Phytoestrogen Supplementation Research Articles

Association between Phytoestrogen Consumption and Female Reproductive Health: A Systematic Review of Experimental Models

AbstractPhytoestrogens have been shown as promising therapeutic agents for the treatment of menopausal symptoms, osteoporosis, breast cancer, and cardiovascular diseases. However, due to its unique chemical structure, phytoestrogen may cause unintended estrogenic and/or antiestrogenic effects on the human body, especially with regard to female reproductive health and performance. Hence, this systematic review aims to provide a critical evaluation of in vitro and in vivo evidence from the literature regarding the adverse effects of phytoestrogens on female reproductive health. The literature search was performed on four electronic databases including Scopus, Science Direct, PubMed, and Google Scholar following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A total of 965 studies were screened but only 58 of them were found to be relevant and assessed for eligibility. Of these, 23 studies met the eligibility criteria while the remaining studies were excluded due to insufficiently described methods and lack of clear findings being reported. From the review, phytoestrogens may alter the development of reproductive organs, prolong the estrus cycle, induce the accumulation of fluid in the uterus, and inhibit ovulation. The concentration and exposure duration of phytoestrogens may have different effects on the reproductive organs. Thus, further studies are warranted on the toxicodynamic, toxicokinetic, mode of action, and mechanism of actions of phytoestrogens on the female reproductive system to establish recommendations regarding phytoestrogen supplement consumption for women.

Osteoporosis and vascular calcifications.

In post-menopausal women, aged individuals, and patients with diabetes mellitus or chronic renal disease, bone mineral density (BMD) decreases while the vasculature accumulates arterial calcifications (ACs). AC can be found in the tunica intima and/or in the tunica media. Prospective studies have shown that patients with initially low BMD and/or the presence of fragility fractures have at follow-up a significantly increased risk for coronary and cerebrovascular events and for overall cardiovascular mortality. Similarly, patients presenting with abdominal aorta calcifications (an easily quantifiable marker of vascular pathology) show a significant decrease in the BMD (and an increase in the fragility) of bones irrigated by branches of the abdominal aorta, such as the hip and lumbar spine. AC induction is an ectopic tissue biomineralization process promoted by osteogenic transdifferentiation of vascular smooth muscle cells as well as by local and systemic secreted factors. In many cases, the same regulatory molecules modulate bone metabolism but in reverse. Investigation of animal and in vitro models has identified several potential mechanisms for this reciprocal bone-vascular regulation, such as vitamin K and D sufficiency, advanced glycation end-products-RAGE interaction, osteoprotegerin/RANKL/RANK, Fetuin A, oestrogen deficiency and phytooestrogen supplementation, microbiota and its relation to diet, among others. Complete elucidation of these potential mechanisms, as well as their clinical validation via controlled studies, will provide a basis for pharmacological intervention that could simultaneously promote bone and vascular health.

The influence of phytoestrogens on alleviating symptoms associated with menopause

Introduction and purpose. Menopause causes complaints such as hot flashes, night sweats, sleep problems and vaginal dryness. Hormone replacement therapy (HRT) is an effective treatment option for women with moderate to severe symptoms. In women who are unable to undergo HRT, plant-based preparations containing phytoestrogens can be used as an alternative. The purpose of this paper is to summarize the effectiveness of phytoestrogen supplementation.
 State of knowledge. Phytoestrogens are natural compounds structurally similar to estrogens, such as estradiol. They are divided into different classes, including isoflavones and lignans. Isoflavones, including genistein, found in soy products, cause a significant reduction in the severity of hot flashes, as well as improvements in vaginal dryness and sexual function. Lignans, found in flaxseed, sesame seeds and whole grains, have effects similar to endogenous estrogens, but studies to date have not shown significant efficacy of this group of substances in reducing menopausal symptoms. Resveratrol, a naturally occurring compound found in grapes and berries, has a weak estrogenic effect, whereby several clinical trials have demonstrated the effectiveness of resveratrol supplementation in alleviating menopausal symptoms.
 Conclusions. Phytoestrogens have been shown to alleviate some symptoms of menopause, such as hot flashes and night sweats, and may also have positive effects on bone density and cognitive abilities. Effects may vary depending on the source, dose and duration of treatment. There are also potential risks associated with their use, for which reason more research is needed to fully understand their effectiveness and safety.

Protective Effects of Coumestrol on Metabolic Dysfunction and Its Estrogen Receptor-Mediated Action in Ovariectomized Mice

Coumestrol, a phytoestrogen compound found in various plants, has been shown to act as a potent estrogen receptor (ER) agonist, with a higher binding affinity for ERβ than for ERα. However, there is currently limited information regarding its beneficial effects in postmenopausal disorders and its ER-mediated mechanisms. Herein, we investigated the effects of coumestrol (subcutaneous or oral treatment) on metabolic dysfunction in ovariectomized (OVX) mice fed a high-fat diet, in comparison with the effects of 17β-estradiol (E2) replacement. Coumestrol was administered daily at a dose of 5 mg/kg for 10 weeks. Coumestrol treatment through the subcutaneous route stimulated uterine growth in OVX mice at a level lower than that of E2. E2 and coumestrol prevented body fat accumulation, adipocyte hypertrophy, and hepatic steatosis, and enhanced voluntary physical activity. Coumestrol showed estrogen-mimetic effects in the regulation of the protein expressions involved in browning of white fat and insulin signaling, including increased hepatic expression of fibroblast growth factor 21. Importantly, the metabolic effects of coumestrol (oral administration at 10 mg/kg for 7 weeks) were mostly abolished following co-treatment with an ERβ-selective antagonist but not with an ERα-selective antagonist, indicating that the metabolic actions of coumestrol in OVX mice are primarily mediated by ERβ. These findings provide important insights into the beneficial effects of coumestrol as a phytoestrogen supplement for the prevention and treatment of postmenopausal symptoms.

LITERATURE REVIEW: INFLUNCING FACTORS OF QUALITY OF LIFE OF MENOPAUSE WOMEN

Introduction : An elderly woman will experience menopause. This condition must immediately get good treatment so that the quality of life of these women is good or improved. For this reason, it is necessary to know the factors that affect the quality of life of post-menopausal women. Objectives: The purpose of this study was to determine the factors that affect the quality of life of postmenopausal women. Method: Literature Review, by searching the Pubmed, ProQuest, Science Direct and Google scholar databases. Obtained 7 articles to be included in the review. Results: The factors that affect the quality of life of postmenopausal women are the use of hormonal supplements in the form of phytoestrogens, active in sexual activity, physical exercise, class activities and counseling. Conclusion: Good sexual activity will improve the quality of life of postmenopausal women, in addition to attending counseling classes, adding phytoestrogen supplements and using lubricants or liquid lubricants to prevent infection..

P-670 Phytoestrogen concentration in women’s urine and follicular fluid are associated with better IVF outcomes in euploid single embryo transfer cycles

Abstract Study question What is phytoestrogen exposure impact on the reproductive outcomes of women undergoing IVF treatment? Summary answer Increased urinary and follicular fluid phytoestrogen concentration were associated with better IVF outcomes. What is known already The impact and safety of phytoestrogens, plant-derived isoflavones with estrogenic activity predominantly present in soy, on female reproductive health and on IVF outcomes continues to be hotly debated. Numerous studies suggest healthy benefits of phytoestrogen consumption: protection against reprotoxic substances, reductions in breast and other cancers, fibroids, menopausal symptoms, cardiovascular disease, inflammation, and metabolic syndrome and obesity. However, many studies suggest a harmful effect due to the endocrine-disruptor properties of phytoestrogens in both male and female reproductive tissues. Its impact on IVF treatments success is still understudied. Study design, size, duration 60 women attending IVI-RMA New Jersey undergoing IVF with single-embryo transfer (SET) of euploid good-quality blastocyst after PGT analysis were recruited. Patients underwent PGT-SET cycles following standard protocols. Concentrations of two phytoestrogens (daidzein and genistein) were measured in follicular fluid (FF) and urine collected at oocyte pick-up (UOP) and urine collected at transfer day (UT). These measurements were correlated with IVF clinical outcomes. Participants/materials, setting, methods Participants were aged 18-42 years old 18.5-29.9 kg/m2 BMI. Measure of both phytoestrogens’ concentration in follicular fluid and urine samples collected at two different time-points was performed by UPLC-MSMS, with internal standards. Urine phytoestrogen concentrations were normalized by creatinine, measured by Jaffe reaction. Generalized linear models were employed to explore IVF outcomes association, estimated as percentile 20th to 80th increase (95% confidence intervals), among log-transformed phytoestrogen concentration. Both unadjusted and age-BMI-adjusted models were applied. Main results and the role of chance In fully adjusted models, higher sum of phytoestrogen concentration in follicular fluid (FF) were significantly associated with higher estradiol at hCG [1.31 (1.04, 1.65), p = 0.023]; whereas the sum of creatinine-corrected phytoestrogens measured in oocyte pick-up urine (UOP) were significantly associated with higher MII oocytes number [1.29 (1.07, 1.56), p = 0.008] and higher fertilized oocytes number [1.34 (1.10, 1.64), p = 0. 004]. Regarding clinical IVF outcomes, in fully adjusted models a higher follicular fluid and oocyte pick-up urine phytoestrogens concentration was significantly associated with higher implantation ratio [8.60 (1.09, 68.03), p = 0. 023] for FF, and [5.01 (0.96, 26.21), p = 0. 05] for UOP; higher clinical pregnancies ratio [5.58 (1.31, 23.73), p = 0.017] for FF, and [3.25 (0.99, 10.63), p = 0.045] for UOP; higher live newborns ratio [5.58 (1.31, 23.73), p = 0.017] for FF, and [3.25 (0.99, 10.63), p = 0.045] for UOP; and higher number of women with live newborns among those who started treatment [4.29 (1.28, 14.38), p = 0.016] for FF, and [2.83 (0.99, 8.07), p = 0.047] for UOP. Limitations, reasons for caution Further studies are needed to confirm this association in other populations, including the measurement of other estrogenic isoflavones and its metabolites. Wider implications of the findings This is the first work evaluating the association between phytoestrogens concentrations in different biofluids and IVF reproductive outcomes. Our results, using an euploid SET, suggest a beneficial effect of phytoestrogen consumption in women undergoing IVF treatment, further studies are needed to assess the benefit of phytoestrogen supplementation on IVF outcomes. Trial registration number -

Phytoestrogen in cowpea (Vigna unguiculata L. Walp) (Fabaceae) extract reduces vaginal oxidative stress and increases proliferation of fibroblast in ovariectomized rats

Purpose: To evaluate the effects of a phytoestrogen extract of cowpea (Vigna unguiculata) on malondialdehyde (MDA) and superoxide dismutase (SOD) levels, mitogen-activated protein kinase (MAPK) activity, as well as proliferation of fibroblasts in ovariectomized rat vagina. This is with a view to identify the optimal dose of a phytoestrogen supplement for use during the menopausal period of women.
 Methods: Wistar rats (Rattus norvegicus) were divided into five groups: negative control, ovariectomy, and ovariectomy groups treated with 1.25, 2.5, or 5 mg/kg of cowpea extract, respectively. The three doses were used to identify the optimal dose required to reduce vaginal oxidative stress and increase fibroblast proliferation in ovariectomized rats. After treatment, the ovariectomized rat vagina was assessed for SOD and MDA levels, MAPK activity, and fibroblast proliferation.
 Results: Cowpea extract at a dose of 2.5 and 5 mg/kg caused significant reduction in SOD levels in the vaginal tissue of rats compared with control (p < 0.05). In contrast, cowpea extract at 1.25 mg/kg resulted in MDA levels similar to that of control rats (p < 0.05). Cowpea extract treatment had positive effects on SOD and MDA levels and on fibroblast proliferation. Increase in SOD levels in rat vagina was induced by increased MDA levels, which is characteristic of oxidative stress, while ovariectomy resulted in decreased MAPK activity.
 Conclusion: Overall, the cowpea extract has no significant effect on MAPK activity or fibroblast proliferation. However, it has a significant effect on SOD and MDA levels and on fibroblast proliferation at a dose of 2.5 mg/kg.

Effects of phytoestrogen supplementation on intermediate cardiovascular disease risk factors among postmenopausal women: a meta-analysis of randomized controlled trials.

Phytoestrogens are becoming popular constituents of human diets and are increasingly used by postmenopausal women. Our study aims to determine the effects of phytoestrogen supplementation on intermediate cardiovascular disease (CVD) risk factors in postmenopausal women. Five electronic databases (Medline, EMBASE, Web of Science, Cochrane CENTRAL, Google Scholar) were systematically searched to identify eligible studies, that is, randomized controlled trials (RCTs) that assessed the association of phytoestrogen supplementation with CVD risk factors (serum lipids, homocysteine, fibrinogen, markers of inflammation, oxidative stress and endothelial function, carotid intima-media thickness [CIMT]) in postmenopausal women. Data were extracted by two independent reviewers using a predefined data collection form. In total, 56 RCTs were identified, including 4,039 individual postmenopausal women. There was substantial heterogeneity in quality across studies. Twenty-six (46%) RCTs showed poor quality and there was an indication of publication bias presence for some of the biomarkers. Results are reported in pooled mean difference (95% CI) of changes. Use of phytoestrogens was associated with a decrease in serum total cholesterol (-0.27 mmol/L [-0.41 to -0.13]), low-density lipoprotein (-0.25 mmol/L [-0.37 to -0.13]), triglycerides (-0.20 mmol/L [-0.28 to -0.11]), and apolipoprotein B (-0.13 g/L [-0.23 to -0.03]) and with an increase in serum apolipoprotein A-1 (0.04 g/L [0.02-0.07]. Also, phytoestrogen supplementation was associated with a decrease in serum intercellular adhesion molecule 1 (-18.86 ng/mL [-30.06 to -7.65]) and E-selectin (-2.32 ng/mL [-4.05 to -0.59]). There was no association observed between phytoestrogen supplementation and inflammatory markers, fibrinogen, homocysteine, or other endothelial function markers. In contrast, use of phytoestrogens was associated with an increase in CIMT (9.34 μm [95% CI, 0.39-18.29]). Effect estimates of phytoestrogen supplementation on oxidative stress could not be pooled. Phytoestrogen supplementation seems to modestly improve the CVD risk profile of postmenopausal women by influencing blood lipids and parameters of endothelial function. In women with an increased risk of atherosclerosis, although modest, a harmful effect on CIMT progression may be present. Because of limited quality and the heterogeneous nature of the current evidence, additional rigorous studies are needed to explore the role of phytoestrogens in menopausal cardiovascular health. : Video Summary: http://links.lww.com/MENO/A593.

Regulation of Human Aldehyde Oxidase Expression by Estrogen Receptor Agonists

Human aldehyde oxidase‐1 (AOX1) is a cytosolic molybdo‐flavoenzyme of importance in drug metabolism and toxicity. However, it is not known how the expression of this gene is transcriptionally regulated. Estrogen receptor (ER), which is a nuclear receptor, plays important roles in physiological functions and is implicated in hormonal cancers, but it also regulates the expression of hepatic drug‐metabolizing enzymes. Conflicting microarray data show that AOX1 expression was increased or decreased in breast cancer compared to healthy tissues. We investigated whether ER agonists regulate AOX1 gene expression in a human cell culture model. As analyzed by real‐time polymerase chain reaction assays, MCF‐7 human breast adenocarcinoma cells expressed AOX1 and the basal AOX1 level varied with different types of fetal bovine serum (FBS). 17β‐Estradiol decreased AOX1 mRNA level in ER‐positive MCF‐7 cells, and this decrease was greatest in cells cultured in 10% charcoal‐stripped FBS. Time‐course experiments indicated that 17β‐estradiol decreased AOX1 expression in a time‐dependent manner with a maximum effect occurring after 72 h treatment. Non‐toxic concentrations (as assessed by a cell viability assay) of endogenous estrogens (estrone, 17β‐estradiol, estriol, and estetrol), synthetic estrogens (ethinylestradiol), and phytoestrogens (daidzein and genistein) decreased the expression of AOX1 (by 40–76%) and other known 17β‐estradiol‐regulated genes (SMAD3 and HBP1) and induced known ER‐regulated genes (GREB1 and TFF1) in MCF‐7 cells. Concentration‐response experiment indicated that estrone, 17β‐estradiol, estriol, and estetrol decreased AOX1 expression with EC50 value of 22.5 pM, 1.4 pM, 9.1 pM, and 513.9 pM, respectively, which are physiologically‐relevant concentrations in humans, suggesting that physiological levels of estrogens suppress AOX1 expression. By comparison, ethinylestradiol, daidzein, and genistein decreased AOX1 level with EC50 value of 1.3 pM, 94.6 nM, and 19.4 nM, respectively, which are clinically‐relevant concentrations after administration of the drug or phytoestrogen supplements. The EC50 values for AOX1 suppression and ERα activation by the agonists were well‐correlated. Non‐toxic concentrations of fulvestrant, a ER antagonist, negated both AOX1 suppression and TFF1 induction by estrogens, indicating that ER regulates AOX1 gene. ERα was the major ER isoform expressed in MCF‐7 cells, whereas ERβ was low or negligible, indicating that AOX1 suppression by ER agonists occurred via ERα, but not ERβ, activation in MCF‐7 cells. Suppression of AOX1 by estrogens did not occur in ER‐negative HepG2 human hepatocellular carcinoma cells. In conclusion, ethinylestradiol and 17β‐estradiol are the most potent AOX1 suppressors, followed by estriol, estrone, estetrol, genistein, and daidzein, and the suppression of AOX1 occurs by ERα activation. This is the first study showing hormonal regulation of AOX1 expression and provide insights into potential drug‐chemical interactions. Our findings also imply that interindividual variations in estrogen levels may lead to differences in AOX1 expression and AOX1‐mediated drug metabolism and toxicity.Support or Funding InformationSingapore Ministry of Education Academic Research Fund Tier 1 and Ministry of Health National Medical Research Council Grants

Effects of Phytoestrogen Supplement on Quality of Life of Postmenopausal Women: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background The effect of phytoestrogen on postmenopausal quality of life is unclear. This study evaluated the effects of phytoestrogen supplement on quality of life for postmenopausal women. Methods We conducted a systematic review and meta-analysis of randomized controlled trials on the effects of phytoestrogen supplements on the quality of life of postmenopausal women. We searched PubMed, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials on March 31, 2018, for relevant randomized controlled trials. Two authors independently selected studies, assessed risk of bias, and extracted data. Disagreement was resolved through discussion with a third author. Results We involved 10 articles in the systematic review. 8 studies and a total of 1,129 subjects were included in the meta-analysis. The questionnaires used in the evaluation of quality of life were as follows: SF-36, 4 studies; MENQOL, 4 studies; For Short Form 36 surveys, phytoestrogen groups scored significantly higher for body pain (mean difference = 3.85, 95% confidence interval [CI] = [1.14, 6.57], P < 0.01), mental health (mean difference = 4.01, 95% CI = [1.49, 6.57], P < 0.01), and role limitations caused by emotional problems domains (mean difference = 3.83, 95% CI = [1.81, 5.85], P < 0.01). No statistically significant difference was obtained from Menopause-Specific Quality of Life surveys (vasomotor domain mean difference 0.14, 95% CI = [−0.08, 0.36], P = 0.20; physical domain mean difference 0.20, 95% CI [−0.08, 0.48], P = 0.15; psychological domain mean difference −0.10, 95% CI [−0.26, 0.07], P = 0.27; sexual domain mean difference −0.17, 95% CI [−0.42, 0.09], P = 0.19). Conclusion Current evidence does not support phytoestrogen supplementation improving postmenopausal quality of life. Further comprehensive trials or long-term follow-up studies are warranted.

Associations between Phytoestrogens, Glucose Homeostasis, and Risk of Diabetes in Women: A Systematic Review and Meta-Analysis.

Phytoestrogens might have advantageous effects on diabetes in women. We performed a systematic review and meta-analysis to determine the effect of phytoestrogens on glucose homeostasis and the risk of type 2 diabetes (T2D) among women. Randomized controlled trials (RCTs) and prospective observational studies that assessed associations of phytoestrogens (supplementation, dietary intake, or biomarkers) with fasting glucose or insulin, homeostatic model assessment of insulin resistance (HOMA-IR), or with the risk of T2D were included. We identified 18 RCTs (n=1687 individuals) investigating the effect of phytoestrogen supplementation on glucose homeostasis and 9 prospective population-based studies (n=212,796 individuals) examining the association between phytoestrogen intake and the risk of T2D. Compared with placebo, phytoestrogen supplementation resulted in improvements in fasting glucose and HOMA-IR: the pooled mean differences of changes were -0.12 mmol/L (95% CI: -0.20, -0.03 mmol/L) and -0.24 mmol/L (95% CI: -0.45, -0.03 mmol/L), respectively. Although there was no significant decrease in insulin concentrations with overall phytoestrogen supplementation, the pooled mean difference in changes was -0.99 pmol/L (95% CI: -4.65, 2.68 pmol/L). However, the results of RCTs varied by type of phytoestrogens: soy-derived isoflavones and genistein improved glucose homeostasis, whereas isoflavone mix and daidzein had no effect or were associated with an adverse glycemic profile. Higher dietary phytoestrogen intake was associated with a 10% lower risk of developing T2D in observational studies (pooled RR: 0.90; 95% CI: 0.85, 0.96; for the highest compared with the lowest quantiles). Results were similar when the analyses were restricted to only medium- and high-quality studies. Overall, phytoestrogens may have a positive influence on glycemia and could be used for diabetes prevention in women. However, for some individual types of phytoestrogens, such as mixed isoflavones, caution is needed in recommending their use in women, because their use could lead to an adverse glycemic profile in women.

Does phytoestrogen supplementation improve cognition in humans? A systematic review.

Recent evidence indicates that resveratrol, a phytoestrogen, can improve cognitive function in postmenopausal women by enhancing cerebral vasodilator responsiveness. We examine the effects of phytoestrogen supplementation on cognition and compare resveratrol with other phytoestrogens. Databases were searched for reports of randomized controlled trials (RCTs) containing terms describing phytoestrogens together with terms relating to cognition. Effect sizes were determined for changes in cognition. We identified 23 RCTs, 15 with isoflavone and eight with resveratrol or grape formulations. Six soy isoflavone studies showed positive cognitive effects of medium size. Greater benefits were seen in women who were <10 years postmenopausal and supplemented for <6 months. Small-to-medium effect-size cognitive benefits of resveratrol were seen in four studies of older adults of mixed gender and in postmenopausal women who took 150-200 mg resveratrol daily for at least 14 weeks. No benefits were seen in three studies using red clover or grape formulations. Supplementation with either soy isoflavone or resveratrol improved executive function and memory domains of cognitively normal older adults in half of the included studies, mostly with medium effect sizes. The cognitive benefit of resveratrol was related to improved cerebral perfusion.

A phytoestrogen supplement prevents the altered gene expression associated with pregnancy implantation induced by IL-1β in endometrial epithelial cells

Phytoestrogens stimulate expression of the uterine estrogen receptor and regulate uterine functions in reproductive tissues. However, comprehensive understanding of the beneficial impacts of phytoestrogens on uterine biology at the molecular level remains unexplored. Interleukin-1β (IL-1β) expression is increased in the inflamed decidua and is associated with first trimester pregnancy loss. AglyMax-Sup has the same composition as that of the phytoestrogen supplement AglyMax but with added vitamins and other components. Expression of genes associated with implantation may be enhanced by AglyMax-Sup compared with AglyMax. We tested the hypothesis that AglyMax-Sup has greater effects on implantation compared with AglyMax, using RT-PCR and Western blotting in the endometrial epithelial cell line. Furthermore, we investigated the protective effect of AglyMax-Sup on IL-1βinduced changes in estrogen-responsive gene expression in endometrial epithelial cells. The purpose of this study was to compare the effects of the phytoestrogen supplement AglyMax-Sup with those of AglyMax on estrogen-responsive gene expression. AglyMax and AglyMax-Sup significantly (p<0.05) induced gene expression of glycodelin-A, HoxA10, IL-11, LIF, MEG-E8 and TGFβ1. AglyMax-Sup induced high levels of these genes compared with the levels induced by AglyMax. The enhanced expression of LIF, IL-11, integrin αV, and HOXA10 induced by AglyMax-Sup was abolished by the ER antagonist fulvestrant and the ERK inhibitor PD98059. Meanwhile, IL-1β inhibited progesterone plus estrogen-induced TGFβ1, glycodelin-A, HOXA10, and integrin αV expression. IL-1β-induced suppression of these expression was reversed by AglyMax-Sup. These results indicate that expression of genes associated with implantation may be increased by AglyMax-Sup compared with AglyMax. AglyMax-Sup might abrogate IL-1β-mediated changes that can affect embryo implantation via the MAPK pathway.

Long-term exercise training and soy isoflavones to improve quality of life and climacteric symptoms

Objective: To verify the efficacy of phytoestrogen supplementation combined with aerobic and resistance training on the improvement of climacteric symptoms and health-related quality of life (HRQoL) in postmenopausal women.Methods: From a pool of women who had participated in a 1-year intervention study and were randomly assigned to either exercise + phytoestrogen (EX + PHY) or exercise + placebo (EX + PL), a total of 31 healthy but overweight women (mean age 59.2 ± 4.8 years, body mass index 29.1 ± 3.5 kg/m2) finished the study (EX + PHY, n = 15; EX + PL, n = 16). All the following variables were measured before, after 6 months and after 12 months of intervention: body composition (fat and lean body mass, DXA), HRQoL (SF-36 questionnaire: physical and mental component summaries and subscales; and the 10-item Perceived Stress Scale questionnaire), climacteric symptoms (Kupperman Index questionnaire).Results: After 1 year of intervention, physical functioning (p = 0.003), role-emotional (p = 0.031), vitality (p = 0.007), and global health (p < 0.001) were significantly and similarly increased in both groups. Regarding climacteric symptoms, an improvement in the Kupperman index total score (p = 0.015) was observed.Conclusion: Our results demonstrate that adding phytoestrogens to exercise training does not provide the additive effect for HRQoL in postmenopausal and overweight women. Moreover, exercise and phytoestrogen may interfere in the improvement of climacteric symptoms in the long term.

The effect of zinc and phytoestrogen supplementation on the changes in mineral content of the femur of rats with chemically induced mammary carcinogenesis

The aim of this study was to assess skeletal effects of zinc or zinc with phytoestrogen (resveratrol or genistein) supplementation in an animal model of rats with DMBA-induced mammary carcinogenesis. The changes in bone parameters such as the length and mass were examined, as well as the changes in concentrations of selected minerals: calcium, magnesium, zinc, iron and phosphorus. Moreover, the investigations focused on finding the differences between the levels of iron and zinc in other tissues: the liver, spleen and serum of the examined rats.Fifty-six female Sprague–Dawley rats, 40 days old, were divided into four groups, regardless of the diets: standard (77mg Zn kg/food), zinc (4.6mg/mL via gavage), zinc (4.6mg/mL) plus resveratrol (0.2mg/kgbw), and zinc (4.6mg/mL) plus genistein (0.2mg/kgbw) for a period from 40 days until 20 weeks of age. The study rats were also treated with 7,12-dimethyl-1,2-benz[a]anthracene (DMBA) to induce mammary carcinogenesis.The applied diet and the advanced mammary cancer did not affect macrometric parameters of the rats’ bones, but they strongly affected their mineral content. It was found that mammary cancer, irrespectively of the applied diet, significantly modified the iron level in the femur, liver, spleen and serum of the examined rats. In addition, zinc supplementation significantly lowered the levels of calcium, magnesium and phosphorus in the femur of rats with mammary cancer as compared with respective levels in the control group. So, it was found that additional supplementation with zinc, which is generally considered to be an antioxidant, with the co-existing mammary carcinoma, increased the unfavorable changes as concerns the stability of bone tissue. The appropriate combination of zinc and phytoestrogens (resveratrol or genistein) could help prevent or slow bone loss associated with a range of skeletal disorders in breast cancer.

Adult emotionality and neural plasticity as a function of adolescent nutrient supplementation in male rats

The present study explored the effects of supplementing male rats with either choline, omega-3 fatty acids, or phytoestrogens, from weaning into early adulthood, on emotionality and hippocampal plasticity. Because of the neuroprotective properties of these nutrients, we hypothesized that they would positively affect both behavior and hippocampal function when compared to non-supplemented control rats. To test this hypothesis, male Sprague Dawley rats were assigned to one of four nutrient conditions after weaning: 1) control (normal rat chow); 2) choline (supplemented in drinking water); 3) omega 3 fatty acids (daily oral supplements); or 4) phytoestrogens (supplemented in chow). After 4weeks on their respective diets, a subset of rats began 3weeks of behavioral testing, while the remaining behaviorally naïve rats were sacrificed after 6weeks on the diets to assess numbers of adult-born hippocampal neurons using the immature neuron marker, doublecortin. The results revealed that choline supplementation affected emotional functioning; compared to rats in other diet conditions, rats in this group were less anxious in an open field and after exposure to predator odor and showed less behavioral despair after forced swimming. Similar behavioral findings were evident following supplementation with omega-3 fatty acids and phytoestrogen supplementation, though not on all tests and not to the same magnitude. Histological findings followed a pattern consistent with the behavioral findings: choline supplementation, followed by omega-3 fatty acid supplementation, but not phytoestrogen supplementation, significantly increased the numbers of new-born hippocampal neurons. Choline and omega-3 fatty acids have similar biological functions—affecting cell membranes, growth factor levels, and epigenetically altering gene transcription. Thus, the present findings suggest that targeting nutrients with these effects may be a viable strategy to combat adult psychopathologies.

The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer.

The successful use of high-dose synthetic estrogens to treat postmenopausal metastatic breast cancer is the first effective 'chemical therapy' proven in clinical trial to treat any cancer. This review documents the clinical use of estrogen for breast cancer treatment or estrogen replacement therapy (ERT) in postmenopausal hysterectomized women, which can either result in breast cancer cell growth or breast cancer regression. This has remained a paradox since the 1950s until the discovery of the new biology of estrogen-induced apoptosis at the end of the 20th century. The key to triggering apoptosis with estrogen is the selection of breast cancer cell populations that are resistant to long-term estrogen deprivation. However, estrogen-independent growth occurs through trial and error. At the cellular level, estrogen-induced apoptosis is dependent upon the presence of the estrogen receptor (ER), which can be blocked by nonsteroidal or steroidal antiestrogens. The shape of an estrogenic ligand programs the conformation of the ER complex, which, in turn, can modulate estrogen-induced apoptosis: class I planar estrogens (e.g., estradiol) trigger apoptosis after 24 h, whereas class II angular estrogens (e.g., bisphenol triphenylethylene) delay the process until after 72 h. This contrasts with paclitaxel, which causes G2 blockade with immediate apoptosis. The process is complete within 24 h. Estrogen-induced apoptosis is modulated by glucocorticoids and cSrc inhibitors, but the target mechanism for estrogen action is genomic and not through a nongenomic pathway. The process is stepwise through the creation of endoplasmic reticulum stress and inflammatory responses, which then initiate an unfolded protein response. This, in turn, initiates apoptosis through the intrinsic pathway (mitochondrial) with the subsequent recruitment of the extrinsic pathway (death receptor) to complete the process. The symmetry of the clinical and laboratory studies now permits the creation of rules for the future clinical application of ERT or phytoestrogen supplements: a 5-year gap is necessary after menopause to permit the selection of estrogen-deprived breast cancer cell populations to cause them to become vulnerable to apoptotic cell death. Earlier treatment with estrogen around menopause encourages growth of ER-positive tumor cells, as the cells are still dependent on estrogen to maintain replication within the expanding population. An awareness of the evidence that the molecular events associated with estrogen-induced apoptosis can be orchestrated in the laboratory in estrogen-deprived breast cancers now supports the clinical findings regarding the treatment of metastatic breast cancer following estrogen deprivation, decreases in mortality following long-term antihormonal adjuvant therapy, and the results of treatment with ERT and ERT plus progestin in the Women's Health Initiative for women over the age of 60. Principles have emerged for understanding and applying physiological estrogen therapy appropriately by targeting the correct patient populations.

Using Topical Applications of Tamoxifen and a Combination of Phytonutrients Based on Breast MRI to Inhibit Estrogen-Related Proliferation of Human Breast Tissue

Objective: In January of 2013, the National Institute of Health and Clinical Excellence of United Kingdom have announced that taking tamoxifen for five years could reduce breast cancer risk, include positive family history or chronic estrogen and phytoestrogen users. However, routinely oral intake of tamoxifen for breast cancer prophylaxis on high risk women is occasionally difficult because of its potential side effects. The intention of this study is to prove transdermal delivery by using minimal dose of tamoxifen and phytonutrients for breast protection. Methods: We retrospectively studied 2795 breast MRI images from Taiwanese women and classified them as either healthy or unhealthy according to BI-RADS categories. A subgroup of the study patients had received estrogen supplements containing estrogen components or phytoestrogen for at least 3 months. Based on breast MRI analysis, these 2 groups were compared and found significant different. The overuse of estrogen or phytoestrogen supplements can increase breast glandular tissue proliferation, as reflected in MRI images. Such proliferation may increase the risk of future breast cancer. We also studied the efficacy of tamoxifen and the phytonutrients to inhibit proliferation of mammary glandular cell, as well as their transdermal absorption in animal models. Results: We demonstrated cell proliferative change of normal breast cells (MCF-10a) under estrogen treatment. For studied of transdermal absorption by topical application, we used Franz cell with artificial skin membrane to demonstrate positive transdermal diffusion using animal urine/feces, blood samples and subcutaneous skin retention for HPLC analysis. Conclusion: We successful demonstrate the transdermal absorption of topical application of tamoxifen and phytonutrients; it may help to reduce breast cancer development in regular estrogen and phytoestrogen users.

Phytoestrogens and prevention of breast cancer: The contentious debate.

Phytoestrogens have multiple actions within target cells, including the epigenome, which could be beneficial to the development and progression of breast cancer. In this brief review the action of phytoestrogens on oestrogen receptors, cell signalling pathways, regulation of the cell cycle, apoptosis, steroid synthesis and epigenetic events in relation to breast cancer are discussed. Phytoestrogens can bind weakly to oestrogen receptors (ERs) and some have a preferential affinity for ERβ which can inhibit the transcriptional growth-promoting activity of ERα. However only saturating doses of phytoestrogens, stimulating both ERα and β, exert growth inhibitory effects. Such effects on growth may be through phytoestrogens inhibiting cell signalling pathways. Phytoestrogens have also been shown to inhibit cyclin D1 expression but increase the expression of cyclin-dependent kinase inhibitors (p21 and p27) and the tumour suppressor gene p53. Again these effects are only observed at high (> 10) µmol/L doses of phytoestrogens. Finally the effects of phytoestrogens on breast cancer may be mediated by their ability to inhibit local oestrogen synthesis and induce epigenetic changes. There are, though, difficulties in reconciling epidemiological and experimental data due to the fact experimental doses, both in vivo and in vitro, far exceed the circulating concentrations of "free" unbound phytoestrogens measured in women on a high phytoestrogen diet or those taking phytoestrogen supplements.

Phytoestrogens for menopausal vasomotor symptoms.

Vasomotor symptoms, such as hot flushes and night sweats, are very common during the menopausal transition. Hormone therapy has traditionally been used as a highly effective treatment, but concerns about increased risk of some chronic diseases have markedly increased the interest of women in alternative treatments. Some of the most popular of these treatments are foods or supplements enriched with phytoestrogens-plant-derived chemicals that have estrogenic action. To assess the efficacy, safety and acceptability of food products, extracts and dietary supplements containing high levels of phytoestrogens when compared with no treatment, placebo or hormone therapy for the amelioration of vasomotor menopausal symptoms (such as hot flushes and night sweats) in perimenopausal and postmenopausal women. Searches targeted the following electronic databases: the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of randomised trials (29 July 2013), the Cochrane Register of Controlled Trials (CENTRAL; 29 July 2013), MEDLINE (inception to 29 July 2013), EMBASE (inception to 29 July 2013), AMED (1985 to 29 July 2013), PsycINFO (inception to 29 July 2013) and CINAHL (inception to 29 July 2013). Attempts were made to access grey literature by sending letters to pharmaceutical companies and performing searches of ongoing trial registers. Reference lists of included trials were also searched. Studies were included if they were randomised, included perimenopausal or postmenopausal participants with vasomotor symptoms (hot flushes or night sweats), lasted at least 12 weeks and provided interventions such as foods or supplements with high levels of phytoestrogens (not combined with other herbal treatments). Trials that included women who had breast cancer or a history of breast cancer were excluded. Selection of trials, extraction of data and assessment of quality were undertaken by at least two review authors. Most trials were too dissimilar for their results to be combined in a meta-analysis, so these findings are provided in narrative 'Summary of results' tables. Studies were grouped into broad categories: dietary soy, soy extracts, red clover extracts, genistein extracts and other types of phytoestrogens. Five trials used Promensil, a red clover extract; results of these trials were combined in a meta-analysis, and summary effect measures were calculated. A total of 43 randomised controlled trials (4,364 participants) were included in this review. Very few trials provided data suitable for inclusion in a meta-analysis. Among the five trials that yielded data assessing the daily frequency of hot flushes suitable for pooling, no significant difference overall was noted in the incidence of hot flushes between participants taking Promensil (a red clover extract) and those given placebo (mean difference (MD) -0.93, 95% confidence interval (CI) -1.95 to 0.10, I(2) = 31%). No evidence indicated a difference in percentage reduction in hot flushes in two trials between Promensil and placebo (MD 20.15, 95% CI -12.08 to 52.38, I(2) = 82%). Four trials that were not combined in meta-analyses suggested that extracts with high (> 30 mg/d) levels of genistein consistently reduced the frequency of hot flushes. Individual results from the remaining trials were compared in broad subgroups such as dietary soy, soy extracts and other types of phytoestrogens that could not be combined. Some of these trials found that phytoestrogen treatments alleviated the frequency and severity of hot flushes and night sweats when compared with placebo, but many trials were small and were determined to be at high risk of bias. A strong placebo effect was noted in most trials, with a reduction in frequency ranging from 1% to 59% with placebo. No indication suggested that discrepant results were due to the amount of isoflavone in the active treatment arm, the severity of vasomotor symptoms or trial quality factors. Also, no evidence indicated that these treatments caused oestrogenic stimulation of the endometrium or the vagina or other adverse effects when used for up to two years. No conclusive evidence shows that phytoestrogen supplements effectively reduce the frequency or severity of hot flushes and night sweats in perimenopausal or postmenopausal women, although benefits derived from concentrates of genistein should be further investigated.