Cellular and molecular basis for endometriosis-associated infertility

Endometriosis is a gynecological disease characterized by the presence of endometrial glandular epithelial and stromal cells growing in the extra-uterine environment. The disease afflicts 10%–15% of menstruating women causing debilitating pain and infertility. Endometriosis appears to affect every part of a woman’s reproductive system including ovarian function, oocyte quality, embryo development and implantation, uterine function and the endocrine system choreographing the reproductive process and results in infertility or spontaneous pregnancy loss. Current treatments are laden with menopausal-like side effects and many cause cessation or chemical alteration of the reproductive cycle, neither of which is conducive to achieving a pregnancy. However, despite the prevalence, physical and psychological tolls and health care costs, a cure for endometriosis has not yet been found. We hypothesize that endometriosis causes infertility via multifaceted mechanisms that are intricately interwoven thereby contributing to our lack of understanding of this disease process. Identifying and understanding the cellular and molecular mechanisms responsible for endometriosis-associated infertility might help unravel the confounding multiplicities of infertility and provide insights into novel therapeutic approaches and potentially curative treatments for endometriosis

Effects of prenatal exposure to xenobiotic estrogen and the development of endometriosis in adulthood

Abstract only availableEndometriosis is an estrogen-dependent disease that affects millions of women worldwide, causing pain and infertility. While it is known that retrograde menstruation places endometrial tissue in the peritoneal cavity, it is unclear why it invades and proliferates in women with endometriosis. Studies have shown that other hormone-dependent diseases have a fetal basis (e.g. breast cancer), suggesting that the presence of different hormones before birth may alter the incidence of endometriosis in adulthood. For example, women whose mothers took the synthetic estrogen diethylstilbestrol (DES) during pregnancy had an eighty percent increased incidence of endometriosis. Thus, our hypothesis is that prenatal exposure to xenobiotic estrogen will increase the severity of endometriosis in adulthood in a mouse model of surgically-induced endometriosis. To test this hypothesis, mice were time mated and dosed with vehicle control, 100 ng/kg DES or 10,000 ng/kg DES from days 11-17 of gestation. Surgical induction of endometriosis was performed in adulthood by autotransplantation of one uterine horm. The horn was removed, opened, divided into three pieces, and sutured to the arterial cascade of the intestinal mesentery. The implants became vascularized and formed endometriotic lesions. The mice were then collected at 2 or 4 weeks post-surgery, and the following endpoints were measured: 1) uterine weight; 2) implant size; and 3) implant weight. Additionally, implants were set aside for further analysis of 1) histology; 2) estrogen receptor indicator reporter gene activity; and 3) endometriosis-related gene expression. At the conclusion of this ongoing study, we expect to show whether there is an estrogen-mediated fetal component to endometriosis.Life Sciences Undergraduate Research Opportunity Progra

Neonatal exposure to xenobiotic estrogen alters the adult immune response and exacerbates endometriosis in mice [abstract]

Faculty Mentor: Dr. Susan C. Nagel, Obstetrics/Gynecology, and Women's HealthAbstract only availableEndometriosis is a common medical condition affecting 5-10% of women worldwide, and results in severe cramps, pelvic pain, and infertility. The cause of the disease is still unknown. Endometriosis occurs when endometrial tissue, which escapes into the peritoneal cavity via retrograde menstruation, adheres to other tissues in the cavity and causes irritated, inflamed lesions. Studies have suggested that the risk of developing endometriosis increases in women who have been exposed to xenobiotic (foreign to the body) estrogens during developmental stages of life. Thus, it is our hypothesis that programming of the immune system by xenoestrogens during development could potentially exacerbate endometriosis. This could occur by altering the peritoneal environment and/or the invading endometrial tissue. Therefore, it is our goal to study the effects of neonatal xenoestrogen exposure on the immune system; and ultimately, on the establishment of endometriosis in adulthood. In order to study this response, we dosed two strains of mice (CD1 and C57) with xenobiotic estrogens on postnatal days 2-14. In experiment A, CD1 mice were dosed with vehicle control (corn oil), 20 µg/kg/day, or 200 µg/kg/day bisphenol A. In experiment B, C57 mice were dosed with a vehicle control (corn oil) or 0.1 µg/kg/day diethylstilbestrol. At 8 weeks of age, endometriosis was induced in each strain via both a surgical induction and an injection technique. At 12 weeks, the endometriotic implants were counted and weighed to determine which mice had a greater susceptibility to the condition. Our next objective will be to analyze peritoneal fluid from the treated mice to identify key immune functions (for example, the release of certain cytokines) that may have been programmed by developmental xenoestrogen exposure.Endometriosis is a common medical condition affecting 5-10% of women worldwide, and results in severe cramps, pelvic pain, and infertility.  The cause of the disease is still unknown.  Endometriosis occurs when endometrial tissue, which escapes into the peritoneal cavity via retrograde menstruation, adheres to other tissues in the cavity and causes irritated, inflamed lesions.  Studies have suggested that the risk of developing endometriosis increases in women who have been exposed to xenobiotic (foreign to the body) estrogens during developmental stages of life.  Thus, it is our hypothesis that programming of the immune system by xenoestrogens during development could potentially exacerbate endometriosis.  This could occur by altering the peritoneal environment and/or the invading endometrial tissue.  Therefore, it is our goal to study the effects of neonatal xenoestrogen exposure on the immune system; and ultimately, on the establishment of endometriosis in adulthood.  In order to study this response, we dosed two strains of mice (CD1 and C57) with xenobiotic estrogens on postnatal days 2-14.  In experiment A, CD1 mice were dosed with vehicle control (corn oil), 20 µg/kg/day, or 200 µg/kg/day bisphenol A.  In experiment B, C57 mice were dosed with a vehicle control (corn oil) or 0.1 µg/kg/day diethylstilbestrol.  At 8 weeks of age, endometriosis was induced in each strain via both a surgical induction and an injection technique.  At 12 weeks, the endometriotic implants were counted and weighed to determine which mice had a greater susceptibility to the condition.  Our next objective will be to analyze peritoneal fluid from the treated mice to identify key immune functions (for example, the release of certain cytokines) that may have been programmed by developmental xenoestrogen exposure

Estrogen receptor-alpha (ER-alpha) and defects in uterine receptivity in women

Endometriosis is a disorder that affects 5% of the normal population but is present in up to 40% of women with pelvic pain and/or infertility. Recent evidence suggests that the endometrium of women with endometriosis exhibits progesterone insensitivity. One endometrial protein that fluctuates in response to progesterone is the estrogen receptor-alpha (ER alpha), being down-regulated at the time of peak progesterone secretion during the window of implantation. Here we demonstrate that the biomarker of uterine receptivity, beta 3 integrin subunit, is reduced or absent in some women with endometriosis and that such defects are accompanied by inappropriate over-expression of ER alpha during the mid-secretory phase. Using a well-differentiated endometrial cell line we showed that the beta 3 integrin protein is negatively regulated by estrogen and positively regulated by epidermal growth factor (EGF). By competing against estrogen with various selective estrogen receptor modulators (SERMs) and estrogen receptor agonists and antagonists, inhibition of expression of the beta 3 integrin by estrogen can be mitigated. In conclusion, we hypothesize that certain types of uterine receptivity defects may be caused by the loss of appropriate ER alpha down-regulation in the mid-secretory phase, leading to defects in uterine receptivity. Such changes might be effectively treated by timely administration of the appropriate anti-estrogens to artificially block ER alpha and restore normal patterns of gene expression. Such treatments will require further clinical studies

Neuroendocrine–immune disequilibrium and endometriosis: an interdisciplinary approach

Endometriosis, a chronic disease characterized by endometrial tissue located outside the uterine cavity, affects one fourth of young women and is associated with chronic pelvic pain and infertility. However, an in-depth understanding of the pathophysiology and effective treatment strategies of endometriosis is still largely elusive. Inadequate immune and neuroendocrine responses are significantly involved in the pathophysiology of endometriosis, and key findings are summarized in the present review. We discuss here the role of different immune mechanisms particularly adhesion molecules, protein–glycan interactions, and pro-angiogenic mediators in the development and progression of the disease. Finally, we introduce the concept of endometrial dissemination as result of a neuroendocrine-immune disequilibrium in response to high levels of perceived stress caused by cardinal clinical symptoms of endometriosis

Critical evaluation of key evidence on the human health hazards of exposure to bisphenol A

Despite the fact that more than 5000 safety-related studies have been published on bisphenol A (BPA), there seems to be no resolution of the apparently deadlocked controversy as to whether exposure of the general population to BPA causes adverse effects due to its estrogenicity. Therefore, the Advisory Committee of the German Society of Toxicology reviewed the background and cutting-edge topics of this BPA controversy. The current tolerable daily intake value (TDI) of 0.05 mg/kg body weight [bw]/day, derived by the European Food Safety Authority (EFSA), is mainly based on body weight changes in two- and three-generation studies in mice and rats. Recently, these studies and the derivation of the TDI have been criticized. After having carefully considered all arguments, the Committee had to conclude that the criticism was scientifically not justified; moreover, recently published additional data further support the reliability of the two-and three-generation studies demonstrating a lack of estrogen-dependent effects at and below doses on which the current TDI is based. A frequently discussed topic is whether doses below 5 mg/ kg bw/day may cause adverse health effects in laboratory animals. Meanwhile, it has become clear that positive results from some explorative studies have not been confirmed in subsequent studies with higher numbers of animals or a priori defined hypotheses. Particularly relevant are some recent studies with negative outcomes that addressed effects of BPA on the brain, behavior, and the prostate in rodents for extrapolation to the human situation. The Committee came to the conclusion that rodent data can well be used as a basis for human risk evaluation. Currently published conjectures that rats are insensitive to estrogens compared to humans can be refuted. Data from toxicokinetics studies show that the half-life of BPA in adult human subjects is less than 2 hours and BPA is completely recovered in urine as BPA-conjugates. Tissue deconjugation of BPA-glucuronide and -sulfate may occur. Because of the extremely low quantities, it is only of minor relevance for BPA toxicity. Biomonitoring studies have been used to estimate human BPA exposure and show that the daily intake of BPA is far below the TDI for the general population. Further topics addressed in this article include reasons why some studies on BPA are not reproducible; the relevance of oral versus non-oral exposure routes; the degree to which newborns are at higher systemic BPA exposure; increased BPA exposure by infusions in intensive care units; mechanisms of action other than estrogen receptor activation; and the current regulatory status in Europe, as well as in the USA, Canada, Japan, New Zealand, and Australia. Overall, the Committee concluded that the current TDI for BPA is adequately justified and that the available evidence indicates that BPA exposure represents no noteworthy risk to the health of the human population, including newborns and babies