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

Human exposure to bisphenol A (BPA).

All scientific investigations begin with distinct objectives: first is the hypothesis upon which studies are undertaken to disprove, and second is the overall aim of obtaining further information, from which future and more precise hypotheses may be drawn Studies focusing on the generation and use of gene-targeted animal models also apply these goals and may be loosely categorized into sequential phases that become apparent as the use of the model progresses Initial studies of knockout models often focus on the plausibility of the model based on prior knowledge and whether the generation of an animal lacking the particular gene will prove lethal or not Upon the successful generation of a knockout, confirmatory studies are undertaken to corroborate previously established hypotheses of the function of the disrupted gene product As these studies continue, observations of unpredicted phenotypes or, more likely, the lack of a phenotype that was expected based on models put forth from past investigations are noted Often the surprising phenotype is due to the loss of a gene product that is downstream from the functions of the disrupted gene, whereas the lack of an expected phenotype may be due to compensatory roles filled by alternate mechanisms As the descriptive studies of the knockout continue, use of the model is often shifted to the role as a unique research reagent, to be used in studies that 1) were not previously possible in a wild-type model; 2) aimed at finding related proteins or pathways whose existence or functions were previously masked; or 3) the subsequent effects of the gene disruption on related physiological and biochemical systems The alpha ERKO mice continue to satisfy the confirmatory role of a knockout quite well As summarized in Table 4, the phenotypes observed in the alpha ERKO due to estrogen insensitivity have definitively illustrated several roles that were previously believed to be dependent on functional ER alpha, including 1) the proliferative and differentiative actions critical to the function of the adult female reproductive tract and mammary gland; 2) as an obligatory component in growth factor signaling in the uterus and mammary gland; 3) as the principal steroid involved in negative regulation of gonadotropin gene transcription and LH levels in the hypothalamic-pituitary axis; 4) as a positive regulator of PR expression in several tissues; 5) in the positive regulation of PRL synthesis and secretion from the pituitary; 6) as a promotional factor in oncogene-induced mammary neoplasia; and 7) as a crucial component in the differentiation and activation of several behaviors in both the female and male The list of unpredictable phenotypes in the alpha ERKO must begin with the observation that generation of an animal lacking a functional ER alpha gene was successful and produced animals of both sexes that exhibit a life span comparable to wild-type The successful generation of beta ERKO mice suggests that this receptor is also not essential to survival and was most likely not a compensatory factor in the survival of the alpha ERKO In support of this is our recent successful generation of double knockout, or alpha beta ERKO mice of both sexes The precise defects in certain components of male reproduction, including the production of abnormal sperm and the loss of intromission and ejaculatory responses that were observed in the alpha ERKO, were quite surprising In turn, certain estrogen pathways in the alpha ERKO female appear intact or unaffected, such as the ability of the uterus to successfully exhibit a progesterone-induced decidualization response, and the possible maintenance of an LH surge system in the hypothalamus [ABSTRACT TRUNCATED]

Estrogen receptor null mice: what have we learned and where will they lead us?

Endometriosis

https://www.healthandenvironment.org/docs/RochesterBPAstudy2013.pdf

Bisphenol A and human health: a review of the literature.

BACKGROUND: To analyse risk factors that influence the recurrence of endometrioma after laparoscopic excision. METHODS: A total of 224 patients who had a minimum of 2 years of post-operative follow-up after laparoscopic ovarian endometrioma excision were studied retrospectively. Recurrence was defined as the presence of endometrioma more than 2 cm in size, detected by ultrasonography within 2 years of surgery. Fourteen variables (age, presence of infertility, pain, uterine myoma, adenomyosis, previous medical treatment of endometriosis, previous surgery for ovarian endometriosis, single or multiple cysts, the size of the largest cyst at laparoscopy, unilateral or bilateral involvement, co-existence of deep endometriosis, revised American Society for Reproductive Medicine (ASRM) score, post-operative medical treatment and post-operative pregnancy) were evaluated to assess their independent effects on the recurrence using logistic regression analysis. RESULTS: The overall rate of recurrence was 30.4% (68/224). Significant factors that were independently associated with higher recurrence were previous medical treatment of endometriosis [odds ratio (OR) = 2.324, 95% confidence interval (95% CI) = 1.232–4.383, P = 0.0092) and larger diameter of the largest cyst (OR = 1.182, 95% CI = 1.004–1.391, P = 0.0442). Post-operative pregnancy was associated with lower recurrence (OR = 0.292, 95% CI = 0.028–0.317, P = 0.0181). CONCLUSIONS: Previous medical treatment of endometriosis or large cyst size was a significant factor that was associated with higher recurrence of the disease. Post-operative pregnancy is a favourable prognostic factor.

Recurrence of ovarian endometrioma after laparoscopic excision.

Adiponectin, a pleiotropic cytokine, exerts its effects via the specific receptors AdipoR1 and AdipoR2. Whereas circulating adiponectin concentrations decrease in women with endometriosis and endometrial cancer, possible effects of adiponectin and the presence of the receptors in the endometrium have not been determined. In this study, we examined the expression of adiponectin receptors AdipoR1 and AdipoR2 in the human endometrium and assessed effects of adiponectin in endometrial cells. Expression of AdipoR1 and AdipoR2 in endometrial tissues was evaluated by real-time quantitative PCR, in situ hybridization, and Western blotting. The effects of adiponectin on phosphorylation of AMP-activated protein kinase, a regulator of energy homeostasis, in cultured endometrial stromal cells (ESCs) and epithelial cells (EECs) were studied by Western blotting. The effects of adiponectin on IL-1beta-induced secretion of IL-6, IL-8, and monocyte chemoattractant protein 1 from cultured ESCs were determined using specific ELISAs. The expression of AdipoR1 and AdipoR2 was detected in the endometrium. The expression of both genes was increased in the midluteal phase, the period of embryo implantation. In situ hybridization revealed that both AdipoR1 and AdipoR2 appeared to be equally expressed in the epithelial cells and in the stromal cells. Adiponectin increased phosphorylation of AMP-activated protein kinase in ESCs and EECs. Adiponectin decreased IL-1beta-induced secretion of IL-6, IL-8, and monocyte chemoattractant protein 1 from ESCs. These findings suggest that adiponectin exerts energy-homeostatic and antiinflammatory effects in the endometrium, and these effects might be relevant to pathological and physiological endometrium-related events such as implantation and endometriosis.

Expression of adiponectin receptors and its possible implication in the human endometrium.

Endometriosis is a disease characterized by the presence of endometriotic tissue outside the uterine cavity. Although its pathogenesis remains to be elucidated, immune status is suggested to play an important role in the initiation and the progression of the disease. In particular, immune cells in lymphoid lineage that comprised T and B lymphocytes and natural killer cells play essential roles in determining either accept or reject survival, implantation, and proliferation of endometrial and endometriotic cells. Numerous studies have shown aberrant functions of these immune cells in women with endometriosis. The abnormalities include reduced activity of cytotoxic T cells and NK cells, cytokine secretion by helper T cells, and autoantibody production by B lymphocytes. These alterations are suggested to be induced by various manners and promote the disease. Understanding of these immune aspects in endometriosis is thus expected to benefit the treatment of the disease.

Lymphocytes in endometriosis.

Exquisitely regulated cytokine balance during early pregnancy is thought to be necessary for promoting survival of the fetal allograft. Our previous studies have demonstrated that membrane-bound human leukocyte antigen (mHLA-G) expressed on trophoblasts is one of the key factors in regulating cytokine balance by shifting the Th1/Th2 balance toward Th2 polarization, a favourable milieu for the maintenance of pregnancy. Given that trophoblasts secrete soluble HLA-G (sHLA-G), we examined its biological roles in comparison with mHLA-G. We cultured peripheral blood mononuclear cells (PBMC) with either the HLA-A and -B-deficient B lymphoblast cell line (721.221 cells) or the same cell line transfected with mHLA-G (721.221-G1 cells), in the presence or absence of recombinant sHLA-G. Cytokine concentrations in the culture media were determined by enzyme-linked immunosorbent assay. In contrast to mHLA-G protein, sHLA-G stimulated the release of tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, whereas it reduced the release of interleukin (IL)-3, regardless of the presence of the presence of a stimulatory effect of the mHLA-G-expressing cells. Although mHLA-G reduced the release of IL-4, sHLA-G did not have any effect. Conversely, sHLA-G stimulated the release of IL-10 whereas mHLA-G was without effect. These results suggest that sHLA-G regulates the release of cytokines from PBMC chiefly by counterbalancing mHLA-G, and thereby may play a role in maintaining pregnancy.

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Soluble HLA-G influences the release of cytokines from allogeneic peripheral blood mononuclear cells in culture

Aim: To investigate the safety and efficacy of 52 weeks of dienogest treatment in patients with endometriosis.

Methods:  One hundred and thirty-five patients with endometriosis received 2 mg of dienogest orally each day for 52 weeks. Adverse drug reactions and bone density were evaluated. Global improvement was assessed based on the changes in severity categories of five subjective symptoms during non-menstruation (lower abdominal pain, lumbago, dyschezia, dyspareunia, and pain on vaginal examination) and two objective findings (induration involving the pouch of Douglas and limited uterine mobility).

Results:  The most common adverse drug reactions included metrorrhagia (71.9%), headaches (18.5%), and constipation (10.4%). No clinically significant changes were noted in the incidence or severity of reactions associated with the course of the treatment period (52 weeks). Changes from the baseline bone mineral density of the lumbar spine measured by dual-energy X-ray absorptiometry were −1.6 ± 2.4% and −1.7 ± 2.2% (mean ± standard deviation) at 24 and 52 weeks, respectively, which were statistically significant decreases; however, there was no cumulative decrease. The proportions of patients assessed as marked or moderate improvement in terms of global improvement were 72.5% (95/131 cases) at 24 weeks and 90.6% (106/117 cases) at 52 weeks.

Conclusion:  The long-term effect of dienogest on bone mineral density was slight, whereas the efficacy increased cumulatively.

Yuji Taketani

Papers

Recurrence of ovarian endometrioma after laparoscopic excision.

Expression of adiponectin receptors and its possible implication in the human endometrium.

Lymphocytes in endometriosis.

Soluble HLA-G influences the release of cytokines from allogeneic peripheral blood mononuclear cells in culture

Long-term use of dienogest for the treatment of endometriosis