Perka BKN 1 TH 2013 Juklak PP 46 TH 2011

Patogenesis Endometriosis
Tedjo Danoedjo Oepomo
Mini Symposium
“ENDOMETRIOSIS UPDATE”
Hotel Hotel Melia Purosani Jogjakarta

Sabtu, 18 November 2017
Endometriosis
Lesi primer di peritoneum pelvis dan ovarium

Tetapi bisa berada di perikardium, pleura, parenkim paru,
kadang juga di otak
Klinis dapat menyebabkan

perlekatan pelvis, nyeri,
fatigue, gangguan usus,
dan infertilitas
Pengobatan medisinalis
& bedah tidak efektif
Kelainan ini tidak saja biaya Disebabkan patogenesis
tinggi, namun juga
belum sepenuhnya
melemahkan fisik dan psikis
terungkap
Tedjo Danoedjo O.
Patogenesis Endometriosis. Jogjakarta 2017
The Pathogenesis of Endometriosis
Retrograde Flow of endometrial content into pelvis,

menstruation allowing implantation of endometrial lesions
Transformation of peritonial tissue/cells into

Metaplasia endometrial tissue through hormonal and or
immunological factors
Oestrogen-driven proliferation of endometrial

Hormones lesions. Resistance to progesterone-mediated
control of endometrial proliferation
Oxidative Recruitment of immune cells and their

stress and production of cytokines that promote
inflammation endometrial growth
Tedjo Danoedjo O. Sourial S, Tempest N, Hapangama KD

Patogenesis Endometriosis. Jogjakarta 2017 International Journal of Reproductive Medicine, 2014
The Pathogenesis of Endometriosis
Prevention of eliminating menstrual debris and

Immune
promotion of implantation and growth of
dysfunction
endometrial lesions
Apoptosis Promoting survival of endometrial cells and

suppression downregulation of apoptotic pathways
Alteration of cellular function that increases

Genetic attachment of endometrial cells and evasion of
these cells from immune clearance
Initiation of endometriotic deposits by

Stem cells undifferentiated cells with natural ability to
regenerate
Tedjo Danoedjo O. Sourial S, Tempest N, Hapangama KD

Patogenesis Endometriosis. Jogjakarta 2017 International Journal of Reproductive Medicine, 2014
Tedjo Danoedjo O.
Retrograde
menstruation
76% - 90% wanita

Dyssynergic
uterine
contractions
ENDOMETRIOMA ENDOMETRIOMA
Retrograde Retrograde
menstruation menstruation
Pelvic cavity Pelvic cavity
ENDOMETRIOSIS ENDOMETRIOSIS
Tidak semua mengalami endometriosis

menstruation (Menargi awal, haid lama/banyak, riwayat keluarga, penyalah
gunaan alkohol/latihan yang berlebihan, outflow yang
terganggu)
Endometriosis berasal dari sel
Metaplasia ekstra-uterin mengalami abnormal
transdiferensiasi atau tranformasi
ke sel endometrial
• Teori Coelomic Metaplasia
• Teori sisa Mullerian dan Wolffian
• Teori Metaplasia Menyertai Endometrial Stimulasi
Tedjo Danoedjo O.
Metaplasia
• Teori Coelomic Metaplasia

Epitel coelomic menutupi serosa dari peritonium dan ovarium yang mengalami
metaplasi menjadi endometrium, diduga disebabkan oleh stimulasi hormon atau
faktor lingkungan.
• Teori sisa Mullerian dan Wolffian

Jaringan ektopik endometrial ditemukan pada bayi perempuan diduga sebagai defek
embriogenesis. Teori ini residual embrionic sel dari Mullerian dan Wolffian
berkembang menjadi lesi endometriotik karena respon estrogen.
• Teori endometrial stimulasi

Teori ini diduga produksi lokal, endometriotik dan adenomiotik yang memproduksi
estrogen menyebabkan pertumbuhan jaringan tersebut. Teori ini mendukung
walaupun endometriosis jarang terjadi pada post menopouse tetapi pemakaian HRT
beresiko untuk terjadinya endometriosis. Estrogen juga menstimulasi resiko kanker
ovarium.
Tedjo Danoedjo O.
Tedjo Danoedjo O.
Hormones Patogenesis Endometriosis. Jogjakarta 2017
• Hormon steroid berperan pada

etiologi endometriosis
• Toksin lingkungan (dioxin)

terlibat etiologi endometriosis
karena menyerupai estrogen
via interaksi dengan reseptor
estrogen
• Bioavailability dari oestradiol

pada jaringan endometriotik
karena lokal aromatisasi
androgen  estradiol
• Penurunan konversi oestradiol

 less potent oestron karena
penurunan 17β-hydroxysteroid
enzymes
• Progesteron resistance karena Progesterone resistance and estradiol accumulation in

lesi endometriotik memiliki endometriosis.
ekspresi reseptor progesteron
rendah
(Tariverdian et al., 2007)
Oxidative stress
and
inflammation
FREE RADICAL
OKSIDATIVE IM BALACE
STRESS
ANTIOXIDANT
DEFENCE
Tedjo Danoedjo O.
FREE RADICAL
ROS NOS
REACTIVE OXYGEN NITRIC OXIDE
SPECIES SYNTHASE ANTIOXIDANT
SUPEROXIDE RADICAL ENDOTHELIAL NO SYNTHASE DEFENCE
HYDROGEN PEROXIDE ( NO SYNTHASE 3 )
HYDROXYL NEURONAL NO SYNTHASE
SINGLET OXYGEN RADICALS ( NO SYNTHASE 1 )
INDUCIBLE NO SYNTHASE
( NO SYNTHASE 2 )
ENZYMATIC NON-ENZYMATIC
ANTIOXIDANTS ANTIOXIDANTS
SUPEROXIDE DISMUTASE VITAMINS E, C
CATALASE TAURINE
GLUTATHIONE PEROXIDASE GLUTATHIONE
GLUTATHIONE REDUCTASE SELENIUM
ZINC
HYPOTAURINE
BETA CAROTENE
CAROTENE
Tedjo Danoedjo O.
Tedjo Danoedjo O.
IRON METABOLISM IN
THE PELVIC CAVITY IN
CASE OF ENDOMETRIOSIS
• Eritrosit masuk ke cavum pelvis bersama retrograde menstruation dan perdarahan dari
jaringan endometrium ektopik
• Sebagian dari padanya difagosit oleh makrofag peritonial
• Metabolisme heme oleh heme oxygenase (HO) melepaskan iron
• Makrofag menyimpan iron (feritin)/hemosiderin dan sebagian dilepas dan terikat pada
transferin (TF)
• Makrofag juga melepaskan feritin pada zalir peritonium, lisis dari eritrosit melepaskan HB
pada ZP
• Konsentrasi iron: TF, feritin, dan HB, dan diasimilasi oleh ektopik endometrium
menghasilkan deposit iron (feritin dan hemosiderin)
Gonzalez-Ramos. NF-KB and endometriosis pathophysiology. Fertil Steril 2012

OXIDATIVE STRESS AND ENDOMETRIOSIS
NOS
DIOXIN, TOXICANTS
NO
+ +
CELL DEBRIS +
+
OXIDATIVE STRESS
VASODILATATION
MACROPHAGES
+
+ +
RETROGRADE ERYTHROCYTES HEMOGLOBIN HEME IRON + BILIVERDIN + CO
MENSTRUATION
HO
LESION BLEEDING
Tedjo Danoedjo O.
Patogenesis Endometriosis. Jogjakarta 2017 VAN LANGENDONCKT.FERTIL STERIL 2012
IRON,
MACROPHAGES,
OXIDATIVE
STRESS
AND NF-kβ IN
ENDOMETRIOSIS
Gonzalez-Ramos. NF-KB and

endometriosis pathophysiology.
Fertil Steril 2012
Fe= iron; ROS= reactive oxygen species; p65/p50= NF-kβ dimer; Ikβ= NF-kβ inhibitory protein; IKK= Ikβ
kinase complex; TNF= tumor necrosis factor; IL= interleukin; ICAM= Intercellular adhesion molecule; MCP=
monocyte chemottractant protein; RANTES= regulated on activation, normal T cell expressed and secreted;
GM-CSF= granulocyte macrophage-coloni stimulating factor; COX=cyclooxygenase; VEGF= vascular
endothelial growth factor; MIF= macrophage migration inhibitory factor; MMP= matrix metalloproteinase;
Bcl= B-cell lymphoma/leukimia; XIAP= X-linked inhibitor of apoptosis protein.
Tedjo Danoedjo O.
ORIGIN OF OXIDATIVE STRESS IN THE
PERITONEAL CAVITY
ENVIRONMENTAL TOXICANTS
( 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN / TCDD )
RETROGRADE MENSTRUATION
• ERYTHROCYTES
• APOPTOTIC ENDOMETRIAL TISSUE HEAVY METALS
• CELL DEBRIS OXIDATIVE STRESS
• UNDIGESTED ENDOMETRIAL CELLS
MACROPHAGES
Tedjo Danoedjo O.
OXIDATIVE STRESS RELATED CELL DAMAGE
I. DNA Damage II. Direct damage III. Rises in VI. Increased lipid
Of proteins Intracellular free Peroxidation
Iron
Poly (ADP) ribose Increased damage to
Syntetase Cytoskeletal DNA, proteins, lipids
Activation Damage
Membrane Membrane
Rises in Peroxidation and Peroxidation and
NAD (H) depletion Intracellular free destruction Destruction
Ca2-
Metal ion release into
Inhibition of ATP Membrane Surrounding tissues
Blebbing
Injury to adjacent
synthesis Membrane cells
Peroxidation and
Destruction
Metal ion release

Into surrounding
Tissues
Injury to adjacent
Tedjo Danoedjo O.
cells
A. AUGOULEA ET AL. GYN-ENDO 2009 Patogenesis Endometriosis. Jogjakarta 2017
STUDIES IN ENDOMETRIOSIS AND OXIDATIVE STRESS
Markers of oxidative stress

in patients with
Reference Type of biospecimen endometriosis
Murphy A Peritoneal fluid Lipid peroxides

Ho HN Peritoneal fluid Total antioxidant status
Szczepanska Peritoneal fluid Superoxidedismutase
Glutathione peroxidase
Zeller JM Peritoneal fluid ROS
Wang Y Eutopic endometrium ROS
Jackson L Peritoneal fluid Antioxidants
Lipid peroxides
Ota H Eutopic endometrium Superoxide dismutase
Glutathione peroxidase
Agarwal A Eutopic endometrium ROS
NOTE , INCREASE , DECREASE , NO DIFFERENCE
Tedjo Danoedjo O.
Patogenesis Endometriosis. Jogjakarta 2017 A. AUGOULEA ET AL. GYN-ENDO 2009
STRES OKSIDASI DAN IMUNOLOGI
Darah haid berbalik, sel endometrial
dalam kavum peritonii
Regulasi adhesion MMPs (sel endometrial Produksi NK sel

berimplantasi dalam kavum peritonii) menurun disertai
menurunnya
kemampuan
Growth factors dan VEGF memberi untuk membunuh
sarana angiogenesis , memelihara dan sel endometrial
menumbuhkan implan ektopik yang reflug dan
mensekresi
sitokin regulasi
yang mengontrol
Setiap haid implan ektopik berdarah autoimunitas
dalam kavum peritonii
Inflamasi kronik rekruitmen monosit Makrofag
Stres oksidasi
(ROS )
Sistem anti oksidasi

tidak efektif
Sel normal rusak oleh oksidatif Merekrut monosit dan meningkatkan

apoptosis, nekrosis produk growth factors
Sel endometriotik
proliferasi
Tedjo Danoedjo O. ENDOMETRIOSI
Immune
dysfunction
• Wanita dengan endometriosis

- Konsentrasi tinggi dari makrofag aktif
- Penurunan imunitas seluler
- Penekanan fungsi dari sel NK
• Regurgitasi haid menyebabkan

- Inflamasi
- Menarik makrofag aktif
- Leukosit lokal
• Inflamasi menyebabkan
- Defective “immune-surveillance”
Tedjo Danoedjo O.
Immunological aspect of
endometriosis
Innate adaptive
immunity immunity
Cell-mediated Humoral Cell-mediated Humoral

immunity immunity immunity immunity
Macrophage Cytokines Lymphocytes autoantibody

Mast cell Growth factors
NK cell
Tedjo Danoedjo O.
LINGKUNGAN
Tedjo Danoedjo O.
Patogenesis Endometriosis. Retrograde menstruation  Defective NK cells
Jogjakarta 2017  Secretion of sICAM-1
 Abnormal apoptosis
Viable endometrial cells in  Reduce T cell cytotoxicity
peritoneal cavity  Increased number and
activation of macrophages
 Increased IL-8, TNF-α, IL-6
Endometrial-Peritoneal adhesion  Upregulation of MMPs
 IL-1, TNF- α, TGFβ
 Suppression of TIMPs
Ectopic implantation and invasion
• Angiogenesis
• VEGF
Genetics • IL-8 ,Rantes,TNF- α
Endometriosis
Cytokines
Dioxin
+ Macrophages
Aromatase
Prosta Cytokines
Estradiol glandins
COX-2
TGFβ
(-) NK activity
Progesterone VEGF
Estrone
Androstenedione (-) MMPs
Estrogens
Tedjo Danoedjo O.
Apoptosis
suppression
Immune cell Ectopic Immune cell Ectopic

endometrial cell endometrial cell
Immune cell Immune cell
Endometrial Endometrial
cells cells
• Endometriosis berasal dari retrograde menstruation , vascular or lymphatic

circulation, stem cells. Pengaruh imunologi apoptosis terdapat diarea ektopik tersebut
dalam peritonial.
• Pada proses gangguan (stimulasi proliferasi, stres oksidasi, dll) mengganti fungsi
apoptosis  terjadi invasi, angiogenesis, implants endometriosis
Genetic
• Gen yang terlibat pada patogenesis endometriosis

- Enzim detoksifikasi
- Polymorphism di oestrogen reseptor
- Gen involved in the innate immune sistem
• Genetic mutations  disebabkan kerusakan sel 

endometriosis progresif
Tedjo Danoedjo O.
LINGKUNGAN KELUARGA DAN
SAUDARA KEMBAR
LINGKUNGAN KELUARGA ENDOMETRIOSIS
1980 SIMPSON KETURUNAN KELUARGA

PERTAMA PEREMPUAN
KELUARGA WANITA SUAMI
6,9 % 1%
1980 MALINAK KETURUNAN
PERTAMA
7%
1986 LAMB KETURUNAN
KEDUA
1,9 %
Tedjo Danoedjo O.
1993 MOEN LINGKUNGAN KELUARGA KONTROL
MAGNUS IBU SAUDARI SAUDARI
PEREMPUAN PEREMPUAN
3,9 % 4,8 % 0,6 %
2000 COXHEAD LINGKUNGAN KELUARGA KONTROL

THOMAS
9,4 % 1,6 %
Tedjo Danoedjo O.
SAUDARA KEMBAR ENDOMETRIOSIS
NORWEGIA :
6 DARI 8 KEMBAR MONOZIGOTIK ENDOMETRIOSIS
HADFIELD :
9 DARI 16 KEMBAR MONOZIGOTIK ENDOMETRIOSIS
Tedjo Danoedjo O.
KANDIDAT GEN
Table 1
Commonly reported endometriosis candidate genes from association studies
Gene Chromosomal Number of Number of
Process regulated Candidate gene
symbol locus positive studies negative studies
metabolisme xenobiotik:
Glutathione M-transferase
Xenobiotic metabolism GSTM1 1p13.3 9 12
1
Glutathione S-transferase
GSTT1 22q11.2 7 7
1
N-acetyl-transferase 2 NAT2 8p22 1 4
Aryl hydrocarbon receptor
AHRR 5p15 3 1
repressor
Hormone receptors or
Estrogen receptor α ESR1 6q24-27 8 3
- Glutathione M-transferase 1 (GSTM1),

metabolism
Progesterone receptor PR 11q22-33 4 2
Cytochrome P450, family
17, subfamily A, CYP17A1 10q24 3 6
polypeptide 1
- Glutathione S-transferase 1 (GSTT1),

polypeptide 1
1, subfamily A, polypeptide CYP1A1 15q24 1 3
- N-acethyl-transferase 2 (NAT2),
1
Hydroxysteroid (17-β)
HSD17B1 17q11-21 3 0
dehydrogenase 1
Inflammation or
Tumor necrosis factor α TNFA 6p21.3 2 7
angiogenesis
- Aryl hydrocarbon receptor repressor (AHRR).

Interleukin-6 IL-6 7p15.3 4 4
Interleukin-10 IL-10 1q31-32 7 0
Vascular endothelial
VEGFA 6p21-12 5 1
growth factor A
Intercellular adhesion
ICAM1 19p13 2 3
molecule 1
Galactose-1-phosphate
Other processes GALT 9p13 2 2
uridyl transferase
Tumor suppressor p53 TP53 17p13 2 7
HLA class II
histocompatibility antigen, HLA-DRB1 6p21 3 4
DRB1-9 β chain
Association studies in English on the most commonly studied candidate genes were identified by performing a PubMed literature search up to 23 June 2010. If a published
study identified one or more positive associations, we identified this study as positive, otherwise negative. Variants of the ESR2, peroxisome proliferator-activated receptor
γ2 (PPAR-γ2), nuclear factor κB1 (NFKB1), E-cadherin, matrix metalloproteinase 1 (MMP1), MMP9, cyclin dependent kinase inhibitor p27 (CDKN1B), neurokinin-1
(TAC1),nitric oxide synthase 3 (NOS3), fibroblast growth factor 1 (FGF1), FGF2 and catechol-O-methyltransferase (COMT) genes have also been investigated as candidate
genes potentially associated with endometriosis.
Dun et al. Genome Med 2010 2:75 doi:10.1186/gm196
Tedjo Danoedjo O.
Table 1
Reseptor / metabolisme hormon:

Xenobiotic metabolism GSTM1 1p13.3 9 12
1
GSTT1 22q11.2 7 7
1
N-acetyl-transferase 2 NAT2 8p22 1 4
AHRR 5p15 3 1
repressor
metabolism
- Estrogen receptor α (ESR1), Cytochrome P450, family

17, subfamily A,
polypeptide 1
CYP17A1 10q24 3 6
- Progesterone receptor (PR),

polypeptide 1
- Cytochrome P450, family 17, subfamily A, polypeptide 1

1
HSD17B1 17q11-21 3 0
dehydrogenase 1
(CYP17A1),Inflammation or
angiogenesis
Tumor necrosis factor α
Interleukin-6
TNFA
IL-6
6p21.3
7p15.3
2
4
7

VEGFA 6p21-12 5 1
growth factor A
(CYP19A1),
ICAM1 19p13 2 3
molecule 1
uridyl transferase

Tumor suppressor p53
HLA class II
TP53
histocompatibility antigen, HLA-DRB1

17p13
6p21
2
3
7
(CYP1A1)
DRB1-9 β chain
- Hydroxysteroid (17- β) dehydrogenase 1 (HSD17B1).

Tedjo Danoedjo O.
Table 1
Proses inflamasi / angiogenesis:

Xenobiotic metabolism
1
1
N-acetyl-transferase 2
GSTM1
GSTT1
NAT2
1p13.3
22q11.2
8p22
9
1
12
4
AHRR 5p15 3 1
repressor
metabolism
- Tumor Necrosis Factor α (TNFA),

polypeptide 1
- Interlukin-6 (LI-6),
polypeptide 1
1
HSD17B1 17q11-21 3 0
- Interlukin-10 (IL10).
dehydrogenase 1
Inflammation or
angiogenesis
- Vascular endothelial growth factor A Vascular endothelial

growth factor A
VEGFA
ICAM1
6p21-12
19p13
5
2
1
(VEGFA)
molecule 1
uridyl transferase
HLA class II
- Intercellular-1-phosphate uridyl transferase

DRB1-9 β chain
(GALT)
Tedjo Danoedjo O.
Table 1
Xenobiotic metabolism
1
1
Proses lain :
N-acetyl-transferase 2
GSTM1
GSTT1
NAT2
1p13.3
22q11.2
8p22
9
1
12
4
AHRR 5p15 3 1
repressor
metabolism
Galactosa-1 phosphate uridyl transferase

polypeptide 1
polypeptide 1
Tumor suppressor p53 (TP53)

1
HSD17B1 17q11-21 3 0
dehydrogenase 1
Inflammation or
angiogenesis
VEGFA 6p21-12 5 1
HLA class II histocompatibility antigen,

growth factor A
ICAM1 19p13 2 3
molecule 1
uridyl transferase
HLA class II
DRB1-9 β chain (HLA-DRB1).

DRB1-9 β chain
Tedjo Danoedjo O.
Perubahan Epigenetik
SF-1 : STEROIDOGENIC FACTOR-1
• Kadar SF-1 sangat tinggi pada jaringan endometriotik
Tedjo Danoedjo O.
Stem cells
• Setiap bulan sesudah pelepasan saat menstruasi terjadi regenerasi dari

endometrium, kondisi ini mendukung eksistensi dari stem cell
• Basalis layer dari endometrium tidak terlepas saat menstruasi bulanan yang
terlepas adalah functional layer, stem cell terletak di basalis layer dari
endometrium
• Pada endometrium manusia stem cell berperan dalam pembentukan lesi ektopik
endometrial
• Stem cell adalah sel yang tidak berdeferensiasi dan mempunyai karakteristik
kemampuan memperbarui diri sendiri dan berdeferensiasi menjadi beberapa tipe
sel
• Endometrial stem cell yang tidak berdeferensiasi respon terhadap steroid

ovarium rendah jika dibandingkan dengan progeni sebagai deferensiasi terminal
Tedjo Danoedjo O.
Tedjo Danoedjo O.
• Hipotesa endometrial cells/progenitor cells bersama perdarahan uterus berperan

pada onset awal endometriosis (Bronsens et al).
• Fragmen dari jaringan endometrial terdiri dari endometrial epithelial progenitor cell
(pink) dan perivascular mesenchymal stem/stromal cells (MSC) (pink) bersama niche
cells. Kemudian menempel pada mesothelium neonatus invasi dan berdekatan
dengan lapisan mesothelial dan menetap tidak berubah selama 10 th
• Peningkatan E2 (thelarche dan menarche) memacu stem progenitor cells bertumbuh
menjadi lesi endometriosis pada permukaan/dibawah peritonium mesotelium
• Tidak terdapat data komparasi antara endometrial cells/progenitor cells antara
neonatus dan endometrium dewasa
Human Rep. Update, Vol 22, No 2pp. 2016
• Lokasi endometrial stem cells dan
epithelial progenitor cell pada stratum
basalis endometrium
• Leyendecker et al., wanita
endometriosis terjadi pelepasan
abnormal dari jaringan endometrial
basalis, yang menginisiasi deposit
endometriotik sesudah retrograde
menstruation
• Penelitian pada model baboon
menempatkan stem cell dari
endometrial basalis pada cavum pelvis
menghasilkan 100% endometriosis
pada semua mamalia, karena stratum
basalis memiliki stem cell yang banyak
 mendukung Levendecker et al.
• Wanita endometriosis kemungkinan
besar pelepasan basalis layer yang
kaya stem cells jika dibandingkan
dengan wanita normal
• Deposit jaringan endometrium yang
terdiri dari endometrial stem cells dan
niche cells pada cavum peritonii dapat
beregenerasi menjadi endometrium-
like tissue
Tedjo Danoedjo O.
Verdi et al. Journal of Biological Engineering 2014, 8:20 Patogenesis Endometriosis. Jogjakarta 2017
A. Endometriosis penyakit multifaktoral,
faktor yang berpengaruh: genetik,
Retrograde
Bone marrow
lingkungan, dan faktor endogen
menstruation stem/progenitor cell (estradiol, abnormalitas imunologi).
lymphovascular
dissemination B. Stem sel berada di lesi ektopik masuk ke
Transplantation cavum peritonii melalui beberapa jalur:
Migration & invasion
retrograde mestruation, lymphovascular
dissemination, transplantasi, migrasi,
invasi, dan abnormal sel migrasi selama
organogenesis.
Disease -favoring
niche
Di samping uterus eutopik endometrium
Abnormal berisi endometrium stem sel (EnSCs),
organogenesis
(primordial stem cells) bone marrow juga merupakan pusat dari
endometriosis stem sel dengan sel
progenitor (bone marrow-derived
LESSION mesenchymal stem cells, MSCs, dan
GROWTH
endothelial progenitor cells EPCs)
INFLAMMATION ANGIOGENESIS
VASCULOGENESIS C. Endometriosis stem cells karena
NEUROGENESIS disfungsi genetik dan epigenetik
D. Lesi bertumbuh  terjadi manifestasi
klinis
(frontiers in surgery/ obstetrics and
gynecology vol 1, januari 2015)
RANGKUMAN TEORI PATOGENESIS
Retrograde
Menstruation
Genetic
Transformation
/ induction
Coelomic
metaplasia
Embryonic
remnants
Tedjo Danoedjo O.
Tedjo Danoedjo O.
RANGKUMAN TEORI PATOGENESIS Patogenesis Endometriosis. Jogjakarta 2017
LEBIH LENGKAP
-PERITONEAL MACROPHAGE ACTIVATION
-INDUCTION OF PRODUCTION OF MAJOR
PROINFLAMMATORY CYTOKINE
MAJOR PRO-
INFLAMMATORY CYTOKINES
TNF-α
IL-1β
TRANSCRIPTION
INFLAMMATORY CYTOKINES FACTORS
IL-6 NF-kβ
IL-8 AP-1 CELL ADHESION MOLECULES:
MPC-1 others -CD44
GM-CSF -ICAM-1
-VCAM-1
MIF Activated
-Β1-integrin
transcription
factors(DNA
binding)
Transcriptional
-IL6 induces VEGF expression activity
-MIF induces endothelial cell
mitosis
ANGIOGENESIS
-VEGF MATRIX ANTI-APOPTOTIC GENE
-Nitric oxide (NO) METALOPROTEINASE PROFILE
induction MMP-1,MMP-2, MMP- induction High Bcl-2, Bcl-XL, cyclin A
3,MMP-7,MMP-9 Low Bax
VEGF induced the CELL SURVIVAL,

INVASION,
production and release of
DIFFERENTIATION AND
MMPs by vascular ADHESION AND TISSUE
endothelial cells DEGRADATION OF THE
REMODELLING
EXTRACELLULAR MATRIX OF
THE PERITONEAL SURFACE
KESIMPULAN
• Patogenesis endometriosis rumit dan masih

berkembang terus
• Terapi endometriosis belum ada yang bisa
menangani keluhan secara sempurna
MATUR NUWUN SANGET

Perka BKN 1 TH 2013 Juklak PP 46 TH 2011

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Patogenesis Endometriosis

Tedjo Danoedjo Oepomo

Hotel Hotel Melia Purosani Jogjakarta

Lesi primer di peritoneum pelvis dan ovarium

Klinis dapat menyebabkan

Retrograde Flow of endometrial content into pelvis,

Transformation of peritonial tissue/cells into

Oestrogen-driven proliferation of endometrial

Oxidative Recruitment of immune cells and their

Tedjo Danoedjo O. Sourial S, Tempest N, Hapangama KD

Prevention of eliminating menstrual debris and

Apoptosis Promoting survival of endometrial cells and

Alteration of cellular function that increases

Initiation of endometriotic deposits by

Tedjo Danoedjo O. Sourial S, Tempest N, Hapangama KD

76% - 90% wanita

Pelvic cavity Pelvic cavity

Tidak semua mengalami endometriosis

• Teori Coelomic Metaplasia

• Teori sisa Mullerian dan Wolffian

• Teori Metaplasia Menyertai Endometrial Stimulasi

• Teori Coelomic Metaplasia

• Teori sisa Mullerian dan Wolffian

• Teori endometrial stimulasi

• Hormon steroid berperan pada

• Toksin lingkungan (dioxin)

• Bioavailability dari oestradiol

• Penurunan konversi oestradiol

• Progesteron resistance karena Progesterone resistance and estradiol accumulation in

Gonzalez-Ramos. NF-KB and endometriosis pathophysiology. Fertil Steril 2012

Gonzalez-Ramos. NF-KB and

Metal ion release

Markers of oxidative stress

Murphy A Peritoneal fluid Lipid peroxides

NOTE , INCREASE , DECREASE , NO DIFFERENCE

Regulasi adhesion MMPs (sel endometrial Produksi NK sel

Inflamasi kronik rekruitmen monosit Makrofag

Sistem anti oksidasi

Sel normal rusak oleh oksidatif Merekrut monosit dan meningkatkan

• Wanita dengan endometriosis

• Regurgitasi haid menyebabkan

Cell-mediated Humoral Cell-mediated Humoral

Macrophage Cytokines Lymphocytes autoantibody

Immune cell Ectopic Immune cell Ectopic

• Endometriosis berasal dari retrograde menstruation , vascular or lymphatic

• Gen yang terlibat pada patogenesis endometriosis

• Genetic mutations  disebabkan kerusakan sel 

LINGKUNGAN KELUARGA ENDOMETRIOSIS

1980 SIMPSON KETURUNAN KELUARGA

3,9 % 4,8 % 0,6 %

2000 COXHEAD LINGKUNGAN KELUARGA KONTROL

6 DARI 8 KEMBAR MONOZIGOTIK ENDOMETRIOSIS

9 DARI 16 KEMBAR MONOZIGOTIK ENDOMETRIOSIS

- Glutathione M-transferase 1 (GSTM1),

- Glutathione S-transferase 1 (GSTT1),

- Aryl hydrocarbon receptor repressor (AHRR).

Dun et al. Genome Med 2010 2:75 doi:10.1186/gm196

Reseptor / metabolisme hormon:

- Estrogen receptor α (ESR1), Cytochrome P450, family

- Progesterone receptor (PR),

- Cytochrome P450, family 17, subfamily A, polypeptide 1

- Cytochrome P450, family 19, subfamily A, polypeptide 1

- Cytochrome P450, family 1, subfamily A, polypeptide 1