Endometriosis and oxidative stress ? Pietro Santulli MD, PhD Université Paris Descartes, Sorbonne Paris Cité, Faculté de médecine, AP-HP, Cochin Saint Vincent de Paul, Department of Gynecology Obstetrics II and Reproductive Medicine, Paris, France Inserm, Unité de recherche U1016 – équipe Pr Batteux, Institut Cochin, Paris, France
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Endometriosis and oxidative stress ?
Pietro Santulli MD, PhD Université Paris Descartes, Sorbonne Paris Cité, Faculté de médecine, AP-HP, Cochin Saint Vincent de Paul, Department of Gynecology Obstetrics II and Reproductive Medicine, Paris, France Inserm, Unité de recherche U1016 – équipe Pr Batteux, Institut Cochin, Paris, France
Presentation outline
• Pathogenesis of inflammation
• Clinical consequences: Pain and infertility
• Oxidative stress
• Targeted treatments of endometriosis
Implantation theory of endometriosis
SUP, superficial lesion; OMA, endometrioma; DIE, deep infiltrating endometriosis
Adenomyosis SUP OMA DIE
Glands Stroma
Ectopic implantation
Cycle of pathogenesis in endometriosis
Kobayashi H et al. Arch Gynecol Obstet 2014; 289(1): 13–21.
Invasion
Proliferation
Steroidogenesis
Angiogenesis
Adhesion
Glands Stroma
Ectopic implantation
Mechanisms of pathogenesis in endometriosis
Adapted from Kobayashi H et al. Arch Gynecol Obstet 2014; 289(1): 13–21.
Epithelial Ce, control endometrial Ee, eutopic endometrial De, deep infiltrating endometriotic Stromal Cs, control endometrial Es, eutopic endometrial Ds, deep infiltrating endometriotic
Increased oxidative stress correlates with increased cellular proliferation: Link to MAPK pathway
NAC, N-acetyl-cysteine; ERK, Extracellular signal-regulated kinases; pERK, phosphorylated-ERK. Ngô C et al. Am J Pathol 2009; 175(1): 225–234.
Cont
rols
Euto
pic
Ecto
pic
NAC
ERK
pERK
Prol
ifera
tion
Prol
ifera
tion
NACLevel of untreated cells
Level of untreated cells
Opt
ic D
ensi
ty p
ERK
/ER
K
H2O
2 Pro
duct
ion
Sphingosines PTGS2
Inflammation
Inflammation in endometriosis: Molecular intermediates and pathways
PTGS2, prostaglandin-endoperoxide synthase 2
Invasion
Proliferation
Steroidogenesis
Angiogenesis
Adhesion
Oxidative Stress MAPK pathway
Cell proliferationTranscriptional regulation
Angiogenesis
NADPH oxidase
GSH ROS
IL-33RPDGFR VEGFR
S1P
MAPK pathway links increased oxidative stress and inflammatory response in endometriosis
IL, interleukin; NADPH, nicotinamide adenine dinucleotide phosphate-oxidase; GSH, glutathione; PDGFR, platelet-derived growth factor receptors; VEGFR, vascular endothelial growth factor receptor; ROS, reactive oxidative species. Ngô C et al. J Pathol 2010; 222(2): 148–159. Santulli P et al. Fertil Steril 2012; 97(4): 904–911. Santulli P et al. Hum Reprod 2012; 27(7): 2001–2009.
MAPK pathway
Endometriosis and MAPK Vemurafenib - braf
Endometriosis and MAPK Sorafenib – raf1- braf - tkr
Endometriosis and inflammation Targeting MAP Kinase pathway
2015
LOCAL SYSTEMIC
Future trends Targeting inflammation in endometriosis: MAPK
Future trends Targeting inflammation in endometriosis: MAPK
à " " New non hormonal targeted tretments of endometriosis
MAPK
Conclusions
• Endometriosis is an • Enigmatic • Heterogeneous • Neurologic • Inflammatory
• New treatments could target inflammation and oxidative stress pathways
disease
Gynecology Surgical unit: C Chapron, B Borghese, L Marcellin, P Santulli, H Foulot, MC Lafay-Pillet, A Bourret, G Pierre, MC Lamau, P Marzouk, F Decuypere, L Campin Medical unit: A Gompel, G Plu-Bureau, L Maitrot; J Hugon Reproductive endocrinology unit: P Santulli, V Gayet, M Bourdon, C Maignien, F Kefelian, S Eskenazi, S Douard, B Boquet, A Marszalek, A Fubini Intestinal surgery B Dousset, S Gaujoux, M Leconte Radiology AE Millischer, L Maitrot
Laboratory: Genetic D Vaiman, F Mondon, S Barbaux Laboratory: Imunulogy F Batteux, S Chouzenoux, C Nicco, C Chéreau, B Weill Laboratory: Reproducive biology JP Wolf, C Patrat, K Pocate, V Lange, JM Kuntzman, C Chalas Statistical unit F Goffinet, PY Ancel
A Gompel, Professor and Head, Medical Gynecological unit, P Santulli, Doctor and Head, Reproductive ART and Infertility unit,
C Chapron, Professor and Chair, Gynecology Obstetrics II and Reproductive Medicine