluating the oxidant-antioxidant status after oophorosalpingohysterectomy (OSH) in female dogs. Here we determined the effect of OSH on antioxidant enzymes in serum, and quantified morphological changes in subcutaneous adipocytes. Lateral OSH was performed in 12 female dogs. The concentration of 17β-estradiol (17β-E2), the activities of extracellular superoxide dismutase (SOD-ec), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and glutathione reductase (GR) were determined. Glutathione (GSH), glutathione disulfide (GSSG), lipid peroxidation (LPO), total antioxidant capacity (TAC), carbonylation and vitamin C were measured in serum. Subcutaneous adipose tissue was obtained to determine morphological changes and cell number, under basal conditions and six months after OSH. The SOD-ec, GPx and GST activities increased significantly (p ≤ 0.05), LPO, carbonylation and GSSG also increased. GSH and vitamin C decreased (p = 0.03). 17β-E2 tended to decrease six months after OSH. Hypertrophy of subcutaneous adipocytes was observed after OSH from the first month and was accentuated after six months (p = 0.001). The results suggest that 17β-E2 decreases after OSH and alters the antioxidant enzyme activities in serum thus, redox balance is altered. These changes are associated with an increase in body weight and hypertrophy of subcutaneous adipose tissue.
... 93 An interesting effect of a diet high in soy isoflavones in dogs was an elevation in total T4 concentrations. 98 The diet did not induce a hyperthyroid state, but could promote a higher metabolic rate, thus facilitating weight loss. In neutered cats, soy isoflavone supplementation induced a short term loss of appetite that rebounded quickly after addition of genistein. ...
Article
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John P Loftus, Joseph J Wakshlag Cornell University College of Veterinary Medicine, Veterinary Medical Center, Ithaca, NY, USAAbstract: Canine and feline obesity rates have reached pandemic proportions and are similar to those in humans, with approximately 30%–40% of dogs and cats being overweight to obese. Obesity has been associated with other health problems, including osteoarthritis, renal disease, skin disease, insulin resistance, and neoplasia in dogs, while in cats obesity is associated with dermatological issues, diabetes mellitus, neoplasia, and urolithiasis. The health issues appear to be slightly different across the two species, which may be due to some inherent differences in the hormonal milieu involved in obesity that differs between the dog and the cat. In this review, we discuss the complicated nature of the pathogenesis of obesity, the hormonal stimulus for orexigenic and anorexigenic behavior, adipose tissue as an endocrine organ, and most importantly, clinical management of the number one disease in canine and feline medicine.Keywords: obesity, canine, feline, veterinary
... Downloaded by [ that isoflavones can increase the incidence of epithelial hyperplasia (Petrakis et al., 1996) and cause goitre and hyperthyroidism (Cerundolo et al., 2009). Ellagitaninns, ellagic acid and urolithins exhibit anticancer properties in vitro and in vivo (Heber, 2008; Seeram 2008). ...
Article
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Phytoestrogens are polyphenols similar to human estrogens found in plants or derived from plant precursors. Phytoestrogens are found in high concentration in soya, flaxseed and other seeds, fruits, vegetables, cereals, tea, chocolate, etc. They comprise several classes of chemical compounds (stilbenes, coumestans, isoflavones, ellagitannins and lignans) which are structurally similar to endogenous estrogens but which can have both estrogenic and antiestrogenic effects. Although epidemiological and experimental evidence indicates that intake of phytoestrogens in foods may be protective against certain chronic diseases, discrepancies have been observed between in vivo and in vitro experiments. The microbial transformations have not been reported so far in stilbenes and coumestans. However, isoflavones, ellagitanins and lignans are metabolised by intestinal bacteria to produce equol, urolithins and enterolignans, respectively. Equol, urolithin and enterolignans are more bioavailable, and them have more estrogenic/antiestrogenic and antioxidant activity than their precursors. Moreover, equol, urolithins and enterolignans have antiinflammatory effects and induce antiproliferative and apoptosis-inducing activities. The transformation of isoflavones, ellagitanins and lignans by intestinal microbiota is essential to be protective against certain chronic diseases, as cancer, cardiovascular disease, osteoporosis and menopausal symptoms. Bioavailability, bioactivity and health effects of dietary phytoestrogens are strongly determined by the intestinal bacteria of each individual.
... A good example is the occurrence of estrogenic effects due to sheep grazing on red clover which have been known since 1950 (Adams, 1998). Since then, many laboratories have published data on the phytoestrogens content of natural dietary components (Boettger-Tong et al., 1998;Casanova et al., 1999;Cerundolo et al., 2009;Degen et al., 2002;Kato et al., 2004;Odum et al., 2001) and their impact of animals and humans health. All the data presents, those commercial dietary formulations contain variable levels of genistein and daidzein of soya origin. ...
Article
A yeast estrogen bioassay (RIKILT REA) was in-house validated for feed on the 5 μg 17β-estradiol-equivalents per kg level according to EC Decision 2002/657/EC. All the performance characteristics met the criteria as defined in the Decision and the REA is able to detect 17β-estradiol in animal feed at a low level of 1.15- 2 μg kg(-1). Subsequently, the developed and validated procedure was applied to determine the estrogenic activity in 24 feed samples intended for food producing animals, pets and laboratory animals. Two batches of rodent diet Murigran and one dog feed have been presented as a suspect, i.e. gave responses above the determined decision limit (CCα) and detection capability (CCβ). In assessing the performance of the estrogenic activity in these diets evaluated by comparison with the 17β-estradiol calibration curve, 17β-estradiol-equivalence levels of 7.07 μg EEQ kg(-1) and 9.54 μg EEQ kg(-1) in two batches of rodent diet and 5.3 μg EEQ kg(-1) in dog feed have been established. The activities observed in the rodent feed could be explained by chemical analysis, revealing high amounts of genistein, daidzein and trace amounts of zearalenone. In addition, the estrogenic activity in one of rodent feed was above the established CCα, but below the CCβ values established and all other samples showed no estrogenic activity with responses below the CCα value, which corresponds to levels below 2 μg EEQ kg(-1).
... The authors suggested that excessive soybean ingestion may cause goiters in healthy people, depending on the duration of the treatment. In dogs, the consumption of soy phytoestrogens for 12 months increased serum T4, without changes in T3 levels (Cerundolo et al., 2009). The authors suggested that this effect could be due to the inhibition of 5 0 -deiodinase activity. ...
Article
Feeding during normal reproduction is often not thought of until there is a problem with conception or gestational losses. Energy demands of lactation and early puppy/kitten are of concern, particularly in large and giant breed dogs where mineral balance is crucial to normal development. There is a paucity of information around optimizing feeding during conception and gestation with many myths around ingredients which will be explored in this article along with supplements that may be able to support spermatogenesis and conception which primarily comes from the human literature and may have validity in times of difficult conception.
Technical Report
The aim of this review was to identify the scientific data from January 2009 till December 2013 on effects of isolated isoflavones from food supplements on reproductive organs (breast, uterus) and thyroid of menopausal women. A search in PubMed, Web of Science, CAB Abstracts and Embase (search date: February 7th 2014), resulted in 2,497 unique hits. Based on title and abstract, 177articles were eligible for full text selection. Of these, 95 were human studies(objective 1), 68 were animal studies (objective 2) and 14 contained data on both. Hand search yielded no additional articles. After full text screening, for objective 1, 14 articles met our inclusion criteria for data extraction; for objective 2, 17 met our inclusion criteria for data-extraction and 7 were included for mapping purposes; from articles with data for objective 1 and 2 combined, all 14 were excluded. All included studies were intervention studies. A grey literature search resulted in 1 relevant risk assessmentpublished by a national body. Uterus was the most studied target organ for both objectives; the most prevalent outcomes were endometrial thickness for objective 1 and uterine weight for objective 2. Under objective 2, no studies evaluating thyroid were identified. Studies under objective 1 did not report adverse effects related to isoflavone supplementation, studies under 2 were less consistent. Many methodological issues exist, such as the scarcity of long-term human data and studies aimed at detecting adverse effects; and issues of metabolic differences between species and dose translation from animals to humans
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Thyroid gland function is commonly evaluated in dogs by means of serum total thyroxine (tT4), free thyroxine (fT4) and thyrotropin (TSH) concentrations. The diagnosis of hypothyroidism is based on the combination of low serum tT4 or fT4 levels and high serum TSH levels. Unfortunately, there may be many factors, other than hypothyroidism, that affect serum baseline thyroid hormones and TSH concentrations. This manuscript reviews physiological conditions, drugs and diseases (non-thyroidal illness syndrome or euthyroid sick syndrome) known to interfere with canine thyroid function. Moreover, based on published data, timing for thyroidal function evaluation is suggested in dogs receiving drugs known to affect serum thyroid hormone concentrations.
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Soy and its isoflavones have been suggested to suppress thyroperoxidase (TPO), induce goiter, inhibit deiodinase, and modulate immune functions. This study initially investigated the effects of dietary soy consumption on maternal thyroid functions and anti-TPO antibody (TPOAb) production during early pregnancy. Data were collected through questionnaire from 505 women enrolled during early pregnancy by random sampling in Shenyang, China. Based on soy intake frequency, the subjects were divided into three groups (frequent [three or more times per week], conventional [more than twice per month but less than three times per week], and occasional [two or fewer times per month]). Serum thyrotropin (TSH), free thyroxine (FT(4)), and TPOAb were measured by chemiluminescence immunoassay. Additionally, the concentrations of two primary isoflavones (daidzein and genistein) and creatinine were assessed in the spot urine samples from representative subjects (about 20%) randomly selected from the three groups. The percentages of frequent, conventional, and occasional consumers were 18.6%, 62.6%, and 18.8%, respectively. No difference was found in age, medical records, family history of thyroid diseases, serum FT(4), TSH, and TPOAb levels, TPOAb-positive percentages, or prevalence of thyroid dysfunctions among the groups. Both urinary daidzein and genistein levels were significantly higher in the frequent consumers compared with the other two groups. No correlations were found between urinary isoflavone levels and serum FT(4) or TSH. Urinary isoflavone levels were not significantly different between TPOAb-positive and -negative women among the randomly selected representative subjects. On the whole, our findings suggest dietary soy consumption during early pregnancy is not associated with the development of thyroid dysfunction or autoimmunity.
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Plant compounds with estrogenic activity may play a role in cancer prevention, moderation of menopausal symptoms, and other health effects. To facilitate research on these possible actions, the literature was reviewed for quantitative data on the levels of known phytoestrogens (daidzein, genistein, coumestrol, formononetin, and biochanin A) in food plants. For comparative purposes, all phytoestrogen levels were recalculated on a wet weight basis. Details on analytic procedures are given as well. High-performance liquid chromatography was the method most often used to analyze these compounds in foods. Most significant sources of isoflavone and coumestan phytoestrogens include soybeans, soy flour, soy flakes, isolated soy protein, traditional soy foods such as tofu and soy drinks, second-generation say foods, sprouts, and other legumes. Finally, medians among reported values of phytoestrogen content are provided for some of the most commonly eaten foods with quantitative data available. These may be used to calculate dietary intake of daidzein, genistein, coumestrol, formononetin, and biochanin A.
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The rat, mouse and human estrogen receptor (ER) exists as two subtypes, ER alpha and ER beta, which differ in the C-terminal ligand-binding domain and in the N-terminal transactivation domain. In this study, we investigated the estrogenic activity of environmental chemicals and phytoestrogens in competition binding assays with ER alpha or ER beta protein, and in a transient gene expression assay using cells in which an acute estrogenic response is created by cotransfecting cultures with recombinant human ER alpha or ER beta complementary DNA (cDNA) in the presence of an estrogen-dependent reporter plasmid. Saturation ligand-binding analysis of human ER alpha and ER beta protein revealed a single binding component for [3H]-17beta-estradiol (E2) with high affinity [dissociation constant (Kd) = 0.05 - 0.1 nM]. All environmental estrogenic chemicals [polychlorinated hydroxybiphenyls, dichlorodiphenyltrichloroethane (DDT) and derivatives, alkylphenols, bisphenol A, methoxychlor and chlordecone] compete with E2 for binding to both ER subtypes with a similar preference and degree. In most instances the relative binding affinities (RBA) are at least 1000-fold lower than that of E2. Some phytoestrogens such as coumestrol, genistein, apigenin, naringenin, and kaempferol compete stronger with E2 for binding to ER beta than to ER alpha. Estrogenic chemicals, as for instance nonylphenol, bisphenol A, o, p'-DDT and 2',4',6'-trichloro-4-biphenylol stimulate the transcriptional activity of ER alpha and ER beta at concentrations of 100-1000 nM. Phytoestrogens, including genistein, coumestrol and zearalenone stimulate the transcriptional activity of both ER subtypes at concentrations of 1-10 nM. The ranking of the estrogenic potency of phytoestrogens for both ER subtypes in the transactivation assay is different; that is, E2 > zearalenone = coumestrol > genistein > daidzein > apigenin = phloretin > biochanin A = kaempferol = naringenin > formononetin = ipriflavone = quercetin = chrysin for ER alpha and E2 > genistein = coumestrol > zearalenone > daidzein > biochanin A = apigenin = kaempferol = naringenin > phloretin = quercetin = ipriflavone = formononetin = chrysin for ER beta. Antiestrogenic activity of the phytoestrogens could not be detected, except for zearalenone which is a full agonist for ER alpha and a mixed agonist-antagonist for ER beta. In summary, while the estrogenic potency of industrial-derived estrogenic chemicals is very limited, the estrogenic potency of phytoestrogens is significant, especially for ER beta, and they may trigger many of the biological responses that are evoked by the physiological estrogens.
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We have recently shown that soybean-derived serine protease inhibitors and soybean extracts alter skin pigmentation, suggesting that soymilk could be used as a natural alternative to skin lightening. The present studies were initiated to examine the possible effect of STI, BBI and soymilk on hair pigmentation. Interestingly, these agents were found to affect not only hair pigmentation, but also the rate of hair growth, the dimensions of the hair follicle and hair shaft, and the appearance of the hair. The studies presented here provide first evidence, at the morphological and histological level, that soymilk and the soybean-derived serine protease inhibitors could be used as effective agents for hair care and management. These agents could reduce the rate of hair growth, decrease hair shaft dimensions and alter the pattern of melanogenic gene expression.
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Phytoestrogens are a diverse group of plant-derived compounds structurally or functionally mimicking mammalian oestrogens. A variety of effects, in vitro, in animal models and in humans, have been attributed to these compounds. It is generally not appreciated that many commercial rodent diets are formulated with soy as a source of protein and thus large daily doses of phytoestrogens in the form of isoflavones are delivered to the animals. The content of isoflavones in laboratory diets depends on a number of factors and, therefore, varies considerably, both between different formulations, and also from batch to batch of the same formulation. Dietary isoflavones can influence a number of different endpoints, rendering the dietary levels of such compounds an important experimental factor to consider. The levels of isoflavones in common laboratory diets are reviewed in relation to the dietary levels influencing different endpoints.
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Estrogenic isoflavones, such as genistein and daidzein, are present in virtually all natural-ingredient rodent diets that use soy as a source of protein. Since these compounds are endocrine-active, it is important to determine whether the amounts present in rodent diets are sufficient to affect sexual development. The present study consisted of in vitro and in vivo parts. In the in vitro portion, human hepatoma cells were transfected with either rat estrogen receptor (ER) α or β plus an estrogen-responsive luciferase reporter gene. Genistein and daidzein were complete agonists at both ERs, genistein being more potent than daidzein, and both compounds were more potent at ERβ than ERα. In combined studies with estradiol, genistein exerted additive effects with estradiol in vitro. In the in vivo portion of the study, groups of six pregnant Sprague-Dawley females were fed one of the following four diets, and the pups were maintained on the same diets until puberty: (1) a natural-ingredient, open-formula rodent diet (NIH-07) containing 16 mg genistein and 14 mg daidzein per 100 g of feed; (2) a soy- and alfalfa-free diet (SAFD) in which casein and corn oil were substituted for soy and alfalfa meal and soy oil, respectively, that contained no detectable isoflavones; (3) SAFD containing 0.02% genistein (GE.02); or (4) SAFD containing 0.1% genistein (GE.1). In the GE.1 group, effects of dietary genistein included a decreased rate of body-weight gain, a markedly increased (2.3-fold) uterine/body weight (U/BW) ratio on postnatal day (pnd) 21, a significant acceleration of puberty among females, and a marginal decrease in the ventral prostate weight on postnatal day (pnd) 56. However, developmental differences among the groups fed SAFD, GE.02, or NIH-07 were small and suggested minimal effects of phytoestrogens at normal dietary levels. In particular, on pnd 21, the U/BW ratio of the GE.02 and NIH-07 groups did not differ significantly from that of the SAFD group. Only one statistically significant difference was detected between groups fed SAFD and NIH-07: the anogenital distance (AGD) of female neonates on pnd 1 whose dams were fed NIH-07 was 12% larger than that of neonates whose dams were fed SAFD. The results suggest that normal amounts of phytoestrogens in natural-ingredient rodent diets may affect one developmental parameter, the female AGD, and that higher doses can affect several other parameters in both males and females. Based on these findings, we do not suggest replacing soy- and alfalfa-based rodent diets with phytoestrogen-free diets in most developmental toxicology studies. However, phytoestrogen-free diets are recommended for endocrine toxicology studies at low doses, to determine whether interactive effects may occur between dietary phytoestrogens and man-made chemicals.
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There is increasing concern that exposure to flavonoids may lead to endocrine disruption of the hypothalamus–pituitary–thyroid hormone axis, and, additionally, there is evidence that secondary plant metabolites contained in our daily diet or used for hormone-replacement therapy act as hormones themselves, similar to known isoflavonoid effects in the steroid hormone network. These compounds of natural origin affect the thyroid hormone feedback system by interference with different components of this homeostatically regulated system: biosynthesis, secretion and metabolism, transport, distribution, and action of thyroid hormones including the feedback mechanism. Genistein and daidzein, the major components of soy, influence thyroid hormone synthesis by inhibition of the iodide oxidizing enzyme thyroperoxidase, interfere with thyroid hormone transport proteins and 5′-deiodinase type I activities in peripheral tissues, which leads to altered thyroid hormone action at the cellular level. Synthetic flavonoids, such as F21388, structurally similar to thyroxine, cross the placenta and reach the fetal brain of animal models also.
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Interleukin (IL)-1 has been shown to be a potent inhibitor of hair growth in vitro. We hypothesized that this cytokine might be a decisive factor causing hair loss during the lymphocytic attack in alopecia areata. Neither the intracellular pathways involved in hair growth inhibition mediated by IL-1β nor the signal transduction processes within hair follicles in general are known. We therefore investigated the intracellular signals involved in human hair growth in vitro. Hair follicles were isolated from scalp biopsies by microdissection and hair growth was measured daily by image analysis. We assessed intracellular signal transducing elements using specific inhibitors or activators either alone or in combination with IL-1β. The calcium ionophore A 23187 induced a rapid and complete arrest of hair growth and phorbol-12-myristate-13-acetate (PMA), genistein, or IL-1β decreased hair growth by approximately 60%- 80%. IL-1β- elicited hair growth arrest was not antagonized by calphostin C, a specific inhibitor of protein kinase C. In contrast, coincubation of IL-1β with pertussis toxin or H 1004 neutralized the effect of IL-1β and dibutyryl-cAMP and cholera toxin, an activator of adenylate cyclase, inhibited hair growth. These data suggest that cAMP acts as a second messenger for IL-1β-induced inhibition of hair growth. Moreover, our data indicate that in vitro hair growth is dependent on intracellular Ca22+ levels and activation of tyrosine kinase as well as protein kinase C. We were unable to detect a signal transducing element responsible for enhanced hair growth in vitro.
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Effects of ovariectomy (ovx) and ovx with estradiol benzoate (EB) therapy on total and free T3 (FT3), T4 and [125I]T3 disappearance rate; basal and post-TRH, TSH, T3 and T4 concentrations were studied in female rats. Two weeks after ovx, no significant change in hormone concentrations was observed. Two micrograms of EB daily for 1 week significantly increased basal serum TSH by 40% and serum total T3 by 25-30%, but decreased serum T4 by 50%. The percentage of free FT3 and free T4 (FT4) did not differ in the sham-operated intact, ovx, and ovx-EB-treated animals, resulting in an increase in total absolute FT3 and a decrease in FT4 by EB. [125I]T3 plasma disappearance rate was not altered by either ovx or EB. Ten minutes after TRH, serum TSH increased 6- to 7-fold in both the intact and ovx rats, but increased 10- to 13-fold in the EB-treated animals. Two hours after TRH, a significant increase in serum T3 concentration was observed in all groups of animals, but the absolute incremental T3 response after EB was significantly greater than in the other two groups. No change in serum T4 was observed 2 h after TRH in all groups. When ovx female rats were treated with graded doses of EB, ranging from 0-10 μg EB/day for 7 days, serum T3 concentrations increased in a dose-dependent manner while T4 decreased reciprocally, with a maximum effect at the 2 μg/day EB dose. When female rats were ovariectomized and thyroidectomized for 3 weeks and then treated with 3 μg/100 g BW with or without 2 or 10 μg EB for 12 days, serum T3 concentrations in the EB-treated animals were 2-fold those of the controls and T4 concentration decreased in the EB-treated rats. These results indicate that 1) EB increases both TSH and T3 serum concentrations for both basal and post-TRH values but decreased basal total and FT4, 2) the increase in serum total and free T3 is not due to changes in either peripheral T3 clearance or plasma binding, and 3) the increased basal and post-TRH TSH levels from EB may be due not only to its direct central effect on pituitary thyrotropes but also to its peripheral action to induce changes in total and free T4 and T3 concentrations by an enhanced extrathyroidal conversion of T4 to T3.
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The effects of treatment with l -thyroxine (1 mg/m ² of body surface/d, po , for 8 weeks) on the thyroxine (T 4 ) and triiodothyronine (T 3 ) responses to thyrotropin ( tsh ) and thyrotropin-releasing hormone ( trh ) administration were determined in 10 euthyroid Beagles; 4 other dogs acted as controls. The tsh response test was performed before treatment and at weeks 2, 4, and 8 of treatment in all dogs and at 2 and 4 weeks after cessation of treatment in 6 dogs. The trh response test was performed before treatment and at week 6 of treatment in all dogs and at 5 weeks after cessation of treatment in 6 dogs. Suppression of the T 3 response to tsh was evident at treatment week 2, whereas the T 4 response was suppressed at week 4 and remained suppressed for the duration of the study. Four weeks after l -thyroxine treatment was stopped, T 3 response to tsh had returned to pretreatment values. Four weeks after stopping treatment, T 4 and T 3 responses to tsh in 2 dogs were within the hypothyroid range. The T 4 response to trh was completely suppressed after 6 weeks of thyroxine treatment, but returned to pretreatment values by 5 weeks after cessation of treatment. Suppression of thyroid and pituitary function is evident after administration of a replacement dose of l -thyroxine to euthyroid dogs.
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5'-Deiodination of T4 or rT3 in the presence of flavonoids was studied in freshly isolated suspended rat hepatocytes. Flavonoids, a novel group of synthetic deiodinase inhibitors, were designed to act as T4 antagonists. 5'-Deiodination of the prohormone T4 to the thyromimetically active T3 is an essential first step in controlling thyroid hormone action. Hepatocytes were incubated with either 2 microM T4 or 2 microM [125I]rT3 as 5'-deiodinase substrates in the absence and presence of inhibitors (0.1-100.0 microM). T3 production from T4 was determined by T3 RIA, and [125I]iodide release from [125I]rT3 was alternatively used as a technically more simple and rapid but sensitive deiodinase assay. Aurones and flavones inhibited both T4 5'-deiodination and rT3 5'-deiodination, with half-maximal inhibitor concentrations from 3-45 microM. Aurones were equally potent in both assays. 3-Methyl-flavones, designed as rT3 analogs, were more active by a factor of 3-5 with T4 5'-deiodination than with rT3 5'-deiodination, with the exception of one relatively cell-toxic compound. Hepatocyte viability was controlled by trypan blue dye exclusion as well as by measuring gluconeogenesis from exogenously added 10 mM lactate. Some of the flavonoids inhibited gluconeogenesis at concentrations that had no effect on trypan blue dye exclusion. Flavonoid inhibitors reduce 5'-deiodinase activity in intact hepatocytes in concentrations equimolar to those of substrates. Therefore, synthetic flavonoids may be suitable substances for further study of iodothyronine physiology or, after modification, could be useful as a new class of antiiodothyronine drugs.
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It has been suggested that feeding practices in infancy may affect the development of various autoimmune diseases later in life. Since thyroid alterations are among the most frequently encountered autoimmune conditions in children, we studied whether breast and soy-containing formula feedings in early life were associated with the subsequent development of autoimmune thyroid disease. A detailed history of feeding practices was obtained in 59 children with autoimmune thyroid disease, their 76 healthy siblings, and 54 healthy nonrelated control children. There was no difference in the frequency and duration of breast feeding in early life among the three groups of children. However, the frequency of feedings with soy-based milk formulas in early life was significantly higher in children with autoimmune thyroid disease (prevalence 31%) as compared with their siblings (prevalence 12%; chi 2 = 7.22 with continuity factor; p less than 0.01), and healthy nonrelated control children (prevalence 13%, chi 2 = 5.03 with continuity factor; p less than 0.02). Therefore, this retrospective analysis documents the association of soy formula feedings in infancy and autoimmune thyroid disease.
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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.
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Several plant estrogens, especially coumestrol and genistein, were found to reduce the conversion of [3H]estrone to [3H] 17 beta-estradiol catalyzed by estrogen-specific 17 beta-hydroxysteroid oxidoreductase Type 1 (E.C. 1.1.1.62) in vitro. Coumestrol, the most potent inhibitor in our experiments, is the best inhibitor of the enzyme known to date. All compounds with inhibitory effects were also estrogenic. However, structural demands for 17 beta-HSOR Type 1 inhibition and estrogenicity of tested compounds in breast cancer cells (judged by increased cell proliferation) were not identical. Zearalenone and diethylstilbestrol, both potent estrogens, did not inhibit 17 beta-HSOR Type 1. Thus, changes in the estrogen molecule may discriminate between active sites of 17 beta-HSOR Type 1 and estrogen binding sites of the ER. The effects of these compounds in vivo cannot be predicted on the basis of these results. Inhibition of 17 beta-HSOR Type 1 enzyme could lead to a decrease in the availability of the highly active endogenous estrogen. However, these compounds are estrogenic per se, and they may thus replace endogenous estrogens. Additional studies are needed to further understand the role of these plant estrogens in the etiology of hormone-dependent cancers. It is not easily conceivable how the chemopreventive action of Asian diets, possibly mediated by phytoestrogens in soya products, can be based on the inhibition of estrone reduction at the target cells by phytoestrogens or related compounds, unless they are "incomplete estrogens" (i.e., unable to induce all effects typical of endogenous estrogens).
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Interleukin (IL)-1 has been shown to be a potent inhibitor of hair growth in vitro. We hypothesized that this cytokine might be a decisive factor causing hair loss during the lymphocytic attack in alopecia areata. Neither the intracellular pathways involved in hair growth inhibition mediated by IL-1beta nor the signal transduction processes within hair follicles in general are known. We therefore investigated the intracellular signals involved in human hair growth in vitro. Hair follicles were isolated from scalp biopsies by microdissection, and hair growth was measured daily by image analysis. We assessed intracellular signal transducing elements using specific inhibitors or activators either alone or in combination with IL-1beta. The calcium ionophore A 23187 induced a rapid and complete arrest of hair growth, and phorbol-12-myristate-13-acetate (PMA), genistein, or IL-1beta decreased hair growth by approximately 60%-80%. IL-1beta-elicited hair growth arrest was not antagonized by calphostin C, a specific inhibitor of protein kinase C. In contrast, coincubation of IL-1beta with pertussis toxin or H 1004 neutralized the effect of IL-1beta, and dibutyryl-cAMP and cholera toxin, an activator of adenylate cyclase, inhibited hair growth. These data suggest that cAMP acts as a second messenger for IL-1beta-induced inhibition of hair growth. Moreover, our data indicate that in vitro hair growth is dependent on intracellular Ca2+ levels and activation of tyrosine kinase as well as protein kinase C. We were unable to detect a signal transducing element responsible for enhanced hair growth in vitro.
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Soy products contain high amounts of isoflavonoids, which have been shown to exhibit possible cancer-protective properties. Chinese populations in Asia, in particular, have a high level of soy intake and a relatively low risk of hormone-dependent cancers. In this study, we assessed the distributions of dietary soy isoflavonoids (daidzein, genistein, and glycitein) and urinary soy isoflavonoids and their metabolites (daidzein, genistein, glycitein, equol, and O-desmethylangolensin) among 147 Singapore Chinese (76 men and 71 women) ages 45-74 years, who are participants of the Singapore Cohort Study on diet and cancer. Urinary values were measured from spot samples collected 10-20 months following recruitment, when usual dietary habits were assessed by a structured food frequency/portion size questionnaire administered in person. Dietary levels of daidzein and genistein were comparable within individuals and about seven times higher than the level of dietary glycitein. All three dietary isoflavonoids showed an approximately 3.5-fold difference between the 25th and 75th percentile values. Similarly, daidzein was the most abundant and glycitein the least abundant of the five isoflavonoid compounds in urine. There was a 4.9-fold difference between the 25th and 75th percentile values for the sum of the five urinary isoflavonoids. Among study subjects, there were statistically significant, dose-dependent associations between frequency of overall soy intake and levels of urinary daidzein (two-sided P = 0.03) and sum of urinary daidzein, genistein, and glycitein (two-sided P = 0.04). In contrast, there were no associations between frequency of overall soy intake and levels of the two daidzein metabolites (equol and O-desmethylangolensin) in urine (two-sided P = 0.85 and 0.34, respectively). We suggest that within the range of exposures experienced by Singapore Chinese, urinary level of daidzein or the sum of daidzein, genistein, and glycitein obtained from a spot sample can serve as a biomarker of current soy consumption in epidemiological studies of diet-disease associations.
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To evaluate a thyroglobulin autoantibody (TgAA) assay and determine a diagnostic threshold. Serum samples from dogs with various endocrine abnormalities and from 30 obese adult female Beagles. TgAA were determined by use of the ELISA. Six experiments were done: 1, definition of positive results for TgAA using samples from normal and T3 autoantibody (T3AA) positive dogs; 2, establishment of prevalence of positive results in 91 clinically normal dogs; 3, evaluation of positive results for sera from dogs with nonthyroidal illnesses; 4, testing of samples from dogs with primary hypothyroidism but absence of T4AA or T3AA, or both; 5, determination of prevalence of false-negative results in dogs that are T4AA and/or T3AA positive, which were (18 dogs) or were not (22 dogs) receiving L-thyroxine replacement therapy; and 6, examination of thyroid biopsy specimens from 18 dogs (8 TgAA positive and 10 TgAA negative). Positive results were defined as at least twice (200%) the optical density of the negative-control sample. False-positive results were obtained for only 3.4% of 146 dogs with nonthyroidal illness. Thirty-seven percent of dogs with primary hypothyroidism, but no evidence of T4AA or T3AA, or both, were TgAA positive. False-negative results were found in 1 of 22 and 2 of 18 T3AA-positive dogs with and without thyroid replacement therapy, respectively. Thyroid biopsy specimens from 8 TgAA-positive dogs had evidence of lymphocytic thyroiditis, whereas those from 10 TgAA-negative dogs did not. The assay is sensitive and specific for identification of lymphocytic autoimmune thyroiditis in dogs, and has potential for aiding early diagnosis of thyroiditis in dogs and identifying dogs likely to perpetuate hypothyroidism in breeding programs.
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Soy isoflavones are hypothesized to be responsible for changes in hormone action associated with reduced breast cancer risk. To test this hypothesis, we studied the effects of isoflavone consumption in 14 premenopausal women. Isoflavones were consumed in soy protein powders and provided relative to body weight (control diet, 10 +/- 1.1; low isoflavone diet, 64 +/- 9.2; high isoflavone diet, 128 +/- 16 mg/day) for three menstrual cycles plus 9 days in a randomized cross-over design. During the last 6 weeks of each diet period, plasma was collected every other day for analysis of estrogens, progesterone, LH, and FSH. Diet effects were assessed during each of four distinctly defined menstrual cycle phases. Plasma from the early follicular phase was analyzed for androgens, cortisol, thyroid hormones, insulin, PRL, and sex hormone-binding globulin. The low isoflavone diet decreased LH (P = 0.009) and FSH (P = 0.04) levels during the periovulatory phase. The high isoflavone diet decreased free T3 (P = 0.02) and dehydroepiandrosterone sulfate (P = 0.02) levels during the early follicular phase and estrone levels during the midfollicular phase (P = 0.02). No other significant changes were observed in hormone concentrations or in the length of the menstrual cycle, follicular phase, or luteal phase. Endometrial biopsies performed in the luteal phase of cycle 3 of each diet period revealed no effect of isoflavone consumption on histological dating. These data suggest that effects on plasma hormones and the menstrual cycle are not likely to be the primary mechanisms by which isoflavones may prevent cancer in premenopausal women.
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The short-term effects of prednisone and phenobarbital on serum total thyroxine (tT4), free thyroxine (fT4), and thyroid stimulating hormone (TSH) were evaluated in euthyroid dogs. Twenty-six beagles were randomly divided into 3 groups receiving, respectively, a placebo, prednisone (1.2 to 2 mg/kg body weight, per os, every 12 hours for 3 weeks), or phenobarbital (1.8 to 3 mg/kg body weight for 1 week, then 2.7 to 4.5 mg/kg body weight, per os, every 12 hours for 2 weeks). Blood samples taken over a 6-week period were assayed for serum tT4, fT4, and TSH. Phenobarbital therapy in our study did not affect serum tT4, fT4, or TSH concentrations. Prednisone therapy, however, significantly decreased serum tT4 and fT4, but did not affect serum TSH concentrations.
Article
Soy isoflavones have been hypothesized to exert hormonal effects in postmenopausal women. To test this hypothesis, we studied the effects of three soy powders containing different levels of isoflavones in 18 postmenopausal women. Isoflavones were consumed relative to bodyweight [control: 0.11 +/- 0.01; low isoflavone (low-iso): 1.00 +/- 0.01; high isoflavone (high-iso): 2.00 +/- 0.02 mg/kg/day] for 93 days each in a randomized crossover design. Blood was collected on day 1 of the study (baseline) and days 36-38, 64-66, and 92-94 of each diet period, for analysis of estrogens, androgens, gonadotropins, sex hormone binding globulin (SHBG), prolactin, insulin, cortisol, and thyroid hormones. Vaginal cytology specimens were obtained at baseline and at the end of each diet period, and endometrial biopsies were performed at baseline and at the end of the high-iso diet period, to provide additional measures of estrogen action. Overall, compared with the control diet, the effects of the low-iso and high-iso diets were modest in degree. The high-iso diet resulted in a small but significant decrease in estrone-sulfate (E1-S), a trend toward lower estradiol (E2) and estrone (E1), and a small but significant increase in SHBG. For the other hormones, the few significant changes noted were also small and probably not of physiological importance. There were no significant effects of the low-iso or high-iso diets on vaginal cytology or endometrial biopsy results. These data suggest that effects of isoflavones on plasma hormones per se are not significant mechanisms by which soy consumption may exert estrogen-like effects in postmenopausal women. These data also show that neither isoflavones nor soy exert clinically important estrogenic effects on vaginal epithelium or endometrium.
Article
The isoflavones daidzein, genistein, biochanin A and formononetin inhibit potently and preferentially the gamma-isozymes of mammalian alcohol dehydrogenase (gammagamma-ADH), the only ADH isozyme that catalyzes the oxidation of 3beta-hydroxysteroids. Based on these results, we proposed that these isoflavones might also act on other enzymes involved in 3beta-hydroxysteroid metabolism. Recently, we showed that they indeed are potent inhibitors of a bacterial beta-hydroxysteroid dehydrogenase (beta-HSD). To extend this finding to the mammalian systems, we hereby purified, characterized and studied the effects of isoflavones and structurally related compounds on, a bovine adrenal 3beta-hydroxysteroid dehydrogenase (3beta-HSD). This enzyme catalyzes the oxidation of 3beta-hydroxysteroids but not 3alpha-, 11beta- or 17beta-hydroxysteroids. The same enzyme also catalyzes 5-ene-4-ene isomerization, converting 5-pregnen 3, 20-dione to progesterone. The K(m) values of its dehydrogenase activity determined for a list of 3beta-hydroxysteroid substrates are similar (1 to 2 microM) and that of its isomerase activity, determined with 5-pregnen 3, 20-dione as a substrate, is 10 microM. The k(cat) value determined for its isomerase activity (18.2 min(-1)) is also higher than that for its dehydrogenase activity (1.4-2.4 min(-1)). A survey of more than 30 isoflavones and structurally related compounds revealed that daidzein, genistein, biochanin A and formononetin inhibit both the dehydrogenase and isomerase activity of this enzyme. Inhibition is potent and concentration dependent. IC(50) values determined for these compounds range from 0.4 to 11 microM, within the plasma and urine concentration ranges of daidzein and genistein of individuals on vegetarian diet or semi-vegetarian diet. These results suggest that dietary isoflavones may exert their biological effects by inhibiting the action of 3beta-HSD, a key enzyme of neurosteroid and/or steroid hormone biosynthesis.
Article
Naturally occurring estrogen-like molecules in plants (phytoestrogens), present via soy, in animal diets can alter morphology and physiology in rodents. Phytoestrogens have the ability to bind estrogen receptors and exert many of the biological responses evoked by physiological estrogens. This study characterized the effects of dietary phytoestrogens on the expression of body and prostate weight, circulating testosterone and estradiol levels, puberty onset, vaginal cyclicity, and volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) in Long-Evans rats. Using different experimental protocols, animals were fed either a phytoestrogen-rich (Phyto-600) or a phytoestrogen-free (Phyto-free) diet. Animals fed the Phyto-600 diet displayed significantly decreased body weights (in males and females), prostate weights and delayed puberty in females compared to that of animals fed the Phyto-free diet. Circulating testosterone or estradiol levels in males or estrous cyclicity were not altered by the diets. The volume of the SDN-POA was significantly altered by a change in diet at 80 days of age where one-half of the males or females fed the Phyto-600 diet (from birth) were switched to the Phyto-free diet until 120 days of age. Males initially fed a Phyto-600 diet but changed to a Phyto-free diet had significantly smaller SDN-POA volumes compared to males fed the Phyto-600 diet (long-term). These data suggest that consumption of phytoestrogens via a soy diet, significantly: (1) decreases body and prostate weight, (2) delays puberty onset, and (3) alters SDN-POA volumes during adulthood.
Article
It has been postulated that inducers of UDP-glucuronosyltransferase (UGT) decrease circulating thyroid hormone concentrations by increasing their biliary excretion. The inducers pregnenolone-16 alpha-carbonitrile (PCN), 3-methylcholanthrene (3MC), and Aroclor 1254 (PCB) are each effective at reducing serum thyroxine concentrations. However, only PCN treatment produces a marked increase in serum levels of thyroid-stimulating hormone (TSH), whereas 3MC and PCB cause little to no increase in TSH. Excessive TSH elevation is considered the primary stimulus for thyroid tumor development in rats, yet the mechanism by which enzyme induction leads to TSH elevation is not fully understood. Whereas PCN, 3MC, and PCB all increase microsomal UGT activity toward T(4), only PCN causes an increase in T(3)-UGT activity in vitro. The purpose of this study was to determine whether PCN, which increases serum TSH, causes an increase in the glucuronidation and biliary excretion of T(3) in vivo. Male rats were fed control diet or diet containing PCN (1000 ppm), 3MC (250 ppm), or PCB (100 ppm) for 7 days. Animals were then given [(125)I]-T(3), i.v., and bile was collected for 2 h. Radiolabeled metabolites in bile were analyzed by reverse-phase HPLC with gamma-detection. The biliary excretion of total radioactivity was increased up to 75% by PCN, but not by 3MC or PCB. Of the T(3) excreted into bile, approximately 75% was recovered as T(3)-glucuronide, with remaining amounts represented as T(3)-sulfate, T(2)-sulfate, T(3), and T(2). Biliary excretion of T(3)-glucuronide was increased up to 66% by PCN, while neither 3MC nor PCB altered T(3)-glucuronide excretion. These findings indicate that PCN increases the glucuronidation and biliary excretion of T(3) in vivo, and suggest that enhanced elimination of T(3) may be the mechanism responsible for the increases in serum TSH caused by PCN.
Article
Phytoestrogens, plant-derived nonsteroidal estrogens found in high abundance in most soy food products, have been studied for their potential beneficial effects against hormone-dependent cancers and age-related diseases. However, little is known about the influence of phytoestrogens on the brain or behavior. This brief review describes mainly our own studies in rodents that have examined the influence of dietary soy isoflavones on certain aspects of brain structure, learning, memory and anxiety along with the brain androgen-metabolizing enzyme, aromatase. These studies used a commercially available diet rich in phytoestrogens (Phyto-rich) vs. a custom diet relatively free of phytoestrogens (Phyto-free). The phytoestrogen content of each diet was determined by high-performance liquid chromatography analysis, circulating plasma phytoestrogen levels were quantified by gas chromatography mass spectroscopy and concentrations of phytoestrogens in specific brain regions were measured by time-resolved fluoroimmunoassay (TR-FIA). Our studies showed that brain aromatase levels were not significantly altered by phytoestrogen diet treatments in perinatal, maternal or adult rats. However, volumes of the sexually dimorphic nucleus of the preoptic area (SDN-POA) were significantly affected by the Phyto-free diet treatment in male rats during adulthood, where SDN-POA volumes were smaller compared to Phyto-rich male values. Additionally, the Phyto-rich diet fed to adult male and female rats produced anxiolytic effects as assessed in the elevated plus maze vs. Phyto-free fed animals. Finally, when learning and memory parameters were examined in a radial arm maze testing visual-spatial memory (VSM), the diet treatments significantly changed the typical sexually dimorphic pattern of VSM. Specifically, adult Phyto-rich fed females outperformed Phyto-free fed females, while in males on the same diets, the opposite pattern of maze performance was observed. When female vs. male performance was compared, Phyto-rich females executed the VSM task in a manner similar to that of Phyto-free fed males, while Phyto-free fed female's VSM was comparable to Phyto-rich males. These results indicate that consumption of dietary phytoestrogens resulting in very high plasma isoflavone levels (in many cases over a relatively short interval of consumption in adulthood) can significantly alter sexually dimorphic brain regions, anxiety, learning and memory. The findings of these studies identify the biological actions of phytoestrogens, specifically isoflavones and their metabolites, found in animal soy-containing diets on brain and behavior and implicate the importance of phytoestrogens given the recognized significance of estrogens in brain and neural disorders, such as Alzheimer's disease, especially in women.
Article
To determine the absolute and relative soy isoflavone content in commercial cat foods. 14 dry, 6 semimoist, and 22 moist commercial cat foods. Soy isoflavone content of each food was determined by use of acid-methanol hydrolysis and high-pressure liquid chromatography with ultraviolet absorbance detection. Isoflavones were identified and quantified by reference to authentic standards. Genistein and daidzein were the major soy isoflavones identified in 24 of 42 foods, with concentrations ranging from 1 to 163 microg/g of food. Foods labeled as containing soybean solids (16/42) had isoflavone concentrations > 11 microg/g. More dry (13/14) and semimoist (6/6) foods contained isoflavones than moist foods (5/22). Isoflavone content and food cost were negatively correlated for dry and semimoist foods but not for moist foods. Total amount of isoflavone consumed by cats fed these soy-containing foods as a sole maintenance diet was estimated to be between 0.6 and 4.5 mg/kg of body weight/d, which is comparable to concentrations in humans that result in a measurable although modest effect on serum concentrations of steroid and thyroid hormones. Genistein and daidzein are common constituents of commercial cat foods. Predictors of isoflavone content included ingredient labeling, food type, and food cost. Soy isoflavones in some commercial cat foods were detected in amounts predicted to have a biological effect.
Article
To determine prevalence of thyroid hormone autoantibodies (THAA) in serum of dogs with clinical signs of hypothyroidism. Cohort study. 287,948 serum samples from dogs with clinical signs consistent with hypothyroidism. Serum THAA were detected by use of a radiometric assay. Correlation and chi2 analyses were used to determine whether prevalence varied with breed, age, sex, or body weight. Only breeds for which > or = 50 samples had been submitted were used for analysis of breed prevalence. Thyroid hormone autoantibodies were detected in 18,135 (6.3%) samples. The 10 breeds with the highest prevalence of THAA were the Pointer, English Setter, English Pointer, Skye Terrier, German Wirehaired Pointer, Old English Sheepdog, Boxer, Maltese, Kuvasz, and Petit Basset Griffon Vendeen. Prevalence was significantly correlated with body weight and was highest in dogs between 2 and 4 years old. Females were significantly more likely to have THAA than were males. Thyroid hormone autoantibodies may falsely increase measured triiodothyronine (T3) and thyroxine (T4) concentrations in dogs; results suggest that T3 concentration may be falsely increased in approximately 57 of 1,000 dogs with hypothyroidism and that T4 concentration may be falsely increased in approximately 17 of 1,000 dogs with hypothyroidism. Results also suggested that dogs of certain breeds were significantly more or less likely to have THAA than were dogs in general.
Article
Inhibitory effects of flavonoid phytochemicals, flavones, flavonols and isoflavones on cortisol production were examined in human adrenal H295R cells stimulated with di-buthylyl cAMP. In addition, the inhibitory effects of these chemicals on the activity of P450scc, 3beta-HSD type II (3beta-HSD II), P450c17, P450c21 and P45011beta, steroidogenic enzymes involved in cortisol biosynthesis, were examined in the same cells. Exposure to 12.5 microM of the flavonoids 6-hydroxyflavone, 4'-hydroxyflavone, apigenin, daidzein, genistein and formononetin significantly decreased cortisol production (by 6.3, 69.6, 47.5, 26.6, 13.8 and 11.3%, respectively), and biochanin A significantly decreased cortisol production (by 47.3%) at a concentration of 25 microM without any significant cytotoxic effects or changes in cell number. Daidzin, the 7-glucoside of daidzein, did not alter cortisol production by H295R cells at concentrations over 10 microg/ml (24 microM). Daidzein-induced reduction of cortisol production by H295R cells was not inhibited by the estrogen receptor antagonist ICI 182,780. The flavonoids 6-hydroxyflavone, daidzein, genistein, biochanin A and formononetin strongly and significantly inhibited microsomal 3beta-HSD II activity at concentrations from 1 to 25 microM, and I(50) values were estimated to be 1.3, 2, 1, 0.5 and 2.7 microM, respectively. In addition, these flavonoids significantly inhibited microsomal P450c21 activity at 12.5 and/or 25 microM. In addition, 6-hydroxyflavone inhibited activity of microsomal P450c17 and mitochondrial P45011beta at 12.5 and/or 25 microM. Results of Lineweaver-Burk's plot analysis indicate that daidzein is a competitive inhibitor of the activity of 3beta-HSD II and P450c21. K(m) and V(max) values of 3beta-HSD II for DHEA were estimated to be 6.6 microM and 328pmol/minmg protein, respectively. K(m) and V(max) values of P450c21 for progesterone were estimated to be 2.8 microM and 16pmol/minmg protein, respectively. K(i) values of 3beta-HSD II and P450c21 for daidzein were estimated to be 2.9 and 33.3 microM, respectively.
Article
Some dietary flavonoids inhibit thyroperoxidase and hepatic deiodinase activity, indicating that these compounds could be classified as anti-thyroid agents. In this study, we evaluated the in vitro effect of various flavonoids on thyroid type 1 iodothyronine deiodinase activity (D1). D1 activity was measured in murine thyroid microsome fractions by the release of 125I from 125I-reverse T3. D1 activity was significantly inhibited by all the flavonoids tested; however, the inhibitory potencies on thyroid D1 activity differed greatly among them. A 50% inhibition of D1 activity (IC(50)) was obtained at 11 microM baicalein, 13 microM quercetin, 17 microM catechin, 55 microM morin, 68 microM rutin, 70 microM fisetin, 72 microM kaempferol and 77 microM biochanin A. Our data reinforce the concept that dietary flavonoids might behave as antithyroid agents, and possibly their chronic consumption could alter thyroid function.
Article
Phytoestrogens contained in a vegetarian diet are supposed to have beneficial effects on the development and progression of a variety of endocrine-related cancers. We have tested the effect of a variety of dietary phytoestrogens, especially flavonoids, on the activity of human 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD 5), a key enzyme in the metabolism of estrogens and androgens. Our studies show that reductive and oxidative activity of the enzyme are inhibited by many compounds, especially zearalenone, coumestrol, quercetin and biochanin A. Among flavones, inhibitor potency is enhanced with increased degree of hydroxylation. The most effective inhibitors seem to bind to the hydrophilic cofactor binding pocket of the enzyme.
Article
The purpose of this study was to determine steroid hormone concentration profiles in healthy intact and neutered male and female dogs. Seventeen intact female dogs, 20 intact male dogs, 30 spayed female dogs, and 30 castrated male dogs were used in this study. Serum samples were collected before and 1h after cosyntropin administration, and serum concentrations were determined for cortisol, progesterone, 17-OH progesterone (17-OHP), dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, and estradiol. Intact male dogs had greater concentrations of DHEAS, androstenedione, and testosterone. Intact female dogs had greater concentrations of progesterone. There was no significant difference in estradiol concentration among the four groups. Intact male dogs had lower concentrations of cortisol post-stimulation. DHEAS and testosterone did not increase in response to ACTH in intact males, and estradiol concentrations did not increase in response to ACTH in any group. Results from this study will enhance interpretation of suspected adrenal and/or gonadal disorders of dogs. Because estradiol concentrations were similar in all groups of dogs, measuring estradiol may not be a useful diagnostic test. Cortisol concentrations for intact male dogs with hyperadrenocorticism may be lower than those of female or neutered dogs.
Article
The purpose of this study was to determine if there are specific steroid hormone aberrations associated with suspect endocrine alopecias in dogs in whom hypothyroidism and hyperadrenocorticism have been excluded. Steroid hormone panels submitted to the UTCVM endocrinology laboratory over a 7.5-year period (783 samples) from dogs with alopecia were reviewed. During this period, 276 dogs met the criteria for inclusion and were comprised of 54 different breeds. Approximately 73% of dogs had at least one baseline or post-ACTH stimulation steroid hormone intermediate greater than the normal range. The most frequent hormone elevation noted was for progesterone (57.6% of samples). When compared with normal dogs, oestradiol was significantly greater in Keeshond dogs and progesterone was significantly greater in Pomeranian and Siberian Husky dogs. Not all individual dogs had hormone abnormalities. Chow Chow, Samoyed and Malamute dogs had the greatest percentage of normal steroid hormone intermediates of the dogs in this study. Baseline cortisol concentrations were significantly correlated with progesterone, 17-hydroxyprogesterone (17-OHP) and androstenedione. Results of this study suggest that the pathomechanism of the alopecia, at least for some breeds, may not relate to steroid hormone intermediates and emphasizes the need for breed specific normals.
Article
Several nonthyroidal illnesses in euthyroid dogs can affect the results of thyroid function testing, making interpretation of the results more difficult with an increased risk of overdiagnosing hypothyroidism. The purpose of this study was to evaluate the effect of chronic, moderate to severe, osteoarthritis on canine thyroid function. Ninety-six, healthy, client-owned dogs, 65 of which were suffering from moderate to severe osteoarthritis and 31 euthyroid dogs without any physical evidence of osteoarthritis, were used in this study. Blood samples were collected to evaluate serum basal total thyroxine (TT4), free thyroxine (FT4), and thyrotropin (TSHc) concentrations. Basal serum TT4 concentration was not affected by osteoarthritis in dogs. Mild, but statistically significant, differences were noticed in FT4 and TSHc concentrations among the 2 groups. However, this had limited clinical relevance, since virtually all values were within their reference range, and no dogs would have been misdiagnosed as hypothyroid. Therefore, based on the results of our study, osteoarthritis does not need to be considered a factor influencing thyroid function evaluation in dogs.
Article
Estrogen produced by aromatization of gonadal androgen has an important facilitative role in male-typical aggressive behavior that is mediated through its interaction with estrogen receptors (ER) in the brain. Isoflavones found in soybeans and soy-based dietary supplements bind ER and have dose- and tissue-dependent effects on estrogen-mediated responses. Yet, effects of isoflavone-rich diets on social and aggressive behavior have not been studied. We studied the effects of long-term (15 months) consumption of diets rich in soy isoflavones on spontaneous social behavior among adult male cynomolgus macaques (Macaca fascicularis) (n = 44) living in nine stable social groups. There were three experimental conditions which differed only by the source of dietary protein: casein and lactalbumin (no isoflavones), soy protein isolate containing 0.94 mg isoflavones/g protein, and soy protein isolate containing 1.88 mg isoflavones/g protein. In the monkeys fed the higher amount of isoflavones, frequencies of intense aggressive (67% higher) and submissive (203% higher) behavior were elevated relative to monkeys fed the control diet (P's < 0.05). In addition, the proportion of time spent by these monkeys in physical contact with other monkeys was reduced by 68%, time spent in proximity to other monkeys was reduced 50%, and time spent alone was increased 30% (P's < 0.02). There were no effects of treatment on serum testosterone or estradiol concentrations or the response of plasma testosterone to exogenous gonadotropin-releasing hormone (GnRH). The results indicate that long-term consumption of a diet rich in soy isoflavones can have marked influences on patterns of aggressive and social behavior.
Article
To identify and determine the concentrations of phytoestrogens in commercial dog foods. 24 commercial dog foods, including 12 moist or dry extruded commercial dog foods that contained soybeans or soybean fractions and 12 foods without any soybean-related ingredients listed on the label. Foods were analyzed for phytoestrogen content, including 4 isoflavones (genistein, glycitein, daidzein, and biochanin A), 1 coumestan (coumestrol), and 2 lignans (secoisolariciresinol and matairesinol) by use of acid-methanol hydrolysis and high-pressure liquid chromatography with UV-absorbance detection. Phytoestrogens were identified and quantified by reference to authentic standards. Isoflavones, coumestans, and lignans were undetectable in diets that did not list soybean-related ingredients on the label. Only 1 of the 12 diets that included soybean or soybean fractions had undetectable concentrations of phytoestrogens and that product contained soy fiber. The major phytoestrogens were the isoflavones daidzein (24 to 615 microg/g of dry matter) and genistein (4 to 238 microg/g of dry matter). Soybean and soybean fractions are commonly used ingredients in commercial dog foods. Dietary intake of phytoestrogens may have both beneficial and deleterious health effects. Our results indicated that certain commercial dog foods contain phytoestrogens in amounts that could have biological effects when ingested long-term.
Article
To compare effects of short-term administration of a soy diet with those of a soy-free diet on serum thyroid hormone concentrations in healthy adult cats. 18 healthy adult cats. Cats were randomly assigned to receive either a soy or soy-free diet for 3 months each in a crossover design. Assays included CBC, serum biochemical profile, thyroid hormone analysis, and measurement of urinary isoflavone concentrations. Genistein, a major soy isoflavone, was identified in the urine of 10 of 18 cats prior to dietary intervention. Compared with the soy-free diet, cats that received the soy diet had significantly higher total thyroxine (T4) and free T4 (fT4) concentrations, but unchanged total triiodothyronine (T3) concentrations. The T3/fT4 ratio was also significantly lower in cats that received the soy diet. Although the magnitudes of the increases were small (8% for T4 and 14% for fT4), these changes resulted in an increased proportion of cats (from 1/18 to 4/18) that had fT4 values greater than the upper limit of the laboratory reference range. There was no significant effect of diet on any other measured parameter. Short-term administration of dietary soy has a measurable although modest effect on thyroid hormone homeostasis in cats. Increase in T4 concentration relative to T3 concentration may result from inhibition of 5'-iodothyronine deiodinase or enhanced T3 clearance. Soy is a common dietary component that increases serum T4 concentration in cats.
Article
Most commercial rodent diets are formulated with soya protein and therefore contain soya isoflavones. Isoflavones form one of the main classes of phytoestrogens and have been found to exert both oestrogenic and anti-oestrogenic effects on the central nervous system. The effects have not been limited to reproductive behaviour, but include effects on learning and anxiety and actions on the hypothalamo-pituitary axis. It is therefore possible that the soya content of diet could have significant effects on brain and behaviour and be an important source of between-laboratory variability. To determine whether behaviour in two animal tests of anxiety, and stress hormone production, would differ between rats that were fed a diet which was free of soya isoflavones and other phytoestrogens (iso-free) and those that were fed a diet which contained 150 microg/g of the isoflavones genistein and daidzein (iso-150). This controlled diet has an isoflavone concentration similar to that in the maintenance diet routinely used in our institution. Male rats were randomly allocated to the iso-free and iso-150 diets and their body weights and food and water consumption were recorded for 14 days. They were then maintained on the same diets, but housed singly for 4 days, before testing in the social interaction and elevated plus-maze tests of anxiety. Corticosterone concentrations in both dietary groups were determined under basal conditions and after the stress of the two tests of anxiety. Vasopressin and oxytocin concentrations were determined after brief handling stress. The groups did not differ in food or water intake, body weight or oxytocin concentrations. Compared with the rats fed the iso-free diet, the rats fed the iso-150 diet spent significantly less time in active social interaction and made a significantly lower percentage of entries onto the open arms of the plus-maze, indicating anxiogenic effects in both animal tests. The groups did not differ in their basal corticosterone concentrations, but the iso-150 group had significantly elevated stress-induced corticosterone concentrations. Stress-induced plasma vasopressin concentrations were also significantly elevated in the iso-150 diet group compared with the iso-free rats. Major changes in behavioural measures of anxiety and in stress hormones can result from the soya isoflavone content of rat diet. These changes are as striking as those seen following drug administration and could form an important source of variation between laboratories.
Article
Hair loss in Chesapeake Bay retrievers has been increasingly recognized by breeders in recent years. Anecdotal reports suggest an endocrine disorder or follicular dysplasia as the underlying cause, but no scientific study has been done to investigate the underlying problem. A prospective study was carried out in collaboration with the American Chesapeake Club. Affected dogs were recruited into the study. Routine dermatological and hormonal (blood and urine) tests, and skin biopsies were performed. Ten dogs (age 1.5–10 years), seven females (two spayed) and three males (two neutered), were included in the study. All dogs had mild or severe hair loss affecting the lateral ventral chest, flanks, rump and thighs. Affected dogs were clinically healthy. Hormonal tests revealed normal thyroid hormone panels, insulin-like growth factor-1 levels, and urinary cortisol:creatinine ratios in samples collected for ten consecutive days. In six of 10 dogs, an adrenal hormone panel showed slight or moderate increased values pre- and/or post-ACTH stimulation of cortisol (three of six), 17-hydroxyprogesterone (five of six), androstenedione (three of six), estradiol (two of six) and progesterone (six of six). The major histopathologic changes resembled canine flank alopecia and follicular dysplasia with pronounced infundibular hyperkeratosis, mild follicular atrophy, and occasional melanin clumping with dystrophic hair shafts. Chesapeake Bay retrievers suffer from a type of hair loss that is likely related to an abnormal production of adrenal sex hormone. Further studies are currently underway to determine if there is a heritable basis for this disease and to evaluate therapeutic options. Funding: University of Pennsylvania.
Article
Genistein is a phytoestrogen that occurs naturally in the diet, especially in soy-based foods. There is widespread interest in phytoestrogens as chemopreventive agents for a variety of diseases and cancers based on epidemiologic evidence. Although soy and its constituents, such as genistein, have been consumed at high levels in several Asian populations without apparent adverse effects, concern has been raised about potential adverse effects due to estrogenic and other activities. The subchronic and chronic safety of genistein were evaluated in the beagle dog including a 4-week study and a 52-week safety study with a 13 week interim sacrifice and a 4 week recovery period. In both studies at doses of 50, 150 and 500 mg/kg/day, genistein was well tolerated. In the 4 week study, except for an increase in uterine weights in female dogs at 500 mg/kg/day, there were no other treatment related findings. In the 52-week study, the primary effects of genistein were observed on the reproductive tract, which included for male dogs: reduced size and/or weight of the testes, epididymus and prostate of 2/2 dogs after 13 weeks of treatment and in 1/4 dogs after 52 weeks of treatment at 500 mg/kg/day. The histological changes observed in the affected dogs at 500 mg/kg/day indicated atrophy of the testes and prostate gland and absent spermatozoa in the epididymus. At the mid-dose of 150 mg/kg/day, although there was a reduction to a lesser extent in testes weight after 13, but not 52 weeks, there were no histopathological changes. In female dogs, the reproductive tract effects included increased uterine weight at 500 mg/kg/day after 13 weeks of treatment, but not after 52 weeks of treatment. There was also a small decrease in ovarian weights at 150 and 500 mg/kg/day after 13 weeks and at 500 mg/kg/day after 52 weeks of treatment. There were no histopathological correlates to the changes in organ weights in female dogs. In the 4-week recovery group dogs, no changes were observed in dogs previously treated for 52 weeks with 500 mg/kg/day of genistein. It is concluded that the administration of genistein to dogs for a period of 4-52 weeks was well tolerated and did not result in systemic toxicity. Effects of genistein on the reproductive tract at very high doses were functional in nature and are of a type that would be expected in view of the relatively weak estrogenic activity of genistein and were considered not adverse effects. In the 4-week study, the no observed adverse effect level (NOAEL) for genistein was considered to be >500 mg/kg/day and the no observed effect level (NOEL) was considered to be 150 mg/kg/day. For the 52-week study, the NOAEL is considered to be >500 mg/kg/day and the NOEL is considered to be 50 mg/kg/day.
Article
It is unknown whether the bioavailability of isoflavones is affected by the concomitant ingestion of glucosides or aglycones. This study was designed to investigate the effects of soymilk-based beverages containing different types of isoflavones on their absorption, excretion, and metabolism. Twelve healthy volunteers consumed 3 kinds of soymilk: untreated soymilk, beta-glucosidase-treated soymilk, and fermented soymilk. Blood samples were collected after 0, 1, 2, 3, 4, 5, 6, 7, 8, and 24 h. Urine samples were collected from 0 to 48 h. Concentrations of isoflavones and daidzein metabolites in serum and urine were measured by liquid chromatography-mass spectrometry. After the ingestion of soymilk, the total concentration of isoflavones in serum rose slowly and reached a maximum of 0.94 +/- 0.39 micromol/L at 6.0 +/- 1.2 h. However, beta-glucosidase-treated soymilk and fermented soymilk increased the serum isoflavone concentration significantly more quickly with maximum concentrations at 1.0 h of 1.75 +/- 0.33 micromol/L and 2.05 +/- 0.32 micromol/L, respectively. The urinary excretion of isoflavones after ingesting of these aglycone-enriched preparations was significantly greater than after consumption of untreated soymilk up to 8 h after injection, but not thereafter. The total and individual concentrations of isoflavones in serum and urine did not differ when subjects consumed the 2 aglycone-enriched soymilks. However, in equol producers (n = 5), the ingestion of ESM tended to increase urinary excretion of equol compared with the consumption of FSM (P = 0.08). These results demonstrated that the isoflavone aglycones of soymilk were absorbed faster and in greater amounts than their glucosides in healthy adults and that the metabolism of isoflavones might be affected by the type of soymilk consumed.
Article
Phytoestrogens are estrogen-like substances produced by plants that account for some of the constituents present in vegetation that may be responsible for the health benefits of a diet rich in fruit and vegetables. Phytoestrogens have a plethora of different actions that they are capable of exerting on cellular metabolism. This review will focus on some of the major non-estrogen receptor-mediated cellular effects used by phytoestrogens and will draw attention to the fact that while they may have a number of beneficial effects, particularly in offering a protective effect against some hormone-dependent cancers, such as breast and prostate cancer, they may also have possible unfavorable effects by interfering with the functioning of normal cellular activities such as receptor-mediated signal transduction and DNA replication, as well as being genotoxic, mutagenic and promoting the proliferation of some cancer cells.
Dietary isoflavones alter regulatory behaviors, metabolic hormones and neuroendocrine function in Long-Evans male rats
  • Lephart