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IRCAD Barretos 1-8-16
Pathophysiology of endometriosis
Philippe R. Koninckx
Prof em KU leuven Belgium, Univ Oxford UK, Univ Sacro Cuore, Italy,
Honorary Consultant UK, Hon Prof Moscow Univ Gruppo Italo Belga, Leuven –Rome, Belgium Italy.
Disclosure : shareholder EndoSAT
Pathophysiology for surgeons
• What is endometriosis ?
• Different presentations : 1 disease ?
• Progressive and recurrent ?
• What do we know ?
• What is surgically useful ?
R S
The Endometrium
• Glands & stroma
• during menstrual cyle = dating
• Pregnancy-> decidualisation
• Functionalis and basalis
• Different hormonal control
• Junctional zone & spiral arteries
The Endometrial function
• The most regenerative tissue
• Hormonal sensitivity
• Peristalsis
• Pregnancy
• Invasion
• immunology
Brosens 68
Leyendecker 85
Archimetra
Endometriosis : Facts 1
different presentations – prevalences - histology
100% Retrograde menstruation
80% Subtle with remodeling
15% typical 10% cystic 1% deep
adenomyosis, mullerianosis, stromatosis, pockets,
active no fibrosis
Inactive with fibrosis
Symptoms vary with lesion Prevalence Pain Infertility
• Subtle : 80% no no
• Typical : 25% in 50% + ?
• Cystic : 10% in 80% +++ ++++
• Deep : 2-3% in 95% ++++ ???
• Adenomyosis
• Peritoneal pockets – Müllerianosis - Choristoma
• Stromatosis
Pathophysiology : Sampson Theory
Sampson : retrograde menstruation Viable cells in menstruation
Retrograde menstruation
Viable cells in PF
Implantation potential
Keebiel WC, Stein RJ. Am J Obstet Gynecol 1951; 61:440-442.
Koninckx PR et al. J.Reprod.Med. 1980; 24:257-260.
In humans, in primates, in nude mice, in vitro
Metaplasia Subtle lesions Retrograde
menstruation,
Microscopical
Remodeling
Prevalence of subtle lesions
Koninckx et al 1991
0
20
40
60
80
Inf Pain Inf+pain
n= 1297 918 267
• In normal peritoneum • 10-15%
• In lymph nodes
• 15% in deep endo
• In bowel deep endo
Microscopical endometriosis
c
5 cm
Bowel resection: 10-20% positive margins
• 40% Remorgida V, Ragni N, Ferrero S, Anserini P, Torelli P, Fulcheri E. How complete is full thickness disc resection of bowel endometriotic lesions? A prospective surgical and histological study. Hum Reprod 2005;20: 2317–20.
• 9% Anaf V, El Nakadi I, Simon P, Van de Stadt J, Fayt I, Simonart T, Noel JC. Preferential infiltration of large bowel endometriosis along the nerves of the colon. Hum Reprod 2004; 19: 996-1002
• 16% Nirgianakis K, McKinnon B, Imboden S, Knabben L, Gloor B, Mueller MD. Laparoscopic management of bowel endometriosis: resection margins as a predictor of recurrences. Acta Obstet Gynecol Scand 2014; 93: 1262-7.
• 19 % Mabrouk M, Spagnolo E, Raimondo D, D‟Errico A, Caprara G, Malvi D, Catena F, Ferrini G, Paradisi R, Seracchioli R. Hum Reprod 2012; 27: 1314-9.
• 27% Roman Horace fertil Steril 2016
microscopic nests
Fertil steril, 2016, 105,305-6
Fertil steril, 2016, 105,305-6
What is endometriosis ?
Glands and stroma outside the uterine cavity
• Always pathology ? • No
• We need another definition
Subtle lesions ? Microscopic ?
• White & red vesicles, flame like • More tetrograde menstruation ?
• Progressive : the large majority not
• Microscopic : no known associated pathology
• Lymph nodes
• Bowel resection
• Pain & infertility
• For the surgeon :
• not too aggressive
• No wide perineum ablation
Pathophysiology : Theories
Sampson Viable cells in menstruation
Retrograde menstruation
Viable cells in PF
Implantation potential
Keebiel WC, Stein RJ. Am J Obstet Gynecol 1951; 61:440-442.
Koninckx PR et al. J.Reprod.Med. 1980; 24:257-260.
In humans, in primates, in nude mice, in vitro
We see We Imagine
Abdominal wall growth stops fibrosis
Evidence for progression ? • Subtle to typical ?
• Typical to severe cystic ?
deep ?
No evidence
in the human
in primates
Circomstantial evidence of the
contrary
historical data in Leuven :
typical in 1980 ; deep in the 90’s
in primates : no evolution
A recurrent disease ?
• Subtle 100%
• Typical 20%
• Cystic 5%
• Deep 1%
Prevalences and age
• nn
Clonality in endometriosis
Monoclonal neoplasm
Genetic damage to single
progenitor cell Clonal
expansion
Cystic ovarian endometriosis Yes
• Jimbo et al (1997) Am J Pathol 150, 1173 ;21 samples from 11
endometriomas ; Marker = X-linked HUMARA gene
21/21 samples monoclonal
• Tamura et al (1998) Lab Invest 78, 213 ;25 epithelial cells from 25
archival endometriomas ; Controls = 25 matched ovarian stroma
tissue ; Marker = X-linked PGK gene
10/25 samples informative (all 10 monoclonal)
Deep endometriosis
Germline predisposition • Familial clustering Humans: Kennedy et al (1995) J Assist Reprod Genet 12,
Rhesus: Hadfield et al (1997) Hum Reprod Update 3, 109 • Twin studies : MZ >> DZ Moen (1994) Acta Obstet Gynecol Scand 73, 59
Hadfield et al (1997) Fertil Steril 68, 941
Treloar et al (1999) Fertil Steril 71, 701 • Heredity symptom onset age in non-twin sisters
Kennedy et al (1996) Hum Reprod 11, 101
6-9x increased prevalence in 1st degree relatives
Simpson et al (1980) Am J Obstet Gynecol 137, 327
Coxhead & Thomas (1993) J Obstet Gynaecol 13, 42
Moen & Magnus (1993) Acta Obstet Gynecol Scand 72, 560
15% prevalence in 1st degree relatives (using MRI)
Kennedy et al (1998) Lancet 352, 1440
Facts ?
• Progression or end stage ?
• Cystic and deep are clonal
• Wise to consider separately
• Associated with (typical) • Pain and infertility
• Low grade inflammation in peritoneal fluid
• Heriditary, age
• ........food, ......fat
• Cancer, nerve cells in endometrium
• For surgeons : association is not causal
Philippe R. Koninckx
Prof em KU leuven Belgium, Univ Oxford UK, Univ Sacro Cuore,
I taly, Honorary Consultant UK, Hon Prof Moscow Univ
Gruppo Italo Belga, Rome
www.gynsurgery.org
Disclosure : CEO EndoSAT www.endosat.com
Pathophysiology of endometriosis
The theories
Sampson
Angiogenic-lymphogenic spread
Endometriotic disease theory
The modulators
peritoneal fluid
immunology
genetics
Evidence for progression ? • Subtle to typical ?
• Typical to severe ?
No evidence
in the human
in primates
Why progression in some women only ?
Endometriosis is a genetic disease • Hereditary
• Deep and cystic are clonal in origin
Total body radiation, Dioxin
The Endometriotic Disease Theory
Genetic mutation
cause a cell to
become tumorous
Koninckx P.R., Kennedy S., Barlow D.,
Gyn Obstet Invest 1999,47,1-10
Implantation Metaplasia Progression
Endometriotic
disease Endometriosis
Deep
Cystic Ovarian
Adhesions
Typical
Subtle lesions
Retrograde
menstruation,
Remodeling,
Genetic mutation favorised by
heredity
immunology
volume
environment
Sampson - Metaplasia The Endometriotic Disease Theory Koninckx P.R., Kennedy S., Barlow D., Gyn Obstet Invest 1999,47,1-10
rr
Conclusion I which cell ?
endometriosis versus endometrium ?
stem cells ?
basalis or functionalis ?
“cancer like” invasion & metastasis ?
altered immunology
endometrium
peritoneal cavity
systemic
Environment
blood
peritoneal fluid
JZ ‘blocks’ invasion
Haematologic and lymphogenic spread
• Haematologic
• Lung endometriosis
Lymphatic
•Deep endo
•Umbilical ? •
Peritoneal fluid
• An ovarian exudate
• Volume
// with ovarian activity
(Koninckx PR, Renaer M, and Brosens IA. (1980) Origin
of peritoneal fluid in women: An ovarian exudation
product. Br. J. Obstet. Gynaecol. 87, 177-183).
Peritoneal fluid
• An ovarian exudate
• Volume
// with ovarian activity
• steroid hormone concentrations
always higher than in plasma
• protein concentrations :
60% of plasma
lower for larger molecules
(Koninckx PR, Renaer M, and Brosens IA. (1980) Origin of peritoneal fluid in women: An ovarian
exudation product. Br. J. Obstet. Gynaecol. 87, 177-183).
Koninckx PR, Heyns W, Verhoeven G, Van Baelen H, Lissens W, and De Moor P. (1980) Biochemical
characterisation of peritoneal fluid in women during the menstrual cycle. J. Clin. Endocrinol. Metab. 51,
1239-1244
LUF as a cofactor for Endometriosis
• Since
• steroid hormone concentrations are low Koninckx PR, De Moor P, and
Brosens IA. (1980) Diagnosis of the luteinized unruptured follicle syndrome by steroid hormone assays on peritoneal fluid. Br. J.
Obstet. Gynaecol. 87, 929-934
• association with endometriosis Brosens IA, Koninckx PR, and Corveleyn PA. (1978)
A study of plasma progesterone, oestradiol-17b, prolactin and LH levels, and of the luteal phase appearance of the ovaries in
patients with endometriosis and infertility. Br. J. Obstet. Gynaecol. 85, 246-250
• A cofactor in endometriosis Koninckx PR, Ide P, Vandenbroucke W, and
Brosens IA. (1980b) New aspects of the pathophysiology of endometriosis and associated infertility. J Reprod
Med, 24, 257-260
Peritoneal fluid in Endometriosis
• Low grade inflammation
with more and activated macrophages • increase in chemotactic activity by 20kD protein Weil SJ, Wang SY, Perez MC, and Lyttle CR.
(1997) Chemotaxis of macrophages by a peritoneal fluid protein in women with endometriosis. FERT. STERIL. 67, 865-869
• decreased by medical therapy Leiva MC, Hasty LA, Pfeifer S, Mastroianni L, Jr., and Lyttle CR. (1993) Increased
chemotactic activity of peritoneal fluid in patients with endometriosis. Am J Obstet. Gynecol. 168, 592-598
• in vitro secretion of a monocyte chemoattractant Akoum A, Lemay A, Brunet C, and
Hebert J. (1995) Cytokine-induced secretion of monocyte chemotactic protein-1 by human endometriotic cells in culture. the groupe d'investigation en
gynecologie. Am. J. Obstet. Gynecol. 172, 594-600
• RANTES Hornung D, Ryan IP, Chao VA, Vigne JL, Schriock ED, and Taylor RN. (1997) Immunolocalization and regulation of the chemokine RANTES in
hunan endothelial and endometriosis tissues and cells. JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM, 82, 1621-1628
Peritoneal fluid in Endometriosis
• More and activated Macrophages = secretion products
• Bax+ macrophages McLaren J, Prentice A, Charnock-Jones DS, Sharkey AM, and Smith SK. (1997) Immunolocalization
of the apoptosis regulating proteins Bcl-2 and Bax in human endometrium and isolated peritoneal fluid macrophages in endometriosis.
HUMAN REPRODUCTION, 12, 146-152
• angiogenic activity
in vivo Oosterlynck D. (1993a) Angiogenic activity of peritoneal fluid from women with endometriosis. Fertil. Steril. 59, 778-782.
TGF Oosterlynck DJ, Meuleman C, Waer M, and Koninckx PR. (1994) Transforming Growth Factor-beta Activity Is
Increased in Peritoneal Fluid from Women with Endometriosis. Obstet. Gynecol. 83, 287-292 VEGF McLaren J, Prentice A, Charnock Jones DS, and Smith SK. (1996) Vascular endothelial growth factor (VEGF)
concentrations are elevated in peritoneal fluid of women with endometriosis. Hum. Reprod. 11, 220-223.
McLaren J, Prentice A, Charnock Jones DS et al. (1996) Vascular endothelial growth
factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids. J. Clin. Invest.
98, 482-489
• Cytokines Koninckx PR, Kennedy SH, Barlow DH.(1999) Pathogenesis of endometriosis: the role of
peritoneal fluid. Gynecol Obstet Invest 47 Suppl 1:23-33.
Peritoneal fluid in Endometriosis
• Others • The IGF system
• Platelet activating factor and altered fibrinolytic system
• Prostaglandins
• decreased NK cell activity Oosterlynck DJ, Meuleman C, Waer M, Vandeputte M, and
Koninckx PR. (1992) The natural killer activity of peritoneal fluid lymphocytes is decreased in women with endometriosis. Fertil. Steril. 58, 290-295
• inhibition of activity Oosterlynck D. (1993b) Immunosuppressive activity of peritoneal fluid in
women with endometriosis. Obstet. Gynecol. 82, 206-212
• increased shedding of ICAM-1 by endometrial cells (Somigliana, Vigano, et al. 1996 )
• high local concentrations of glycodelins
Decreased NK cell activity
• Decreased activity
• In plasma & peritoneal fluid
• More in more severe endo
• Local shielding and glycodelins ?
• The chicken or the egg
• 4 mths after excision of deep endo
CA125 decreased
NK and endometrium resistance unchanged
Before
Oosterlynck,D.J., Meuleman,C., Waer,M. Koninckx PR CO2-laser excision of endometriosis does
not improve the decreased natural killer activity. Acta Obstet.Gynecol.Scand.1994, 73, 333-337.
after
Bolton AE, Pockley AG, Clough KJ, Mowles EA, Stoker RJ,
Westwood OM et al. Identification of placental protein 14 as an
immunosuppressive factor in human reproduction. Lancet
1987; 1(8533):593-595
Okamoto N, Uchida A, Takakura K, Kariya Y, Kanzaki H,
Riittinen L, et al. Suppression by human placental protein 14
of natural killer cell activity. Am J Reprod Immunol 1991;
26:137-142
PP14 Inhibit NK cells
requires 18 h of contact
min -max dose : 5-50µgr/ml
potent suppressive activity
in mixed lymphocyte cultures
Koninckx P.R., Kennedy S., Barlow
D., Gyn Obstet Invest 1999,47,1-10
Angiogenetic factors
• Bioassay • VEGF • TGF
Like most benign tumors
Chicken allantoic membrane
Oosterlynck, Waer, Koninckx 1994
Endometriosis as a benign tumour
A benign tumour means
genetic predisposition
an insult
age radiation dioxin
progression
environment, immunology
A benign tumor
• loss in E-cadherin receptors in some foci of
endometriosis Gaetje R, Kotzian S, Herrmann G, Baumann R, and
Starzinski-Powitz A. (1997) Nonmalignant epithelial cells, potentially invasive in human
endometriosis, lack the tumor suppressor molecule E-cadherin. AMER. J. PATHOL. 150,
461-467
• suppressing metalloproteinase secretion in
vitro with progesterone or with a natural
inhibitor, inhibits endometriosis formation Bruner KL, Matrisian LM, Rodgers WH, Gorstein F, and Osteen KG. (1997) Suppression of
matrix metalloproteinases inhibits establishment of ectopic lesions by human
endometrium in nude mice. JOURNAL OF CLINICAL INVESTIGATION, 99, 2851-2857
Pollution and Endometriosis
• Dioxins and PCB’s
• Is Endometriosis increasing in the human ?
• Is endometriosis linked to pollution ?
• Animal models
• Human
0
1
2
3
4
5
6
7
C 5 25
IV
III
II
I
0
Endometriosis in Rhesus Monkeys chronically exposed to dioxin
Rier SE, Martin DC, Bowman RE, Dmowski, WP, Becker JL Fundam. Appl. Toxicol,
1991,111,422-431
Dioxin dose (ppt)
n
rAFS
Endometriosis in Rhesus Monkeys
• Spontaneous :
• clinical endo in autopsy 30% after 13 years
• Following
• dioxin : increased and dose dependent (Rier 1991)
• PCB : increased ( Campbell , unpublished)
• single energy & mixed energy proton irradiation, X rays (Wood 83, Fanton 91, Wood 91)
THE SHORTEST TIME
BETWEEN IRRADIATION AND
ENDOMETRIOSIS IS 6 YEARS
Dioxin Concentrations in women with endometriosis
Mayani A, Barel S, Soback S, Almagor M. Human Repr 1997, 12, 373-375
0
5
10
15
20
25
No I+II III+IV
% of women with detectable dioxin in blood
Stage of Endometriosis
1/35
3/24
5/20
Dioxin concentration (part per trillion)
0 I-II III-IV0.00
0.25
0.50
0.75
1.00
1.25
Stage of Endometriosis
Plasma Dioxin concentrations & risk
• Rhesus monkeys 25ppt 4 years (Bowman, 1989)
• T1/2 : 180-780 days
• adipose tissue concentration : 250-810 ppt
• Humans (Mocarelli, 1991)
• T1/2 : 7 years
• Seweso subjects : 2.000-35.000 ppt
• Area under time-concentration curve for 14 years • rhesus monkeys 388-1.400 (*1000)
• humans Seweso 5.500-112.000 (*1000) AUC T1/2=7 years
Bois FY, Eskenazi B, Environ. Health Perspect. 1994, 102,476
Dioxin and Radiation
• Dioxin binds to the DNA through specific receptor • Pseudo steroid
• Direct DNA effect
• transmissible effect eg sperm up to third generation
• Radiation has a direct DNA effect
Mutagenic factors
Genetic predisposition
• Loss of heterozygosity • Germ cell predisposition
Loss of Heterozygocity
X
X
X
Germline
Mutation
=Heredity
Somatic
Mutation
1st Hit Deletion or
Translocation
X X X
Duplication
X X
Point
Mutation
First
Hit
Second
Hit
Where should we look for a first hit ?
in the endometrium of women
with & without endometriosis
• loss of heterozygosity on p16(Ink4), GALT, and p53, as well as on APOA2, a region
frequently lost in ovarian cancer, occurs in endometriosis Goumenou AG, Arvanitis DA, Matalliotakis IM, Koumantakis EE, Spandidos DA. Microsatellite DNA assays reveal an allelic imbalance in p16(Ink4), GALT, p53, and APOA2 loci in patients with endometriosis. Fertil Steril 2001; 75(1):160-165.
• endometrium from women with endometriosis releases more ICAM-1, which can inhibit NK activity Somigliana E, Vigano P, Gaffuri B, Guarneri D, Busacca M, and Vignali M. (1996) Human endometrial stromal cells as a source of soluble intercellular adhesion molecule (ICAM)-1 molecules. Hum. Reprod. 11, 1190-1194
• P450aromatase transcripts & IL-6 and IL-11 transcripts in endometriosis women Noble LS, Simpson ER, Johns A, and Bulun SE. (1996) Aromatase expression in endometriosis. J. Clin. Endocrinol. Metab. 81, 174-179
• . Increased expression of heat shock protein 27 Ota H, Igarashi S, Hatazawa J, and Tanaka T. (1997) Distribution of heat shock proteins in eutopic and ectopic endometrium in endometriosis and adenomyosis. FERT. STERIL. 68, 23-28
Endometrium in Endometriosis
Genetics of endometriosis
Which Gene ?
Oxegene project
Stephen Kennedy
University of Oxford
Specific genes
Non hypothesis driven
Linkage analysis
S. Kennedy , 2005
Molecular genetic evidence
Linkage analysis 2006
• Extremely expensive
• Probably 2 chromosomes identified
• Highly secretive for patent reasons
• Clinically irrelevant for the next 10 years
• Potentially very important
For the surgeon : Cancer Stem cells –
progression - endometriosis ??
Philippe R. Koninckx Anastasia Ussia
New Frontiers in Endometriosis
Ara Pacis Museum, Rome 28-10-2011
www.mondoginecologico.it Gruppo Italo Belga
Sub;itted
Gynaecological surgery, in press
Ackowledged : Jacquez Donnez, Camran Nezhat, Charles Koh, Antonio Setubal
Moscow 7-11/6/2016
Deep Endometriosis surgeons > 20 Years
Conclusions
• Typical, cystic, and deep : different endpoints
• Impression that deep is progressing
Endometriosis 2015
Tissue proliferative
Invasive Immunologic
Genomic incident
Peritoneal cavity 3 or more diseases
rarely proliferative Non recurrent
Definition has to be changed No animal model -as for placentation
Koninckx PR Ussia A Moscow 2015
For the surgeon ?
• excise
For the surgeon ?
• If no adhesions :Cystic corpus luteum
• Excise / coagulate small
• Pathology
• Glands and stroma are
always found
For the surgeon ?
• Every day more arguments not to be too agressive
• Leave a rim of fibrosis
• Small resections
• Some are different
For the surgeon : the literature
• Research : Significance
Increases with N
Does not permit a conclusion of the population
Length of women men
• Clinically useful
• Outcome
• Accidents
• Sensitivity/specificity
for population
170 180 cm
170 180 cm