Endometriosis Basic Science - Prof TZ Jacoeb

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ENDOMETRIOSIS:
FROM BASIC SCIENCE TO
CLINICAL APPLICATION
T.Z. Jacoeb

Division of Reproductive Immunoendocrinology
Department of Obstetrics and Gynecology
Faculty of Medicine University of Indonesia
Jakarta
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WHAT IS
ENDOMETRIOSIS?
15 September 2012 Endometriosis: Basic Science and Clinical Application 2
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What is endometriosis?
Endometriosis is the implantation of endometrium-like
glandular and stromal cells outside their normal location in the
uterus.
Varma R, Rollason T, Gupta JK and Maher ER. Endometriosis and the neoplastic process. Reproduction
2004;127: 293304
The presence of endometrium-like tissue outside the uterus,
which induces a chronic, inflammatory reaction
Kennedy et al, 2005; Falconer, 2008
Endometriosis is a chronic benign gynecological disease
characterized by the presence of abnormally located tissue
(outside the uterine cavity) resembling the endometrium with
glands and stroma (endometrial epithelial and stromal cells).
Zasheva D, Dimitrov R, Stamenova M. Endometriosis and the role of the integrins in the pathogenesis of the
endometriosis. Akush Ginekol (Sofiia). 2007;46(5):37-48.
Endometriosis is a benign, estrogen-dependent disease with
an obscure etiology.
Contemporary genetic technologies and female reproduction. The Evian Annual Reproduction (EVAR)
Workshop Group 2010. Hum. Reprod. Update (November-December 2011) 17 (6): 829-847. doi:
10.1093/humupd/dmr033

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What is endometriosis?
Endometriosis has been considered an enigmatic
disease because it is often identified when investigating
women with infertility, chronic pelvic pain, dyspareunia
and dysmenorrhea.

Women with endometriosis have an increased risk of
different types of malignancies, especially ovarian cancer
and non-Hodgkin's lymphoma.

Contemporary genetic technologies and female reproduction. The Evian Annual Reproduction (EVAR) Workshop
Group 2010. Hum. Reprod. Update (November-December 2011) 17 (6): 829-847. doi: 10.1093/humupd/dmr033

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Basic Sciences Involved in Endometriosis
Anatomy and Embryology
Physiology
Medical Physics
Biology and Molecular
Biology
Genetics
Rheology
Histology, Pathology, and
Cytology
Angiology and Angiogenesis
Biochemistry
Pharmacology
Immunology
Reproductive
Immunoendocrinology
Endocrinology and
Metabolic Diseases
Oncology

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Applied Sciences Involved in
Endometriosis
Ultrasonography
Radio-Imaging
Endoscopy
Surgery

Pharmacy
Informational
Technology
Bioengineering

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ANATOMY
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Female Genital System
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Typical Locations of Endometriosis Sites
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Blood Supply to the Female Internal Genitalia
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Blood Supply to the Female Internal Genitalia
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Pathogenesis of Endometriosis
It is likely to be polygenic and multifactorial, but the exact pathogenic
mechanisms are still not entirely clear.
The most widely accepted theory is that of retrograde menstruation in
the context of:
an abnormal immune response, and
a genetic predisposition to developing endometriotic lesions;
this possibly occur after exposure to an unidentified environmental factor.
Sasson and Taylor, 2008.
Zasheva D, Dimitrov R, Stamenova M. Endometriosis and the role of the integrins in the
pathogenesis of the endometriosis. Akush Ginekol (Sofiia). 2007;46(5):37-48.

A better understanding of the pathogenesis of endometriosis may
help to identify new pharmacological targets and facilitate the
development of new treatments.
Contemporary genetic technologies and female reproduction. The Evian Annual
Reproduction (EVAR) Workshop Group 2010. Hum. Reprod. Update (November-December
2011) 17 (6): 829-847. doi: 10.1093/humupd/dmr033

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Pathogenesis of Endometriosis
Genetic Susceptibility
Environmental Factors
Dioxin
Immunological & Cellular Alterations
ENDOMETRIUM FRAGMENTS
Angiogenesis
VEGF
Retrograde
Menstruation
IL-8
MCP1
Aromatase
E
2

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A theoretical model of the development of endometriosis.
Fauser B et al. Hum. Reprod. Update 2011;17:829-847
The Author 2011. Published by Oxford University Press on behalf of the European Society of
Human Reproduction and Embryology. For Permissions, please email:
journals.permissions@oup.com.
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Critical factors in the pathogenesis of
endometriosis
Attachment of endometrial cells to the mesothelial cells
Invasion of endometrial cells into the mesothelium
Angiogenesis near nascent endometriosis implants
Proliferation of ectopic endometrial cells
Recruitment of inflammatory cells that support persistence
of the implants

Mahutte et.al. In: Olive DL. Endometriosis in Practice (2005:82)
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Un-uniformity of Endometriosis
The basic underlying cause of endometriosis is likely to
be multifactorial and involves interplay between several
factors.
The mechanisms involved in the development of an
endometriotic lesion in the pelvic peritoneum may include:
attachment,
invasion into the mesothelium,
survival and proliferation of ectopic endometrial cells.
Reproduction (EVAR) Workshop Group 2010. Hum. Reprod. Update (November-
December 2011) 17 (6): 829-847. doi: 10.1093/humupd/dmr033

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Problems in Endometriosis
Although endometriosis can be treated surgically,
recurrence of endometriotic lesions can occur.
Although most women have retrograde menstruation; only
some develop endometriosis due to the many gaps in our
understanding of its pathophysiology.
Pitsos M, Kanakas N. The role of matrix metalloproteinases in the
pathogenesis of endometriosis. Reprod Sci. 2009 Aug;16(8):717-26. Epub
2009 Apr 7.
Contemporary genetic technologies and female reproduction. The Evian
Annual Reproduction (EVAR) Workshop Group 2010. Hum. Reprod. Update
(November-December 2011) 17 (6): 829-847. doi: 10.1093/humupd/dmr033

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Obstacles in the Study of Endometriosis
The study of endometriosis is complicated by a number of factors:
the presence of different cell types within endometriotic lesions, and
the involvement of different pathogenic mechanisms in the formation of distinct
types of endometriotic lesion (such as peritoneal, ovarian and rectovaginal)
(Nisolle and Donnez, 1997).

It may be difficult to distinguish between cause and effect:
differences in eutopic endometrium between patients with and without
endometriosis, or in eutopic versus ectopic endometrium.
Contemporary genetic technologies and female reproduction. The Evian Annual Reproduction (EVAR)
Workshop Group 2010. Hum. Reprod. Update (November-December 2011) 17 (6): 829-847. doi:
10.1093/humupd/dmr033

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EMBRYOLOGY
Development of Peritoneum
Development of Edometrium
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Three Main Layers in Embryogenesis
Endoderm
Mesoderm
Ectoderm
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The initial stages of human embyogenesis.
http://www.digplanet.com/wiki/Human_embryogenesis
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Blastocyst with an inner cell mass and trophoblast.
http://www.digplanet.com/wiki/Human_embryogenesis
Nidation and Implantation of Embryo
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Development of female genital organs and tract
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Embryological Development Overview of
Female Genital Organs
Developmental Age Feature
Day 28 first primordial germ cells observed
Week 4-7 germ cell proliferation and migration
Week 4-5 (day 28-30) mesonephric tubules form
Week 4-5 (day 28-30) mesonephric ducts (Wolffian) forms
Week 5 (day 31-35)
genital ridge forms from coelomic
epithelium thickening
Week 6 (day 35-42) germ cells migrate to dorsal mesentry
Week 6 (day 38-42) budding indifferent gonad
Week 6 (day 40-42)
paramesonephric duct (Mullerian)
forms
Week 7 (day 42-48)
germ cells migrate into indifferent
gonad
(Table modified from: Kavlock R, Cummings A., 2004. Data originally from Parrott JA, Skinner MK., 1999)
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Development of genital ducts: Indifferent stage
7th week
9th week
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Embryology of the Female Genital Tract
Paramesonephric ducts
(Mllerian ducts)
http://embryology.med.unsw.edu.au/notes/genitalxxuterus.htm#Movies
Mllerian refers to Johannes Peter Mller (1801-1858) a German scientist who specialized in comparative anatomy.
He was the first in 1830 to described the duct named after him, the "Mllerian duct" also called the paramesonephric duct.
Two paramesonephric ducts form from coelomic
epithelium extending beside the mesonephric ducts.
These ducts initially form and then degenerate in the
male.

In the absence of Mllerian Inhibitory Factor these
ducts proliferate and grow extending from the vaginal
plate on the wall of the urogenital sinus to lie beside
the developing ovary.

The paired ducts begin to fuse from the vaginal plate
end, forming the primordial body of the uterus and the
unfused lateral arms form the uterine tubes.
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Early Fetal Structure
The Mllerian duct (=
paramesonephric duct, preferred
terminology) paired ducts that form
the epithelial lining of female
reproductive organs: uterine tube,
uterus, upper vaginal canal.

The term "paramesonephric" duct
means beside the mesonephric
(Wolffian) duct, which is its
anatomical location in early
development.
Urogenital sinus of female human embryo of 8.5 to 9 weeks old
(From model by Keibel) (Image: Gray's Anatomy)
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Drews U, Sulak O, Schenck PA. Androgens and the development of the vagina. Biol Reprod. 2002 Oct;67(4):1353-9.
PMID: 12297555)
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Genital duct development in female
Paramesonephric ducts
develop into the main genital
ducts
Initially 3 parts can be
recognized in each duct:
Cranial vertical portion that
opens into the abdominal
cavity....develop into uterine
tube
Horizontal part that crosses
the mesonephric
duct...develop into uterine
tube
Caudal vertical part that
fuses with its partner from
the opposite side...fuse to
form uterine canal
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A recent study using both chicken and mouse
embryos has shown that these initially paired tubular
structures derive from the coelomic epithelium.
Mllerian ducts have three elements:
1) a canalized epithelial tube
2) mesenchymal cells surrounding the tube
3) coelomic epithelial cells.

Guioli S, Sekido R, Lovell-Badge R. The origin of the Mllerian duct in chick and mouse. Dev Biol. 2006 Oct 3
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Vagina Development
The vagina arising by downward growth of Wolffian and
Mllerian ducts.
The sinovaginal bulbs are the caudal ends of the
Wolffian ducts.
Vaginal development is also under negative control of
androgens.
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Development of the peritoneum
The peritoneum develops ultimately from the mesoderm
of the trilaminar embryo.
As an embryo develops, the various abdominal organs
grow into the abdominal cavity from structures in the
abdominal wall.
In this process they become enveloped in a layer of
peritoneum.
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Peritoneum
Parietal peritoneum:
lines the inner surfaces of the walls of the abdominopelvic cavity
peritoneum.
has same a/v/n/lymphatics, as the region of wall that it covers
is sensitive to pressure, pain, heat+ cold+ laceration.
Visceral peritoneum:
lies on the surfaces of the abdominal and pelvic organs.
covers visceral organs like the stomach and intestines.
has same a/v/n/lymphatics, as the organ it covers.
stimulated primarily by stretching and chemical irritation.

http://anatomy.uams.edu/anatomyhtml/peritoneum.html
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ENDOMETRIUM
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Graph illustrating the Noyes method of endometrial dating, which highlights the uncertainty
in timing introduced during the post-ovulatory period, the mid-luteal phase and by measuring
the LH surge.
Diedrich K et al. Hum. Reprod. Update 2007;13:365-377
Human Reproduction and Embryology. All rights reserved. For Permissions, please email:
journals.permissions@oxfordjournals.org
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The roles of progesterone and estrogen (E2; E3, estriol) and estrogen receptors (ER) during
endometrial development.
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Factors regulated during the early stages of implantation.
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GENETICS, HORMONAL, AND
IMMUNOLOGICAL ASPECTS
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Genetics of endometriosis
Endometriosis regarded as a genetic disease due to its
reported familial aggregation and has a familial association.
Endometriosis is a polygenic disease
Many genes such as oncogenic K-ras are deregulated in
endometriosis.
An association of endometriosis and some genetic
polymorphisms coding for:
dioxin detoxification enzymes,
sex steroid biosynthesis and their receptors
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Genetics of endometriosis
First degree relatives of patients with endometriosis have a 6.9%
incidence of endometriosis in comparison with a 1% risk in controls.
Susceptibility to endometriosis has focused mainly on genes involved
in inflammation, steroid hormone regulation, metabolism,
biosynthesis, detoxification, vascular function and tissue remodelling.
Specific miRNAs have a function in the pathophysiology of
endometriosis.
Reproduction (EVAR) Workshop Group 2010. Hum. Reprod. Update (November-
December 2011) 17 (6): 829-847. doi: 10.1093/humupd/dmr033

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Hormonal Role in Endometriosis
Aberrant production of estrogen by endometriotic stromal cells

is indispensable for the development and maintenance of
endometriosis especially during the period of menstruation
when no ovarian estrogen is available.
This was supported by identification in endometriotic stromal

cells of the presence of all proteins/enzymes required for de
novo synthesis of estrogen:
steroidogenic acute regulatory protein (StAR)
P450 side-chain cleavage enzyme (P450scc)
3b-hydroxy steroid dehydrogenase (3b-HSD)
17 a-hydroxylase 17,20 lyase
P450 aromatase
17b- HSD type1

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cAMP
Aromatase
VEGF
IL1-b
A

E
1
E
2
GROWTH
Adrenal
Ovary
COX-2
Arachidonic Acid
PGE
2
INFLAMMATION
Endometriotic Cell
Epithelial Cell
Cholesterol

StAR

Attar E and S.E. Bulun, Hum Reprod Update.2005; 0: 341 1
5

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Endometriosis: Basic Science and Clinical Application 49
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Attar E and S.E. Bulun, Hum Reprod Update.2005; 0: 341

Aromatase Inhibitors: complete inhibition in estrogen synthesis
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Growth and maintenance of endometriosis
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Endometriosis: immunologic abnormality
15 September 2012
Systemic
Increased immunoglobulin production
Increased in T-helper (CD
4
) cells
Lymphocyte-mediated cytotoxicity deficiency to the
endometrium
Embryotoxic serum
Suppressing serum to the NK cell activity
Cellular immunity deficiency
Defect in NK cell activity
Abnormal autoimmune function
Decrease in suppressor cell activity
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Endometriosis: immunologic abnormality
15 September 2012
Peritoneal
Proliferation of endometrial stroma cells
Increase in cytotoxicity of peritoneal macrophages
Decrease in sperm affinity to the zona pellucida
Lymphocyte proliferation
Increase in sperm phagocytosis by the peritoneal macrophages
Increase in cytokine level
Enhancement of cyclic activity of the macrophages
Presence of antiendometrium antibody
Decrease in natural killer activity of the lymphocytes
Secretion of interleukin-1 receptor antagonist of peritoneal macrophages
Presence of non-organ-specific autoantibody
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FETAL ENDOMERIOSIS
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Mllerianosis and Fetal Endometriosis
Sampson's classification of heterotopic or misplaced
endometrial tissue is based on pathogenesis:
1. direct invasion or primary endometriosis [adenomyosis];
2. a similar condition occurs in the wall of the tube from its invasion
by the tubal mucosa [endosalpingiosis];
3. peritoneal or implantation endometriosis;
4. transplantation endometriosis;
5. metastatic endometriosis;
6. developmentally misplaced endometrial tissue [Mllerianosis]
(Sampson, 1925).

Batt RE, Smith RA, Buck Louis GM, Martin DC, Chapron C, Koninckx
PR, Yeh J. Mllerianosis. Histol Histopathol. 2007 Oct;22(10):1161-6.

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Mllerianosis may be defined as an organoid structure of
embryonic origin.
A choristoma composed of Mllerian rests (normal
endometrium, normal endosalpinx, and normal
endocervix) - singly or in combination, incorporated within
other normal organs during organogenesis.
A choristoma is a mass of histologically normal tissue that
is "not normally found in the organ or structure in which it
is located (Choristoma, 2006).

Batt RE, Smith RA, Buck Louis GM, Martin DC, Chapron C, Koninckx PR, Yeh J.
Mllerianosis. Histol Histopathol. 2007 Oct;22(10):1161-6.

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Mllerian choristomas are a subset of non-Mllerian
choristomas found throughout the body.

Histologically, endometrial-Mllerianosis and
endometriosis are both composed of endometrial glands
and stroma, but there the similarity ends. Their
pathogenesis is different.

Batt RE, Smith RA, Buck Louis GM, Martin DC, Chapron C,
Koninckx PR, Yeh J. Mllerianosis. Histol Histopathol. 2007
Oct;22(10):1161-6.

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Researchers remain unsure as to the definitive cause of
endometriosis.
Theory of Mllerianosis for endometriosis, that is the
misplacing of primitive endometrial tissue along the
migratory pathway of fetal organogenesis.
Signorile PG, Baldi F, Bussani R, D'Armiento M, De Falco M, Baldi A.
Ectopic endometrium in human fetuses is a common event and sustains
the theory of mllerianosis in the pathogenesis of endometriosis, a
disease that predisposes to cancer. J Exp Clin Cancer Res. 2009 Apr
9;28:49
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Autopsy 36 human female fetuses at different gestational age.
Morphological and immunohistochemical study (expression of estrogen
receptor and CA125) on the pelvic organs of the 36 fetuses included en-block
and totally analyzed.
In 4 out of 36 fetuses we found presence of misplaced endometrium in five
different ectopic sites, in the:
recto-vaginal septum,
proximity of the Douglas pouch,
mesenchimal tissue close to the posterior wall of the uterus,
rectal tube at the level of muscularis propria, and
wall of the uterus. All these sites are common location of endometriosis in women.
A cause of endometriosis is proposed as the dislocation of primitive
endometrial tissue outside the uterine cavity during organogenesis.
Signorile PG, Baldi F, Bussani R, D'Armiento M, De Falco M, Baldi A. Ectopic
endometrium in human fetuses is a common event and sustains the theory of
mllerianosis in the pathogenesis of endometriosis, a disease that predisposes
to cancer. J Exp Clin Cancer Res. 2009 Apr 9;28:49
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COELOMIC METAPLASIA AND
ADHESION MOLECULES
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Rokitansky Endometriosis = Coelomic
Metaplasia
Retrograde menstruation required the existence of a uterine
structure and endometrial tissue.
A 20-year-old with Mayer-Rokitansky-Kster-Hauser syndrome
presented with increasing pelvic pain and underwent
laparoscopy.
Uterine, cervical, vaginal, and tubal agenesis was confirmed.
Stage I endometriosis was visualized in the posterior cul-de-sac and
destroyed.
She received medical therapy for 5 years until she represented with
pain and underwent another laparoscopy, at which endometriosis was
again identified and destroyed.
This case of endometriosis in a patient with complete uterine
agenesis supports the theory of coelomic metaplasia.
Mok-Lin EY, Wolfberg A, Hollinquist H, Laufer MR. Endometriosis in a
Patient with Mayer-Rokitansky-Kster-Hauser Syndrome and Complete
Uterine Agenesis: Evidence to Support the Theory of Coelomic Metaplasia.
J Ped Adolescent Gynecol. 2010;23 (1): e35-e37

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Adhesion Molecules in Endometriosis
A dynamic relationship between the endometrium and
peritoneum because both tissues may participate in the
spontaneous development of endometriosis.
Various adhesion molecules, pro-inflammatory cytokines
and chemoattractants cytokines have emerged as central
coordinators of endometrial-peritoneal interactions.

Kyama CM, Mihalyi A, Simsa P, Falconer H, Fulop V, Mwenda JM,
Peeraer K, Tomassetti C, Meuleman C, D'Hooghe TM. Role of cytokines
in the endometrial-peritoneal cross-talk and development of
endometriosis. Front Biosci (Elite Ed). 2009 Jun 1;1:444-54.

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Adhesion Molecules in Endometriosis
Menstrual endometrium has the ability to bond and invade
the peritoneal tissue.
In baboons intrapelvic injection of menstrual endometrium
permits the study of early endometrial-peritoneal
interaction in an in vivo culture microenvironment and can
lead to important insight in the early development of
endometriotic lesions.
Kyama CM, Mihalyi A, Simsa P, Falconer H, Fulop V, Mwenda JM,
Peeraer K, Tomassetti C, Meuleman C, D'Hooghe TM. Role of
cytokines in the endometrial-peritoneal cross-talk and development
of endometriosis. Front Biosci (Elite Ed). 2009 Jun 1;1:444-54.

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Integrins in the Pathogenesis of
Endometriosis
The essential stage in the process of development of
endometrial lesions is the process of adhesion of
endometrial cells on the peritoneal surface and on the
organs.
The adhesion molecules (integrins) have the most
essential role in this first stage.
Zasheva D, Dimitrov R, Stamenova M. Endometriosis and the role
of the integrins in the pathogenesis of the endometriosis. Akush
Ginekol (Sofiia). 2007;46(5):37-48.

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Integrins in the Pathogenesis of
Endometriosis
Cell surface receptors with glycoprotein structure.
Have part in process of adhesion of the endometrial cells
to the proteins from extra-cellular matrix (ECM) outside
the uterus.
Have part like signal molecules in the processes of
proliferation and invasion of endometrial implants.
Very essential molecules influencing the viability of
endometrial implants as well as the angiogenesis in the
new forming endometrial implants.

Zasheva D, Dimitrov R, Stamenova M. Endometriosis and the role of the
integrins in the pathogenesis of the endometriosis. Akush Ginekol (Sofiia).
2007;46(5):37-48.

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Matrix Metalloproteinase in Endometriosis
Participate in the histologic changes of the endometrium
during the menstrual cycle
Higher expression during the menstrual and proliferative
phase of the endometrium
Decreased expression during the secretory phase.
Degradation of extracellular matrix is essential for the
endometrial cells to invade the peritoneum and to develop
an endometriotic lesion as well.

Pitsos M, Kanakas N. The role of matrix metalloproteinases in the
pathogenesis of endometriosis. Reprod Sci. 2009 Aug;16(8):717-26.
Epub 2009 Apr 7.

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MALIGNANT POTENCY OF
ENDOMETRIOSIS
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Clinicopathological similarities of
endometriosis and cancer
(i) endometriotic implants may directly undergo malignant
transformation, perhaps through an atypical
endometriosis transition phase;
(ii) both endometriosis and cancer share common
antecedent mechanisms and/or predisposing factors (e.g.
genetic susceptibility, immune/ angiogenic dysregulation,
environmental toxin exposure), with obvious divergence in
molecular pathways downstream.

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Malignant Potencies of Endometriosis:
Histopathology
Endometriosis displays features of:
Atypia,
Adherence,
Invasion and
Metastases.
Atypical endometriosis:
endometrial glands with cytological or architectural atypia
(LaGrenade & Silverberg 1988),
observed in 1235% of ovarian endometriosis
(Seidman 1996, Nishida et al. 2000, Bayramoglu & Duzcan 2001).
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Malignant Potencies of Endometriosis:
Histopathology
6080% of cases of endometriosis-associated ovarian
cancer (EAOC) occur in the presence of atypical ovarian
endometriosis.
(Fukunaga et al. 1997, Ogawa et al. 2000, Oral et al. 2003).
25% show direct continuity of the atypical ovarian
endometriosis with ovarian cancer.
(Fukunaga et al. 1997)
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Malignant Potencies of Endometriosis: Ovarian malignancy may
arise directly from ovarian endometriosis
Around 60% of EAOCs (endometriosis-associated ovarian
cancer) occur with the cancer adjacent to endometriosis
or arising directly from ovarian endometriosis, with the
remaining 40% occurring with distant endometriotic
disease
(Erzen & Kovacic 1998, Modesitt et al. 2002).

Clear-cell and endometrioid carcinomas are the
commonest EAOCs with ovarian endometriosis, while
clear-cell adenocarcinoma and adenosarcoma are the
commonest EAOCs in extra-ovarian endometriosis
(Erzen & Kovacic 1998, Stern et al. 2001, Zaino et al. 2001).
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Malignant Potencies of Endometriosis: Ovarian malignancy may
arise directly from ovarian endometriosis
The risk of direct malignant transformation of ovarian
endometriosis has been estimated as 0.71.6% over an
average of 8 years
(Seidman 1996, Nishida et al. 2000).
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CLINICAL PRESENTATIOS
OF ENDOMETRIOSIS
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3 Clinical Forms of Pelvic Endometriosis
1) peritoneal endometriosis,
2) ovarian endometriosis,
3) rectovaginal septum endometriosis.

These three entities are distinct and have a different
histopathogenesis (Nisolle, 1996).

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Endometriosis manifestation [1]
Vesicle
Spider nevi
Ecchymosis
Light brown
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Yellowish brown
Red vesicle
Dark red
Laser-cystectomy
Endometriosis manifestation [1]
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Three types of deep rectovaginal endometriosis
(Adamyan classification, 1993)
1) Retrocervical endometriosis (in which the rectum is
usually free of disease)
2) Rectovaginal septum
3) Bowel endometriosis (with infiltrative characteristics
over the bowel thickness)
This type of classification may be more compatible with the
surgical approach of this disease
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Types of deep retrocervical endometriosis
(Adamyan and Martin classification, 2001)
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Types of deep retrocervical endometriosis
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Types of deep rectovaginal endometriosis
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TREATMENT OF
ENDOMERIOSIS
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Basics of treatment for Pelvic
endometriosis:
All foci have to be eliminated: destruction of
tissue, cytoreduction (benign cancer), elimination
of antigen.
There is no single method of treatment for all type
of endometriosis: medical (hormonal) and surgical
intervention are always necessary.
Operative laparoscopy is the current choice:
clean, less traumatic, prompt recovery.
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Classic Medical Treatments of Endometriosis
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Intracrine and Rational Treatment of
Endometriosis

A = Androgen Arom = aromatase
E
1
= Estron E
2
= Estradiol
GnRHa= GnRH agonist
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The optimal medical treatment
No menopausal symptoms
No proliferation
Menopausal
Symptoms
Proliferation of implants
Estradiol level
pg/ml

Therapeutic
Window
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Lunenfeld on Endometriosis
........back in 1958, I wasnt working on implantation only
to prevent pregnancies; I also wanted to study
implantation because I wanted to prevent metastasis
implanting anywhere in the body
Six years later in Chicago when he met Professor Melvyn Cohen, who
was doing the first laparoscopies and showed him endometriotic tissue
in the pelvis, Lunenfeld commented:
Listen! This is a very interesting thing, maybe we should
work on implantation and then we could probably prevent
implantation of endometriosis wherever it comes from?

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Lunenfeld on Endometriosis
I am sure that working on factors which can control
angiogenesis and factors which can prevent implantation
have a future.
We are learning to control pain through certain
progestogen agents and GnRH analogues, but for the
time being the only thing that we really have, and which
really works, is surgical removal of the disease.
Through laparoscopy you can diagnose and treat at the
same time, removing lesions as good as you can.
But it is still surgery and I only hope in the very near future
endometriosis can be treated medically.

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FUTURE TREATMENT OF
ENDOMETRIOSIS
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Stem Cells in Endometriosis
Adult stem cells have been identified in several tissues,
including the endometrium.
These cells are probably involved in the regenerative
ability of the endometrial cycle, and also in the
pathogenesis of proliferative gynecological diseases, such
as endometriosis.

Flvia R. Oliveira, Cynthia Dela Cruz, Helen L. Del Puerto, Qusia
T.M.F. Vilamil, Fernando M. Reis and Aroldo F. Camargos. Stem cells:
Are they the answer to the puzzling etiology of endometriosis? Histol
Histopathol 27, 23-29 (2012)

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Stem Cells in Endometriosis
Bone marrow-derived stem cells transplanted into
humans and animals have also been identified in eutopic
endometrium and endometriotic implants.
Available evidence regarding stem/progenitor cells in the
human endometrium may be the possible involvement of
these cells in the etiology of endometriosis.

Flvia R. Oliveira, Cynthia Dela Cruz, Helen L. Del Puerto, Qusia T.M.F. Vilamil, Fernando
M. Reis and Aroldo F. Camargos. Stem cells: Are they the answer to the puzzling etiology of
endometriosis? Histol Histopathol 27, 23-29 (2012)

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Stem cells in Endometriosis: a new perspective
Stem cells located in the basal layer of the endometrium
are thought to be responsible for cyclical tissue
regeneration.
Endometrial stem cells in human endometrium
demonstrate multipotency and are different from other
endometrial cell types.
These cells have been termed side population cells (SP
cells)
SP cells have been demonstrated to proliferate and
differentiate into various endometrial cell types in vitro and
have unique angiogenic and migratory properties
(Masuda et al., 2010).
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Human endometrium can be reconstructed in
immunodeficient mice upon injection with human
endometrial SP cells
(Cervell et al., 2010).

The retrograde menstruation of SP cells and subsequent
implantation onto the surface of ectopic sites are
responsible for the establishment of endometriotic lesions
(Sasson and Taylor, 2008; Masuda et al., 2010).
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An initial genetic mutation may cause aberrant behavior of
a subpopulation of endometrial stem cells;
Clonal expansion of such cells may then occur and result
in development of endometriosis.
Peritoneal cells could undergo de-differentiation back to
endometrial cells, which take on an altered activity.

(Gargett et al., 2009).

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Summary
Endometriosis is an enigmatic disease.
It can emerge at the earliest time in the fetal life.
The knowledge of human implantation and
embryogenesis is a coined and basic science to
understand the pathogenesis of endometriosis.
Stem cell is expected to be the future therapy of
endometriosis.
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THANK YOU
T.Z. Jacoeb
15 September 2012

Endometriosis Basic Science - Prof TZ Jacoeb

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P

Aberrant production of estrogen by endometriotic stromal cells

This was supported by identification in endometriotic stromal

steroidogenic acute regulatory protein (StAR)

P450 side-chain cleavage enzyme (P450scc)

3b-hydroxy steroid dehydrogenase (3b-HSD)

17 a-hydroxylase 17,20 lyase

17b- HSD type1

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