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Initiation & Initiation & Maintenance of Maintenance of Endometriosis & Endometriosis &
AdenomyosisAdenomyosisDr. Nagendra S. Sardeshpande
Consultant Gynecologist & EndoscopistBombay Hospital Institute of Medical Sciences
Mumbai
“Even if peritoneal endometriosis arises from the implantation of endometrial and
tubal tissue on the surface of the peritoneum, as I believe it does, this does
not prove that all instances of endometrium-like tissue involving the peritoneum arises from this source”
John A. Sampson, 1927
Sampson RevisitedSampson Revisited Sampson noted retrograde flow &
intravasation of dye during menstruation & not with intact endometrium
The term “endometriosis” did not exist Sampson, from radiologic studies,
inferred retrograde endometrial sloughing into Fallopian tubes & veins
Coined the term “implantation adenomas”
Sampson JA. Am J Obstet, 78: 161-75; 1918
Sampson’s Theory of Retrograde Sampson’s Theory of Retrograde DisseminationDissemination
Evidence Supporting Implantation Theory Viable cells obtained from menstrual affluent & peritoneal
fluid Endometrial cells grow in peritoneal cavity Retrograde menstruation almost universal phenomenon Association of endometriosis with obstruction of menstrual
flow Transtubal, lymphatic, hematologic or iatrogenic
deposition D’Hooghe TM, Debrock S.Hum Reprod Update, 8: 84-8; 2002
Sampson’s Theory of Retrograde Sampson’s Theory of Retrograde DisseminationDissemination
Evidence Contradicting Implantation Theory Studies were with “chocolate cysts” with few histologically proven
endometriomas Focused only on severe disease Inferred that pelvic endometriosis was from “leaking” endometriomas Assumed that mode of spread similar to ovarian cancer Multiple extrapolations & hypotheses without supporting evidence No photomicrographic proof of initial attachment of endometrial cells
to peritoneum / ovary Cannot explain distant / male endometriosis Redwine DB in Redwine DB (ed): Surg Mgt Endomet, NY, Martin Dunitz,
Taylor & Francis Gr; 2004
Metaplasia Theory of EndometriosisMetaplasia Theory of Endometriosis Peritoneal Disease -Metaplastic potential of pelvic
mesothelium Ovarian Endometriomas -Invagination of the cortex -Metaplasia of coelomic
epithelium Rectovaginal Nodules -Metaplasia of mullerian rests
into endometriotic glands -Secondary infiltration of
peritoneal endometriosis of POD
Glandular element with surrounding stromal & smooth
muscle hyperplasia in endometriosis
Metaplasia Theory of EndometriosisMetaplasia Theory of EndometriosisEvidence Supporting Metaplasia Theory Epithelial invagination in continuation with
ectopic endometrial tissue Endometriomas in MRKH syndrome Primordial follicles found surrounding
endometrioma Presence of smooth muscle, stoma admixed
with endometrium Absence of evolution after removal of
nodule Vigano P in Garcia-Velasco JA, Rizk BRMB
(ed): Endometriosis, St. Louis (USA), Jaypee Publishers; 2010
Smooth muscle & stroma in rectovaginal nodule
Predisposition to Predisposition to EndometriosisEndometriosis
Endometrial ChangesEndometrial Changes Prolonged proliferative phase
of ectopic endometrium Electron microscopic findings
include persistent mitosis, increased glycogen deposition, incomplete ciliogenesis, giant mitochondria & nucleolar channel systems in secretory phase of cycle
Increased aromatase activity Szymanowski K. Eur J Obstet
Gynecol, 132: 107-10; 2007
Increased glycogen
Increased mitosis & nucleolar channel systems
Predisposition to EndometriosisPredisposition to EndometriosisEndometrial ChangesEndometrial Changes
Alteration in TNFalpha induced cell apoptosis via altered sphingomyelinase mediated pathway with increased cell survival
Increased TNF alpha receptors Increased FAS ligand expression by endometrial
epithelial & stromal cells which induces T-cell apoptosis IL-6 (secreted by monocytes, macrophages, endothelial
cells & endometrium) increases Endo-1 (a haptoglobin) which blocks macrophage phagocytosis
Hudelist G et al. Reprod Sci, 14: 798-805; 2007
Predisposition to EndometriosisPredisposition to EndometriosisImmunological ChangesImmunological Changes
Predisposition to EndometriosisPredisposition to EndometriosisImmunological ChangesImmunological Changes
NK Cell Dysfunction Increased number Killer Cell Inhibitory
Receptors (KIR) in circulating & peritoneal NK cells
Increased ICAM-1 & p40 subunit of IL-2 (potent inhibitors of NK cells) in endometrial cells
Increased PGE2? (inhibitor of NK cells, T cells & macrophages)
Finas D et al. Hum Reprod, 23 (5): 1053-62; 2008
Predisposition to EndometriosisPredisposition to EndometriosisImmunological ChangesImmunological Changes
Macrophage Dysfunction Increased production of cytokines (BLyS) associated with
humoral immunity & autoantibodies Increased TNF alpha productionT Cell Dysfunction Altered Th1:Th2 ratios with induction of humoral immunity
in ectopic endometrium Increased T-cell apoptosisB Cell Dysfunction Increased levels of autoantibodies Parham P. The Immune System (2nd ed), NY, Garland Sci; 2005
Predisposition to EndometriosisPredisposition to EndometriosisGenetic FactorsGenetic Factors
EndometriumIncreased expression of cell cycling & anti-
apoptotic genes -Dysregulation of cell cycle genes GOS2 &
SALP controlling mitosis -Increased Ki67 gene expression (indicative of
dividing cells) -Increased expression of Bcl-2 Gaetje R et al. Fertil Steril, 87: 651-6; 2007
Predisposition to EndometriosisPredisposition to EndometriosisGenetic FactorsGenetic Factors
Endometrium Increased expression of embryonic genes -Aberrant methylation of HOXA10 and 11 -Higher expression of WNT7A & PAX8 Aberrant methylation of PR-B receptor gene in response to
TNF alphaImmune System Increased CD-158A gene expression (NK cell inhibitor) in NK
cells Wu Y et al. Am J Obstet Gynecol, 192; 2005
Initiation of EndometriosisInitiation of EndometriosisOxidative StressOxidative Stress
Reduced levels of SOD, glutathione peroxidase, xanthine oxidase & serum paroxanase-1 (prevents oxidation of LDL) in few studies
Reactive oxygen species (released by macrophages & mononuclear cells) increase VEGF production via glycodelin
NO & H2O2 activate cell adhesion molecules via NFkb & AP-1
DeFrere S et al. Gynecol Obstet Inv, 65: 145-54; 2008
Initiation of EndometriosisInitiation of EndometriosisEnvironmental AgentsEnvironmental Agents
Environmental Estrogens Bisphenol A reduce vaginal size, thins endometrial
lamina propria & induces ER alpha & PR in endometrium
Dioxins Activates ER beta Suppresses CMI & humoral immunity Increases endometriotic lesions in primates Edwards TM, Myers JP. Environ Health Persp, 115: 1264-
70; 2007
Initiation of EndometriosisInitiation of EndometriosisEnvironmental Agents & Epigenetic Environmental Agents & Epigenetic
ModulationModulation SF1 methylated (inactive)
in normal endometrium Toxins demethylate SF1
which is activated by SF2 Overexpression of ER
alpha & downregulation of ER beta & PR
Increased steroidogenesis & endometrial proliferation
Dolinoy DC et al. Reprod Toxicol, 23: 297-307; 2007
Maintenance of EndometriosisMaintenance of EndometriosisEndogenous HormonesEndogenous Hormones
Evidence Supporting Role of Hormones Requires estrogen (rare in childhood & after
menopause) Rare in ovarian dysgenesis Hyperprogestogenic, hypoestrogenic states
(pregnancy, breast feeding, aromatase inhibitors, GnRH analogues, progestins) beneficial
Tissues express E & P receptors Gurates B, Bulun SE. Semin Reprod Med, 21: 125-34;
2003
Maintenance of EndometriosisMaintenance of EndometriosisEndogenous HormonesEndogenous Hormones
EstrogenAromatase expression in endometriotic tissueEstrogen activates EMMPRIN (glycosylated
transmembrane protein) which activates MMP (involved in endometrial cell adherence & proliferation)
Braundmeier AG et al. J Clin Endocrinol Metab, 91: 2358-65; 2006
Maintenance of EndometriosisMaintenance of EndometriosisEndogenous HormonesEndogenous Hormones
Progesterone Downregulates PR-B but not PR-A receptor (failure of
hypermethylation) in endometriosis Unpredictable responseAndrogens 5alpha reductase activity demonstrated in
endometriosis May stimulate aromatase activity in low concentrations Wu Y et al. Epigenetics, 1: 106-11; 2006 Carneiro MM et al. BJOG, 115: 113-7; 2008
Maintenance of EndometriosisMaintenance of EndometriosisRole of IronRole of Iron
Peritoneal macrophage heme-oxygenase 1 (HO1) oxidises hemoglobin to generate iron, CO & bilirubin
Iron (as transferrin) ingested by macrophages & removed as ferretin
Defective HO1 leads to Hb-Hp (haptoglobin) complexes which damage mesothelium & stimulates inflammatory cytokines
Demir AY et al. Proteonomics, 4: 2608-23; 2004 Hemosiderin laden
macrophages
Maintenance of EndometriosisMaintenance of EndometriosisRole of IronRole of Iron
Maintenance of EndometriosisMaintenance of EndometriosisInflammationInflammation
Macrophages secrete fibronectin, MCP-1, VEGF, MDGF, IL-8 & TNFalpha which induce angiogenesis, endometrial proliferation & synthesis of collagen
Macrophages secrete Th2 cytokines IL-4, Il-5, IL-6, IL-10 &IL-13, TGF beta which promote B cell immunity & suppress T cell cytotoxicity
Berbic M et al. Hum Reprod, 24: 325-32; 2009
Inflammatory stromal reaction in endometriosis
EndometriosisEndometriosisMechanism of Adhesion FormationMechanism of Adhesion Formation
PAI-1 -Inhibits fibrinolysis TGF -Growth inhibitor of epithelium PDGF -Migration & proliferation of fibroblasts, smooth muscle cells & monocytes FGF -Angiogenesis & proliferation of fibroblasts & macrophages VEGF -Angiogenesis -Produced by hypoxic endometrium, macrophages & T cells EGF -Promotes granulation tissue formation Vaze MN et al. Vet World. 3 (12): 561-6; 2010
EndometriosisEndometriosisMechanism of Adhesion FormationMechanism of Adhesion Formation
EndometriosisEndometriosisEffect on FertilityEffect on Fertility
Endometrial Changes Out of phase endometrium Glycodelin gene downregulation (affecting embryo implantation) Lack of integrin beta3 in proliferative phase with lack of MMP
activation and defective embryo adhesion, migration & implantation
Immunological Changes TNFalpha cytotoxic Cytokines, PG cytotoxic & increase uterine & tubal motility Ovulatory dysfunction? Minici F et al. Hum Reprod, 23: 530-7; 2008
Etiopathogenesis of EndometriosisEtiopathogenesis of EndometriosisClinical ImplicationsClinical Implications
Role of Multiple Therapies Combined GnRH analogue & aromatase inhibitorsNovel Therapies COX2 inhibitors Immunomodulators VEGF / TNF alpha inhibitors PR modulators StatinsRebirth of Older Therapies Danazol Gestrinone
AdenomyosisAdenomyosisPredispositionPredisposition
Endometrial Changes Aromatase activity in endometrium Increased PRL, PRL receptor, HCG, LH receptor expression Higher levels of MMP-2 in endometrial epithelium & stroma
predispose to basement membrane breakdown & invasion Increased IL-8 & ENF-78 by endometrium induces
chemokine secretion by macrophages Increased ECAM (E-cadherin) expression Tanwar PS et al. Biol Reprod, 81: 545-52; 2009 Ueki K et al. Int J Gynec Pathol, 23: 248-58; 2004
AdenomyosisAdenomyosisPredispositionPredisposition
Immunological Changes Increased GM-CSF secretion by macrophages induces
endometrial epithelial & stromal proliferation Increased humoral responseGenetic Changes Increased Survivin gene (chromosome 17q25)
expression which inhibits capsase induced endometrial cell apoptosis
Zaitseva M et al. Mol Hum Reprod, 13: 577-85; 2007 White C et al. Reprod Biol Endocrinol, 2: 76; 2004
AdenomyosisAdenomyosisInitiation & MaintenanceInitiation & Maintenance
Neovascularization VEGF, PDGF, MIF &
TNF induce vascularization, increase vascular permeability & increase endometrial proliferation
Peng L et al. Fertil Steril, 91: 2664-75; 2009
“Any path which narrows future possibilities may become a trap. Humans
are not threading their way through a maze; they scan a vast horizon filled with
unique opportunities”Kevin Anderson