Endometriosis and oxidative stress?

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 Adenomyosis SUP OMA DIE SUP, superficial lesion; OMA, endometrioma; DIE, deep infiltrating endometriosis

Cycle of pathogenesis in endometriosis Adhesion Ectopic implantation Invasion Angiogenesis Proliferation Glands Stroma Steroidogenesis Kobayashi H et al. Arch Gynecol Obstet 2014; 289(1): 13 21.

Mechanisms of pathogenesis in endometriosis Altered immune functions Attenuated progesterone action Adhesion Invasion Excess oxidative stress Ectopic implantation Angiogenesis Proliferation Neuroangiogenesis Glands Stroma Steroidogenesis Chronic inflammatory response ++++ Adapted from Kobayashi H et al. Arch Gynecol Obstet 2014; 289(1): 13 21.

Molecular pathways involved in endometriosis + VEGF Angiogenesis MMP INSL3 Adhesion-Migration PGE 2 PTGER + PTGS2 + Inflammation Cholesterol STAR + NR5A1 Estradiol CYP11A1 CYP17 Steroidogenesis + Proliferation Androstenedione CYP19A1 Estrone VEGF, vascular endothelial growth factor; PGE 2, prostaglandin E 2 ; PTGS2, prostaglandin-endoperoxide synthase 2; PTGER, prostaglandin E receptor; MMP, matrix metalloproteinase; INSL3, insulin-like 3; STAR, steroidogenic acute regulatory protein; CYP, cytochrome P; NR, nuclear receptor. Adapted from Bulun SE. N Engl J Med 2009; 360(3): 268 279.

Inflammatory response pathway leads to tissue injury and chronic pain Inflammation Regurgitation! Iron ê CXCL 10 ê IL-19,22! NF- Kβ Oxidative stress Decreased anti-inflammatory factors Increased pro-inflammatory factors é é é é é TNF-α IL-1β IL-6,8,33 Rantes PGs Pelvic Pain Tissue injury Neuroangiogenesis é PGs Excessive sensory innervation é NGF IL, interleukin; TNF, tumor necrosis factor; PG, prostaglandin; CXCL, chemokine; NGF, nerve growth factor; NF-Kβ, nuclear factor kappa beta.

Inflammatory response can contribute to infertility Pelvic cavity: Proliferation of macrophages Phagocytic dysfunction Release of proinflammatory factors Uterus: Increased synthesis of prostaglandin & altered receptivity Production of estrogens in situ and resistance to progestogen Ovaries: Decreased ovarian response Altered oocyte quality? Iron overload (proinflammatory factors) de Ziegler D et al. Lancet 2010; 376(9742): 730 738.

Inflammation in endometriosis: Molecular intermediates and pathways Sphingosines PTGS2 Adhesion Invasion Inflammation Angiogenesis Proliferation Oxidative Stress Steroidogenesis MAPK pathway PTGS2, prostaglandin-endoperoxide synthase 2

Inflammatory response is linked to an altered balance of oxidative stress Anti-Oxidants Persistent inflammation Pro-Oxidants IL, interleukin; CXCL, chemokine; GSH, glutathione; NADPH, nicotinamide adenine dinucleotide phosphate-oxidase; AOPP, advanced oxidation protein products; PGs, prostaglandins.

Oxidative stress is increased in endometriosis, especially in DIE Oxidative stress is increased further in intestinal DIE N=36 N=28 N=85 N=55 N=31 N=64 N=150 DIE, deep infiltrating endometriosis; SUP, superficial lesion; OMA, endometrioma; AOPP, advanced oxidation protein products. Santulli P et al. Hum Reprod 2015; 30(1): 49 60.

Increased oxidative stress correlates with increased cellular proliferation Endometrioma 1 Superoxide Anion (O 2 --) Hydrogen Peroxide (H 2 O 2 ) Deep infiltrating endometriosis 2 Superoxide Anion (O 2 --) Hydrogen Peroxide (H 2 O 2 ) Epithelial Ce, control endometrial Ee, eutopic endometrial De, deep infiltrating endometriotic Stromal Cs, control endometrial Es, eutopic endometrial Ds, deep infiltrating endometriotic 1. Ngô C et al. Am J Pathol 2009; 175(1): 225 234. 2. Leconte M et al. Am J Pathol 2011; 179(2): 880 889.

Increased oxidative stress correlates with increased cellular proliferation: Link to MAPK pathway Proliferation ERK perk Controls Eutopic Ectopic NAC H 2 O 2 Production Proliferation Level of untreated cells Level of untreated cells NAC Optic Density perk/erk NAC, N-acetyl-cysteine; ERK, Extracellular signal-regulated kinases; perk, phosphorylated-erk. Ngô C et al. Am J Pathol 2009; 175(1): 225 234.

MAPK pathway links increased oxidative stress and inflammatory response in endometriosis S1P PDGFR VEGFR IL-33R NADPH oxidase ROS GSH MAPK pathway Angiogenesis Transcriptional regulation Cell proliferation 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.

Endometriosis and MAPK Vemurafenib - braf

Endometriosis and MAPK Sorafenib raf1- braf - tkr

Endometriosis and inflammation Targeting MAP Kinase pathway 2015

Future trends Targeting inflammation in endometriosis: MAPK LOCAL SYSTEMIC

Future trends Targeting inflammation in endometriosis: MAPK MAPK à " " New non hormonal targeted tretments of endometriosis

Conclusions Endometriosis is an Enigmatic Heterogeneous Neurologic Inflammatory disease New treatments could target inflammation and oxidative stress pathways

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