Endometriosis and oxidative stress -...

25
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

Transcript of Endometriosis and oxidative stress -...

Page 1: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

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

Page 2: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

Presentation outline

• Pathogenesis of inflammation

• Clinical consequences: Pain and infertility

• Oxidative stress

• Targeted treatments of endometriosis

Page 3: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

Implantation theory of endometriosis

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

Adenomyosis SUP OMA DIE

Page 4: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

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

Page 5: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

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

Page 6: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

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

Page 7: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

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.

Page 8: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

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 PGsExcessive sensory

innervationé NGF

Neuroangiogenesis

Pelvic Pain

! NF- Kβ

Inflammation Regurgitation

Page 9: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

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

Page 10: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

Sphingosines

MAPK pathway

PTGS2

Inflammation

Inflammation in endometriosis: Molecular intermediates and pathways

PTGS2, prostaglandin-endoperoxide synthase 2

Invasion

Proliferation

Steroidogenesis

Angiogenesis

Adhesion

Oxidative Stress

Page 11: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

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

Page 12: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

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-OxidantsPersistent inflammation

Page 13: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

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

Page 14: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

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

Page 15: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

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

Page 16: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

Sphingosines PTGS2

Inflammation

Inflammation in endometriosis: Molecular intermediates and pathways

PTGS2, prostaglandin-endoperoxide synthase 2

Invasion

Proliferation

Steroidogenesis

Angiogenesis

Adhesion

Oxidative Stress MAPK pathway

Page 17: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

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

Page 18: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

Endometriosis and MAPK Vemurafenib - braf

Page 19: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

Endometriosis and MAPK Sorafenib – raf1- braf - tkr

Page 20: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

Endometriosis and inflammation Targeting MAP Kinase pathway

2015

Page 21: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

LOCAL SYSTEMIC

Future trends Targeting inflammation in endometriosis: MAPK

Page 22: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

Future trends Targeting inflammation in endometriosis: MAPK

à " " New non hormonal targeted tretments of endometriosis

MAPK

Page 23: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

Conclusions

• Endometriosis is an • Enigmatic • Heterogeneous • Neurologic • Inflammatory

• New treatments could target inflammation and oxidative stress pathways

disease

Page 24: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis

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

Page 25: Endometriosis and oxidative stress - endomaix.frendomaix.fr/files/155/COMMUNICATIONS/2018/02-santulli-pietro.pdf · Endometriosis and oxidative stress ? ... pathway . Endometriosis