Harvard-MIT Division of Health Sciences and Technology HST.071: Human Reproductive Biology Course Director: Professor Henry Klapholz IN SUMMARY HST 071 ENDOMETRIOSIS ENDOMETRIOSIS • Attachment of endometrial cells to the peritoneal surface • Invasion of these cells into the mesothelium • Recruitment of inflammatory cells • Angiogenesis around the nascent implant • Endometrial cellular proliferation • Monkeys are only animal (cyclic) • No cases reported prior to puberty • Often seen in teenage years • Short cycle and longer flows have tw• Early menarche • Delayed childbearing • Menstrual outflow obstruction • Implantation (Sampson's theory) ice the risk of endometriosis • Viable endometrial tissue is refluxed through the fallopian tubes during menstruation • Implants on peritoneal surface or pelvic organs Retrograde menstruation • Occurs through the fallopian tubes • Refluxed endometrial cells are viable • Refluxed endometrial cells are able to adhere to peritoneum Coelomic Metaplasia • Ovary & Mullerian ducts derive from coelomic mesothelium • Germinal epithelium attempts to recapitulate endometrium • Only explains ovarian endometriosis • Peritoneal mesothelium is totipotential • Develops from metaplasia of cells that line the pelvic peritoneum • Infectious, hormonal, or other inductive stimuli may result in metaplasia Dissemination • Disseminated tissue can cause metaplasia • Injection into ear vein of rabbit causes endometriosis of lungs • Laparotomy scar • Episiotomies • Cesarean sections • Transplantation confirmed in animal experimentsIN SUMMARY HST 071 ENDOMETRIOSIS Embryonic rest theory • Cell rests of Mullerian origin • Lymphatic and hematogenous dissemination of endometrial cells • Evidence suggests that endometrial cells can metastasize • Pleura, umbilicus, retroperitoneal space, lower extremity, vagina, and cervix -are anatomically possible • Endometrial tissue in uterine veins in women with adenomyosis • Induced pulmonary endometriosis by injecting endometrial tissue intravenously in rabbits • Lymph node endometriosis was found to be present in 6.7% autopsies Found In • Bone • Muscle • Brain • Nerve • Lung parenchyma • Vertebral space • Extremities Genetics • Much more common in patients with a FH • Maternal inheritance pattern • 7% in first degree relatives • More severe in women with a + first degree re• 6/8 monozygotic twins had endometriosis • 3.8% of non-monozygous sisters • Polygenic/multifactorial • No HLA system seems involved • Perhaps different diseases Adherence lative • Endometrial fragments obtained in either phase of the cycle – adhere to the epithelial side of the amnion but only at locations where the amniotic epithelium was damaged or absent • Cultured peritoneal explants adhered to peritoneal explants only at locations where the mesothelium was absent or damaged and the basement membrane was exposed • Intact mesothelium constitutes a defense barrier • Occasionally there is attachment to intact mesothelium Integrins • Intracellular adhesion molecule-1 • Vascular cell adhesion molecule-1 • Integrin-blocking antibodies do not interfere with endometrial stromal or epithelial cell adherence to mesothelium Hyaluronic Acid • Peritoneal mesothelium produces hyaluronic acid • Hyaluronic acid is expressed along the cell membrane and contributes to the pericellular matrix • Major component of the extracellular matrix ground substance • CD44 is the principal receptor for hyaluronic acid • Involved in binding of gastric cancer and ovarian cancer cells to mesothelium • Endometrial stromal end epithelial cells express CD44 • Hyaluronidase pretreatment of mesothelial cells decreases the binding of endometrial stromal and epithelial cells to mesotheliumIN SUMMARY HST 071 ENDOMETRIOSIS • Invasion follows initial adhesion • Matrix metalloproteinase (MMP) enzymes -implicated • MMPs (and inhibitors) play a significant role in normal endometrial remodeling that accompanies menses • MMP family contains several structurally related Zn++ dependent endopeptidases • Responsible for the degradation of various extracellular matrix components o collagen o gelatins o proteoglycans o laminin o fibronectin o elastin TGF-β • Produced by endometrial tissue in response to progesterone • TGF-β suppresses expression of MMP-7 • Antibody to TGF-β abolishes this suppression • Blocking the action of TGF-β opposes progesterone-mediated suppression of MMP-3 and MMP-7 • Blocks the ability of progesterone to prevent experimental endometriosis • TGF-β alone does not lead to sustained suppression of MMPs • Possibly because of resumption of MMP production in the absence of progesterone • Consistent with the fact that peritoneal fluid levels of TGF-β are elevated in endometriosis IL-1α • Potent stimulator of MMP-3 in proliferative phase endometrium • Progesterone exposure in vivo reduces the IL-1α stimulation of MMP-3 in secretory phase tissue • IL-1α stimulation of MMP-3 is restored in a dose-dependent manner with progesterone withdrawal • Cultured endometriotic cells obtained from a rat endo model express higher levels of MMP-3 mRNA than eutopic rat endometrial stromal cells when treated with progesterone • Elevated and persistent MMP-3 expression by endometriotic stromal cells cultured in the presence of progesterone correlates with elevated levels of IL-1α mRNA detected in the endometriotic stromal cells • Production of IL-1α by the endometriotic lesions -overcomes the progesterone-induced suppression of MMP-3 • IL-1α -related mechanism promotes MMP-3 production by endometriotic cells even in the presence of progesteroneIN SUMMARY ENDOMETRIOSIS Contributes to pain and infertility • Cytokines • Prostaglandins • Dyspareunia • Chronic pelvic pain • Inflammation --> Infertility • adhesion formation • scarring • disrupt fallopian tube patency • impair folliculogenesis • fertilization • embryo implantation Hormonal Dependence • Endometriosis is an estrogen-dependent disorder • Aberrant estrogen synthesis and metabolism – • Aromatase catalyzes the synthesis of estrone and
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