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Effect of Soy Isoflavones on Endometriosis: Interaction With Estrogen Receptor 2 Gene Polymorphism
Abstract
Progression of endometriosis is considered estrogen-dependent. Dietary soy isoflavones may affect the risk of endometriosis, and polymorphisms in estrogen receptor genes may modify this association. We examined associations among soy isoflavone intake, estrogen receptor 2 (ESR2) gene polymorphisms and risk of endometriosis.
We recruited women age 20-45 years old who had consulted a university hospital for infertility in Tokyo, Japan in 1999 or 2000. A total of 138 eligible women were diagnosed laparoscopically and classified into 3 subgroups: control (no endometriosis), early endometriosis (stage I-II) and advanced endometriosis (stage III-IV). We measured urinary levels of genistein and daidzein as markers for dietary intake of soy isoflavones, and genotyped ESR2 gene RsaI polymorphisms.
Higher levels of urinary genistein and daidzein were associated with decreased risk of advanced endometriosis (P for trend = 0.01 and 0.06, respectively) but not early endometriosis. For advanced endometriosis, the adjusted odds ratio for the highest quartile group was 0.21 (95% confidence interval = 0.06-0.76) for genistein and 0.29 (0.08-1.03) for daidzein, when compared with the lowest group. Inverse associations were also noted between urinary isoflavones and the severity of endometriosis (P for trend = 0.01 for genistein and 0.07 for daidzein). For advanced endometriosis, ESR2 gene RsaI polymorphism appeared to modify the effects of genistein (P for interaction = 0.03).
Dietary isoflavones may reduce the risk of endometriosis among Japanese women.
... Curcumin reduces cell proliferation by decreasing estradiol levels [64]. Genistein has been reported to show antagonistic activity against endometriotic implants in the presence of estrogen in rats [65]. There are also studies showing that polyphenolic compounds, such as quercetin, apigenin, wogonin, rosmarinic acid, and curcumin, prevent the growth of endometrial tissue in various mechanisms [48,[65][66][67][68][69]. ...
... Genistein has been reported to show antagonistic activity against endometriotic implants in the presence of estrogen in rats [65]. There are also studies showing that polyphenolic compounds, such as quercetin, apigenin, wogonin, rosmarinic acid, and curcumin, prevent the growth of endometrial tissue in various mechanisms [48,[65][66][67][68][69]. Curcumin, quercetin, and resveratrol intervene in the regulation of cell proliferation and apoptosis, contributing to the decrement of ectopic tissue growth. ...
Leaves and aerial parts of Malva neglecta Wallr. have been traditionally used in Anatolia for the treatment of pain, inflammation, hemorrhoids, renal stones, constipation, and infertility. This study investigated the effects of M. neglecta leaves in a rat endometriosis model. The dried plant material was extracted with n-hexane, ethyl acetate, and methanol, successively. Experimental endometriosis was surgically induced in six-week-old female, non-pregnant, Wistar albino rats by autotransplant of endometrial tissue to the abdominal wall. After twenty-eight days, rats were evaluated for a second laparotomy. Endometrial foci areas were assessed, and intraabdominal adhesions were scored. Rats were divided into five groups as control, n-hexane, ethyl acetate, methanol, and aqueous extracts, as well as reference. At the end of the treatment, all rats were sacrificed and endometriotic foci areas and intraabdominal adhesions were re-evaluated and compared with the previous findings. Moreover, peritoneal fluid was collected to detect tumor necrosis factor- α (TNF-α), vascular endothelial growth factor (VEGF), and interleukin-6 (IL-6) levels, and cDNA synthesis, and a quantitative real-time polymerase chain reaction (PCR) test was done. The phytochemical content of the most active extract was determined using High-Performance Liquid Chromatography (HPLC). Both endometrial volume and adhesion score decreased significantly in the group treated with methanol extract. In addition, significant decreases were observed in TNF-α, VEGF, and IL-6 levels in animals administered methanol extract. HPLC results showed that the activity caused by the methanol extract of M. neglecta was due to the polyphenols. Taken together, these novel findings indicate that M. neglecta may be a promising alternative for the treatment of endometriosis.
... 25 The study by Takaoka et al. (2018) investigated the in vitro and in vivo effects of daidzeinrich isoflavone aglycones (DRIA) and dietary supplements on cell proliferation in endometriosis, with results that DRIA inhibits proliferation in endometriosis. 26 A study by Tsuchiya et al. (2007) in Japan investigated the relationship between consumption of soy isoflavones, estrogen receptor 2 gene polymorphisms, and the risk of endometriosis. It has been shown that women with higher levels of genistein and daidzein in their urine had a lower risk of advanced endometriosis (p = 0.01). ...
... It has been shown that women with higher levels of genistein and daidzein in their urine had a lower risk of advanced endometriosis (p = 0.01). 27 ...
Endometriosis is a common disease that occurs in 6-10% of women of reproductive age. The disease is often associated with chronic pelvic pain and infertility. Endometriosis is an inflammatory disease and is estrogen dependent. Its definition is the presence of endometrial-like tissue outside the uterus. The etiology of the disease remains unclear. It is believed that a variety of immunological, genetic, hormonal, and environmental factors may be responsible for the development of endometriosis. Surgical confirmation of the presence of endometrial tissue outside the uterus is necessary for the diagnosis of endometriosis. For this reason, endometriosis is considered to be underdiagnosed. Currently, available treatments have many limitations and cause many side effects during their long-term use. For this reason, other treatment and prevention methods for this disease are being sought. Research on the influence of dietary factors on endometriosis allows concluding that diet and particular food ingredients can be considered a factor reducing the risk of endometriosis. Therefore, understanding the role of nutrition in the development of endometriosis is of great importance for the development of effective guidelines related to the prevention of this disease. Therefore, we have reviewed the available literature related to the impact of individual components of the daily diet on the risk of developing endometriosis. Omega-3 fatty acids, dairy products, and soy in particular appear to be promising dietary factors that could potentially reduce the risk of endometriosis. Further research is needed to solidify this knowledge.
... A significant association was noted between specific genotypes of ER-2 RsaI polymorphism and genistein levels in risk of advanced endometriosis. Since altered estrogen or soy isoflavone signal transduction thanks to ER-2 gene polymorphisms may be directly responsible for susceptibility to severe endometriosis, the authors suggested that isoflavones may play a more effective role among the ER-2 RsaI R/r + R/R genotype than the r/r genotype, although the latter itself is likely to be protective for endometriosis [21]. Three studies have evaluated the effects of resveratrol on endometriosis women [31,49,65]. ...
... Due to their divergence from humans in key aspects of reproductive physiology, current experimental systems for the study of endometriosis are a very imperfect model [102]. As a matter of fact, most of the treatment for endometriosis used in experimental models provided satisfactory results while being of poor efficacy in humans [18,21,31,49,56,65,77]. ...
The aim of this systematic review was to provide comprehensive and available data on the possible role of phytoestrogens (PE) for the treatment of endometriosis. We conducted an advanced, systematic search of online medical databases PubMed and Medline. Only full-length manuscripts written in English up to September 2020 were considered. A total of 60 studies were included in the systematic review. According to in vitro findings, 19 out of 22 studies reported the ability of PE in inducing anti-proliferative, anti-inflammatory and proapoptotic effects on cultured cells. Various mechanisms have been proposed to explain this in vitro action including the alteration of cell cycle proteins, the activation/inactivation of regulatory pathways, and modification of radical oxidative species levels. Thirty-eight articles on the effects of phytoestrogens on the development of endometriotic lesions in in vivo experimental animal models of endometriosis have been included. In line with in vitro findings, results also derived from animal models of endometriosis generally supported a beneficial effect of the compounds in reducing lesion growth and development. Finally, only seven studies investigated the effects of phytoestrogens intake on endometriosis in humans. The huge amount of in vitro and in vivo animal findings did not correspond to a consistent literature in the women affected. Therefore, whether the experimental findings can be translated in women is currently unknown.
... Tsuchiya et al. measured the urine levels of genistein and daidzein in 138 premenopausal women suffering infertility [56]. The endometriosis group included 79 patients with early (Stage I-II) or advanced (Stage III-IV) endometriosis, and the control group included 59 women without endometriosis diagnosis. ...
... Tsuchiya et al. compared the urinary levels of genistein and daidzein in infertility women with early endometriosis (stage I-II) and women with advanced endometriosis (stage III-Iva). It was found that high levels of urinary genistein and daidzein were negatively related to the risk of advanced endometriosis, but unrelated to the risk of early endometriosis [56]. In addition, the urinary isoflavone levels were inversely associated with the severity of endometriosis. ...
Endometriosis, a chronic disease characterized by recurrent pelvic pain and infertility, severely impacts the health and life quality of many women worldwide. Since phytoestrogens are commonly found in a variety of foods, and estrogen is a major pathological factor for the pathogenesis of endometriosis, their possible involvement cannot be ignored. This review summarizes data on the relationship between phytoestrogen intake and endometriosis risk, and analyzes the findings from in vitro experiments, rodent endometriotic models, and human intervention trials. While favorable results were often obtained from endometrial primary cultures and animal models for resveratrol, isoflavones and puerarin, only resveratrol showed promising results in human intervention trials. Critical issues concerning the current study efforts are discussed: the possible reasons beneath the discrepant observations of estrogenic/anti-estrogenic effects by phytoestrogens; the complicated interplays between phytoestrogens and endogenous estrogens; the shortage of currently used animal models; the necessity to apply reasonable doses of phytoestrogens in experiments. It is expected that the analyses would help to more properly assess the phytoestrogens’ effects on the endometriosis pathogenesis and their potential values for preventive or therapeutic applications.
... Clinical research showed the reduced risk of endometriosis development following soy isoflavones' ingestion. A significant correlation between higher urinary isoflavone levels (genistein and daidzein) and decreased risk of advanced endometriosis (stage III and IV), but not early endometriosis (stage I and II) occurrence, was observed within a casecontrol study involving Japanese women [99]. Future clinical studies and meta-analyses focusing on the benefits of phytoestrogen-rich product consumption by endometriosis patients are strongly required. ...
... However, most recent clinical trials have not confirmed the adverse effects of isoflavones and other phytoestrogens on women with risk and active estrogen-dependent cancers [170,171]. According to the latest reports, isoflavone-rich food and supplements are safe dietary factors for peri-and post-menopausal women and endometriosis patients [99,172]. ...
Endometriosis represents an often painful, estrogen-dependent gynecological disorder, defined by the existence of endometrial glands and stroma exterior to the uterine cavity. The disease provides a wide range of symptoms and affects women’s quality of life and reproductive functions. Despite research efforts and extensive investigations, this disease’s pathogenesis and molecular basis remain unclear. Conventional endometriosis treatment implies surgical resection, hormonal therapies, and treatment with nonsteroidal anti-inflammatory drugs, but their efficacy is currently limited due to many side effects. Therefore, exploring complementary and alternative therapy strategies, minimizing the current treatments’ adverse effects, is needed. Plants are sources of bioactive compounds that demonstrate broad-spectrum health-promoting effects and interact with molecular targets associated with endometriosis, such as cell proliferation, apoptosis, invasiveness, inflammation, oxidative stress, and angiogenesis. Anti-endometriotic properties are exhibited mainly by polyphenols, which can exert a potent phytoestrogen effect, modulating estrogen activity. The available evidence derived from preclinical research and several clinical studies indicates that natural biologically active compounds represent promising candidates for developing novel strategies in endometriosis management. The purpose of this review is to provide a comprehensive overview of polyphenols and their properties valuable for natural treatment strategy by interacting with different cellular and molecular targets involved in endometriosis progression.
... One US study found that although rates of endometriosis were higher among Asian relative to non-Asian women, the connection to soy consumption was not clear since the comparison was true for Asian women of Filipino, Indian, Japanese and Korean origin, despite the fact that soyfoods are consumed by only the latter two groups (Yamamoto et al. 2017). Another cross-sectional study, this time focused on Japanese women, reported inverse associations between urinary genistein and daidzein and advanced endometriosis (genistein OR, 0.21; 95% CI: 0.06, 0.76 and daidzein OR, 0.29; 95% CI: 0.08, 1.03) as well as severity of endometriosis (p for trend ¼ 0.01 for genistein and 0.07 for daidzein) (Tsuchiya et al. 2007). More recently, isoflavone intake was inversely related to endometriosis risk in a small Iranian case-control study, although the low intakes of this population question the utility of the results (Youseflu et al. 2020). ...
... Building upon the higher rates of endometriosis among Asian women relative to Western women (Miyazawa 1976;Arumugam and Templeton 1992;Sangi-Haghpeykar and Poindexter 1995), some studies have suggested an increased risk of endometriosis with early soy exposure (SIF) (Upson et al. 2015;Upson et al. 2019). In contrast, studies focused on adult exposure have raised doubt about the connection between soy and endometriosis (Yamamoto 2017 #23084) or even found a protective association (Tsuchiya et al. 2007). With respect to endometrial cancer risk, results seem more consistent for a protective or null role for soy isoflavones with meta-analysis finding an inverse association between soy isoflavones and endometrial cancer risk (Zhang et al. 2015) and a review of clinical studies showing no adverse effects of soy isoflavones on endometrial thickness or histo(patho)logy (EFSA ANS Panel (EFSA Panel on Food Additives and Nutrient Sources added to Food) 2015), although these effects may be ethnicity-specific (Liu et al. 2016). ...
Soybeans are a rich source of isoflavones, which are classified as phytoestrogens. Despite numerous proposed benefits, isoflavones are often classified as endocrine disruptors, based primarily on animal studies. However, there are ample human data regarding the health effects of isoflavones. We conducted a technical review, systematically searching Medline, EMBASE, and the Cochrane Library (from inception through January 2021). We included clinical studies, observational studies, and systematic reviews and meta-analyses (SRMA) that examined the relationship between soy and/or isoflavone intake and endocrine-related endpoints. 417 reports (229 observational studies, 157 clinical studies and 32 SRMAs) met our eligibility criteria. The available evidence indicates that isoflavone intake does not adversely affect thyroid function. Adverse effects are also not seen on breast or endometrial tissue or estrogen levels in women, or testosterone or estrogen levels, or sperm or semen parameters in men. Although menstrual cycle length may be slightly increased, ovulation is not prevented. Limited insight could be gained about possible impacts of in utero isoflavone exposure, but the existing data are reassuring. Adverse effects of isoflavone intake were not identified in children, but limited research has been conducted. After extensive review, the evidence does not support classifying isoflavones as endocrine disruptors.
... Authors reported that women with a higher urinary concentration of daidzein and genistein, two isoflavones belonging to the phytoestrogen group, had a lower risk of severe endometriosis (stages III and IV). 16 ...
... 82,83 Concerning its link with endometriosis, all the studies published so far have lead to weak results, and only two studies reported a statistically significant positive correlation between coffee intake and endometriosis. [11][12][13][14]16,17 A recent meta-analysis, 15 published in 2014, confirmed the lack of association, but several bias came up: (a) the majority of the studies did neither report an estimation of caffeine intake nor gave any information on coffee variety or method of preparation; (b) coffee intake was based on patients' self-reports; and (c) endometriosis represents an heterogeneous clinical entity both for location and stage, and the available data do not allow to investigate the effect of coffee on site and extent of the disease. ...
Endometriosis is a chronic, inflammatory, estrogenic-dependent disease characterized by the presence of endometrial glands outside the uterine cavity, affecting approximately 2%–10% of women in reproductive age and 30%–50% of women in general. Despite the high prevalence of the disease, not much is known about etiology, possible risk factors, and an adequate and satisfactory therapy. In the past years, many studies have focused on food intake (nutrients and food groups) and on its possible correlation with endometriosis, demonstrating how diet could be identified as a possible risk factor. Comprehensive searches in the largest medical information databases (Medline-PubMed, Embase, Lilacs, and Cochrane Library) were conducted using the Medical Subject Heading terms “diet,” “food,” “nutrition,” “fatty acids,” vitamins,” “fruit,” “vegetables,” “coffee,” “caffeine,” “fish,” “soy food,” “dairy products,” “tea,” “curcumin” combined with “endometriosis.” Purpose of this review is to revise the literature, in order to determine potential modifiable risk factors of the disease.
... 52 Thus, this dietary regimen may be equally useful in tempering the heightened inflammatory status associated with endometriosis. 26 Yu et al. 27 Danciu et al. 28 Tsuchiya et al. 29 Wang et al. 30 Cheng et al. 31 Ji et al. 32 Yavuz et al. 33 Chen 40 Abbas et al. 41 Mariani et al. 42 Omega-3 fatty acids Fatty fish, walnuts, edible seeds, soybeans ...
... transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), IL-6), and inhibition of oxidative stress. [26][27][28] In line with the anti-inflammatory effects of isoflavones, women with endometriosis consuming isoflavones (measured by urinary levels of genistein and daidzein) showed decreased risk of advanced endometriosis (Stages III and IV) 29 and incorporation of soy isoflavone genistein in diets of mice with endometriotic implants resulted in regression of ectopic lesions relative to diets without genistein. 33 Another isoflavone found in arrowroots endemic to Japan and China is puerarin. ...
... 52 Thus, this dietary regimen may be equally useful in tempering the heightened inflammatory status associated with endometriosis. 26 Yu et al. 27 Danciu et al. 28 Tsuchiya et al. 29 Wang et al. 30 Cheng et al. 31 Ji et al. 32 Yavuz et al. 33 Chen 40 Abbas et al. 41 Mariani et al. 42 Omega-3 fatty acids Fatty fish, walnuts, edible seeds, soybeans ...
... transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), IL-6), and inhibition of oxidative stress. [26][27][28] In line with the anti-inflammatory effects of isoflavones, women with endometriosis consuming isoflavones (measured by urinary levels of genistein and daidzein) showed decreased risk of advanced endometriosis (Stages III and IV) 29 and incorporation of soy isoflavone genistein in diets of mice with endometriotic implants resulted in regression of ectopic lesions relative to diets without genistein. 33 Another isoflavone found in arrowroots endemic to Japan and China is puerarin. ...
Endometriosis is a chronic inflammatory condition that may cause pelvic pain, dysmenorrhea, and/or infertility in women of reproductive age. While treatments may include medical or surgical management, the majority of therapeutic options are non-curative, and women may experience longstanding pain and/or disability. In general, chronic diseases are believed to result from modifiable risk factors, including diet. In this review, we discuss recent data on evidence-based associations between diet and endometriosis and the mechanistic points of action of constituent dietary factors with emphasis on inflammatory events that may contribute to the promotion or inhibition of the disease. Understanding the convergence of diet and endometriosis may lead to the development of clinical strategies to improve the quality of life for symptomatic women.
... Previous researches proved that genistein could induce apoptosis of colon cancer LoVo and HT-29 through inhibition of NF-jB, down regulation of Bcl-2 and up regulation of Bax [26]. Regarding endometriosis incidence, there is a correlation between the high level of genistein in blood and the decreasing endometriosis risk [27]. Genistein at dosage of 500 mg/kg day which is administered orally for 21 days inhibited endometriotic lesion growth in the form of the decreased lesion size in mice of endometriosis model [28]. ...
... Genistein powder (Bioword, USA) was dissolved in sesame oil (1 ml volume of oil containing 1 gramme of genistein). Genistein administration was done orally and begun after the induction of endometriosis [27,28]. Genistein was administered once a day at dosage (0.78, 1.04, and 1.3 mg/day) for 15 days. ...
This research aimed to investigate the effect of genistein on TGF-β, dysregulation of apoptosis, NF-κB pathway, COX-2 pathway in mice of endometriosis model. Twenty-eight female mice (Mus musculus) were divided into seven groups (n=4), involving control (normal non-treated) group; endometriosis group; the endometriosis group treated with various genistein dosages (0.78; 1.04; 1.3mg/day for 15days), and endometriosis group treated with standard drug, namely leuprolide acetate (0.00975mg each day for 15days) or dienogest (0.0052mg/day for 15days). Mice of endometriosis model were made by implanting myometrial and endometrial tissues under the condition of immunodeficiency. The TGF-β, Bcl-2, Bax, NF-κB, COX-2, and PGE-2 were analyzed immunohistochemically. The increase of Bcl-2 expression in endometriosis was decreased significantly by genistein dosage of 0.78 and 1.3mg/day (p<0.05). The decrease of Bax expression in endometriosis was increased significantly by genistein dosage of 1.04 and 1.3mg/day (p<0.05). The implantation increased the expression of NF-κB, COX-2, and PGE significantly compared with the control group (p<0.05). This increase was reduced significantly by the administration of genistein at dosage of 0.78 and 1.3mg/day (p<0.05). It can be concluded that genistein potentially inhibits endometriosis development through the normalization of apoptosis dysregulation, the inhibition of NF-κB and COX-2 pathways in the peritoneal tissues. Therefore, genistein can be used as a holistic treatment strategy for endometriosis.
... Therefore, a case-control study evaluating this relationship was conducted in Japan on a population of 138 women, among whom 79 were diagnosed with endometriosis. Significant correlation between higher level of isoflavones [genistein (p = 0.01) and daidzein (p = 0.007)] in the urine and occurrence of endometriosis was demonstrated in the group of women suffering from advanced endometriosis (stage III-IV), but not in the group of women with stage I-II endometriosis [29]. ...
... The few studies conducted in this area are contradictory. On the basis of the data presented here, we can suggest that the increased consumption of vegetables (p = 0.0001), fruits (p = 0.002) [21], Omega-3 fatty acids (p = 0.045) [25], (p = 0.001) [11], Omega-6 fatty acids (p = 0.006) [25], fats (p = 0.12) [27], soy and phytoestrogens [29] as well as dairy products rich in calcium (p = 0,001) and vitamin D (p = 0.003) [31] decreases the risk of developing endometriosis. Conversely, factors identified to increase the risk for endometriosis include fruits (p = 0.04) [22], dietary fiber (p = 0.023) [23], fats in general (p = 0.05) (including vegetable fats (p = 0.001), monounsaturated fats (p = 0.05), polyunsaturated fats (p = 0.001) [28], and trans-unsaturated fatty acids (p = 0.001) [11]), pork and beef (p = 0.0004), ham (p = 0.001) [21], and alcohol (p = 0.003) [31]. ...
Endometriosis is a hormone-dependent chronic inflammatory disease characterized by the presence of endometrium beyond the uterine cavity. The disease affects 5–15% of women of child-bearing age, 30–50% of whom suffer from infertility. Understanding the role of dietary factors in the development of endometriosis is critical to development of effective dietary instructions for prevention. Existing studies concerning nutrition and endometriosis suggest that diet is a potentially modifiable risk factor for endometriosis. Fruits and vegetables, fish oils, dairy products rich in calcium and vitamin D, and Omega-3 fatty acids are likely connected with a lower risk of developing endometriosis. Risk factors that increase the risk of endometriosis include consumption of products rich in trans-unsaturated fatty acids, consumption of fats generally, and consumption of beef and other kinds of red meat and alcohol. Currently, there are no clear correlations between particular food products and the risk of endometriosis. Further research is needed in order to fully understand the influence of consumed food products on the risk of development of this disease.
... However, the effects on endometriosis are largely unknown. Available evidence is conflicting, with one small study among nulliparous infertile Japanese women finding that the phytoestrogen genistein was associated with a reduced risk of endometriosis, particularly among those with the estrogen receptor 2 (ESR2) RsaI gene polymorphism (17). In contrast, high intakes of soy products were associated with endometrial pathology among 3 women (18), and long-term supplementation of isoflavones was associated with endometrial hyperplasia among healthy postmenopausal women (19). ...
... Prior studies on the association between phytoestrogens and endometriosis are limited, and most tended to focus on isoflavones as measured through dietary assessment of soy products or urinary isoflavone concentrations. In a study of 138 infertile nulliparous Japanese women (17), Tsuchiya et al. observed urinary isoflavones to be associated with a reduced risk of endometriosis; they further examined potential interactions with the ESR2 gene polymorphism and found that the RsaI polymorphism seemed to modify the effects of genistein on advanced endometriosis (17). Although we were unable to evaluate interactions with the ESR2 gene, there are other important differences between the study by Tsuchiya et al. and ours. ...
Background:
Phytoestrogens have been associated with subtle hormonal changes, but their effects on endometriosis are largely unknown.
Objective:
We assessed the association between urinary concentrations of phytoestrogens and incident endometriosis.
Methods:
We included an operative sample of 495 premenopausal women aged 18-44 y undergoing laparoscopies and laparotomies at 14 clinical sites between 2007 and 2009 and a general population sample of 131 women from the same geographic area who were matched on age and menstruation status. Endometriosis in the surgical sample was assessed by surgical visualization (clinical gold standard), whereas disease in the general population sample was assessed with the use of a pelvic MRI. Urine concentrations of genistein, daidzen, O-desmethylangolensin, equol, enterodiol, and enterolactone were measured at baseline. Poisson regression with robust error variance was used to estimate the risk of an endometriosis diagnosis for each sample after adjusting for age and body mass index (in kg/m(2)). Separate models were run for each phytoestrogen.
Results:
Overall geometric mean urine concentrations of phytoestrogens were as follows: genistein [88 nmol/L (95% CI: 72, 108 nmol/L)], daidzein [194 nmol/L (95% CI: 160, 236 nmol/L)], O-desmethylangolensin [4 nmol/L (95% CI: 3, 6 nmol/L)], equol [4 nmol/L (95% CI: 4, 6 nmol/L)], enterodiol [29 nmol/L (95% CI: 22, 38 nmol/L)], and enterolactone [355 nmol/L (95% CI: 395, 544 nmol/L)]. Geometric mean concentrations of phytoestrogens did not significantly differ by endometriosis status in either sample. Adjusted RRs for endometriosis ranged from 0.87 to 1.09 for the 6 phytoestrogens measured, with all CIs including a value ≥1. Phytoestrogens were not associated with the severity of endometriosis when restricting the analysis to women with moderate-to-severe disease per the revised American Society for Reproductive Medicine criteria. Furthermore, no associations were observed between self-reported high soy intake and endometriosis.
Conclusions:
Despite endometriosis being an estrogen-dependent disease, we found no evidence that urinary phytoestrogens were associated with a higher risk of an endometriosis diagnosis in either a sample of premenopausal women or in a surgical sample.
... A clinical study found that higher levels of urinary GEN and DDZ were associated with a reduced risk of advanced-stage endometriosis but not early endometriosis [48]. For advanced-stage endometriosis, the adjusted ORs of the highest quartile group were 0.21 (95% CI = 0.06-0.76) ...
Plant polyphenols have various health effects. Genistein, which is abundant in soybeans, and epigallocatechin-3-gallate, which is abundant in green tea, are major flavonoids, a subclass group of polyphenols. Several epidemiological studies have shown that these flavonoids have beneficial effects against cancer and cardiovascular diseases. However, other studies did not show such effects. Several confounding factors, including recall bias, are related to these inconsistent findings, and the determination of metabolites in the urine may be useful in reducing the number of confounding factors. Equipment, which can be used by research participants to collect samples from a portion of voided urine within 24 h without the help of medical workers, has been developed for epidemiological investigations. Previous studies, in which flavonoid metabolites in these urine samples were measured, revealed that soy intake was correlated with a reduced risk of certain types of cancer and cardiovascular diseases worldwide. Although soybeans and green tea consumption may have protective effects against cancer and cardiovascular diseases, further clinical studies that consider different confounding factors are required to provide evidence for the actual impact of dietary flavonoids on human diseases, including cancer and cardiovascular diseases. One possible mechanism involved is discussed in relation to the downregulation of reactive oxygen species and the upregulation of 5′-adenosine monophosphate-activated protein kinase elicited by these flavonoids.
... p = 0.002) consumption. In a Japanese study, higher levels of urinary isoflavones were also associated with a reduced risk of advanced endometriosis [21]. Variety, harvest location, or type of cooking may also result in variations in phytoestrogen content and should be considered when interpreting the results. ...
This review provides an overview of current knowledge on the relationship between various environmental factors and endometriosis. We successively searched for a given exposure factor combined with the word "endometriosis." The literature was comprehensively analyzed and summarized by quoting only the most important and recent studies on each exposition factor. The data focused primarily on endocrine disruptors, such as dioxins and polychlorinated biphenyls, that appear to have the strongest effect. Intriguing data suggest a link with night work, sun exposure and red meat consumption. For the other risk factors studied, particularly those related to lifestyle (tobacco consumption, alcohol, coffee, soy, physical exercise), the data are not sufficient to draw conclusions. In summary, the epidemiological evidence does not support a strong, scientific link between exposure to environmental factors and endometriosis. The complexity of this disease requires advanced study designs and standardized methodology. Future studies should be carefully designed to address these issues to advance our understanding of the impact of the environment and its consequences on endometriosis.
... There is a correlation between high levels of genistein urine with decreased risk of endometriosis. Genistein (at 500 mg/kg day orally for 21 days) also trigger endometriosis implantation regression, which marked by decreasing size of lesion in rat model of endometriosis [23,24]. ...
This in silico and in vivo investigation were to know the effect of genistein on alteration of MMPs in a mice model of endometriosis. Forty female mice (Mus musculus) were divided into eight groups (n=5 each), including the control (untreated) group, endometriosis group, and the endometriosis (EM) groups were given various doses of genistein (at dose of 50; 100; 200; 300; 400; 500 mg/day). In silico analysis was performed using Open Babel, 3D DART webserver, HEX software, and NUCPLOT software. Analysis of MMP-2 and MMP-9 level were done by enzyme linked immuno sorbent assay (ELISA) technically. In the absence of genistein, ΣE total required for the interaction between NF-κB with MMP-2 or MMP-9 gene promoter were increased in genistein treatment (-2393.71 kJ/mol and-2393.86 kJ/mol) compared with no genistein treatment (-2415.62 kJ/mol and-2457.00 kJ/mol). In endometriosis group we were founded the massive endometriosis lesion and hyper vascularization. All doses the treatment with genistein reduces the size of endometriosis lesion. The level of MMP-2 and MMP-9 was significantly higher in the EM group compared to the untreated control group (P<0.05). This increase in MMP-2 was significantly (P<0.05) attenuated by all doses of genistein. These increased levels of MMP-9 in the EM group were significantly reduced by 100 mg/day administration of genistein. In conclusion, genistein prohibits the increase in MMP-2 and MMP-9 in a mice model of endometriosis. Therefore, this may provide a natural therapy for attenuating the alteration of MMPs found in endometriosis disease.
... The same study further concluded that, among the women with moderate-to-severe endometriosis, there was no correlation between phytoestrogen consumption and disease severity. This study conflicts with results from another study which found that higher levels of urinary genistein were correlated with a reduction in advanced endometriosis risk [162]. However, this study is less generalizable because it only included women that were infertile and nulliparous. ...
Advanced research in recent years has revealed the important role of nutrients in the protection of women’s health and in the prevention of women’s diseases. Genistein is a phytoestrogen that belongs to a class of compounds known as isoflavones, which structurally resemble endogenous estrogen. Genistein is most often consumed by humans via soybeans or soya products and is, as an auxiliary medicinal, used to treat women’s diseases. In this review, we focused on analyzing the geographic distribution of soybean and soya product consumption, global serum concentrations of genistein, and its metabolism and bioactivity. We also explored genistein’s dual effects in women’s health through gathering, evaluating, and summarizing evidence from current in vivo and in vitro studies, clinical observations, and epidemiological surveys. The dose-dependent effects of genistein, especially when considering its metabolites and factors that vary by individuals, indicate that consumption of genistein may contribute to beneficial effects in women’s health and disease prevention and treatment. However, consumption and exposure levels are nuanced because adverse effects have been observed at lower concentrations in in vitro models. Therefore, this points to the duplicity of genistein as a possible therapeutic agent in some instances and as an endocrine disruptor in others.
... Moreover, broad phytoestrogen supplementation facilitated ureteral Mullerian carcinosarcoma occurring in endometriosis lesions [284,310]. Furthermore, some studies suggested that early consumption of soybean-derived isoflavone foods increases the risk of endometriosis, whereas other studies focused on adult exposure raised doubts about the relationship between soybean consumption and endometriosis [307,311,312]. Regarding the risk of endometrial cancer, results on the protective effects of soybean isoflavones are more consistent. ...
Soybeans are rich in proteins and lipids and have become a staple part of the human diet. Besides their nutritional excellence, they have also been shown to contain various functional components, including isoflavones, and have consequently received increasing attention as a functional food item. Isoflavones are structurally similar to 17-β-estradiol and bind to estrogen receptors (ERα and ERβ). The estrogenic activity of isoflavones ranges from a hundredth to a thousandth of that of estrogen itself. Isoflavones play a role in regulating the effects of estrogen in the human body, depending on the situation. Thus, when estrogen is insufficient, isoflavones perform the functions of estrogen, and when estrogen is excessive, isoflavones block the estrogen receptors to which estrogen binds, thus acting as an estrogen antagonist. In particular, estrogen antagonistic activity is important in the breast, endometrium, and prostate, and such antagonistic activity suppresses cancer occurrence. Genistein, an isoflavone, has cancer-suppressing effects on estrogen receptor-positive (ER+) cancers, including breast cancer. It suppresses the function of enzymes such as tyrosine protein kinase, mitogen-activated kinase, and DNA polymerase II, thus inhibiting cell proliferation and inducing apoptosis. Genistein is the most biologically active and potent isoflavone candidate for cancer prevention. Furthermore, among the various physiological functions of isoflavones, they are best known for their antioxidant activities. S-Equol, a metabolite of genistein and daidzein, has strong antioxidative effects; however, the ability to metabolize daidzein into S-equol varies based on racial and individual differences. The antioxidant activity of isoflavones may be effective in preventing dementia by inhibiting the phosphorylation of Alzheimer’s-related tau proteins. Genistein also reduces allergic responses by limiting the expression of mast cell IgE receptors, which are involved in allergic responses. In addition, they have been known to prevent and treat various diseases, including cardiovascular diseases, metabolic syndromes, osteoporosis, diabetes, brain-related diseases, high blood pressure, hyperlipidemia, obesity, and inflammation. Further, it also has positive effects on menstrual irregularity in non-menopausal women and relieving menopausal symptoms in middle-aged women. Recently, soybean consumption has shown steep increasing trend in Western countries where the intake was previously only 1/20–1/50 of that in Asian countries. In this review, I have dealt with the latest research trends that have shown substantial interest in the biological efficacy of isoflavones in humans and plants, and their related mechanisms.
... Nutrition is widely recognized as a prognostic and modifiable factor related to morbidity and life expectancy [20][21][22][23]. Several observational studies have investigated certain nutrition habits as risk factors for endometriosis [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]. Women with endometriosis seem to consume fewer vegetables, omega-3 polyunsaturated fatty acids, and dairy products and more red meat, coffee, and trans fats; but these findings could not be consistently replicated [39]. ...
A patients’ increasing interest in dietary modifications as a possible complementary or alternative treatment of endometriosis is observed. Unfortunately, the therapeutic potential of dietary interventions is unclear and to date no guidelines to assist physicians on this topic exist. The aim of this study, therefore, was to systematically review the existing studies on the effect of dietary interventions on endometriosis. An electronic-based search was performed in MEDLINE and COCHRANE. We included human and animal studies that evaluated a dietary intervention on endometriosis-associated symptoms or other health outcomes. Studies were identified and coded using standard criteria, and the risk of bias was assessed with established tools relevant to the study design. We identified nine human and 12 animal studies. Out of the nine human studies, two were randomized controlled trials, two controlled studies, four uncontrolled before-after studies, and one qualitative study. All of them assessed a different dietary intervention, which could be classified in one of the following principle models: supplementation with selected dietary components, exclusion of selected dietary components, and complete diet modification. Most of the studies reported a positive effect on endometriosis; they were however characterized by moderate or high-risk bias possibly due to the challenges of conducting dietary intervention trials. According to the available level of evidence, we suggest an evidence-based clinical approach for physicians to use during consultations with their patients. Further well-designed randomized controlled trials are needed to accurately determine the short-term and long-term effectiveness and safety of different dietary interventions.
... As a result of their oestrogenic effects, phytoestrogens, which primarily occur in soya, may be linked with the occurrence of endometriosis and other oestrogen-dependent diseases [46]. One Japanese study [47] was able to determine a correlation between increased isoflavone concentrations in the urine (genistein [p trend = 0.01] and daidzein [p trend = 0.06]) and the occurrence of endometriosis in women with severe disease (grades III-IV). How-ever, this correlation did not apply to patients with milder forms of endometriosis (grades I-II). ...
Endometriosis is a hormone-related, chronic inflammation in women of childbearing age. The aetiology and pathogenesis of endometriosis are not yet fully understood. For other illnesses classed as lifestyle diseases, the link between nutrition and pathogenesis has already been researched and proven. With regard to these findings, the question continues to arise as to whether and how a specific diet and lifestyle could also influence pathogenesis and the progression of endometriosis. The aim of this review is to examine the data and determine what influence nutrition has on the development of endometriosis or on existing disease. The study results currently available do not permit a clear, scientific recommendation or indicate a detailed diet. In summary, it can be said that fish oil capsules in combination with vitamin B12 have been associated with a positive effect on endometriosis symptoms (particularly of dysmenorrhoea). Alcohol and increased consumption of red meat and trans fats are associated with a negative effect. The results of the studies listed with regard to fruit and vegetables, dairy products, unsaturated fats, fibre, soy products and coffee are not clear. Therefore, the general recommendations for a balanced and varied diet in line with the guidelines of the Deutsche Gesellschaft für Ernährung e. V. [German Nutrition Society] apply, along with the recommendation to cut out alcohol. In order to be able to derive more concrete recommendations, we require further studies to investigate the influence of nutrition on endometriosis.
... Another study with infertile Japanese women revealed that diets rich in genistein and daidzein could reduce the risk of deep endometriosis. 29 Reduction in oxidative stress by isoflavones has been demonstrated in several in vivo models. Genistein and daidzein have also been associated with a decrease in the risk of chronic pathologies, such as neurodegenerative, cardiovascular, and metabolic diseases, as well as cancers, partly due to their antioxidant activities. ...
... 28 Kebar grass also contains daidzein phytohormone in high concentrations can reduce the risk of advanced endometriosis by interacting with estrogen receptors. 29 This research has some limitations. Firstly, the research was applied to the experimental animal due to the absence of toxicity test against Kebar extract. ...
Background: The pathogenesis of endometriosis remains unclear, and involves multifactorial etiologies. The increase in oxidative stress is known to be associated with this disease. Oxidative stress increases angiogenesis and supports the proliferation of endometriosis tissue in the peritoneal cavity. Kebar grass, a medicinal plant, is expected to increase antioxidant defense resulting in decreased oxidative stress, inflammation, angiogenesis, and reduced endometrial tissue implants.
Objective: To investigate the effects of Kebar grass extract administration to MDA serum levels, TNF-a and VEGF expression, and the extension of the endometriotic lesions in mice model.
Methods: This study was experimentally designed. It was conducted in the Department of Obstetrics Gynecology, Faculty of Medicine Diponegoro, University and Faculty of Veterinary Medicine, Airlangga University. Twenty-one mice were divided into three groups: the first group is control of 7 untreated endometriosis mice model, the second group consisted of 7 mice injected with leuprolide acetate 1mg/kgBB single dose, and the last group consisted of 7 mice fed with Kebar grass extract 3mg/day for 14 days. MDA serum level was measured by spectrophotometry, TNF-a and VEGF expression by IHC using Rammele Scale Index (ImmunoReactive Score), whereas the extension of the endometriotic lesions was measured using computerize tracing.
Results: Both Kebar grass extract and leuprolide acetate administration significantly decrease MDA serum levels in endometriosis mice model, compare with the control group, (0.09±0.02 nmol, 0.11±0.07 nmol, and 0.30±0.06 nmol, respectively; p=0.001). TNF-α expression of the group treated with Kebar grass extract was lower than leuprolide acetate and control group (2.43±1.521 %, 4.86±0.458 %, and 7.26±2.898 %, respectively; p=0.002). However, there was no significant difference in VEGF expression among study groups (4.34±2.40 %, 5.11±1.95 %, and 7.40±3.49 % respectively; p=0.116). Finally, the extension of the endometriotic lesions of the mouse models administered with Kebar grass extract and leuprolide acetate was smaller than the control group (0 mm2, 4.54±7.75 mm2, and 34.80±13.09 mm2 respectively; p=0.005).
Conclusion: Kebar grass extract has the effect of decreasing MDA serum levels and reducing TNF-α expression, resulted in smaller endometriotic lesions in mice, even though it does not affect VEGF expression.
Keywords: malondialdehyde, tumour necrosis factor alpha, vascular endothelial growth factor, endometriotic lesion, kebar grass extract, endometriosis mouse
... 35 Furthermore, Kebar grass extract also contains a high concentration of daidzein phytohormones may decrease the risk of advanced stage endometriosis by interacting with estrogen receptor two gene polymorphism. 36 Green tea catechins and procyanidins have anti-oxidant activity. In a previous study, ECG and EGCG showed better antioxidant activity on lipid peroxidation. ...
Background: Increased oxidative stress causes inflammation and increases angiogenesis. It presumed to promote the proliferation of endometriosis tissue. Kebar grass (Biophytum petersianum) and other herbs such as green tea and Cucumis melo, which contain high antioxidants, are expected to decrease oxidative stress, inflammation, angiogenesis, and reduced endometriosis implants.
Objective: To investigate the effects of Kebar grass, green tea, and Cucumis melo to malondialdehyde serum, tumor necrosis factor alpha, and vascular endothelial growth factor expression, and the area of the endometriotic implants.
Methods: Twenty-eight mice were divided into four groups, i.e., the first group of endometriosis mice was given Kebar grass extract; the second group was assigned green tea extract, the third group was given the combination of Cucumis melo extract–gliadin, and the last containing the untreated endometriosis mice as the control. Each treatment was given for 14 days. The data of MDA serum level, the area of the endometriotic implants, TNF-α, and VEGF expression were collected and analyzed.
Results: The MDA serum levels of the groups treated with Kebar grass extract, green tea extract, and Cucumis melo extract – gliadin were significantly lower (p=0.001) than the control group. TNF-α expression of the groups provided with each treatment also lower than the control groups (p=0.002). However, only the administration of the Cucumis melo extract–gliadin resulted in lower VEGF expression compare with the control (p=0.017). Finally, the area of the endometriotic implants of the mice models administered with each treatment was smaller than the control group (p=0.003).
Conclusion: Kebar grass as well as green tea and Cucumis melo–gliadin inhibits endometriotic implants extension by decreasing MDA serum and TNF-α expression.
... Moreover, using an animal model, it was shown that pharmacologic genistein, but not dietary form, helps to the maintenance of the implants (28). In a Japanese study, higher levels of urinary genistein and daidzein were related to reduced advanced endometriosis risk (29). However, to the best of our knowledge, no study has assessed possible associations between dietary phytoestrogen intake and women endometriosis risk. ...
... Moreover, using an animal model, it was shown that pharmacologic genistein, but not dietary form, helps to the maintenance of the implants (28). In a Japanese study, higher levels of urinary genistein and daidzein were related to reduced advanced endometriosis risk (29). However, to the best of our knowledge, no study has assessed possible associations between dietary phytoestrogen intake and women endometriosis risk. ...
Background:
Endometriosis is an important gynecologic disease affecting reproductive-age women. Based on the effect of phytoestrogens on inflammatory, immunological and hormonal factors, limited studies have suggested that phytoestrogen consumption could probably modulate endometriosis risk. The aim of this study was to evaluate the relationship between phytoestrogen intake and endometriosis risk.
Materials and methods:
In the present case-control study, 78 women with a laparoscopically confirmed endometriosis and 78 normal pelvis women (as the control group), were recruited. Common dietary intake was recorded by a validated 147-item semi-quantitative food frequency questionnaire (FFQ). Type of phytoestrogen in each dietary item was analyzed by the database from the United States Department of Agriculture (USDA). A logistic regression model was used to determine the association between phytoestrogen intake and endometriosis risk.
Results:
Higher intake of total phytoestrogen (P-trend=0.01), total isoflavones (P-trend=0.002) specially formononetin (P-trend=0.04) and glycitein (P-trend=0.04), total lignan (P-trend=0.01) specially secoisolariciresinol (P-trend=0.01) and lariciresinol (P-trend=0.02) and matairesinol (P-trend=0.003), and total coumestrol [third quartile odds ratios (OR): 0.38; 95% confidence intervals (CI): 0.15-0.96; P-trend=0.1] was related to reduced endometriosis risk. Among food groups, only isoflavin (OR: 0.48; 95% CI: 0.44-0.63), lignan (OR: 0.66; 95% CI: 0.62-0.94), coumestrol (OR: 0.64; 95% CI: 0.51-0.99), phytoestrogen (OR: 0.46; 95% CI: 0.38-0.83) in dairy products and coumestrol in fruits (OR: 0.69; 95% CI: 0.03-0.77) were negatively associated with endometriosis risk.
Conclusion:
Phytoestrogens have a major impact on the level of hormones, and immune and inflammatory markers; thus, it can play an important role in the control and prevention of many diseases. Due to the inflammatory nature of endometriosis and the effect of hormones on the progression of the disease, the role of phytoestrogens consumption in the progression and regression of the disease should be assessed in future works.
... The use of oral isoflavone as a dietetic supplement was associated with the reduced risk of endometriosis recurrence [40]. Conversely, in a case report Noel et al. suggested a relationship between use of oral isoflavones and endometriosis relapse [41]. ...
Hormonal replacement therapy (HRT) is effective in treating the symptoms of menopause. Endometriosis is defined as the presence of functional endometrial tissue outside the uterine cavity with a tendency towards invasion and infiltration. Being an estrogen-dependent disease, it tends to regress after menopause. Nevertheless, it affects up to 2.2% of postmenopausal women. Conclusive data are not available in the literature on the appropriateness of HRT in women with endometriosis or a past history of the disease. The hypothesis that exogenous estrogen stimulation could reactivate endometriotic foci has been proposed. The aim of this state-of-the-art review was to revise the current literature about endometriosis in perimenopause and menopause and to investigate the possible role of HRT in this setting of patients. An electronic databases search (MEDLINE, Scopus, ClinicalTrials.gov, EMBASE, Sciencedirect, the Cochrane Library at the CENTRAL Register of Controlled Trials, Scielo) was performed, with the date range of from each database’s inception until May 2019. All of the studies evaluating the impact of different HRT regimens in patients with a history of endometriosis were selected. 45 articles were found: one Cochrane systematic review, one systematic review, five narrative reviews, two clinical trials, two retrospective cohort studies, 34 case reports and case series. Some authors reported an increased risk of malignant transformation of endometriomas after menopause in patients assuming HRT with unopposed estrogen. Low-quality evidence suggests that HRT can be prescribed to symptomatic women with a history of endometriosis, especially in young patients with premature menopause. Continuous or cyclic combined preparations or tibolone are the best choices. HRT improves quality of life in symptomatic post-menopausal women, who should not be denied the replacement therapy only due to their history of endometriosis. Based on low-grade literature evidence, we recommend to prescribe combined HRT schemes; tibolone could be considered.
... Zauważono spadek zaawansowania tej choroby u kobiet, w których moczu wykryto wysokie stężenia genisteniny i daidzeniny. Efekt ochronny nie dotyczył wczesnego stadium choroby (Tsuchiya i in., 2007). Zapobieganie endomeriozie dzięki izoflawonom sojowym polega na interakcji fitoestrogenów soi z receptorem estrogenowym. ...
The infertility emerges as an epidemic problem of the modern civilization. Unintended lack of the offspring have a negative impact for individual couples and the society. Therapy is characterized by low cost effectiveness and possible adverse events. Complex substratum of infertility and their proven relation to nutrition and life style indicate a need of multi-modal treatment, including nutritional intervention. Taking into consideration a large scale of a problem, nutritional therapy can be pivotal for a large number of couples. Development of evidence based strategies of prevention and treatment can help to reduce the burden of infertility in future
... Another study with infertile Japanese women revealed that diets rich in genistein and daidzein could reduce the risk of deep endometriosis. 29 Reduction in oxidative stress by isoflavones has been demonstrated in several in vivo models. Genistein and daidzein have also been associated with a decrease in the risk of chronic pathologies, such as neurodegenerative, cardiovascular, and metabolic diseases, as well as cancers, partly due to their antioxidant activities. ...
Isoflavones are the most common forms of phytoestrogens and they are found in soy, soy products (soy milk, tofu, soy beverages, and soy flours), lentils, green peas, and alfalfa and bean sprouts. The main isoflavones are genistein, daidzein, and glycytine. They may be found in nonconjugate form (aglycone) and in conjugated form (glycosylated). Isoflavones are nonsteroidal compounds structurally similar to natural estrogen, as they exhibit a phenolic ring with a hydroxyl radical attached to carbon three. This structure gives them a capacity for high-affinity selective binding to estrogen receptors, thereby enabling them to engage in estrogenic activity in human tissues. Isoflavones have an estrogenic or anti-estrogenic effect depending on their concentration, on endogenous sex steroids, and on the specific target organ in the interaction with the estrogen receptors. The fact that there are two types of estrogen receptors, alpha and beta, endows the different target organs with specificity to phytoestrogens
... Another study with infertile Japanese women revealed that diets rich in genistein and daidzein could reduce the risk of deep endometriosis. 29 Reduction in oxidative stress by isoflavones has been demonstrated in several in vivo models. Genistein and daidzein have also been associated with a decrease in the risk of chronic pathologies, such as neurodegenerative, cardiovascular, and metabolic diseases, as well as cancers, partly due to their antioxidant activities. ...
Isoflavones are the most common forms of phytoestrogens
and they are found in soy, soy products
(soy milk, tofu, soy beverages, and soy flours), lentils,
green peas, and alfalfa and bean sprouts. The main
isoflavones are genistein, daidzein, and glycytine.
They may be found in nonconjugate form (aglycone)
and in conjugated form (glycosylated).1
Isoflavones are nonsteroidal compounds structurally similar
to natural estrogen, as they exhibit a phenolic ring
with a hydroxyl radical attached to carbon three.
This structure gives them a capacity for high-affinity
selective binding to estrogen receptors, thereby
enabling them to engage in estrogenic activity in
human tissues. Isoflavones have an estrogenic or
anti-estrogenic effect depending on their concentration,
on endogenous sex steroids, and on the specific
target organ in the interaction with the estrogen receptors.
The fact that there are two types of estrogen
receptors, alpha and beta, endows the different target
organs with specificity to phytoestrogens.
... Transunsaturated fat intake may be related to the pathogenesis of endometriosis as a result of the upregulation of inflammatory markers including IL-6 and markers of TNF system activation [68,69]. Conflicting results have been reported for fruit and vegetable intake [67,70,71], red meat consumption, saturated fat and animal fat intake [60,65e67,70,72], olive oil consumption and monounsaturated fat intake [65,70,72], phytoestrogens and soy isoflavones [73,74], dairy intake [60,67,70,75], and serum vitamin D levels [76]. Variation in study design and nutritional epidemiologic methods may underlie this lack of replication. ...
Endometriosis affects approximately 10% of women of reproductive age. Characteristics robustly associated with a greater risk for endometriosis include early age at menarche, short menstrual cycle length, and lean body size, whereas greater parity has been associated with a lower risk. Relationships with other potential characteristics including physical activity, dietary factors, and lactation have been less consistent, partially because of the need for rigorous data collection and a longitudinal study design. Critical methodologic complexities include the need for a clear case definition; valid selection of comparison/control groups; and consideration of diagnostic bias and reverse causation when exploring demographic characteristics, medical history, and lifestyle factors. Reviewers and editors must demand a detailed description of rigorous methods to facilitate comparison and replication to advance our understanding of endometriosis.
... Five-year use of a highly concentrated isoflavone supplement was associated with florid recurrence of endometriosis and ureteral malignant mullerian carcinosarcoma (Noel et al., 2006). This report raises further concerns over the use of phytoestrogens in postmenopausal women with a history of endometriosis (Cotroneo and Lamartiniere, 2001), despite some clinical and animal literature suggesting a reduced risk of endometriosis with dietary isoflavones (Tsuchiya et al., 2007;Yavuz et al., 2007). Given the high prevalence of supplement use, it is important to further explore the relationship between phytoestrogens and endometriosis. ...
Background:
Endometriosis is typically regarded as a premenopausal disease, resolving after natural or iatrogenic menopause due to declining oestrogen levels. Nonetheless, case reports over the years have highlighted the incidence of recurrent postmenopausal endometriosis. It is now clear that both recurrence and malignant transformation of endometriotic foci can occur in the postmenopausal period. Postmenopausal women are commonly treated with hormone replacement therapy (HRT) to treat climacteric symptoms and prevent bone loss; however, HRT may reactivate endometriosis and stimulate malignant transformation in women with a history of endometriosis. Given the uncertain risks of initiating HRT, it is difficult to determine the best menopausal management for this group of women.
Objective and rational:
The aim of this study was to systematically review the existing literature on management of menopausal symptoms in women with a history of endometriosis. We also aimed to evaluate the published literature on the risks associated with HRT in these women, and details regarding optimal formulations and timing (i.e. initiation and duration) of HRT.
Search methods:
Four electronic databases (MEDLINE via OVID, Embase via OVID, PsycINFO via OVID and CINAHL via EbscoHost) were searched from database inception until June 2016, using a combination of relevant controlled vocabulary terms and free-text terms related to 'menopause' and 'endometriosis'. Inclusion criteria were: menopausal women with a history of endometriosis and menopausal treatment including HRT or other preparations. Case reports/series, observational studies and clinical trials were included. Narrative review articles, organizational guidelines and conference abstracts were excluded, as were studies that did not report on any form of menopausal management. Articles were assessed for risk of bias and quality using GRADE criteria.
Outcomes:
We present a synthesis of the existing case reports of endometriosis recurrence or malignant transformation in women undergoing treatment for menopausal symptoms. We highlight common presenting symptoms, potential risk factors and outcomes amongst the studies. Sparse high-quality evidence was identified, with few observational studies and only two randomized controlled trials. Given this paucity of data, no definitive conclusions can be drawn concerning risk.
Wider implications:
Due to the lack of high-quality studies, it remains unclear how to advise women with a history of endometriosis regarding the management of menopausal symptoms. The absolute risk of disease recurrence and malignant transformation cannot be quantified, and the impact of HRT use on these outcomes is not known. Multicentre randomized trials or large observational studies are urgently needed to inform clinicians and patients alike.
... Some authors have suggested that estradiol might modulate the mediators of immune system molecules or those involved in tissue cell adhesion and invasion 73,74 . Moreover, a favorable effect of smoking has been observed in other benign and malignant estrogen-related diseases, such as endometrial cancer 75 , and fibroids 76 . The antiestrogenic effect of smoking on these conditions could support a protective effect of smoking on endometriosis. ...
... MasakiTsuchiya.,(2007)24 , examined associations among soy isoflavone intake, estrogen receptor 2 (ESR2) gene polymorphisms and risk of endometriosis among women of age 20–45 years old. A total of 138 eligible women were diagnosed laparoscopically and classified into 3 subgroups: control (no endometriosis), early endometriosis (stage I–II) and advanced endometriosis (stage III–IV). ...
... A total of 16 remaining articles were then retrieved for further assessment of eligibility. Among these studies, seven were excluded because they were (1) reviews or meta-analysis [30][31][32][33], (2) not regarding gene polymorphisms [34], (3) an infertile control study [35], or (4) lacked useful data [36]. Finally, a total of nine eligible articles were included in this meta-analysis. ...
Background:
Many epidemiological studies have suggested an association between estrogen receptor-beta (ER-β) polymorphisms with endometriosis risk. However, the results of these studies have been inconsistent. In the present study, we performed a meta-analysis to clarify the associations between the ER-β rs4986938 and rs1256049 polymorphisms and endometriosis risk.
Methods:
Eligible publications were retrieved from the PubMed, ISI Web of Science, and several Chinese language databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random or fixed effect model.
Results:
A total of eight studies (1100 cases/1485 controls) for the rs4986938 polymorphism and four studies (353 cases/450 controls) for the rs1256049 polymorphism were included in this meta-analysis. Regarding the rs4986938 polymorphism, no obvious associations were found for all genetic models when all studies were pooled into the meta-analysis. In the subgroup analyses by ethnicity, study sample size, endometriosis-associated infertility, and stage of endometriosis, a significantly increased risk was observed among mixed populations (dominant model, OR=2.03, 95% CI=1.56-2.64) and among cases with endometriosis-associated infertility (dominant model, OR=1.83, 95% CI=1.26-2.67). Regarding the rs1256049 polymorphism, no obvious associations were found for all genetic models in the overall population. Subgroup analyses by ethnicity and study sample size revealed that only one study of a mixed population with small sample size showed an increased risk of endometriosis. No publication bias was found in the present study.
Conclusions:
The results of this meta-analysis suggest that the ER-β rs4986938 and rs1256049 polymorphisms may not be associated with endometriosis risk, while the observed increased risk of endometriosis-associated infertility may be due to bias by the inclusion of small-scale studies.
Virtual slides:
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_184.
... Soy isoflavones used in dietary supplements have grown to approximately $34 million at retail, about double the value in 1999 (Supplement Business Report, 2002), emphasizing the mounting importance of soy as a part of a typical, healthful diet (Cavazos et al., 2012). Epidemiological studies suggest that an elevated intake of genistein and daidzein may reduce the risk of hormone-dependent (breast and prostate) cancers (Messina et al., 2002;Messina et al., 2006;Wang et al., 2011;Rong et al., 2011), the incidence of hormone-related disorders (endometriosis, post-menopausal symptoms) (Han et al., 2002;Tsuchiya et al., 2007), and increase the proliferation and survival of the hippocampus neural cells (Pan et al., 2012). The interest for isoflavones in skin care is not surprising because they have the ability to bind to ES receptors -which are present in the skin -and ES therapy improves a number of skin parameters including elasticity, moisturizing, pigmentation and vascularity. ...
... L.W. Jackson et al., (2005) 26 indicated that the markers of oxidative stress and antioxidant status vitamin A, lycopene, β carotene and vitamin E were not found to be associated with endometriosis. Masaki Tsuchiya.,(2007) 24 , found that higher urinary levels of isoflavones was associated with a reduced risk of advanced endometriosis , but not early endometriosis. ...
Endometriosis is a gynaecological disorder characterized by the presence and growth of endometrial tissue outside the uterine cavity1. The prevalence of endometriosis among asymptomatic women ranges from 2–22%, while in women with infertility the incidence of endometriosis is 35% to 50%. This pathology represents one of the most frequent gynaecological disorders during women's reproductive age. Considering the high prevalence of the disease and its difficult diagnosis and therapeutic management as a result of its complex pathogenesis, which is yet to be fully clarified, a question has been raised regarding whether women affected by endometriosis have certain nutritional peculiarities . The objectives of this review were to assess a possible association between dietary components and endometriosis from the existing literature and, if possible, to identify potential modifiable risk factors of the disease and to specify dietary recommendations for women suffering with this enigmatic gynaecologic disorder. A search of the databases provided 12 studies from 2003 to 2013 to review the association of dietary intake and endometriosis. Based on the results shown in the present manuscript, we can suggest that health education in regard to the dietary management in endometriosis is the need of the hour in improving the quality of life of women with endometriosis.
... 8,9 Along these lines, several studies have analyzed the association between alcohol drinking and risk of endometriosis but conflicting results have been published regarding the potential effect. [10][11][12][13][14][15][16][17][18][19][20] To offer a general figure of the available data on the relation between alcohol intake and risk of endometriosis, we conducted a systematic review and a metaanalysis of studies published up to May 2012. May 31, 2012) using the Medical Subject Heading terms "diet" or "nutrition" or "alcohol" or "vitamin" or "fat" or "vegetable," combined with "endometriosis." ...
Objective:
To offer a general figure of the available data on the relation between alcohol intake and risk of endometriosis, we conducted a systematic review and a metaanalysis of studies published up to May 2012.
Study design:
We carried out a literature search of all case-control and cohort studies published as original articles in English up to May 2012. Only those papers that were published as full-length articles were considered. Pooled estimates of the relative risks (RRs) and the corresponding 95% confidence intervals (CIs) were calculated using fixed or, when significant heterogeneity among estimates emerged, random effects models. A total of 15 studies were identified for the review.
Results:
The summary estimate was 1.24 (95% CI, 1.12-1.36) for any alcohol intake vs no alcohol intake. Considering the results of the analyses of infrequent, moderate/regular, and heavy alcohol intake vs no alcohol intake, the summary RR estimates were, respectively, 1.14 (95% CI, 0.86-1.52), 1.23 (95% CI, 1.08-1.40), and 1.19 (95% CI, 0.99-1.43). Three studies reported separate results for current and former drinkers, and the summary RR were 1.42 (95% CI, 1.14-1.76) and 1.09 (95% CI, 0.83-1.43), respectively.
Conclusion:
The present metaanalysis provides evidence for an association between alcohol consumption and endometriosis risk. Further studies are needed to clarify whether alcohol consumption may exacerbate an existing disease or could be related to the severity of the disease.
Endometriosis is a serious, chronic disorder where endometrial tissue grows outside the uterus, causing severe pelvic pain and infertility. It affects 11% of women. Endometriosis is a multifactorial disorder of unclear etiology, although retrograde menstruation plays a major role. It has a genetic component with over 40 genetic risk factors mapped, although their mechanism of action is still emerging. New evidence suggests a role for retrograde menstruation of endometrial stem/progenitor cells, now that identifying markers of these cells are available. Recent lineage tracing and tissue clearing microscopy and 3D reconstruction has provided new understanding of endometrial glandular structure, particularly the horizontal orientation and interconnection of basalis glands. New sequencing technologies, particularly whole genome DNA sequencing are revealing somatic mutations, including in cancer driver genes, in normal and eutopic endometrium of patients with endometriosis, as well as ectopic endometriotic lesions. Methylome sequencing is offering insight into the regulation of genes and the role of the environmental factors. Single cell RNA sequencing reveals the transcriptome of individual endometrial cells, shedding new light on the diversity and range of cellular subpopulations of the major cell types present in the endometrium and in endometriotic lesions. New endometrial epithelial organoid cultures replicating glandular epithelium are providing tractable models for studying endometriosis. Organoids derived from menstrual fluid offer a non‐invasive source of endometrial tissue and a new avenue for testing drugs and developing personalized medicine for treating endometriosis. These new approaches are rapidly advancing our understanding of endometriosis etiology.
Endometriosis is an oestrogen dependent, benign, chronic inflammatory disease characterised by ectopic endometrial implants. Current medical practices for the treatment of the disease are associated with several side effects over long periods, making the effect of diet on endometriosis an important aspect. To alleviate this need, we review related literature to identify the association between nutrients and endometriosis and to find the probable therapeutic effects of the nutrients and foods on endometriosis. Despite variations among the findings, several of the prior studies point to an inverse relationship between endometriosis and the consumption of fruits, vegetables, dairy products, and omega-3 fatty acids. Another common finding among the studies is the increased risk of endometriosis with higher consumption of trans-unsaturated fatty acids and red meat. Due to the limited size of the samples in existing literature, however, significance of the association between diet and endometriosis is not conclusive. Further research is needed to better identify the role of diet on endometriosis.
Although endometriosis is a disease that affects a large percentage of women, studies demonstrating the relationship between certain foods or lifestyle modifications are limited. Data from the Nurses’ Health Study II cohort allowed for retrospective observation of certain dietary measures and risk of developing endometriosis utilizing a large sample size over a span of 4 years. Analysis has found that increasing consumption of certain fruits, omega-3 fatty acids, and dairy foods may reduce the risk of developing endometriosis. Dietary and lifestyle modifications and how they relate to endometriosis risk and/or symptoms associated with endometriosis are discussed in this chapter.
The prevalence of female infertility cases has been increasing at a frightening rate, affecting approximately 48 million women across the world. However, oxidative stress has been recognized as one of the main mediators of female infertility by causing various reproductive pathologies in females such as endometriosis, PCOS, preeclampsia, spontaneous abortion, and unexplained infertility. Nowadays, concerned women prefer dietary supplements with antioxidant properties over synthetic drugs as a natural way to lessen the oxidative stress and enhance their fertility. Therefore, the current review is an attempt to explore the efficacy of various natural antioxidant compounds including vitamins, carotenoids, and plant polyphenols and also of some medicinal plants in improving the fertility status of females. Our summarization of recent findings in the current article would pave the way toward the development of new possible antioxidant therapy to treat infertility in females. Natural antioxidant compounds found in fruits, vegetables, and other dietary sources, alone or in combination with other antioxidants, were found to be effective in ameliorating the oxidative stress-mediated infertility problems in both natural and assisted reproductive settings. Numerous medicinal plants showed promising results in averting the various reproductive disorders associated with female infertility, suggesting a plant-based herbal medicine to treat infertility. Although optimum levels of natural antioxidants have shown favorable results, however, their excessive intake may have adverse health impacts. Therefore, larger well-designed, dose-response studies in humans are further warranted to incorporate natural antioxidant compounds into the clinical management of female infertility.
A wide variety of plant species provide edible seeds. Seeds are the dominant source of human calories and protein. The most important and popular seed food sources are cereals, followed by legumes and nuts. Their nutritional content of fiber, protein, and monounsaturated/polyunsaturated fats make them extremely nutritious. They are important additions to our daily food consumption. When consumed as part of a healthy diet, seeds can help reduce blood sugar, cholesterol, and blood pressure.
The pathological pathway of endometriosis remains unclear and involves complex etiologies. Increased oxidative stress is understood to be related to this disease. Oxidative stress produces reactive oxygen species, causes inflammation that is characterized by recruiting lymphocytes and phagocyte activation, produces cytokines that induce oxidation enzyme, and supports epithelium growth. Oxidative stress conjointly will increase angiogenesis and promotes the proliferation of endometriosis tissue within the peritoneal cavity. Kebar grass and green tea contain high antioxidants, are expected to extend antioxidant defense leading to reduced oxidative stress, inflammation, angiogenesis, and reduced endometriosis tissue implants. The objective is to analyze the consequences of Kebar grass and green tea extract to MDA serum level, TNF-α, and VEGF expression, and the area of the endometriotic implants in the mice models. The study was an experiment designed. It has been conducted within the. Twenty-one mice were divided into three groups, i.e., the first group of mouse models was given Kebar extract 3 mg/day; the second group was assigned green tea extract 1.1 mg/day; therefore the third group was a control group contains the untreated endometriosis mice. Each treatment was given for fourteen days. MDA serum level was measured by specto-photometric examination, the area of the endometriotic implants was measured by computer tracing technique, whereas TNF-α and VEGF expression of endometriotic implants were measured by IHC using Rammele Scale Index (ImmunoReactive Score). The MDA serum levels of the groups treated with Kebar grass extract and green tea extract were significantly lower than the control group (0.090.022 mmol, 0.070.019 mmol, and 0.300.062 mmol, respectively; p=0.001). TNF-α expression of the groups supplied with each treatment also lower than the control groups (2.431.521, 3.661.422, and 7.262.898, respectively; p=0.002). However, VEGF expression was not significantly different between Kebar grass extract group, green tea group, and the control (4.342.402, 4.571.998, 7.403.495, respectively; p=0.089). Finally, the area of the endometriotic implants of the mice models administered with all treatment was smaller than the control group (0.010.025 mm2, 8.7618.776 mm2, and 34.8013.079 mm2, respectively; p=0.003). Conclusion: Kebar grass extract, as well as green tea extract administration to endometriosis model mice, resulted in lower MDA serum level and TNF-α expression, smaller the area of endometriotic implants compared, but not resulted in a significant difference of VEGF expression.
Endometriosis is a benign gynecological condition prevalent among reproductive-aged women. Although active research and studies have been carried out to discover new drugs, surgery and hormone therapy are still the gold standard for endometriosis treatment. Nowadays, various flavonoids are considered long-term supplements for different diseases. Myricetin, a flavonol, has antiproliferative, anti- or pro-oxidant, and anticancer effects in gynecological diseases. Here, we reveal for the first time, to our knowledge, the antigrowth effects of myricetin in endometriosis. Myricetin inhibited cell proliferation and cell cycle progression of human VK2/E6E7 and End1/E6E7 cells and induced apoptosis, with the loss of mitochondrial membrane potential and accumulation of reactive oxygen species and calcium ions. Additionally, myricetin decreased the activation of AKT and ERK1/2 proteins, whereas it induced p38 activation in both cell lines. Moreover, myricetin decreased lesion size in the endometriosis mouse model via Ccne1 inhibition. Thus, myricetin has antiproliferative effects on endometriosis through cell cycle regulation.
Natural products have represented attractive alternatives for disease prevention and treatment over the course of human history and have contributed to the development of modern drugs. These natural products possess beneficial efficacies as well as adverse efffects, which vary largely among individuals because of genetic variations in their pharmacokinetics and pharmacodynamics. As with other synthetic chemical drugs, the dosing of natural products can be optimized to improve efficacy and reduce toxicity according to the pharmacogenetic properties. With the emergence and development of pharmacogenomics, it is possible to discover and identify the targets/mechanisms of pharmacological effects and therapeutic responses of natural products effectively and efficiently on the whole genome level. This review covers the effects of genetic variations in drug metabolizing enzymes, drug transporters, and direct and indirect interactions with the pharmacological targets/pathways on the individual response to natural products, and provides suggestions on dosing regimen adjustments of natural products based on their pharmacokinetic and pharmacogenetic paratmeters. Finally, we provide our viewpoints on the importance and necessity of pharmacogenetic and pharmacogenomic research of natural products in natural medicine's rational development and clinical application of precision medicine.
The etiology and risk factors associated with endometriosis are unclear. Over the recent decades substantial work has investigated epidemiological risk factors for the disease. While some clear patterns emerge with regard to risk, many studies are plagued with complex methodological issues and bias. This chapter will present the current state of the epidemiologic knowledge on risk factors for endometriosis including in utero factors, menstrual and reproductive factors, lifestyle factors, physical characteristics, anthropometric factors, dietary factors, and environmental factors. It will further explore the relationships between endometriosis and other chronic diseases. Future work should aim to fill gaps in knowledge while taking the complex methodological issues into account.
Purpose of review:
Endometriosis is a disease of adolescents and reproductive-aged women characterized by the presence of endometrial tissue outside the uterine cavity and commonly associated with chronic pelvic pain and infertility. Here we review the epidemiology of endometriosis as well as potential biomarkers for detection and with the goal of highlighting risk factors that could be used in combination with biomarkers to identify and treat women with endometriosis earlier..
Recent findings:
Early age at menarche, shorter menstrual length, and taller height are associated with a higher risk of endometriosis while parity, higher body mass index (BMI) and smoking are associated with decreased risk. Endometriosis often presents as infertility or continued pelvic pain despite treatment with analgesics and cyclic oral contraceptive pills.
Summary:
Despite a range of symptoms, diagnosis of endometriosis is often delayed due to lack of non-invasive, definitive and consistent biomarkers for diagnosis of endometriosis. Hormone therapy and analgesics are used for treatment of symptomatic endometriosis. However, the efficacy of these treatments are limited as endometriosis often recurs. In this review, we describe potential diagnostic biomarkers and risk factors that may be used as early non-invasive in vitro tools for identification of endometriosis to minimize diagnostic delay and improve reproductive health of patients.
There are concerns regarding reproductive toxicity from consumption of soy foods, including an increased risk of endometriosis and endometrial cancer, as a result of phytoestrogen consumption. In this study, female rats were fed AIN93G diets made with casein (CAS) or soy protein isolate (SPI) from postnatal day (PND) 30, ovariectomized on PND 50 and infused with 5μg/kg/d 17β-estradiol (E2) or vehicle. E2 increased uterine wet weight (P<0.05). RNAseq analysis revealed that E2 significantly altered expression of 1991 uterine genes (P<0.05). SPI feeding had no effect on uterine weight and altered expression of far fewer genes than E2 at 152 genes (P<0.05). Overlap between E2 and SPI genes was limited to 67 genes. Functional annotation analyzes indicated significant differences in uterine biological processes affected by E2 and SPI and little evidence for recruitment of estrogen receptor (ER)α to the promoters of ER-responsive genes after SPI feeding. The major E2 up-regulated uterine pathways were carcinogenesis and extracellular matrix organization, whereas SPI feeding up-regulated uterine peroxisome proliferator activated receptor (PPAR) signaling and fatty acid metabolism. The combination of E2 and SPI resulted in significant regulation of 504 fewer genes relative to E2 alone. The ability of E2 to induce uterine proliferation in response to the carcinogen dimethybenz(a)anthracene (DMBA) as measured by expression of PCNA and Ki67 mRNA was suppressed by feeding SPI (P<0.05). These data suggest that SPI is a selective estrogen receptor modulator (SERM) interacting with a small sub-set of E2-regulated genes and is anti-estrogenic in the presence of endogenous estrogens.
Since conflicting results have been published on the role of tobacco smoking on the risk of endometriosis, we provide an up-to-date summary quantification of this potential association.
We performed a PubMed/MEDLINE search of the relevant publications up to September 2014, considering studies on humans published in English. We searched the reference list of the identified papers to find other relevant publications. Case-control as well as cohort studies have been included reporting risk estimates on the association between tobacco smoking and endometriosis. 38 of the 1758 screened papers met the inclusion criteria. The selected studies included a total of 13 129 women diagnosed with endometriosis.
Academic hospitals.
Risk of endometriosis in tobacco smokers.
We obtained the summary estimates of the relative risk (RR) using the random effect model, and assessed the heterogeneity among studies using the χ(2) test and quantified it using the I(2) statistic. As compared to never-smokers, the summary RR were 0.96 (95% CI 0.86 to 1.08) for ever smokers, 0.95 (95% CI 0.81 to 1.11) for former smokers, 0.92 (95% CI 0.82 to 1.04) for current smokers, 0.87 (95% CI 0.70 to 1.07) for moderate smokers and 0.93 (95% CI 0.69 to 1.26) for heavy smokers.
The present meta-analysis provided no evidence for an association between tobacco smoking and the risk of endometriosis. The results were consistent considering ever, former, current, moderate and heavy smokers, and across type of endometriosis and study design.
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Objective: To investigate whether genistein is anti-inflammation and anti-angiogenesis in endometriosis cells.
Methods: Primary endometriosis cells were divided into seven groups, including control group and genistein-treatment group at dose 5 until 50 μmol/L. The times of incubation is 6, 24, and 48 hours. Levels of TNF-α, IL-6, IL-1β, MMP-2, and VEGF-A in supernatant cells were determined using the enzyme linked immunosorbent assay.
Results: The level of IL-1β was significantly lower in genistein-treatment at dose 20 until 50 μM compared to the control group (6 hours of treatment) (P
The combined investigation of environmental and genetic risk-factors in complex traits will refocus attention on the case-control study. Endometriosis is an example of a complex trait for which most case-control studies have not followed the basic criteria of epidemiological study design. Appropriate control selection has been a particular problem. This article reviews the principles underlying the design of case-control studies, and their application to the study of endometriosis. Only if it is designed well is the case-control study a suitable alternative to the prospective cohort study. Use of newly diagnosed over prevalent cases is preferable, as the latter may alter risk estimates and complicate the interpretation of findings. Controls should be selected from the source population from which cases arose. Potential confounding should be addressed both in studies of environmental and genetic factors. For endometriosis, a possible design would be to: (i) use newly diagnosed cases with 'endometriotic' disease; (ii) collect information predating symptom onset; and (iii) use at least one population-based female control group matched on unadjustable confounders and screened for pelvic symptoms. In conclusion, future studies of complex traits such as endometriosis will have to incorporate both environmental and genetic factors. Only adequately designed studies will allow reliable results to be obtained and any true aetiologic heterogeneity expected to underlie a complex trait to be detected.
Genistein, a component of soy products, may play a role in the prevention of breast and prostate cancer. However, little is
known about the molecular mechanisms involved. In the present study, we examined the effects of genistein on the estrogen
receptor positive human breast cancer cell line MCF-7. We observed that genistein stimulated estrogen-responsive pS2 mRNA
expression at concentrations as low as 10−8 M and these effects can be inhibited by tamoxifen. We also showed that genistein competed with (3H)estradiol binding to the estrogen receptor with 50% inhibition at 5 × 10−7 M. Thus, the estrogenic effect of genistein would appear to be a result of an interaction with the estrogen receptor. The
effect of genistein on growth of MCF-7 cells was also examined. Genistein produceda concentration-dependent effect on the
growth of MCF-7 cells. At lower concentrations (10−8-10−6 M) genistein stimulated growth, but at higher concentrations (>10−5M) genistein inhibited growth. The effects of genistein on growth at lower concentrations appeared to be via the estrogen
receptor pathway, while the effects at higher concentrations were independent of the estrogen receptor. We also found that
genistein, thoughestrogenic, can interfere with the effects of estradiol. In addition, prolonged exposure to genistein resulted
in a decrease in estrogen receptor mRNA level as well as a decreased response to stimulation by estradiol.
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.
Single-nucleotide polymorphisms (SNPs) are the most common type of genetic variation in man. Genes containing one or more SNPs can give rise to two or more allelic forms of mRNAs. These mRNA variants may possess different biological functions as a result of differences in primary or higher order structures that interact with other cellular components. Here we report the observation of marked differences in mRNA secondary structure associated with SNPs in the coding regions of two human mRNAs: alanyl tRNA synthetase and replication protein A, 70-kDa subunit (RPA70). Enzymatic probing of SNP-containing allelic fragments of the mRNAs revealed pronounced allelic differences in cleavage pattern at sites 14 or 18 nt away from the SNP, suggesting that a single-nucleotide variation can give rise to different mRNA folds. By using phosphorothioate oligodeoxyribonucleotides complementary to the region of different allelic structures in the RPA70 mRNA, but not extending to the SNP itself, we find that the SNP exerts an allele-specific effect on the accessibility of its flanking site in the endogenous human RPA70 mRNA. This further supports the allele-specific structural features identified by enzymatic probing. These results demonstrate the contribution of common genetic variation to structural diversity of mRNA and suggest a broader role than previously thought for the effects of SNPs on mRNA structure and, ultimately, biological function.
Biological effects of dietary isoflavones, such as daidzein and genistein are of interest in preventive medicine. We estimated the dietary intake of isoflavones from dietary records and compared the values with the plasma concentrations and urinary excretions in Japanese middle-aged women. The dietary intake of daidzein and genistein was 64.6 and 111.6 mumol /day/capita (16.4 and 30.1 mg/day/capita), respectively. The isoflavones intake was mostly attributable to tofu, natto and miso. The median of plasma daidzein and genistein concentration was 72.46 and 206.09 nmol/L, respectively. The median of urinary excretion was 20.54 mumol /day for daidzein, 10.79 for genistein, 15.74 for equol and 1.64 for O-desmethylangolensin (O-DMA). Equol and O-DMA were excreted by 50% and 84% of all participants, respectively. Equol metabolizers were significantly lower the plasma and urinary daidzein and urinary O-DMA. The dietary intake of daidzein and genistein after the adjustment for total energy intake was significantly correlated with the urinary excretion (r = 0.365 for daidzein and r = 0.346 for genistein) and plasma concentration (r = 0.335 for daidzein and r = 0.429 for genistein). The plasma concentration of isoflavones was also significantly correlated with the urinary excretion. We conclude that in epidemiological studies measurements of plasma concentration or urinary excretion of these isoflavones are useful biomarkers of dietary intake and important for studies on their relation to human health.
Valid food-frequency questionnaires (FFQ) need to be developed to assess isoflavone intake in investigations of its possible association with the lower incidence of breast and prostate cancer in Asian countries. We investigated the validity and reproducibility of isoflavone (daidzein and genistein) intakes from self-administered semiquantitative FFQ used in the JPHC Study (Japan Public Health Center-based Prospective Study on Cancer and Cardiovascular Diseases). We also investigated the number of food items that would be sufficient to ensure validity and reproducibility. We collected FFQ, dietary records (DR), blood and urine samples from 215 subjects among JPHC Study participants, estimated isoflavone intakes from FFQ and DR, and measured serum isoflavone concentration and urine isoflavone excretion. For daidzein, mean intakes estimated from FFQ and DR, serum concentration and urine excretion were 18.3 mg/d, 14.5 mg/d, 119.9 nmol/L and 17.0 micromol/d and for genistein, 31.4 mg/d, 23.4 mg/d, 475.3 nmol/L and 14.2 micromol/d, respectively. Results were similar when analyzed by sex. Spearman correlation coefficients for daidzein of energy-adjusted intakes from FFQ with those from DR, serum concentration and creatinine-adjusted urinary excretion were 0.64, 0.31 and 0.43, respectively. Correlations between two FFQ estimates with a 1-y interval were 0.76. Results were similar for genistein. The shorter version of the FFQ with three items (natto, miso and tofu for miso soup) showed a similar correlation. The original FFQ and the shorter versions have sufficient validity and reproducibility to be used in epidemiologic studies.
Although isoflavones, such as those found in soy, have been shown to inhibit breast cancer in laboratory studies, associations between consumption of isoflavone-containing foods and breast cancer risk have been inconsistent in epidemiologic studies. We evaluated the relationship between isoflavone consumption and breast cancer risk among women in the Japan Public Health Center-Based Prospective Study on Cancer and Cardiovascular Diseases (JPHC Study).
In January 1990, 21 852 Japanese female residents (aged 40-59 years) from four public health center areas completed a self-administered questionnaire, which included items about the frequency of soy consumption. Through December 1999 and 209 354 person-years of follow-up, 179 women were diagnosed with breast cancer. Cox proportional hazards regression was used to estimate the relative risks (RRs) and 95% confidence intervals (CIs) for breast cancer in relation to consumption of miso soup, soyfoods, and estimated isoflavones. All statistical tests were two-sided.
Consumption of miso soup and isoflavones, but not of soyfoods, was inversely associated with the risk of breast cancer. The associations did not change substantially after adjustment for potential confounders, including reproductive history, family history, smoking, and other dietary factors. Compared with those in the lowest quartile of isoflavone intake, the adjusted RRs for breast cancer for women in the second, third, and highest quartiles were 0.76 (95% CI = 0.47 to 1.2), 0.90 (95% CI = 0.56 to 1.5), and 0.46 (95% CI = 0.25 to 0.84), respectively (P(trend) =.043). The inverse association was stronger in postmenopausal women (P(trend) =.006).
In a population-based, prospective cohort study in Japan, frequent miso soup and isoflavone consumption was associated with a reduced risk of breast cancer.
The authors investigated the relations of demographic, anthropometric, and lifestyle factors with endometriosis in the Nurses' Health Study II prospective cohort. During 10 years of follow-up (1989-1999), 1,721 cases of laparoscopically confirmed endometriosis were reported among women with no past infertility. The incidence rate was greatest among women aged 25-29 years and lowest among women over 44 years (p(trend) < 0.0001). In multivariate Cox proportional hazards models, African-American women had a lower rate of disease compared with Caucasian women (rate ratio = 0.6, 95% confidence interval: 0.4, 0.9). The authors also observed an inverse relation with body mass index at age 18 years (for body mass index of >30 vs. 19-20.4 kg/m(2): rate ratio = 0.8, 95% confidence interval: 0.6, 1.1; p(trend) = 0.004) and with current alcohol intake (for >10 vs. 0 g/day: rate ratio = 0.7, 95% confidence interval: 0.6, 0.8; p(trend) < 0.0001) but no association with height, waist/hip ratio, or caffeine intake. An inverse relation with current body mass index and current cigarette smoking was observed only when cases were concurrently infertile. The authors conclude that age, race, body mass index, alcohol use, and cigarette smoking are associated with the incidence of endometriosis and that some of these relations may differ by infertility status at the time of laparoscopic diagnosis.
The indigenous intestinal microflora are involved in a variety of processes within the human body, and are important for maintaining host health. As such, interindividual differences in the ability to harbor certain intestinal bacteria might be associated with interindividual differences in health and/or disease susceptibility. In the last decade there has been considerable interest in phytoestrogen intakes in relation to human health. Daidzein, an isoflavone phytoestrogen found in soy, is metabolized to equol and O-desmethylangolensin (O-DMA) by intestinal bacteria. The specific bacterium/bacteria responsible for equol and O-DMA production in humans have yet to be identified definitively, but in vitro and animal studies have suggested that equol and O-DMA are more biologically active than their precursor daidzein. Interestingly, substantial interindividual differences in daidzein metabolism exist; following soy or daidzein consumption, approximately 30%-50% of the human population produce equol, and approximately 80%-90% produce O-DMA. Observational and intervention studies in humans have suggested that the ability to produce equol and O-DMA may be associated with reduced risk of certain diseases including breast and prostate cancers. However, relatively few studies have been conducted to date. In this review, we discuss the available evidence for a relationship between daidzeinmetabolizing phenotypes and human health, and suggest potential mechanisms for some of the reported relationships.
High intake of soy foods has been proposed to contribute to the low breast cancer risk in Asian countries. However, results of epidemiologic studies of this association are highly variable, and experimental data suggest that soy constituents can be estrogenic and potentially risk enhancing. Thus, rigorous evaluation of available epidemiologic data is necessary before appropriate recommendations can be made, especially for women at high risk of breast cancer or those who have survived the disease.
We performed a meta-analysis of 18 epidemiologic studies (12 case-control and six cohort or nested case-control) published from 1978 through 2004 that examined soy exposure and breast cancer risk. Pooled relative risk estimates were based on either the original soy exposure measure defined in each study or on an estimate of daily soy protein intake.
Risk estimates, levels and measures of soy exposure, and control for confounding factors varied considerably across studies. In a pooled analysis, among all women, high soy intake was modestly associated with reduced breast cancer risk (odds ratio [OR] = 0.86, 95% confidence interval [CI] = 0.75 to 0.99); the association was not statistically significant among women in Asian countries (OR = 0.89, 95% CI = 0.71 to 1.12). Among the 10 studies that stratified by menopausal status the inverse association between soy exposure and breast cancer risk was somewhat stronger in premenopausal women (OR = 0.70, 95% CI = 0.58 to 0.85) than in postmenopausal women (OR = 0.77, 95% CI = 0.60 to 0.98); however, eight studies did not provide menopause-specific results, six of which did not support an association. When exposure was analyzed by soy protein intake in grams per day, a statistically significant association with breast cancer risk was seen only among premenopausal women (OR = 0.94, 95% CI = 0.92 to 0.97).
Soy intake may be associated with a small reduction in breast cancer risk. However, this result should be interpreted with caution due to potential exposure misclassification, confounding, and lack of a dose response. Given these caveats and results of some experimental studies that suggest adverse effects from soy constituents, recommendations for high-dose isoflavone supplementation to prevent breast cancer or prevent its recurrence are premature.
Polyphenols are abundant micronutrients in our diet, and evidence for their role in the prevention of degenerative diseases is emerging. Bioavailability differs greatly from one polyphenol to another, so that the most abundant polyphenols in our diet are not necessarily those leading to the highest concentrations of active metabolites in target tissues. Mean values for the maximal plasma concentration, the time to reach the maximal plasma concentration, the area under the plasma concentration-time curve, the elimination half-life, and the relative urinary excretion were calculated for 18 major polyphenols. We used data from 97 studies that investigated the kinetics and extent of polyphenol absorption among adults, after ingestion of a single dose of polyphenol provided as pure compound, plant extract, or whole food/beverage. The metabolites present in blood, resulting from digestive and hepatic activity, usually differ from the native compounds. The nature of the known metabolites is described when data are available. The plasma concentrations of total metabolites ranged from 0 to 4 mumol/L with an intake of 50 mg aglycone equivalents, and the relative urinary excretion ranged from 0.3% to 43% of the ingested dose, depending on the polyphenol. Gallic acid and isoflavones are the most well-absorbed polyphenols, followed by catechins, flavanones, and quercetin glucosides, but with different kinetics. The least well-absorbed polyphenols are the proanthocyanidins, the galloylated tea catechins, and the anthocyanins. Data are still too limited for assessment of hydroxycinnamic acids and other polyphenols. These data may be useful for the design and interpretation of intervention studies investigating the health effects of polyphenols.
Estimates of the frequency of endometriosis vary widely. Based on the few reliable data, the prevalence of the condition can reasonably be assumed to be around 10%. Although no consistent information is available on the incidence of the disease, temporal trends suggest an increase among women of reproductive age. This could be explained—at least in part—by changing reproductive habits. Numerous epidemiological studies have indicated that nulliparous women and women reporting short and heavy menstrual cycles are at increased risk of developing endometriosis; data on other risk factors are less consistent. These epidemiological findings strongly support the menstrual reflux hypothesis. Additional evidence in favour of this theory includes the demonstration of viable endometrial cells in the menstrual effluent and peritoneal fluid, experimental implantation and growth of endometrium within the peritoneal cavity, observation of some degree of retrograde menstruation in most women undergoing laparoscopy during menses, and an association between obstructed menstrual outflow and endometriosis.
Advances in understanding the epidemiology of endometriosis have lagged behind other diseases because of methodologic problems related to disease definition and control selection. Nevertheless, a better picture of the epidemiology of endometriosis has emerged over the past few decades. Prevalence estimates of the disease in clinic populations vary from about a 4% occurrence of largely asymptomatic endometriosis found in women undergoing tubal ligation to 50% of teenagers with intractable dysmenorrhea. General population incidence during the 1970s in this country has been suggested to be 1.6 per 1000 white females aged 15-49, while a more current study based upon hospital discharges finds endometriosis as a first listed diagnosis in 1.3 per 1000 discharges in women aged 15-44. There is a clinical impression that blacks have lower rates of endometriosis and Orientals have higher rates than whites. A variety of personal risk factors for endometriosis have also been described. Women with endometriosis may be taller and thinner. Menstrual factors reported to increase risk include dysmenorrhea, early menarche, and shorter cycle lengths. There is support for the idea that lifestyle exposures that might raise or lower estrogen levels could affect risk, including a decreased risk associated with smoking and exercise and an increased risk associated with caffeine or alcohol use. These risk factors appear to be compatible with the central importance of retrograde menstruation influenced by outflow obstruction that might affect its amount, immune factors that might affect its ability to be cleared, or hormonal stimuli that might affect its growth. In this model, dysmenorrhea could be either a disease symptom or a manifestation of outflow obstruction. Nulliparity could be either a consequence of disease or a cause since nulliparous women would not have the benefit of cervical dilation associated with labor and delivery. Since there is evidence that family history is a risk factor for disease, a challenge is how to integrate genetic factors into the model. The genetics of endometriosis might be advanced if we could identify an “endometriosis phenotype”. We propose that this may consist of early menarche, short cycles, painful periods, subfertility, and possibly tall stature that could be explained by genetic factors that predispose to poor endowment of germ cells and canalization defects of the cervix. The value of establishing an “endometriosis phenotype” is that, as candidates for genetic markers are identified, particular genotypes can be correlated with these factors even if a formal diagnosis of endometriosis has not been made. Additional well-designed case-control and cohort studies will be necessary to test theories related to pathogenesis, establish the precise relationship between reproductive morbidity and endometriosis, identify specific genetic factors, and establish long-term risks.
The study of phytoestrogens in food sources and their metabolism, effects, and mechanism of action in animals requires very selective and often sensitive analytical techniques. We have applied coulometric array detection, which uses a series of flow-through electrochemical sensors each providing 100% electrolytic efficiency, for measurement of a variety of phytochemicals in complex matrices. Recent work has involved the resolution of coumestrol (COM), daidzein (DE), daidzin (DI), diethylstilbestrol (DES), enterodiol (ED), enterolactone (EL), equol (EQ), estradiol (E2), estriol (E3), estrone (E), genistein (GE), and quercetin (QE). Binary gradient reversed-phase (C18) chromatography was used with a sodium acetate buffer (pH 4.8)-methanol-acetonitrile solvent system. Eight coulometric sensors were set at 260, 320, 380, 440, 500, 560, 620, and 680 mV (vs Pd reference). Compounds were resolved in 30 min via both their oxidation/reduction characteristics and chromatographic behavior. Respective maximal oxidation potentials (mV) were: COM = 380; DE = 500; DI = 620; DES = 440; ED = 620; EL = 620; EQ = 560; E2 = 560; E3 = 560; E1 = 560; GE = 500; and QE = 260 with limits of detection of 5-50 pg. Uterine tissue homogenates (30 mg/ml in Tris-EDTA) and plasma from Sprague-Dawley rats sacrificed 1 hr after sc injection with either vehicle, dimethylsulfoxide, 10 microg DES, or 1.0 mg EQ were analyzed before and after enzymatic hydrolysis with beta-glucuronidase/sulfatase. Urine samples from humans receiving a Boston-area diet with or without soy protein isolate supplements were also analyzed. Ethanol extracts were evaporated and reconstituted in 20% methanol before HPLC analysis. DE, ED, EL, EQ, and GE were determined in urine with less than 5% (R.S.D.) intraassay imprecision and 85%-102% recovery. Levels (ng/ml) of GE (1.8), QE (11.2), and EQ (1.7) were found in control plasma before hydrolysis and GE (293), QE (183), and EQ (22) after hydrolysis. Higher concentrations, corresponding to sc injection, in free and total EQ were found in both tissue and plasma.
The aim of this study was to determine the pharmacokinetics and urinary excretion patterns of the soy isoflavones daidzein and genistein in humans. Six healthy men with a mean age of 37 y and a mean body mass index (in kg/m2) of 24 consumed a soybean flour-based meal on two occasions approximately 6 d apart. Blood samples and total urine were collected at intervals for the measurement of daidzein and genistein with HPLC. Isoflavone concentrations rose slowly and reached maximum values of 3.14 +/- 0.36 micromol/L at 7.42 +/- 0.74 h for daidzein and 4.09 +/- 0.94 micromol/L at 8.42 +/- 0.69 h for genistein. Elimination half-lives were 4.7 +/- 1.1 and 5.7 +/- 1.3 h for daidzein and genistein, respectively. The slow increase in plasma concentrations is consistent with the facilitation of absorption by hydrolysis in the small and large intestines of the glycosidic forms of the isoflavones present in soybean-containing foods to their corresponding aglycones. The rate of urinary excretion of daidzein was greater than that of genistein throughout the postmeal period, with mean recoveries of 62 +/- 6% and 22 +/- 4% (P < 0.001) for daidzein and genistein, respectively. However, the ratio of the areas under the plasma concentration versus time curves for genistein and daidzein was equal to the ratio of the concentrations of the respective isoflavones in the soy meal. It is concluded that the bioavailabilities of daidzein and genistein are similar, not withstanding the difference in urinary excretion.
Phytoestrogens represent a family of plant compounds that have been shown to have both estrogenic and antiestrogenic properties. A variety of these plant compounds and their mammalian metabolic products have been identified in various human body fluids and fall under two main categories: isoflavones and lignans. A wide range of commonly consumed foods contain appreciable amounts of these different phytoestrogens. For example, soy and flax products are particularly good sources of isoflavones and lignans, respectively. Accumulating evidence from molecular and cellular biology experiments, animal studies, and, to a limited extent, human clinical trials suggests that phytoestrogens may potentially confer health benefits related to cardiovascular diseases, cancer, osteoporosis, and menopausal symptoms. These potential health benefits are consistent with the epidemiological evidence that rates of heart disease, various cancers, osteoporotic fractures, and menopausal symptoms are more favorable among populations that consume plant-based diets, particularly among cultures with diets that are traditionally high in soy products. The evidence reviewed here will facilitate the identification of what is known in this area, the gaps that exist, and the future research that holds the most potential and promise.
Isoflavones are present in soybeans and its products in concentrations up to 300 mg/100 g, have estrogenic and antiestrogenic properties, and may be protective against hormone-related cancers. The purpose of this cross-sectional study was to investigate the association between urinary isoflavone excretion and self-reported soy intake. A total of 102 women of Caucasian, Native Hawaiian, Chinese, Japanese, and Filipino ancestry completed a dietary questionnaire for soy products consumed during the last year and during the 24-h period before urine collection. Overnight urine samples were analyzed for coumestrol and the soy isoflavones genistein, daidzein, and glycitein and their main human metabolites by reverse-phase high-pressure liquid chromatography. Soy protein and isoflavone intake (predominantly from tofu) were estimated using published nutritional databases. Wilcoxon's rank-sum test scores and Spearman rank correlation coefficients were computed. Japanese women excreted more daidzein, genistein, and glycitein than did Caucasian women, whereas Caucasian women excreted slightly more coumestrol. Soy intake differed significantly among ethnic groups. Dietary soy protein and isoflavone intakes during the previous 24 h were positively related to urinary isoflavone excretion [rs = 0.61 (P < 0.0001) and 0.62 (P < 0.0001), respectively]. Urinary excretion of isoflavones was also related to annual dietary soy protein and isoflavone intake [rs = 0.32 (P < 0.0012) and 0.31 (P < 0.0016), respectively]. The strong correlation between urinary isoflavone excretion and self-reported soy intake validates the dietary history questionnaire that is now used in a study exploring dietary risk factors for breast cancer.
There is mounting evidence that endometriosis is inherited as a complex trait, like diabetes or asthma. This implies there are environmental factors, such as dioxin, that are interacting with multiple genetic susceptibility loci to produce the phenotype. The Oxford Endometriosis Gene (OXEGENE) study, an international collaborative project, seeks to identify the susceptibility loci using linkage analysis; the aim then is to use positional cloning techniques to identify genes that predispose women to the disease. Analysis of the biochemical function of the gene products will lead to a better understanding of the pathophysiology and aetiology of endometriosis. New therapies may be designed based upon knowledge of the gene function and disease associated genetic markers may be used to identify women at high risk of developing the disease.
To explore the association of the estrogen receptor two-allele (point) polymorphism and multiallele (microsatellite) polymorphism with endometriosis.
Case-control study.
Genetics and Endoscopy Unit, Department of Obstetrics and Gynecology, Ioannina University HOSPITAL, Ioannina, Greece.
Fifty-seven women with surgically and histologically diagnosed endometriosis of stages I-IV.
Diagnostic laparoscopy.
Frequency and distribution of the estrogen receptor gene polymorphisms.
There was a statistically significant difference between the patients and the controls in the frequency of the two-allele Pvu II polymorphism (0.72 vs. 0.49) and in the median repeats of the (TA)n multiallele polymorphism (15 vs. 20 repeats). In both groups, linkage was found between the fewer (TA)n repeats (range, 12-19) and the positive Pvu II polymorphism.
The variability of the estrogen receptor gene likely contributes to the pathogenesis of endometriosis.
Endometriosis, adenomyosis and leiomyomata develop in women of reproductive age and regress after menopause or ovariectomy,
suggesting that they grow in an oestrogen-dependent fashion. We investigated whether polymorphism in the oestrogen receptor-alpha
(ERα) gene is related to oestrogen-dependent benign uterine disease. A total of 203 women with regular menstrual cycles underwent
laparotomy or laparoscopy and were diagnosed histologically with endometriosis, adenomyosis and/or leiomyomata. Patients with
cervical carcinoma in situ, tubal occlusion or adhesion but no other gynaecological disease were considered to be disease-free. A total of 179 women
undergoing annual health examination were grouped as reference population. The distribution of PvuII genotypes (PP, Pp, and pp) of the ERα gene was different between each pair of the four groups of endometriosis, adenomyosis/leiomyomata, disease-free, and reference
population (P = 0.022–0.0005), except between the former two groups. The PP genotype was less frequent in the groups of endometriosis (P = 0.0002) and adenomyosis/leiomyomata (P = 0.002) as compared to that in the disease-free group. In the endometriosis group, there was no difference in the distribution
of PvuII genotypes due to complicating diseases (adenomyosis and/or leiomyomata) or severity of the clinical stages. These results
suggest that the PvuII polymorphism of the ERα gene is associated with the risk for endometriosis, adenomyosis, and leiomyomata.
Estrogen plays a significant role in human ovulation. It acts as an important positive regulator of the preovulatory gonadotropin surge necessary to initiate the cascade of events leading to ovulation. The steroid hormone exerts its physiological responses through the estrogen receptor (ER), of which two subtypes, ERalpha and ERbeta, are known. ERbeta messenger ribonucleic acid occurs maximally in the ovaries and granulosa cells; thus, ERbeta may be essential for normal ovulation. In a recent gene knockout study, it has been shown that ERbeta gene null female mice develop normal reproductive tract and ovaries during pre- and neonatal periods, but have an abnormal frequency of spontaneous ovulation in adulthood. In the present case-control study, we explored the association of two recently described ERbeta gene polymorphisms, RSAI and ALUI, with ovulatory dysfunctions. The respective frequencies of these polymorphisms were significantly higher in patients than in controls (P= 0.009 and P= 0.059). The polymorphisms were significantly associated with ovulatory dysfunctions, especially in patients homozygous for the polymorphisms (P = 0.016 and P = 0.038, respectively). The compound homozygosity of the polymorphisms was seen only in patients (n = 5) and not controls (P = 0.009). The serum levels of LH, FSH, and progesterone were lower in the homozygous and compound homozygous than in the respective nonpolymorphic patients. All five compound homozygous patients had ovulatory dysfunctions with no etiological pathology. Our results suggest that ERbeta gene RSA:I and ALU:I polymorphisms may be associated with ovulatory defects in some patients, especially those with unknown causes.
The recent discovery of a new isoform of estrogen receptor (ER) beta has prompted the reexamination of estrogen action on target organs. Here, we describe the endometrial expression of human ERbeta and compare its distribution with that of ERalpha in the endometrial functional zone. Using immunocytochemistry with well characterized polyclonal antibodies against ERbeta, we have detected specific ERbeta expression in all endometrial compartments (glandular, stromal, and vascular); the specificity of the immunostaining is confirmed by lack of staining of the uterine sections with anti-ERbeta antibodies previously incubated with peptide preparation. The highest levels of ERbeta expression are observed in epithelial cells during the periovulatory period (days 14 and 15), as well as in stromal cells and cells of the vascular wall in the late-secretory phase; both smooth muscle cells and endothelial cells express ERbeta, as deduced from immunocytochemistry and RT-PCR analysis. ERbeta staining is usually low compared with that of ERalpha, except at days 24-26. The presence of ERbeta in decidualized stromal cells is deduced from immunocytochemistry using antismooth alpha-actin and anti-ERbeta antibodies or from RT-PCR analysis of ERbeta and insulin-like growth factor-BP transcripts in the same cells; the presence of ERbeta-positive stromal cells located close to vascular smooth muscle cells during this period suggests some specific role of this receptor during decidualization. ERalpha is also present in the cells of the endometrial vascular wall, in addition to the nuclei of glandular epithelial and stromal cells. Vascular ERalpha expression is highest during the periovulatory period, suggesting a regulation by estradiol, and a role in vascular function. Moreover, different variations of ERbeta and ERalpha in arterioles might have implications for the modulation of vascular function, possibly of vascular tone, during the menstrual cycle. Finally, these data suggest that ERbeta may have important roles in endometrial function, in addition to the well known role of ERalpha in endometrial proliferation and differentiation.
Estrogens and estrogen-like substances are widely distributed in animals and plants, and it is now clear that estrogens have both nuclear and nonnuclear actions. This review article summarizes the production, metabolism, and actions of estrogens, with particular attention to the nuclear actions of estrogens and the mechanisms that underlie the different estrogen-agonist and estrogen-antagonist actions of selective estrogen-receptor–modulating drugs.
Phytoestrogens are polyphenol compounds of plant origin that exhibit a structural similarity to the mammalian steroid hormone 17beta-oestradiol. In Asian nations the staple consumption of phyto-oestrogen-rich foodstuffs correlates with a reduced incidence of breast cancer. Human dietary intervention trials have noted a direct relationship between phyto-oestrogen ingestion and a favourable hormonal profile associated with decreased breast cancer risk. However, these studies failed to ascertain the precise effect of dietary phyto-oestrogens on the proliferation of mammary tissue. Epidemiological and rodent studies crucially suggest that breast cancer chemoprevention by dietary phyto-oestrogen compounds is dependent on ingestion before puberty, when the mammary gland is relatively immature. Phyto-oestrogen supplements are commercially marketed for use by postmenopausal women as natural and safe alternatives to hormone replacement therapy. Of current concern is the effect of phyto-oestrogen compounds on the growth of pre-existing breast tumours. Data are contradictory, with cell culture studies reporting both the oestrogenic stimulation of oestrogen receptor-positive breast cancer cell lines and the antagonism of tamoxifen activity at physiological phyto-oestrogen concentrations. Conversely, phyto-oestrogen ingestion by rodents is associated with the development of less aggressive breast tumours with reduced metastatic potential. Despite the present ambiguity, current data do suggest a potential benefit from use of phyto-oestrogens in breast cancer chemoprevention and therapy. These aspects are discussed.
Estimates of the frequency of endometriosis vary widely. Based on the few reliable data, the prevalence of the condition can reasonably be assumed to be around 10%. Although no consistent information is available on the incidence of the disease, temporal trends suggest an increase among women of reproductive age. This could be explained-at least in part-by changing reproductive habits. Numerous epidemiological studies have indicated that nulliparous women and women reporting short and heavy menstrual cycles are at increased risk of developing endometriosis; data on other risk factors are less consistent. These epidemiological findings strongly support the menstrual reflux hypothesis. Additional evidence in favour of this theory includes the demonstration of viable endometrial cells in the menstrual effluent and peritoneal fluid, experimental implantation and growth of endometrium within the peritoneal cavity, observation of some degree of retrograde menstruation in most women undergoing laparoscopy during menses, and an association between obstructed menstrual outflow and endometriosis.
Subjects of this study consisted of 333 women (aged 45-75 years) drawn from a large United Kingdom prospective study of diet and cancer, the European Prospective Investigation of Cancer and Nutrition-Norfolk study. Using newly developed gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry methods incorporating triply (13)C-labeled standards, seven phytoestrogens (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) were measured in 114 spot urines and 97 available serum samples from women who later developed breast cancer. Results were compared with those from 219 urines and 187 serum samples from healthy controls matched by age and date of recruitment. Dietary levels were low, but even so, mean serum levels of phytoestrogens were up to 600 times greater than postmenopausal estradiol levels. Phytoestrogen concentrations in spot urine (adjusted for urinary creatinine) correlated strongly with that in serum, with Pearson correlation coefficients > 0.8. There were significant relationships (P < 0.02) between both urinary and serum concentrations of isoflavones across increasing tertiles of dietary intakes. Urinary enterodiol and enterolactone and serum enterolactone were significantly correlated with dietary fiber intake (r = 0.13-0.29). Exposure to all isoflavones was associated with increased breast cancer risk, significantly so for equol and daidzein. For a doubling of levels, odds ratios increased by 20-45% [log(2) odds ratio = 1.34 (1.06-1.70; P = 0.013) for urine equol, 1.46 (1.05-2.02; P = 0.024) for serum equol, and 1.22 (1.01-1.48; P = 0.044) for serum daidzein]. These estimates of risk are similar to those established for estrogens and androgens in postmenopausal breast cancer but need confirmation in larger studies.
To determine whether polymorphisms in the estrogen receptor (ER) alpha and beta genes are associated with endometriosis in a Japanese population.
Association study.
University hospital.
Japanese women diagnosed with endometriosis by laparotomy or laparoscopy.
Determination of polymorphisms in the ERalpha and ERbeta genes was performed by polymerase chain reaction restriction fragment-length polymorphism analysis in 132 affected women and 182 controls.
Frequency and distribution of AluI and RsaI polymorphisms in ERbeta gene and of PvuII and XbaI polymorphisms in ERalpha gene.
No significant differences in the frequency of either AluI and RsaI polymorphisms in the ERbeta gene or of XbaI and PvuII polymorphisms in the ERalpha gene were found between endometriosis patients and controls. However, a positive association was noted between the AluI polymorphism in the ERbeta gene and stage IV endometriosis patients in the population studied.
The AluI polymorphism in the ERbeta gene is associated with an increased risk of stage IV endometriosis in a Japanese population.