Background: Endometriosis is a common, chronic gynaecological condition that affects women of reproductive age. Typically associated with symptoms of pelvic pain and infertility, endometriosis significantly impairs quality of life and poses a considerable socioeconomic burden. Surgery is the mainstay in the diagnosis and treatment of endometriosis. In symptomatic women, the condition can only be diagnosed or excluded by a laparoscopy (key-hole surgery). Recurrence of symptoms is common after both medical and surgical treatment and there is no known cure to date. The impact of endometriosis on long term health of women is poorly understood and relatively less well explored. Aim and Objectives: The aim of this thesis was to evaluate the impact of endometriosis on long-term health, with a focus on three key areas: pregnancy, further gynaecological surgery, and subsequent cancer. Methods: This was achieved through a set of cohort studies using Scotland wide data comprising more than 290,000 women with nearly 5 million (4,923,628) person years of follow up from 1981 to 2010. Women with a new surgical diagnosis of endometriosis during this period were compared to those without a diagnosis of endometriosis to evaluate pregnancy outcomes, risk of further gynaecological surgery and future cancer. Results: A diagnosis of endometriosis was associated with an increased risk of early pregnancy loss in the form of miscarriage or ectopic pregnancy. In ongoing pregnancies, those with endometriosis had a higher likelihood of placenta praevia, preterm birth or delivery by caesarean section. Endometriosis was associated with an increased risk of multiple surgical interventions, hysterectomy and/or removal of ovaries. Among cancers, ovarian cancer and malignant melanoma were more common in women with endometriosis compared to those without. Conclusions: The results from this thesis have improved our understanding of endometriosis and can be used to counsel women and inform clinical practice and health services planning.
Brown, Kristina Schelbert
Thesis (PH.D.) -- Syracuse University, 2007. / "Publication number AAT 3266285"
Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.
Oxidative stress mediated by macrophages promotes early angiogenesis and development of endometriosis.January 2013 (has links)
子宮內膜異位症是一種常見的，但複雜的婦科疾病，發病機制不明。它的特點是異位生长的子宮內膜組織。目前已提出多种發病機制的相关理論。现广泛接受經典的Sampson经血逆行的理論，，子宮內膜細胞出现在腹腔中。然而，对于子宮內膜異位症的發展中出现的細胞和分子事件却研究甚少。血管生成在早期子宮內膜異位病灶的生長和发展中起關鍵作用。在缺氧條件下，低灌注的異位子宮內膜組織促进血管形成因子被激活，以建立新的血管來提供氧和營養物質。血管生成的確切病理機制目前仍不清楚。我們推測，氧化應激是子宮內膜異位症的血管生成和發展的關鍵。目前的研究只是表明氧化應激可能促進子宮內膜細胞的生長和粘附，加剧子宮内膜异位症。但是，子宮內膜異位症的氧化應激具体機制仍不清楚。 / 在這項研究中，我們旨在了解氧化應激在子宮內膜異位症的早期血管生成和發展的重要作用。我们利用實驗性子宮內膜異位症小鼠模型用来研究子宮内膜异位症潛在的氧化應激機制。活体成像显示在子宮內膜异位植入后2 -6小時可检测到高活性氧簇（ROS）。同時，植入位处的也可见巨噬細胞浸潤和HIF-1α的表達。緊接著1天之內血管生成細胞因子表達上調，植入后一周后即有新血管形成。這表明巨噬細胞可能在子宮內膜異位症的早期發展中啟動氧化應激和促進血管生成。為了驗證在氧化應激，血管生成，子宮內膜異位癥的發展中巨噬細胞的作用，，採用抗F4/80抗體造成巨噬細胞功能缺失和12/15 LOX基因敲除小鼠模型下的氧化應激失調兩種模型進行研究。 通過干擾和破壞巨噬細胞介導的氧化應激，在子宮內膜植入處ROS產物生成顯著減少。血管生成因子受到抑制且血管發育不全。子宮內膜異位病灶均小於對照組。這表明巨噬細胞是氧化應激中重要介質。他們在促進子宮內膜異位症的早期血管生成和發展中起重要作用。由PX-478，HIF-1α抑製劑介導的治療也在子宮內膜異位症模型中進行更深入地研究。在血管生成途徑中抑制HIF-1α可減小病灶的大小和抑制新血管形成，但不影響巨噬細胞浸潤和子宮內膜植入物中的活性氧的生產。這表明巨噬細胞和ROS作用於子宮內膜異位症的血管形成機制的上游。總之，我們證明了巨噬細胞介導的氧化應激在子宮內膜異位症的早期血管生成和發展中起重要作用。 / Endometriosis is a common but complex gynecological disorder of unknown pathogenesis. It is characterized by ectopic growth of endometrial tissues Many theories have been proposed to the pathogenesis of endometriosis. The classical Sampson’s theory of retrograde menstruation is widely accepted to determine the presence of endometrial cells in the peritoneal cavity. However, little is known on the cellular and molecular events in the development of endometriosis. Angiogenesis plays a key step in the early growth and survival of the endometriotic lesions. Under hypoxic condition, pro-angiogenic factors are activated in poorly perfused ectopic endometrial tissues in order to establish new blood vessel to supply oxygen and nutrients. The precise pathological mechanisms of this angiogenesis pathway are still unclear. We hypothesized that oxidative stress is critical for the angiogenesis and development of endometriosis. Current studies only suggested oxidative stress may increase growth and adhesion of endometrial cells, promoting endometriosis. However, the underlying mechanism of oxidative stress in endometriosis remains unclear. / In this study, we aimed to understand the important role of oxidative stress in early angiogenesis and development of endometriosis. Experimental endometriosis mouse model was used to determine the underlying mechanism of oxidative stress. By in vivo imaging, high reactive oxygen species (ROS) production in the endometrial implants was detected from 2 -6 hours of transplantation. Concurrently, macrophage infiltration and HIF-1α expression in the implants were anticipated. Subsequently, angiogenic cytokines were upregulated within 1 day and new blood vessels were formed at least 1 week after transplantation. This suggested that macrophage may initiate the oxidative stress surge and angiogenesis pathway in early development of endometriosis. To confirm the role of macrophage in the oxidative stress, angiogenesis and development of endometriosis, macrophage depletion by anti-F4/80 antibody and oxidative stress disruption by 12/15 Lox transgenic knockout mice were employed in the experimental endometriosis models. By depleting macrophage and disrupting macrophage to mediate oxidative stress, the ROS production was significantly decreased in the endometrial implants. Angiogenesis factors were suppressed and blood vessels were under-developed. The endometriotic lesions were smaller than control. This showed macrophage is the key mediator of oxidative stress. They played an important role on promoting early angiogenesis and development of endometriosis. Potential therapeutic treatment by PX-478, a HIF-1α inhibitor, was further investigated in the experimental endometriosis model. Inhibition of HIF-1α in the angiogenic pathway decrease the lesion size and new vessel formed, but macrophage infiltration and ROS production in the endometrial implants was not affected. This suggested that macrophage and ROS are the upstream mechanism of the angiogenic pathway in endometriosis. In conclusion, we demonstrated that oxidative stress mediated by macrophages play an important role in the early angiogenesis and development of endometriosis. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Man, Chi Wai. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 66-82). / Abstracts also in Chinese. / Title --- p.i / Acknowledgment --- p.ii / List of publication and conferences --- p.iv / Additional achievements --- p.v / Abbreviations --- p.vi / Table of Contents --- p.viii / List of Figures --- p.xiii / List of Tables --- p.xviii / Abstract --- p.xix / Chinese Abstract --- p.xxi / Chapter Chapter 1. --- Endometriosis / Chapter 1.1. --- Definition of Endometriosis --- p.1 / Chapter 1.1.1. --- Treatment of Endometriosis --- p.2 / Chapter 184.108.40.206. --- Expectant Management --- p.2 / Chapter 220.127.116.11. --- Medical Therapy --- p.2 / Chapter 18.104.22.168.1. --- Analgesics --- p.2 / Chapter 22.214.171.124.2. --- Hormones --- p.3 / Chapter 126.96.36.199. --- Surgery --- p.4 / Chapter 188.8.131.52.1. --- Surgical Treatment --- p.4 / Chapter 184.108.40.206.2. --- Conservative Surgery --- p.4 / Chapter 220.127.116.11.3. --- Definitive Surgery --- p.5 / Chapter 1.1.2. --- Pathogenesis and Pathophysiology of Endometriosis --- p.5 / Chapter 1.2. --- Oxidative stress --- p.7 / Chapter 1.2.1. --- Pro-oxidants --- p.7 / Chapter 1.2.2. --- Antioxidants --- p.8 / Chapter 18.104.22.168. --- Non-enzymatic Antioxidants --- p.9 / Chapter 22.214.171.124. --- Enzymatic Antioxidants --- p.9 / Chapter 126.96.36.199.1. --- Superoxide Dismutase --- p.10 / Chapter 188.8.131.52.2. --- Catalase --- p.10 / Chapter 184.108.40.206.3. --- Peroxiredoxins --- p.11 / Chapter 220.127.116.11.4. --- Glutathione Peroxidases --- p.11 / Chapter 1.2.3. --- Oxidative Stress and Diseases --- p.11 / Chapter 1.2.4. --- Endometriosis and Oxidative Stress --- p.12 / Chapter 1.2.5. --- Inflammatory Response --- p.13 / Chapter 1.2.6. --- Animal Models of Endometriosis --- p.14 / Chapter 1.3. --- Angiogenesis --- p.15 / Chapter 1.3.1. --- Angiogenesis and Diseases --- p.16 / Chapter 1.3.2. --- Animal Models of Angiogenesis --- p.17 / Chapter 1.3.3. --- Endometriosis and Angiogenesis --- p.18 / Chapter 1.3.4. --- Anti-angiogenesis Therapy --- p.19 / Chapter 1.3.5. --- Rodent Models of Endometriosis --- p.21 / Chapter Chapter 2. --- Objective and Hypothesis --- p.23 / Chapter Chapter 3. --- Methodology / Chapter 3.1. --- Mouse Models of Endometriosis --- p.24 / Chapter 3.1.1. --- Animals --- p.24 / Chapter 3.1.2. --- Ovariectomy --- p.24 / Chapter 3.1.3. --- Transplantation of Endometrium --- p.25 / Chapter 18.104.22.168. --- Donor mice --- p.25 / Chapter 22.214.171.124. --- Recipient mice --- p.25 / Chapter 3.1.4. --- Luciferase ⁺/⁺ transgenic mice --- p.26 / Chapter 3.1.5. --- Macrophage Depletion Model --- p.26 / Chapter 3.1.6. --- 12/15 Lox Transgenic Knockout Mice --- p.26 / Chapter 126.96.36.199. --- 12/15 Lox Knockout to Wildtype --- p.27 / Chapter 188.8.131.52. --- Wildtype to 12/15 Lox Knockout --- p.27 / Chapter 3.1.7. --- HIF-1α Inhibition Model --- p.27 / Chapter 3.2. --- Growth and Development of Endometriotic Lesions --- p.28 / Chapter 3.2.1. --- Termination --- p.28 / Chapter 3.2.2. --- Lesion Size --- p.28 / Chapter 3.2.3. --- In Vivo Non-Invasive Imaging --- p.28 / Chapter 184.108.40.206. --- Luciferase Imaging --- p.28 / Chapter 220.127.116.11. --- Oxidative Stress Imaging --- p.29 / Chapter 18.104.22.168. --- Angiogenesis Imaging --- p.30 / Chapter 3.2.4. --- Histological Evaluation --- p.30 / Chapter 3.2.5. --- Immunostaining --- p.30 / Chapter 22.214.171.124. --- Immunohistochemistry on Oxidative Stress Markers --- p.30 / Chapter 126.96.36.199. --- Immunohistochemistry on Macrophages and Neutrophils --- p.31 / Chapter 188.8.131.52. --- Immunofluorescence on New Vessel Formation --- p.32 / Chapter 3.2.6. --- Terminal Deoxynucleotidyltransferase (TdT)-mediated dUTP End Labeling (TUNEL) Assay --- p.33 / Chapter 3.2.7. --- Quantitative real-time --- p.33 / Chapter 184.108.40.206. --- qPCR on Apoptotic Factors --- p.33 / Chapter 220.127.116.11. --- qPCR on Hypoxic Factors --- p.34 / Chapter 18.104.22.168. --- qPCR on Angiogenic Factors --- p.34 / Chapter 3.2.8. --- 8-Isoprostane --- p.34 / Chapter 3.3. --- Reproductive safety of PX-478 --- p.35 / Chapter 3.4. --- Data Analysis --- p.36 / Chapter Chapter 4. --- Results --- p.37 / Chapter 4.1. --- Endometriosis Growth and Development --- p.37 / Chapter 4.1.1. --- In vivo Non-Invasive Imaging --- p.37 / Chapter 4.1.2. --- Ectopic Endometriotic Lesions --- p.37 / Chapter 4.1.3. --- Histological Examination --- p.37 / Chapter 4.1.4. --- Immunohistochemistry (Macrophage and Neutrophil) --- p.38 / Chapter 4.1.5. --- Real-time PCR --- p.38 / Chapter 4.1.6. --- Oxidative Stress --- p.38 / Chapter 22.214.171.124. --- Non-invasive Imaging (IVIS) --- p.38 / Chapter 126.96.36.199. --- Measurement of 8-isoprostane --- p.39 / Chapter 188.8.131.52. --- Real-time PCR Analysis on Hypoxic Markers --- p.39 / Chapter 184.108.40.206. --- Immunohistochemistry (HIF-1α and VEGF) --- p.40 / Chapter 4.1.7. --- Angiogenesis --- p.40 / Chapter 220.127.116.11. --- Cellvizio Imaging --- p.40 / Chapter 18.104.22.168. --- Real-time PCR Analysis on Hypoxia & Angiogenic Markers --- p.40 / Chapter 22.214.171.124. --- Immunofluorescence --- p.41 / Chapter 4.2. --- Effects of Estrogen on Oxidative Stress and Angiogenesis --- p.41 / Chapter 4.3. --- Macrophage Depletion --- p.43 / Chapter 4.3.1. --- Lesion Growth and Development --- p.43 / Chapter 126.96.36.199. --- In Vivo Non-Invasive Imaging --- p.43 / Chapter 188.8.131.52. --- Ectopic Endometrium Lesions --- p.44 / Chapter 184.108.40.206. --- Histological Examination --- p.44 / Chapter 220.127.116.11. --- Immunohistochemistry (Macrophage and Neutrophil) --- p.44 / Chapter 18.104.22.168. --- Real-time PCR --- p.45 / Chapter 4.3.2. --- Oxidative stress --- p.45 / Chapter 22.214.171.124. --- In Vivo Imaging --- p.45 / Chapter 126.96.36.199. --- 8-isoprostane --- p.45 / Chapter 188.8.131.52. --- Real-time PCR Analysis on Hypoxic Markers --- p.45 / Chapter 184.108.40.206. --- Immunohistochemistry --- p.46 / Chapter 4.3.3. --- Angiogenesis --- p.46 / Chapter 220.127.116.11. --- Real-time PCR analysis on angiogenic markers --- p.46 / Chapter 18.104.22.168. --- Immunofluorescence --- p.47 / Chapter 4.4. --- 12/15 Lox Transgenic Knockout --- p.47 / Chapter 4.4.1. --- Lesion Growth and Development --- p.47 / Chapter 22.214.171.124. --- Ectopic Endometrium Lesions --- p.47 / Chapter 126.96.36.199. --- Histological Examination --- p.48 / Chapter 188.8.131.52. --- Immunohistochemistry (Macrophage and Neutrophil) --- p.48 / Chapter 184.108.40.206. --- Real-time PCR --- p.49 / Chapter 4.4.2. --- Oxidative Stress --- p.50 / Chapter 220.127.116.11. --- 8-isoprostane --- p.50 / Chapter 18.104.22.168. --- Real-time PCR Analysis on Hypoxic Markers --- p.50 / Chapter 22.214.171.124. --- Immunohistochemistry --- p.51 / Chapter 4.4.3. --- Angiogenesis --- p.51 / Chapter 126.96.36.199. --- Real-time PCR Analysis on Angiogenic Markers --- p.51 / Chapter 188.8.131.52. --- Immunofluorescence --- p.53 / Chapter 4.5. --- HIF-1α inhibition --- p.53 / Chapter 4.5.1. --- Lesion Growth and Development --- p.53 / Chapter 184.108.40.206. --- In Vivo Imaging --- p.53 / Chapter 220.127.116.11. --- Ectopic Endometrium Lesions --- p.54 / Chapter 18.104.22.168. --- Histological examination --- p.54 / Chapter 22.214.171.124. --- Immunohistochemistry (Macrophage and Neutrophil) --- p.54 / Chapter 126.96.36.199. --- Real-time PCR --- p.55 / Chapter 4.5.2. --- Oxidative stress --- p.55 / Chapter 188.8.131.52. --- In Vivo Imaging --- p.55 / Chapter 184.108.40.206. --- 8-isoprostane --- p.55 / Chapter 220.127.116.11. --- Real-time PCR Analysis on Hypoxic Markers --- p.55 / Chapter 18.104.22.168. --- Immunohistochemistry --- p.56 / Chapter 4.5.3. --- Angiogenesis --- p.56 / Chapter 22.214.171.124. --- Real-time PCR Analysis on Angiogenic Markers --- p.56 / Chapter 126.96.36.199. --- Immunofluorescence --- p.57 / Chapter 4.5.4. --- Safety Assessment of PX-478 --- p.58 / Chapter Chapter 5. --- Discussion --- p.59 / Chapter 5.1. --- Animal Model and Transplantation Method --- p.59 / Chapter 5.2. --- Oxidative Stress and Its Role in Early Development of Endometriosis --- p.59 / Chapter 5.3. --- Macrophage and Oxidative Stress in Endometriosis --- p.60 / Chapter 5.4. --- Potential Antioxidative Therapy for Endometriosis Treatment --- p.61 / Chapter 5.5. --- Safety --- p.62 / Chapter 5.6. --- Limitation and Further Studies --- p.63 / Chapter Chapter 6. --- Conclusions --- p.65 / Chapter Chapter 7. --- References --- p.66
Reaves, Adrienne D.
Thesis (M.F.A.)--Rochester Institute of Technology, 1994. / Typescript. Includes bibliographical references (leaves -).
Schembri Deguara, Christine Anna Maria
The aim of this thesis was to improve understanding of the underlying genetic and proteomic alterations potentially contributing to endometriosis. Assessment of the genetic mechanisms and pathways controlling angiogenesis, apoptosis and inflammation allowed identification of potential aberrations contributing to disease. Tissue miRNA expression experiments show that, the ebv-mir-BART2-5p is detected in endometriosis. Endometriosis cells contained higher levels of ebv-mir-BART2-5p compared to eutopic endometrium and this finding was confirmed by quantitative PCR. In situ hybridisation for EBV on tissue microarrays did not confirm the presence of active EBV within the endometriotic epithelial cells (Figure 4-24) but 5 of the 42 endometriotic samples on TMA-A gave a positive reading for EBV presence in some of the lymphocytes. PCR on the peripheral blood monocytes confirms overall higher levels of EBV DNA in the monocytes of people with endometriosis compared to controls (see Table 9-39 in the Appendix). There were no detected EBV levels in the surgically confirmed control patient samples. The presence of ebv-mir-BART2-5p is a permissive event for the development of endometriosis potentially acting as an initiator for engraftment of endometrial cells to the peritoneum causing the development of endometriosis. It also aids in disease development by suppressing T-cell function and encouraging adhesions and angiogenesis in affected tissues. Alterations in cellular genotype also enable the ectopic endometrial cells to evade NK cells and Lymphocytes, promoting proliferation and metastasis. Effects of genes on various stages of the cell cycle checkpoints and pathways have been explored as contributors to disease development. Downstream proteins from EBV upregulation are also confirmed to be affected. Tissue microarray studies demonstrate the upregulation of Cyclin D1 (Figure 4-22) and downregulation of E-Cadherin, Maspin and BCLAF-1) (Figure 4-11, Figure 4-13 and Figure 4-15). Galectin 3 (a prominent anti-apoptotic and angiogenic member of the lectin family) proteins were also upregulated in endometriosis. Galectin-3 had already been shown to be a good therapeutic target in humans and may provide alternatives to current surgical or hormonally repressive therapy. A set of in vitro experiments have been performed and show effective disease repression with Galectin therapeutics (Galectin 3 inhibitor GCS-100), potentially opening a window for the development of novel therapeutics. Serum was analysed for miRNA and antibody protein expression profiles. Pathways linked to identified biomarkers have been explored aiding in the understanding of disease development at a molecular level. Identified miRNAs are seen to interact with a number of important pathways listed below. There could potentially be effects on cellular mitosis and meiosis, cellular structure, intra and intercellular signalling, vesicular transport including exo and endocytosis and cellular apoptosis. All of these changes can result in endometriotic cells that replicate at accelerated rates, adhere to ectopic sites, enable angiogenesis and growth, evade normal apoptotic mechanisms and evade immune responses. Certain identified pathways act as tumour suppressors that could potentially explain the non-malignant properties in the majority of cases of endometriosis. These include the p38 MAPK1 pathway and the p53 tumour suppressor genes2. Other pathways involved are known to be associated with tumorigenesis and have pro-oncogenic properties, these include the RAS, WNT, TRK receptors and MAPKKKK pathways. It is the fine balance between tumour suppressors and oncogenes that probably control the transition between endometriosis and endometrial carcinomas. Identification of protein and miRNA expression profiles predicting the presence of endometriosis allowed us to work towards developing a panel of non-invasive biomarkers (Patent P063434GB) for earlier identification and treatment of disease and aids in unlocking new methods of molecular targeting as treatment.
The endometrium is a complex multicellular tissue that undergoes dynamic alterations under the control of ovarian-derived sex steroid hormones. During the proliferative phase of the human menstrual cycle, oestrogen induces proliferation of the endometrial epithelium while during the progesterone-dominated secretory phase, the endometrial stromal compartment differentiates in preparation for pregnancy. This differentiation event is termed decidualisation and it is accompanied by immune cell infiltration, vascular remodelling and secretion of cytokines and growth factors, as well as a newfound capacity of active steroid synthesis in the endometrium. Defective decidualisation has been described in several endometrial-associated disorders such as endometriosis, a pathology of ectopic endometrial tissue in the peritoneal cavity, often associated with infertility. Rodent models have been used for the investigation of endometrial physiology and pathology due to the similarity in uterine tissue architecture, appropriate endometrial responses to steroid hormones and the opportunity to inform cellular mechanisms using genetic manipulation. While the impact of 17β-oestradiol and progesterone on endometrial function have been extensively studied, androgens have only recently emerged as potent potential regulators of the endometrium, however, their impact on cell function has not been fully elucidated. The aims of this study were to: Identify the impact of androgens on endometrial function using a mouse model of steroid depletion (ovariectomy) followed by administration of the potent androgen dihydrotestosterone (DHT). Investigate the capacity of endometrial stromal cells to synthesise androgens during decidualisation using human primary endometrial stromal cells (hESCs) decidualised in vitro. Elucidate the decidualisation response of hESCs from women with endometriosis after modulation of androgen receptor (AR) function during decidualisation. Novel results obtained provided evidence of a role for androgens in inducing a trophic effect in the mouse uterus characterised by: pronounced endometrial epithelial proliferation, altered expression pattern of AR, changes in the expression of genes involved in cell-cycle progression and stromal-epithelial cross-talk. In addition, androgen treatment resulted in a striking and unexpected increase in the number of endometrial glands. Decidualisation of hESCs resulted in time-dependent changes in expression of the androgen synthesising enzymes AKR1C3 and 5α-reductase (accompanied by biosynthesis of both testosterone and DHT in a dynamic time-dependent manner). Notably, blocking of AR action arising from local androgen signalling during decidualisation of hESCs culminates in sub-optimal decidualisation as detected by the expression of the classical decidualisation markers IGFBP1 and PRL. Women with endometriosis are reported to exhibit defective decidualisation, which may be accompanied with infertility. Treatment of hESCs from women with endometriosis with an AR agonist (DHT) or antagonist (flutamide) during decidualisation resulted in striking differences in decidualisation response as demonstrated in a case-study approach. Taken together, these findings highlight novel roles of androgens in regulating endometrial function by impacting on cell proliferation, gland formation and decidualisation. These striking new findings have implications for endometrial disorders such as endometriosis. Future studies will focus on the use of selective androgen receptor modulators, a novel class of compounds, with tissue-selective actions and without the undesired side-effects of potent androgens. The use of AR modulators would benefit from a personalised medicine approach, instructed by patient profiling to direct therapeutic targeting of endometrial disorders.
An investigation of the action of cytokines on human endometrial and endometriotic colony forming unitsChan, Yat-yan., 陳溢恩. January 2011 (has links)
Cyclic proliferation and differentiation occur in the human endometrium in each menstrual cycle. Aside from the precise regulation of estrogen and progesterone, the physiology of the human endometrium is also tightly regulated by cytokines. It is therefore not surprising that imbalance of cytokine expression could be observed when women suffer from gynecological disease such as endometriosis, a common gynecological disease associated with altered cytokine profile and chronic inflammatory response. Although the etiology of endometriosis is not yet well elucidated, a commonly accepted Sampson theory suggests reflux of endometrial tissue to other parts of the reproductive tract would be one of the causes. As recent findings demonstrate the presence of somatic stem cells residing in human endometrium and endometriotic cyst, the hypothesis of the thesis was that cytokines confer a regulatory role in the proliferation and self-renewal of the endometrial and endometriotic stem/progenitor cells. In this project the following objectives were studied: 1) To investigate the effect of cytokines interleukin (IL) - 1β, IL-8, IL-10, IL-13, tumor necrosis factor (TNF) – α and interferon (IFN) – γ on the clonogenic ability of endometrial and endometriotic colony forming units (CFUs); 2) To determine the effect of IL-1β and IL-13 on the self-renewal and proliferative potential of the CFUs; 3) To elucidate the expression patterns of IL-1 and IL-13 receptors in endometrial and endometriotic sections and CFUs. Clonogenic analysis of endometrial and endometriotic stem cells showed an increase in clonogenicity in endometrial epithelial cells when treated with IL-1β. Treatment of IL-13 led to a drop in clonogenicity in endometrial epithelial and stromal cells while IFN-γ treatment resulted in a decreased clonogenicity in endometrial epithelial, stromal and endometriotic stromal cells. Other cytokines (IL-8, IL-10, TNF-α) displayed no effect on the clonogenicity of endometrial and endometriotic cells. Functional study by replating IL-1β and IL-13 treated endometrial and endometriotic CFUs revealed that these cytokines did not affect the self-renewal ability of endometrial and endometriotic CFUs. The proliferative potential of CFUs was determined by total cell output assay. The results suggested that IL-1β up-regulated the proliferative potential of the endometriotic stromal CFUs but not the endometrial epithelial and stromal CFUs, while IL-13 did not alter the proliferative potentials of endometrial and endometriotic CFUs. Comparative analysis on the effect of IL-1β and IL-13 between endometrial and endometriotic stromal CFUs demonstrated that IL-1β would preferentially promote the proliferative potential of ectopic stromal CFUs while IL-13 selectively increases that of normal stromal CFUs. Receptor expression analysis by immunostaining demonstrated the presence of IL-1 receptor and IL-13 receptors protein in the glandular epithelium of endometrial tissue. Their expression was more diffuse in the endometriotic tissues. Using reverse transcription–polymerase chain reaction, IL-1RI, IL-13Rα1, IL-13Rα2 mRNA was detected in endometrial and endometriotic stromal cells, while only in endometrial epithelial cells express IL-1RII mRNA as well as IL-1RI, IL-13RαI and IL-13Rα2 mRNA. The present study suggests a role of cytokines on endometrial and endometriotic stem/progenitor cells and further investigation of actions of cytokines would be constructive on the development of endometriosis. / published_or_final_version / Obstetrics and Gynaecology / Master / Master of Philosophy
Lyties organų kandiodzės paplitimas ligonėms sergančioms endometrioze / The spread of genital candidiasis among patients suffering from endometriosisTunkevič, Dana 25 June 2014 (has links)
Darbe analizuotas makšties mikrofloros pakitimai moterų, sergančių skirtingų stadijų endometrioze. Tirtos 46 sergančios moterys. Remiantis mūsų atliktais tyrimais kandidozė nustatyta moterims sergančioms I stadijos endometrioze 3 (23 proc.), sergančioms II stadijos endometrioze 19 (76 proc.) ir sergančioms III stadijos endometrioze 2 (50 proc.). / In this work the chantes of vaginal mikroflora among women suffering from different stages of endometriosis are analized. 46 women have been investigated. Having analysed the research data it has been noticed that Candidiasis is more among women suffering from the virst stage of endometriosis 3 (23%), the second stage of endometriosis 19 (76%) or the third stage 2 (50%).
01 May 2014
Endometriosis, characterized by the growth of endometrium outside the uterine cavity, is a disease which causes pelvic pain, inflammation and associated with infertility. Endometrium, which exits the uterus through retrograde menstruation, must establish a new blood supply as it attaches and invades into ectopic tissues to form an endometriosis lesion. Angiogenesis is therefore essential in endometriosis disease progression. The inhibition of blood vessel growth by anti-angiogenic agents is a potential strategy to manage endometriosis disease progression. This thesis investigated angiogenesis of endometriosis lesions, and evaluated a novel anti-angiogenic peptide as a potential therapeutic to manage endometriosis. An atlas on the microscopic anatomy of the pregnant mouse uterus is also presented. Synuclein-γ (SNCG), a protein involved in cellular proliferation, was found to have elevated expression in endothelial cells of endometriosis tissue compared to eutopic endometrium. In an alymphoid xenograft mouse model of human endometriosis, where human endometrium is engrafted into the peritoneal cavity of Rag2-/-/IL2r-/- female mice, peptide inhibition of SNCG resulted in reduced vascularization of endometriotic lesions. This study indicates that SNCG has a potential role in angiogenesis of endometriosis lesions. Using the same alymphoid mouse model, we evaluated the effect of an anti-angiogenic thrombospondin-1 mimetic peptide, ABT-898, on angiogenesis of endometriotic lesions. ABT-898 inhibited endothelial cell proliferation and tube formation in vitro. Mice treated with ABT-898 showed reduced vascularity of endometriosis lesions compared with control. Angiogenesis is also an essential process in the female reproductive system. Females with endometriosis are of reproductive age, so it is essential to establish that anti-angiogenic therapies do not iii interfere with reproduction. We evaluated the effect of ABT-898 on angiogenesis in the female reproductive tract in non-pregnant mice. ABT-898 did not affect estrous cyclicity, or vascularity of the uterus or ovary in non-pregnant animals. ABT-898 did not alter litter size or pup weight when given to pregnant mice throughout gestation. In summary this thesis implicated a role for SNCG in angiogenesis of endometriosis lesions, and found that ABT-898 could be a useful therapeutic to manage endometriosis disease progression as it reduces angiogenesis of endometriotic lesions, while having no observable effect in reproductive organs. / Thesis (Ph.D, Anatomy & Cell Biology) -- Queen's University, 2014-05-01 14:42:32.655
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