Estrogen receptor-mediated health benefits of phytochemicals: a review.

Estrogen receptors (ERs) are transcription factors with two subtypes: estrogen receptor alpha (ERα) and estrogen receptor beta (ERß), which are essential for the maintenance of human health and play a regulatory role in common diseases such as breast cancer, osteoporosis, neurodegenerative disorders, liver injuries and lung cancers. A number of phytochemicals extracted from various fruits and vegetables have been demonstrated to exhibit estrogenic effects and are termed phytoestrogens. As modulators of ERs, phytoestrogens can be involved in the prevention and treatment of multiple diseases as complementary or alternative therapeutic agents and have a variety of health benefits for humans. This article reviews the health benefits of phytoestrogens in clinical and epidemiologic studies for several diseases and also provides a detailed description of the molecular mechanisms of their action. A brief comparison of the advantages and disadvantages of natural phytochemicals compared to synthetic drugs is also presented. The role of phytoestrogens in the treatment of diseases and human health requires further research to fully realize their therapeutic potential.

Phytoestrogen-Based Hormonal Replacement Therapy Could Benefit Women Suffering Late-Onset Asthma.

It has been observed that plasmatic concentrations of estrogens, progesterone, or both correlate with symptoms in asthmatic women. Fluctuations in female sex steroid concentrations during menstrual periods are closely related to asthma symptoms, while menopause induces severe physiological changes that might require hormonal replacement therapy (HRT), that could influence asthma symptoms in these women. Late-onset asthma (LOA) has been categorized as a specific asthmatic phenotype that includes menopausal women and novel research regarding therapeutic alternatives that might provide relief to asthmatic women suffering LOA warrants more thorough and comprehensive analysis. Therefore, the present review proposes phytoestrogens as a promising HRT that might provide these females with relief for both their menopause and asthma symptoms. Besides their well-recognized anti-inflammatory and antioxidant capacities, phytoestrogens activate estrogen receptors and promote mild hormone-like responses that benefit postmenopausal women, particularly asthmatics, constituting therefore a very attractive potential therapy largely due to their low toxicity and scarce side effects.

Multi-Anticancer Activities of Phytoestrogens in Human Osteosarcoma.

Phytoestrogens are plant-derived bioactive compounds with estrogen-like properties. Their potential health benefits, especially in cancer prevention and treatment, have been a subject of considerable research in the past decade. Phytoestrogens exert their effects, at least in part, through interactions with estrogen receptors (ERs), mimicking or inhibiting the actions of natural estrogens. Recently, there has been growing interest in exploring the impact of phytoestrogens on osteosarcoma (OS), a type of bone malignancy that primarily affects children and young adults and is currently presenting limited treatment options. Considering the critical role of the estrogen/ERs axis in bone development and growth, the modulation of ERs has emerged as a highly promising approach in the treatment of OS. This review provides an extensive overview of current literature on the effects of phytoestrogens on human OS models. It delves into the multiple mechanisms through which these molecules regulate the cell cycle, apoptosis, and key pathways implicated in the growth and progression of OS, including ER signaling. Moreover, potential interactions between phytoestrogens and conventional chemotherapy agents commonly used in OS treatment will be examined. Understanding the impact of these compounds in OS holds great promise for developing novel therapeutic approaches that can augment current OS treatment modalities.

Hyperlipoproteinemia (a) and Phytoestrogen Therapy in Dialysis Patients: A Review.

PURPOSE: Hyperlipoproteinemia (a) is a prevalent complication in dialysis patients, with no valid treatment strategy. The aim of this narrative review was to investigate the clinical significance of hyperlipoproteinemia (a) and phytoestrogen therapy in dialysis patients. METHODS: A comprehensive literature search of the published data was performed regarding the effects of phytoestrogen therapy on hyperlipoproteinemia (a) in dialysis patients. FINDINGS: Hyperlipoproteinemia (a) occurs in dialysis patients due to decreased catabolism and increased synthesis of lipoprotein (a) [Lp(a)]. A few clinical trials have studied the effects of phytoestrogens on serum Lp(a). All studies of dialysis patients or nonuremic individuals with hyperlipoproteinemia (a), except one, showed that phytoestrogens could significantly reduce serum Lp(a) levels. However, all investigations of phytoestrogen therapy in individuals with normal serum Lp(a) levels showed that it had no effect on serum Lp(a). Phytoestrogens seem to have effects similar to those of estrogen in lowering Lp(a) concentrations. IMPLICATIONS: Considering the high prevalence of hyperlipoproteinemia (a) in dialysis patients, phytoestrogen therapy is a reasonable approach for reducing serum Lp(a) levels and its complications in these patients.

Genistein: a promising modulator of apoptosis and survival signaling in cancer.

Genistein, a commonly occurring isoflavone, has recently gained popularity owing to its ever-expanding spectrum of pharmacological benefits. In addition to health benefits such as improved bone health and reduced postmenopausal complications owing to its phytoestrogen properties, it has been widely evaluated for its anti-cancer potential. Several studies have established the potential for its usage in the management of breast, lung, and prostate cancers, and its usage has significantly evolved from early applications in traditional systems of medicine. This review offers an insight into its current status of usage, the chemistry, and pharmacokinetics of the molecule, an exploration of its apoptotic mechanisms in cancer management, and opportunities for synergism to improve therapeutic outcomes. In addition to this, the authors have presented an overview of recent clinical trials, to offer an understanding of contemporary studies and explore prospects for a greater number of focused trials, moving forward. Advancements in the application of nanotechnology as a strategy to improve safety and efficacy have also been highlighted, with a brief discussion of results from safety and toxicology studies.

Molecular mechanisms underlying the potential neuroprotective effects of Trifolium pratense and its phytoestrogen-isoflavones in neurodegenerative disorders.

Neurodegenerative disorders are heterogeneous, debilitating, and incurable groups of brain disorders that have common features including progressive degeneration of the structure and function of the nervous system. Phytoestogenic-isoflavones have been identified as active compounds that can modulate different molecular signaling pathways related to the nervous system. The main aim is to shed the light on the molecular mechanisms followed by phytoestrogen-isoflavones profound in the Trifolium pratense and discuss the latest pharmacological findings in the treatment of neurodegenerative disorders. Data were collected using different databases. The search terms used included "Phytoestrogens," "Isoflavones," "neurodegenerative disorders," "Neuronal plasticity," etc., and combinations of these keywords. As a result, this review article mainly demonstrates the potential neuroprotective properties of phystoestrogen-isoflavones present in the Trifolium pratense (Red clover), particularly in neurodegenerative disorders. Phytochemical studies have shown that Trifolium pratense mainly includes more than 30 isoflavone compounds. Among them, phytoestrogen-isoflavones, such as biochanin A, daidzein, formononetin, genistein (Gen), etc.,are characterized by potent neuroprotective properties against different neurodegenerative disorders. There are preclinical and clinical scientific evidence on their mechanisms of action involve molecular interaction with estrogenic receptors, anti-inflammatory, anti-oxidative, antiapoptotic, autophagic inducing, and so on. phytoestrogen-isoflavones are the major bioactive components in the Trifolium pratense that exhibit therapeutic efficacy in the case of neurodegenerative disorders. This review provides detailed molecular mechanisms targeted by phytoestrogen-isoflavones and experimental key findings for the clinical use of prescriptions containing Trifolium pratense-derived isoflavones for the treatment of neurodegenerative disorders.

A review on phytoestrogens: Current status and future direction.

Phytoestrogens are plant secondary metabolite that is structurally and functionally similar to mammalian estrogens, which have been shown to have various health benefits in humans. Isoflavones, coumestans, and lignans are the three major bioactive classes of phytoestrogens. It has a complicated mechanism of action involving an interaction with the nuclear estrogen receptor isoforms ERα and ERß, with estrogen agonist and estrogen antagonist effects. Depending on their concentration and bioavailability in various plant sources, phytoestrogens can act as estrogen agonist or antagonists. Menopausal vasomotor symptoms, breast cancer, cardiovascular disease, prostate cancer, menopausal symptoms, and osteoporosis/bone health have all been studied using phytoestrogens as an additional standard hormone supplemental remedy. The botanical sources, techniques of identification, classification, side effects, clinical implications, pharmacological and therapeutic effects of their proposed mode of action, safety issues, and future directions for phytoestrogens have all been highlighted in this review.

Functional biotransformation of phytoestrogens by gut microbiota with impact on cancer treatment.

The human gut is a host for trillions of microorganisms, divided into more than 3,000 heterogeneous species that is called the gut microbiota. The gut microbiota composition can be altered by many different endogenous and exogenous factors, especially diet and nutrition. A diet rich in phytoestrogens, a variable group of chemical compounds similar to 17-ß-estradiol (E2), the essential female steroid sex hormone is potent to change the composition of gut microbiota. However, the metabolism of phytoestrogens also highly depends on the action of enzymes produced by gut microbiota. Novel studies have shown that phytoestrogens could play an important role in the treatment of different types of cancers, such as breast cancer in women, due to their potential to decrease estrogen levels. This review aims to summarize recent findings about the lively dialogue between phytoestrogens and gut microbiota and to address their possible future application, especially in treating patients with diagnosed breast cancer. A potential therapeutic approach for the prevention and improving outcomes in breast cancer patients could be based on targeted probiotic supplementation with the use of soy phytoestrogens. A positive effect of probiotics on the outcome and survival of patients with breast cancer has been established. However, more in vivo scientific studies are needed to pave the way for the use of probiotics and phytoestrogens in the clinical practice of breast cancer treatment.

Phytoestrogens, novel dietary supplements for breast cancer.

While endocrine therapy is considered as an effective way to treat breast cancer, it still faces many challenges, such as drug resistance and individual discrepancy. Therefore, novel preventive and therapeutic modalities are still in great demand to decrease the incidence and mortality rate of breast cancer. Numerous studies suggested that G protein-coupled estrogen receptor (GPER), a membrane estrogen receptor, is a potential target for breast cancer prevention and treatment. It was also shown that not only endogenous estrogens can activate GPERs, but many phytoestrogens can also function as selective estrogen receptor modulators (SERMs) to interact GPERs. In this review, we discussed the possible mechanisms of GPERs pathways and shed a light of developing novel phytoestrogens based dietary supplements against breast cancers.

Targeting Estrogen Signaling in the Radiation-induced Neurodegeneration: A Possible Role of Phytoestrogens.

Radiation for medical use is a well-established therapeutic method with an excellent prognosis rate for various cancer treatments. Unfortunately, a high dose of radiation therapy comes with its own share of side effects, causing radiation-induced non-specific cellular toxicity; consequently, a large percentage of treated patients suffer from chronic effects during the treatment and even after the post-treatment. Accumulating data evidenced that radiation exposure to the brain can alter the diverse cognitive-related signaling and cause progressive neurodegeneration in patients because of elevated oxidative stress, neuroinflammation, and loss of neurogenesis. Epidemiological studies suggested the beneficial effect of hormonal therapy using estrogen in slowing down the progression of various neuropathologies. Despite its primary function as a sex hormone, estrogen is also renowned for its neuroprotective activity and could manage radiation-induced side effects as it regulates many hallmarks of neurodegenerations. Thus, treatment with estrogen and estrogen-like molecules or modulators, including phytoestrogens, might be a potential approach capable of neuroprotection in radiation-induced brain degeneration. This review summarized the molecular mechanisms of radiation effects and estrogen signaling in the manifestation of neurodegeneration and highlighted the current evidence on the phytoestrogen mediated protective effect against radiationinduced brain injury. This existing knowledge points towards a new area to expand to identify the possible alternative therapy that can be taken with radiation therapy as adjuvants to improve patients' quality of life with compromised cognitive function.

Anti-allergic property of dietary phytoestrogen secoisolariciresinol diglucoside through microbial and ß-glucuronidase-mediated metabolism.

Phytoestrogens play pivotal roles in controlling not only the endocrine system but also inflammatory metabolic disorders. However, the effects of dietary phytoestrogens on allergic diseases and underlying mechanisms remain unclear. In this study, we revealed the unique metabolic conversion of phytoestrogen to exert anti-allergic properties, using an ovalbumin-induced allergic rhinitis mouse model. We found that dietary secoisolariciresinol diglucoside (SDG), a phytoestrogen abundantly present in flaxseed, alleviated allergic rhinitis by the microbial conversion to enterodiol (ED). We also found that ED circulated mainly in the glucuronide form (EDGlu) in blood, and deconjugation of EDGlu to ED aglycone occurred in the nasal passage; this activity was enhanced after the induction of allergic rhinitis, which was mediated by ß-glucuronidase. We further found that IgE-mediated degranulation was inhibited by ED aglycone, but not by EDGlu, in a G protein-coupled receptor 30 (GPR30)-dependent manner. These results provide new insights into the anti-allergic properties of phytoestrogens and their metabolism in vivo for the development of novel therapeutic strategies against allergic rhinitis.

Potential roles of genistein in polycystic ovary syndrome: A comprehensive systematic review.

Polycystic ovary syndrome (PCOS) is one of the most prevalent polygenic endocrine disorders in reproductive-age women. Genistein is a soy-isolated phytoestrogen and isoflavone with antioxidant, anti-inflammatory, estrogenic, and antineoplastic activity. This systematic review aimed to investigate the therapeutic effects and mechanisms of actions of genistein in PCOS. The present study was conducted according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. We searched PubMed, Scopus, Embase, and Google Scholar databases up to February 2022 using relative keywords. Studies published in English evaluated genistein's effects on PCOS, and its related symptoms were considered. Out of 298 records screened, only 13 articles met the inclusion criteria: Nine animal and 4 human studies. The results of the current study indicated that genistein supplementation may effectively improve PCOS-related symptoms by decreasing insulin resistance and anthropometric indices, improving ovarian morphology and regulating reproductive hormones, and reducing oxidative stress and inflammation by influencing biological pathways. According to the current literature, genistein may diminish the dues of PCOS. Therefore, this study shows that genistein can be considered an effective agent. in reducing the complications of PCOS. However, further studies are recommended for a broad conclusion on the exact mechanism of genistein in PCOS patients.

Effects of Genistein on Common Kidney Diseases.

Genistein is a naturally occurring phytoestrogen (soy or soybean products) that is classified as an isoflavone, and its structure is similar to that of endogenous estrogens; therefore, genistein can exert an estrogen-like effect via estrogen receptors. Additionally, genistein is a tyrosine kinase inhibitor, which enables it to block abnormal cell growth and proliferation signals through the inhibition of tyrosine kinase. Genistein is also an angiogenesis inhibitor and an antioxidant. Genistein has effects on kidney cells, some of the kidney's physiological functions, and a variety of kidney diseases. First, genistein exerts a protective effect on normal cells by reducing the inflammatory response, inhibiting apoptosis, inhibiting oxidative stress, inhibiting remodeling, etc., but after cell injury, the protective effect of genistein decreases or even has the opposite effect. Second, genistein can regulate renin intake to maintain blood pressure balance, regulate calcium uptake to regulate Ca2+ and Pi balances, and reduce vasodilation to promote diuresis. Third, genistein has beneficial effects on a variety of kidney diseases (including acute kidney disease, kidney cancer, and different chronic kidney diseases), such as reducing symptoms, delaying disease progression, and improving prognosis. Therefore, this paper reviews animal and human studies on the protective effects of genistein on the kidney in vivo and in vitro to provide a reference for clinical research in the future.

Naringenin and Phytoestrogen 8-Prenylnaringenin Protect against Islet Dysfunction and Inhibit Apoptotic Signaling in Insulin-Deficient Diabetic Mice.

It has been shown that citrus flavanone naringenin and its prenyl derivative 8-prenylnaringenin (8-PN) possess various pharmacological activities in in vitro and in vivo models. Interestingly, it has been proposed that prenylation can enhance biological potentials, including the estrogen-like activities of flavonoids. The objective of this study was to investigate the anti-diabetic potential and molecular mechanism of 8-PN in streptozotocin (STZ)-induced insulin-deficient diabetic mice in comparison with naringenin reported to exhibit hypoglycemic effects. The oral administration of naringenin and 8-PN ameliorated impaired glucose homeostasis and islet dysfunction induced by STZ treatment. These protective effects were associated with the suppression of pancreatic ß-cell apoptosis and inflammatory responses in mice. Moreover, both naringenin and 8-PN normalized STZ-induced insulin-signaling defects in skeletal muscles and apoptotic protein expression in the liver. Importantly, 8-PN increased the protein expression levels of estrogen receptor-α (ERα) in the pancreas and liver and of fibroblast growth factor 21 in the liver, suggesting that 8-PN could act as an ERα agonist in the regulation of glucose homeostasis. This study provides novel insights into the mechanisms underlying preventive effects of naringenin and 8-PN on the impairment of glucose homeostasis in insulin-deficient diabetic mice.

Targeting Breast Cancer Stem Cells Using Naturally Occurring Phytoestrogens.

Breast cancer therapies have made significant strides in improving survival for patients over the past decades. However, recurrence and drug resistance continue to challenge long-term recurrence-free and overall survival rates. Mounting evidence supports the cancer stem cell model in which the existence of a small population of breast cancer stem cells (BCSCs) within the tumor enables these cells to evade conventional therapies and repopulate the tumor, giving rise to more aggressive, recurrent tumors. Thus, successful breast cancer therapy would need to target these BCSCs, as well the tumor bulk cells. Since the Women's Health Initiative study reported an increased risk of breast cancer with the use of conventional hormone replacement therapy in postmenopausal women, many have turned their attention to phytoestrogens as a natural alternative. Phytoestrogens are plant compounds that share structural similarities with human estrogens and can bind to the estrogen receptors to alter the endocrine responses. Recent studies have found that phytoestrogens can also target BCSCs and have the potential to complement conventional therapy eradicating BCSCs. This review summarized the latest findings of different phytoestrogens and their effect on BCSCs, along with their mechanisms of action, including selective estrogen receptor binding and inhibition of molecular pathways used by BCSCs. The latest results of phytoestrogens in clinical trials are also discussed to further evaluate the use of phytoestrogen in the treatment and prevention of breast cancer.

Chemotherapeutic Activities of Dietary Phytoestrogens against Prostate Cancer: From Observational to Clinical Studies.

Prostate cancer remains one of the most frequent and deadliest malignancies in males, where the rate of disease progression is closely associated with the type of dietary intake, specifically a Western-style diet. Indeed intake of the Asian diet, which contains abundant phytoestrogens, is inversely correlated with a higher risk of prostate cancer, suggesting a chemoprotective effect of phytoestrogen against cancer progression. Although the role of phytoestrogens in cancer treatment has been well documented, their impact on prostate cancer is not well understood. Therefore, the present review discusses the possible chemopreventive effect of phytoestrogens, emphasizing their efficacy at the different stages of carcinogenesis. Furthermore, phytoestrogens provide a cytoprotective effect in conventional chemotherapy and enhance chemosensitivity to tumor cells, which have also been discussed. This compilation provides a solid basis for future research on phytoestrogens as a promising avenue for anticancer drug development and also recommends these beneficiary compounds in the daily diet to manage and prevent prostate cancer.

Genistein, a tool for geroscience.

Geroprotection is defined as protection from the adverse effects of aging. The need for geroprotection implies changes towards individually tailored interventions that preserve an individual's independence, physical function, and cognition. Genistein, a phytoestrogen obtained from soya, has been reported to have beneficial properties on age-related diseases such as neurodegenerative and cardiovascular diseases or cancer. Indeed, genistein is a multimodal agent: it acts as a cancer protective agent, promoting apoptosis and cell cycle arrest, and inhibiting angiogenesis and metastasis, but it also acts as an antioxidant, anti-inflammatory, and anti-amyloid-ß and autophagy promoter. Altogether, these properties make genistein a possible treatment for the specific aspects of age-related diseases such as hypertension, metabolic diseases, Alzheimer's disease, and osteoporosis.

Influence of phytoestrogens on endometrial thickness: a systematic review and meta-analysis.

The objective of this systematic review was to evaluate the influence of the use of phytoestrogens on variations in endometrial thickness in postmenopausal women. Randomized controlled trials were searched in the following electronic databases until March 2020: MEDLINE, Embase, Cochrane Library, Web of Science and LILACS. We used the terms 'phytoestrogens' and 'endometrium' or 'endometrial hyperplasia' to search for relevant trials. The data were analyzed using RevMan 5.3 software. A total of 10 studies involving 1476 patients were included. The difference in endometrial thickness was evaluated in 10 studies, with a total of 805 participants in the phytoestrogen group and 761 in the control group. Such a difference was not significant between groups after 3 months (standardized mean difference [SMD] 0.00, 95% confidence interval [CI] - 0.37 to 0.37; I2 = 63%), 6 months (SMD -0.30, 95% CI -0.79 to 0.19; I2 = 70%), 12 months (SMD -0.02, 95% CI 0.22 to -0.18; I2 = 0%) and 24 months (SMD -0.09, 95% CI -0.25, 0.08; I2 = 0%) of use. Our meta-analysis shows no changes in endometrial thickness in women using phytoestrogens. Evidence is still uncertain owing to the presence of heterogeneity among the studies currently available, whose reported outcomes cover a period between 3 and 6 months.

Effect of Medicago sativa compared To 17ß-oestradiol on osteoporosis in ovariectomized mice.

Phytoestrogens, with a wide range of beneficial effects, prevent bone loss caused by oestrogen deficiency.The purpose of this study was to evaluate the effect of Medicago sativa ethanol extract compared to 17ß-oestradiol on osteoporosis in ovariectomized mice.The study was carried out on female mice, divided into five groups: control mice (GI), Medicago sativa treated mice (0.75 g/kg BW/day) (GII), ovariectomized mice (GIII) and ovariectomized mice treated either with Medicago sativa (GIV) or with 17ß-oestradiol (50 µg/Kg BW/day) (GV).Our results showed that Medicago sativa or 17ß-oestradiol treatments significantly attenuated perturbations of mineral levels, histological changes and oxidative stress in the femurs of ovariectomized mice.Medicago sativa prevented bone loss induced by oestrogen deficiency, which could be attributed to its richness in kaempferol, syringic acid, naringenin and myrictin. Its effects were more beneficial or similar compared to 17ß-oestradiol.

Effects of a Cereal Bar with a Combination of Phytoestrogens on the Climacteric Symptoms: A Placebo-Controlled, Randomized Trial.

OBJECTIVE: This study evaluated whether the consumption of a cereal bar combining different phytoestrogens could contribute to the reduction of climacteric symptoms in women. METHODS: This is a clinical, prospective, randomized, simple-blind trial. Forty-eight women, aged 40-65 years, with climacteric symptoms, from a city in southwestern Paraná, Brazil. Participants were randomly assigned into two groups; Phytoestrogens group (PHY = 24), which received for 90-day period a cereal bar containing 80.73 milligrams of soybean and flaxseed phytoestrogens, and the placebo group (PLA = 24), which consumed rice flakes biscuit. Clinical, sociodemographic and anthropometric data were collected and climacteric symptoms were assessed using the Kupperman Index (KI). RESULTS: Forty-three women were analyzed (PHY = 21 and PLA = 22). There were significant reductions in the overall KI score in both groups at the end of the intervention period (p < 0.05). However, the comparison between the groups using linear regression models presented expressively better symptom improvement in the PHY group -6.43 over time (95% CI: -11.6; -1.26; p < 0.05) KI points, with perimenopausal -15.15 (95% CI: -28.95; -1.35) and postmenopausal women -19.34 (95% CI: -33.68; -4.99) showed considerably greater reductions in symptoms at the end of the intervention period compared to premenopausal women. There was also significant reduction in symptoms of hot flushes, paresthesia, sexual complaints, insomnia and melancholy. CONCLUSION: The consumption of a cereal bar containing phytoestrogens was able to improve the symptoms of climacteric syndrome.