Endometriosis and oxidative stress - .Endometriosis and oxidative stress ? ... pathway ....

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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.

    Chronic inflammatory response ++++

    Excess oxidative stress

    Attenuated progesterone

    action

    Altered immune functions

    Neuroangiogenesis

    Invasion

    Proliferation

    Steroidogenesis

    Angiogenesis

    Adhesion

  • Cholesterol

    Androstenedione

    STAR

    CYP11A1

    CYP17

    EstroneCYP19A1

    NR5A1 Estradiol

    PGE2 PTGS2

    +

    +

    +

    +

    VEGF

    +

    MMP

    INSL3

    Proliferation

    Inflammation

    Steroidogenesis

    Adhesion-Migration

    Angiogenesis

    Molecular pathways involved in endometriosis

    VEGF, vascular endothelial growth factor; PGE2, prostaglandin E2; 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.

    PTGER

  • Cholesterol

    Androstenedione

    STAR

    CYP11A1

    CYP17

    EstroneCYP19A1

    NR5A1 Estradiol

    PGE2 PTGS2

    +

    +

    +

    +

    VEGF

    +

    MMP

    INSL3

    Proliferation

    Inflammation

    Steroidogenesis

    Adhesion-Migration

    Angiogenesis

    Molecular pathways involved in endometriosis

    PTGER

    VEGF, vascular endothelial growth factor; PGE2, prostaglandin E2; 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

    IL, interleukin; TNF, tumor necrosis factor; PG, prostaglandin; CXCL, chemokine; NGF, nerve growth factor; NF-Kβ, nuclear factor kappa beta.

    ! Iron

    Oxidative stress

    Increased pro-inflammatory

    factors

    Decreased anti-inflammatory

    factors

    Tissue injury

    ê CXCL 10 ê IL-19,22

    é TNF-α é IL-1β é IL-6,8,33 é Rantes é PGs

    é PGs Excessive sensory

    innervation é NGF

    Neuroangiogenesis

    Pelvic Pain

    ! NF- Kβ

    Inflammation Regurgitation

  • Inflammatory response can contribute to infertility

    de Ziegler D et al. Lancet 2010; 376(9742): 730–738.

    Ovaries: • Decreased ovarian response • Altered oocyte quality? • Iron overload (proinflammatory factors)

    Uterus: • Increased synthesis of prostaglandin &

    altered receptivity • Production of estrogens in situ and

    resistance to progestogen

    Pelvic cavity: • Proliferation of macrophages • Phagocytic dysfunction • Release of proinflammatory factors

  • Sphingosines

    MAPK pathway

    PTGS2

    Inflammation

    Inflammation in endometriosis: 
 Molecular intermediates and pathways 


    PTGS2, prostaglandin-endoperoxide synthase 2

    Invasion

    Proliferation

    Steroidogenesis

    Angiogenesis

    Adhesion

    Oxidative Stress

  • Sphingosines

    MAPK pathway

    PTGS2

    Inflammation

    Inflammation in endometriosis: 
 Molecular intermediates and pathways 


    PTGS2, prostaglandin-endoperoxide synthase 2

    Invasion

    Proliferation

    Steroidogenesis

    Angiogenesis

    Adhesion

    Oxidative StressOxidative Stress

  • Inflammatory response is linked to an altered balance of oxidative stress


    IL, interleukin; CXCL, chemokine; GSH, glutathione; NADPH, nicotinamide adenine dinucleotide phosphate-oxidase; AOPP, advanced oxidation protein products; PGs, prostaglandins.

    Pro-OxidantsAnti-Oxidants Persistent inflammation

  • N=85 N=55 N=31 N=64

    Oxidative stress is increased in endometriosis, especially in DIE

    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.

    N=36 N=28

    N=150

    Oxidative stress is increased further in intestinal DIE

  • Hydrogen Peroxide (H2O2)

    Endometrioma1

    Increased oxidative stress correlates with increased cellular proliferation

    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.

    Superoxide Anion (O2--) Hydrogen Peroxide (H2O2)

    Superoxide Anion (O2--)Deep infiltrating endometriosis2 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.

    Co nt

    ro ls

    Eu to

    pi c

    Ec to

    pi c

    NA C

    ERK

    pERK

    Pr ol

    ife ra

    tio n

    Pr ol

    ife ra

    tio n

    NAC Level of untreated cells

    Level of untreated cells

    O pt

    ic D

    en si

    ty p

    ER K

    /E R

    K

    H 2O

    2 P ro

    du ct

    io n

  • 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-33R PDGFR 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,