Thereisgrowinginterestinthepossiblehealththreatposedbyendocrine-disruptingchemicals (EDCs), which are substances in our environment, food, and consumer products that interfere with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic control or reproduction. In this first Scientific Statement of The Endocrine Society, we present the evidence that endocrine disruptors have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology. Results from animal models, human clinical observations, and epidemiological studies converge to implicate EDCs as a significant concern to public health. The mechanisms of EDCs involve divergent pathways including (but not limited to) estrogenic, antiandrogenic, thyroid, peroxisome proliferator-activated receptor , retinoid, and actions through other nuclear receptors; steroidogenic enzymes; neurotransmitter receptors and systems; and many other pathways that are highly conserved in wildlife and humans, and which can be modeled in laboratory in vitro and in vivo models. Furthermore, EDCs represent a broad class of molecules such as organochlorinated pesticides and industrial chemicals, plastics and plasticizers, fuels, and many other chemicals that are present in the environment or are in widespread use. We make a number of recommendations to increase understanding of effects of EDCs, including enhancing increased basic and clinical research, invoking the precautionary principle, and advocating involvement of individual and scientific society stakeholders in communicating and implementing changes in public policy and awareness. (Endocrine Reviews 30: 293–342, 2009)

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Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement

Polyphenols and disease risk in epidemiologic studies

The clinical implications of endothelial dysfunction.

A 30-year-old woman presents with a history of no menses since she stopped taking oral contraceptives 6 months ago in order to conceive. She had undergone puberty that was normal in both timing and development, with menarche at 12 years of age. At 18 years of age, she started taking oral contraceptives for irregular menses. She reports stress at work. Her weight is 59 kg, and her height 1.66 m; her body-mass index (the weight in kilograms divided by the square of the height in meters) is 21.3. There is no galactorrhea, hirsutism, or acne. The pelvic examination is normal, a pregnancy test is negative, the prolactin level is normal, and the follicle-stimulating hormone (FSH) level is in the menopausal range. How should she be evaluated and treated?

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Primary Ovarian Insufficiency

study question: What is the optimal management of women with premature ovarian insufficiency (POI) based on the best available
evidence in the literature?
summary answer: The guideline development group (GDG) formulated 99 recommendations answering 31 key questions on the
diagnosis and treatment of women with POI.
what is known already: NA.
study design, size, duration: This guideline was produced by a multidisciplinary group of experts in the field using the methodology
of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included
papers up to September 2014 and consensus within the guideline group on all recommendations. The GDG included a patient representative
to ensure input from women with POI. After finalization of the draft, the European Society for Human Reproduction and Embryology
(ESHRE) members and professional organizations were asked to review the guideline.
participants/materials, setting, methods: NA.
main results and the role of chance: The guideline provides 17 recommendations on diagnosis and assessment of POI and 46
recommendations on the different sequelae of POI and their consequences for monitoring and treatment. Furthermore, 24 recommendations
were formulated on hormone replacement therapy in women with POI, and two on alternative and complementary treatment. A chapter on
puberty induction resulted in five recommendations.
limitations, reasons for caution: The main limitation of the guideline is that, due to the lack of data, many of the recommendations
are based on expert opinion or indirect evidence from studies on post-menopausal women or women with Turner Syndrome.
wider implications of the findings: Despite the limitations, the guideline group is confident that this document will be able to
guide health care professionals in providing the best practice for managing women with POI given current evidence. Furthermore, the guideline
grouphas formulated research recommendations on the gaps in knowledge identified in the literature searches, in an attempt to stimulate research
on the key issues in POI.

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ESHRE Guideline: management of women with premature ovarian insufficiency

Many plants that are consumed contain phytoestrogens. Only a few published studies have examined the dietary intake of phytoestrogens in the general Western population. The potentially positive health effects of phytoestrogens might be of relevance to postmenopausal women. The aim of the present study was to estimate the intake of dietary isoflavones, coumestans and lignans by healthy Western postmenopausal women. For this purpose, we studied 964 postmenopausal, Caucasian women who participated in the Framingham Offspring Study and completed the Willett food-frequency questionnaire (FFQ). By searching the medical and agricultural literature and contacting experts, we identified food sources of phytoestrogens. The concentrations of the different isoflavones, coumestrol and lignans in each food in the FFQ were scored in seven categories and multiplied by the serving size of the food and the frequency of its consumption. The estimated daily median intake of the isoflavone daidzein was 39 microg (24-57 microg); of genistein, 70 microg (28-120 microg); of formononetin, 31 microg (13-44 microg); and of biochanin A, 6 microg (2-11 microg). Median total intake of isoflavones was 154 microg (99-235 microg). The main sources of isoflavones were beans and peas. The estimated daily intake of coumestans was 0.6 microg (0.2-1.7 microg), with broccoli as the main source. The estimated daily median intake of matairesinol was 19 microg (12-28 microg) and of secoisolariciresinol 560 microg (399-778 microg). The median total intake of lignans was 578 microg (416-796 microg). The main source of the lignans was fruits. The daily dietary intake of phytoestrogens in healthy postmenopausal Caucasian women in the United States is <1 mg.

Intake of Dietary Phytoestrogens Is Low in Postmenopausal Women in the United States: The Framingham Study

Hypertension, central obesity and dyslipidemia are associated with high cardiovascular risk. Estrogen therapy in women has beneficial effects on some of these metabolic cardiovascular risk factors. It is not known whether dietary estrogens have similar effects, especially in Western populations. We studied the association between dietary phytoestrogen intake and metabolic cardiovascular risk factors in postmenopausal women. For this purpose, 939 postmenopausal women participating in the Framingham Offspring Study were included in this cross-sectional study. Mean blood pressure, waist-hip ratio (WHR) and lipoprotein levels were determined in quartile categories of dietary phytoestrogen (isoflavones and lignans) intake, determined by a food-frequency questionnaire. In addition, a metabolic syndrome score was defined according to WHO criteria (range 0-6). The WHR was lower in women in the highest quartile of intake of lignans compared with the lowest [-0.017; 95% confidence interval (CI) -0.030 to -0.0016]. In the highest quartile of intake of isoflavones, plasma triglyceride levels were 0.16 mmol/L lower (95% CI, -0.30 to -0.02) compared with the lowest quartile of isoflavones; for lignan intake, this difference was 0.23 mmol/L (95% CI, -0.37 to -0.09). In the highest quartile of isoflavone intake, the mean cardiovascular risk factor metabolic score was 0.43 points lower (95% CI, -0.70 to -0.16) than the lowest quartile. The difference in this score between the extreme quartiles of intake of lignans was -0.55 points (95% CI, -0.82 to -0.28). In conclusion, high intake of phytoestrogens in postmenopausal women appears to be associated with a favorable metabolic cardiovascular risk profile.

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Dietary Intake of Phytoestrogens Is Associated with a Favorable Metabolic Cardiovascular Risk Profile in Postmenopausal U.S. Women: The Framingham Study

Higher consumption of phytoestrogens might be protective against certain chronic diseases Accurate quantification of habitual phytoestrogen intake is important for assessing associations between phytoestrogens and risk for certain diseases The aim of this study was to estimate dietary intake of phytoestrogens in Dutch middle-aged and elderly women and to describe their main sources Women were recruited between 1993 and 1997 and aged 50-69 y at enrollment (Prospect-EPIC; n = 17,357) A detailed food frequency questionnaire referring to the preceding year was filled in at recruitment A literature search was conducted to obtain data regarding content of the isoflavones daidzein, genistein, formononetin, biochanin A, the coumestan coumesterol and the lignans matairesinol and secoisolariciresinol in relevant food items Concentrations of each phytoestrogen in each food item were subsequently grouped by seven categories; group scores were multiplied by daily intakes of food items and then summed across food items to produce for each participant a total daily intake score for each phytoestrogen Approximately 75% of participants were postmenopausal at recruitment The mean age was 57 y Geometric means of daily intake of daidzein, genistein, formononetin, biochanin A, coumesterol, matairesinol and secoisolariciresinol were 015, 016, 008, 0001, <0001, 007 and 093 mg, respectively The main sources for isoflavones were peas and beans, nuts, grain products, coffee, tea and soy products The main sources for coumestans were peas, beans and other vegetables The main sources of lignans were grain products, fruit and alcoholic beverages (red and white wines) We conclude that intake levels of phytoestrogen in our study population are low; however, they are comparable with intake levels previously reported for other Western cohorts In this population, phytoestrogen intake consisted largely of lignans

Intake of Dietary Phytoestrogens by Dutch Women

In this study, the authors investigated whether combined information on reproductive factors has additive value to the single reproductive factor age at menopause for assessing endogenous estrogen exposure and cardiovascular mortality risk in postmenopausal women. They conducted a population-based cohort study that included 9,450 postmenopausal women from Nijmegen, the Netherlands, who were aged 35--65 years at enrollment in 1975, with a median follow-up of 20.5 years. A Cox proportional hazards model and Receiver Operating Curves were used to analyze the data. Women aged 52 years or more at menopause had an 18% reduction in cardiovascular mortality (hazard ratio = 0.82, 95% confidence interval (CI): 0.69, 0.98) compared with those aged 44 years or less. Women with more than 18 years of exposure to endogenous estrogen had a statistically significant 20% reduction in cardiovascular mortality (hazard ratio = 0.80, 95 percent CI: 0.67, 0.96) compared with those who had 13 years of exposure or less. The area under the curve of the Receiver Operating Curves for the two models was identical (area under the curve = 0.67, 95 percent CI: 0.66, 0.68). This study shows that age at menopause is related to cardiovascular disease mortality and that a newly developed composite measure of endogenous estrogen exposure does not add to the predictive value of age at menopause for cardiovascular mortality.

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Miriam J.J. de Kleijn

Papers

Intake of Dietary Phytoestrogens Is Low in Postmenopausal Women in the United States: The Framingham Study

Dietary Intake of Phytoestrogens Is Associated with a Favorable Metabolic Cardiovascular Risk Profile in Postmenopausal U.S. Women: The Framingham Study

Intake of Dietary Phytoestrogens by Dutch Women

Endogenous Estrogen Exposure and Cardiovascular Mortality Risk in Postmenopausal Women

Reproductive history and cardiovascular disease risk in postmenopausal women: A review of the literature