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MIT HST 071 - Endometriosis

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CASE PRESENTATIONEndometriosisEndometriosisFive Critical StepsEndometriosisRetrograde Menstruation TheoryRetrograde MenstruationViabilityAdherenceRetrograde Menstruation TheoryClinical DataEndometriosisEndometriosis of UterusEndometriosisCoelomic Metaplasia - MeyerDerivatives of Epithelium of the Coelomic WallInduction TheoryEndometriosisOther TheoriesEnvironmental FactorsEnvironmental FactorsEnvironmental FactorsProton IrradiationEndometriosisEndometriosisEndometriosisEndometriosis - Terminal IleumEndometriosis in Colon WallRare Sites of EndometriosisGenetics of EndometriosisGenetics of EndometriosisGenetics of EndometriosisGenetic FactorsGENETIC FACTORS (summary)Endometriosis & PainEndometriosis & PainEndometriosis & PainEndometriosis & PainEndometriosis & PainEndometeriosis & PainRat ModelEndometeriosis & PainRat ModelEndometriosis & PainRat ModelAttachmentAttachmentEndometriosis of Fallopian TubeImmune System’s RoleSurgical ManagementTheoretical Model of EndometriosisCandidate GenesAberrant Genes & Gene ProductsTheories Regarding Development of EndometriosisAttachment to MesotheliumAdhesion MoleculesMatrix MetalloproteinasesMatrix MetalloproteinasesMatrix MetalloproteinasesTransforming growth factor- (TGF-)Transforming growth factor- (TGF-)Interleukin-1 (IL-1)Impaired ImmunityPelvic InflammationMacrophagesImpair Scavenger FunctionNatural Killer Cells (NK)LymphocytesEndocrine FactorsEndometriomas and extra-ovarian endometriotic implants express high levels of aromatasePossible role of Aromatase in EndometriosisCASE PRESENTATION A 42 year old woman presents with a 4 year history of progressive abdominal pain. She is nulligravid intentionally, a career woman, never used oral contraceptives. She initially noted the pain in her lower abdomen, occasionally accompanied by increased urinary frequency and urgency but of late the pain is diffuse and occasionally she feels it in her shoulders It has gotten much worse during her periods. Her cycles are every 28-32 days lasting about 4 days with no intermenstrual spotting. She had seen a doctor for this about 3 years ago but the doctor wanted to do some sort of surgery and she had no time to be bothered with this so she took NAPROSYN and found she had been getting good relief until about a year ago. What is the next step ? Harvard-MIT Division of Health Sciences and TechnologyHST.071: Human Reproductive BiologyCourse Director: Professor Henry KlapholzEndometriosis In ovarian tissue Image removed due to copyright reasons. cysts often developas a result of proliferation andbleeding into the ovaryEndometriosis Areas of endometriosis Image removed due to copyright reasons. are characteristically cystic and often hemorrhagicFive Critical Steps 1. Attachment of endometrial cells to the peritoneal surface 2. Invasion of these cells into the mesothelium 3. Recruitment of inflammatory cells 4. Angiogenesis around the nascent implant 5. Endometrial cellular proliferationEndometriosis Monkeys are only animal (cyclic) No cases reported prior to puberty Often seen in teenage years Short cycle and longer flows have twice therisk of endometriosis Early menarche Delayed childbearing Menstrual outflow obstructionRetrograde Menstruation Theory Implantation (Sampson's theory) Viable endometrial tissue is refluxed through the fallopian tubes duringmenstruation Implants on peritoneal surface orpelvic organsModel of Endometriosis Development �v�3 Ovary Fallopian Tube Retrograde Menstruation Endometriomas Cytokines, Growth Factors Mesothelium Peritoneal Fluid Activated Macrophages Endometriotic Implants MMP TIMP Haptoglobin VEGF Uterus Menstrual Blood Endometrium C3 complement HOX A10, A11 integrin Glutathione peroxidase Catalase Free radicals Aromatase EBAF Interleukin 6 HGF VEGF Glycodelin Mucins Oestradiol Figure by MIT OCW.Retrograde Menstruation 1938 - Watkins observed blood dripping from fallopian tubes in women who underwent laparotomyduring menstruation Goodall reported that retrograde menstruation occurred in 50% of women who underwent laparotomy during menstruation Presence of blood in the peritoneal fluid was alsoobserved in women who underwent peritonealdialysis Retrograde menstruation is a commonphenomenon that occurs in 76% to 90% of womenwith patent fallopian tubesViability 1951 - Keetel and Stein cultured endometrial cells obtained from menstrual discharge ofseven women who wore diaphragms Endometrial cells obtained from peritoneal fluidafter uterine lavage also were culturedsuccessfully Endometrial cells collected from the peritonealcavity after uterine lavage stayed viable inculture for up to 2 months Endometrial cells obtained from peritoneal fluidalso were cultured successfullyAdherence 1950 - Scott and TeLinde reported that shed endometrial cells were able to implant In monkeys shown that 50% of the monkeysdeveloped endo Baboons - after injection of menstrual endometrium into their retroperitoneal space Menstrual effluent from women during the secondday of menstruation - injected it into thesubcutaneous abdominal fat of patients Æ viable endometrial glands and stromaRetrograde Menstruation Theory Assumptions Retrograde menstruation occurs through the fallopian tubes Refluxed endometrial cells are viable Refluxed endometrial cells are able to adhere to peritoneumClinical Data Increased risk of endometriosis in patients with Mullerian anomalies and obstructed flow Increased frequency of endometriotic implants in the dependent areas of the pelvisEndometriosis Implantation & Metastases Menstrual effluent (Sampson) Retrograde menstruation Common event Viable endometrial cells noted Why does a physiologic event yield pathology ? Antegrade cells cultured and contain adhering and proliferating cells that are either epitheliod or fibroblastic in appearance (Keetel & Stein)Endometriosis of Uterus Image removed due to copyright reasons.Endometriosis Coelomic Metaplasia Ovary & mullerian ducts derive from coelomic mesothelium Germinal epithelium attempts to recapitulate endometrium Only explains ovarian endometriois Peritoneal mesothelium is totipotentialCoelomic Metaplasia - Meyer Develops from metaplasia of cells that line the pelvic peritoneum Infectious, hormonal, or other inductive stimuli may result in metaplasiaDerivatives of Epithelium of the Coelomic Wall Pelvic peritoneum Germinal epithelium of ovary Mullerian ducts Examples Ovarian surface endometriosis Men (undergoing estrogen therapy for prostate cancer)


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