| Abstract
Endometriosis is defined as the presence of ectopic
endometrial-like tissue outside the uterine cavity.
This disease afflicts women during their reproductive
age and is mainly associated with pelvic pain and
infertility. Sampson’s theory, which supports
the ability of endometrial fragments from retrograde
menstruations to slough through fallopian tubes
and reach peritoneal environment, has been recognised
as the most plausible explanation for endometriosis
for many years. Further studies provided evidence
that fundamental abnormal changes may occur within
the eutopic endometrium of women with endometriosis
compared to that of women without endometriosis.
These dysfunctions include aberrantly expressed
genes such as matrix metalloproteinases, Hox, integrins,
anti-apoptotic, steroid hormones, immuno-inflammatory
and angiogenesis genes. This mini-review aims at
summarising major biochemical and molecular changes
detected in the eutopic endometrium of women with
endometriosis, which may play a role in the pathogenesis
of the disease.
Introduction
The pathophysiology of endometriosis is defined
as the presence of ectopic endometrial-like tissue,
which often includes glandular and stromal epithelial
cells, outside the uterine cavity. This disease
generally affects women during the period of their
childbearing age and is mainly associated with pelvic
pain and infertility [1]. Despite decades of extensive
investigations, the pathogenesis of this disease
still remains not only elusive but also controversial.
Early in 1927, Sampson’s theory related to
retrograde menstruations, which became the most
widely accepted explanation, at least for peritoneal
endometriosis, proposes that endometrial fragments
from retrograde menstruation sloughed through fallopian
tubes, reach the peritoneal cavity where they can
attach to the epithelium of the peritoneum, invade
and implant into the host tissue and establish a
new blood supply that sustain ectopic endometrial
tissue survival and growth [2].
However, a compelling
number of studies have provided evidence that no
correlation could be established between the prevalence
of the retrograde menstruations and endometriosis,
since retrograde menstruations is frequently observed
in healthy women and endometriosis is observed only
in 10% of women during their reproductive age. Now,
there is increasingly accumulating evidence which
suggests that the eutopic endometrium of women with
endometriosis displays fundamental changes compared
to that of women without endometriosis.
In this mini-review,
our attempt is to give an insight into endometriosis-related
molecular dysfunctions, such as genetic aberrations,
immune, endocrine and tissue remodelling changes,
found in the eutopic endometrium of women with endometriosis,
which may facilitate the ectopic development of
endometrial tissue and play a key role in the pathogenesis
of endometriosis.
Gene dysfunctions
present in the eutopic endometrium from women with
endometriosis
A compelling finding that the endometrium of women
with endometriosis exhibits genes abnormally expressed
has been extensively reported in the literature.
Hormonal
dysfunctions
Steroid hormones represent the key systemic factors
that drive the endometrium through the sequential
phases of menstrual cycle. Several studies have
identified isoforms for oestrogen (ER-alpha and
ER-beta), and progesterone (PR-A and PR-B) receptors
in the epithelial, stromal and vascular cells of
human endometrium [3]. Both oestrogen and progesterone
receptors’ expression in endometrial cells
varies during the different phases of the menstrual
cycle. In normal endometrium, ER-alpha and PR-B
isoforms have been characterised as being the predominant
steroid receptors, and abnormal variations in the
ER-alpha/ER-beta or PR-A/PR-B ratio expression have
been observed in tissues or cells of women with
endometriosis [4, 5].
In addition, endometriotic
lesions show abnormal oestradiol biosynthesis compared
with endometrium from healthy women [6]. The biosynthesis
of oestradiol is triggered by an ovarian enzyme
called aromatase, which catalyzes the conversion
of androstenedione and testosterone to oestrone
and oestradiol, respectively. Aromatase expression
was generally found in ovarian granulosa cells,
placental syncytiotrophoblasts, adipose tissue,
skin fibroblasts and brain, but was not detected
in normal endometrium. However, aberrant expression
of aromatase was found in endometriotic and endometrial
tissues of women with endometriosis. Such aberrant
local oestrogen production may enhance the growth
and invasion of endometriosis tissue and play a
role in endometriosis-associated inflammation [6].
Immuno-inflammatory
changes
It is now believed that the immune system and immunological
changes play a key role in the onset and development
of endometriosis and the manifestation of its major
and highly frequent symptoms such as chronic pelvic
pain and infertility. Although immunological changes
reported by several studies have brought a better
understanding of the pathogenesis of the disease,
the question frequently arisen is to know whether
these immunological changes are a cause or an effect
of the disease. However, it is quite possible that
endometrial cells of endometriosis patients may
chronically stimulate the immune system, modulate
immune cells’ functions at the local level
and facilitate thereby the aberrant ectopic growth
of endometrial cells which, otherwise, had to be
eliminated by immune cells.
Monocyte chemoattractant
protein-1 (MCP-1), a potent monocyte/macrophage
activating and chemoattracting cytokine, is produced
by many cells including monocytes, macrophages,
T lymphocytes, fibroblasts, endothelial cells and
endometrial cells. Deregulation of MCP-1 in patients
with endometriosis was first described in our laboratory
in 1995. This study showed that incubation of endometrial
epithelial cells from women with endometriosis with
interleukin-1-beta (IL-1-beta) or tumour necrosis
factor alpha(TNF-alpha) resulted in an increased
secretion of MCP-1, as compared to endometrial cells
from normal patients [7]. Interestingly, studies
from our laboratory also revealed that MCP-1 expression
was increased in the eutopic endometrium of women
with endometriosis [8]. This suggests that abnormal
expression of MCP-1 in the eutopic endometrial tissue
may be involved in macrophage activation within
this tissue, but also following interaction of endometrial
tissue debris with peritoneal immune cells.
Interleukin-1 (IL-1),
a multifunctional cytokine, is believed to play
a fundamental role in inflammation, immune response
and reproductive activities in normal endometrium
during the menstrual cycle, or during embryo implantation
and development [9]. The mechanisms that modulate
both expression and action of IL-1 in the endometrium
take involve all the family members of this cytokine,
notably IL-1-alpha, IL-1-beta, IL1 receptor antagonist
(IL-1ra) and its three receptors designed as IL-1RI,
IL-1RII and IL-1RIII (also known as IL-1 receptor
accessory protein). IL-1Ra is a natural inhibitor
of IL-1 and competes with IL-1-alpha and IL-1-beta
for binding to IL-1RI, which mediates cell activation
by IL-1 and most signalling pathways. In contrast,
IL-1RII appears to be dispensable for IL-1 signalling
and acts as a “decoy” receptor [10].
Work from our laboratory described for the first
time the existence of the decoy IL-1RII in human
endometrial tissue and a drastic lack of its expression
in eutopic endometrium from women with endometriosis
[11]. Defective endometrial IL-1RII gene expression
in women with endometriosis may reduce the capability
of endometrial tissue to down-regulate IL-1 activity
and may, in view of IL-1 immuno-modulatory and growth
promoting effects, account for the capability of
endometrial cells of women with endometriosis to
interact differently with the stimuli present in
the peritoneal environment and facilitate their
own abnormal growth [12].
The prostaglandins (PGs) are involved in many aspects
of physiological processes such as ovulation, pregnancy,
but also in inflammatory pathological disease including
arthritis, rheumatoid polyarthritis, cancer and
endometriosis. PGE2 biosynthesis and secretion are
mediated by an inducible cyclooxygenase type-2 (COX-2).
PGE2 was identified as the most potent inducer of
aromatase activity in endometriomas and extraovarian
endometriotic implants which express high levels
of aromatase [13]. Thus, a positive feedback loop
observed for continuous local production of oestrogen
and PGE2 production may contribute to maintain and
enhance proliferative and inflammatory features
of endometriosis.
Abnormal
expression of tissue remodelling, apoptotic and
angiogenic factors
Matrix
metalloproteinases (MMPs) and their inhibitors
MMPs and their inhibitors, tissue inhibitors of
the matrix metalloproteinase (TIMPs) are expressed
during menstruation, and play a fundamental role
in the breakdown of all components of the extracellular
matrix (ECM) as well as tissue repair [14]. MMPs
and their inhibitors TIMPs are strongly required
for the degradation of ECM so that to facilitate
the invasion of endometrial cells and their attachment
onto the peritoneal mesothelium [15]. Several studies
have shown an aberrant increase in the mRNA expression
of MMPs in endometriotic and endometrial tissues
[16, 17].
More recently,
studies from our laboratory have shown an imbalance
between MMP-9 expression and that of its inhibitor
TIMP-1 at both protein and mRNA levels in the eutopic
endometrium of women with endometriosis. This may
reflect the inherent capacity of endometrial tissue
to breakdown the ECM and therefore enable ectopic
implantation and growth [17]. However, this also
requires a new vascular supply or angiogenesis.
Angiogenesis, defined as the growth of new capillaries
from pre-existing vessels, refers to important physiological
processes involved in embryogenesis and wound healing,
but often associated with pathological processes
such as atherosclerosis, chronic inflammation and
tumours malignancies and endometriosis [18, 19].
Recent in vivo
studies, assuming that angiogenesis is of pivotal
importance in the pathogenesis of endometriosis,
have demonstrated that angiogenic inhibitors agents
such as anti-hVEGF, TNP-470, endostatin and anginex
were effective inhibitors of established endometriotic
lesions in nude mice [20]. Donnez et al [21] reported
that eutopic endometrial cells epithelial cells
of women with endometriosis versus endometrium from
healthy women, exhibited significantly increased
vascular endothelial growth factor (VEGF) levels,
particularly during the late secretory phase of
the menstrual cycle. Several studies have also provided
evidence of potent angiogenic characteristics of
macrophage migration inhibitory factor (MIF), mainly
in tumour-igenesis processes. In fact, MIF is required
for tumour-initiated endothelial cell proliferation
and tumour neo-vascularisation and anti-MIF antibody
has been shown to significantly inhibit tumour growth
and tumour-associated angiogenesis [22].
Our recent data
showed an abnormal MIF expression in the peritoneal
fluid, the peripheral blood and the endometrial
tissue of women with endometriosis, particularly
in those who were infertile [23]. The role of IL-8,
IL-6, as well as many growth factors reported to
have angiogenic activity, namely epidermal growth
factor (EGF), hepatocyte growth factor (HGF) have
also been studied, and abnormally elevated expression
of these factors was observed in endometrial cells
of women with endometriosis compared to healthy
women [24]. Besides, endometrial cells of women
with endometriosis appeared to resist apoptosis
and to survive in ectopic locations. The B-cell
lymphoma/leukemia-2, known as Bcl-2, is a proto-oncogene
whose main feature is to prevent apoptosis or “programmed
cell death”. Cell fate to survival or death
depends on Bcl-2/Bax ratio expression, where Bax
acts as an antagonist pro-apopotic protein. Study
of their expression have been extensively documented
in endometrial cells and showed an increased Bcl-2
expression concomitantly to an absence of Bax expression
in the late proliferative phase of eutopic endometrium
from women having endometriosis [25]. Taken together,
these findings make therefore plausible the capability
of endometrial cells to resist apoptosis, invade
the host tissue, stimulate angiogenesis and favour
their ectopic growth.
Gene
dysfunctions in the eutopic endometrium of women
with endometriosis-related infertility
There is growing evidence supporting abnormal eutopic
endometrium and implantation failure in some women
with endometriosis as an underlying cause of infertility
in this population. In addition, evidence is accumulating
of aberrant gene and gene-product expression in
eutopic and ectopic endometrium at other times of
the cycle that may be related to infertility or
to the establishment of the disease. In many infertility-associated
gynaecological disorders, the failure of embryonic
implantation into the endometrium has been considered
as a limiting factor to the establishment of successfully
pregnancy [26]. Integrins are known to play a crucial
role during the endometrial receptivity. Lessey
et al reported that co-expression of some integrins
such as alpha-v-beta-3 and alpha-4-beta1 are the
key molecules to frame the putative window of implantation
[27]. However, these authors have also found a significant
lack in alpha-v-beta-3 integrin expression in the
endometrium of women with endometriosis, during
the period of implantation [28].
The transcriptional
factors HOX genes play an essential role during
the embryonic development and implantation. The
two defined HOXA10 and HOXA11 are expressed in the
adult uterus in human and mouse. However, the expression
of these genes was found to be down-regulated in
the eutopic endometrium of women with endometriosis
compared to women without endometriosis [29].
The transcriptional factor EMX2 is necessary for
the reproductive tract development and is negatively
regulated by HOXA10 gene. Recent data indicate that
EMX2 mRNA is aberrantly expressed in the eutopic
endometrium of women with endometriosis during the
peri-implantation phase, whereas a significant decrease
of their mRNA levels was observed in the endometrium
of women without endometriosis [30].
Leukaemia inhibitory factor (LIF) has been shown
to be important in embryonic attachment to the epithelium
and also for endometrial decidualisation. In addition,
in vivo studies demonstrated the importance
of LIF in the earliest stages of implantation since
the absence of functional LIF gene resulted in blastocyst
implantation defect and total infertility observed
in female mice [31]. Recent studies suggest that
reduced endometrial LIF may contribute to infertility
in some endometriosis women [32].
Conclusion
Endometriosis remains an enigmatic and complex gynaecological
disorder. The existence of fundamental changes in
eutopic endometrium of women with endometriosis
is supported by the presence of aberrantly expressed
pro-inflammatory, immuno-modulatory, hormonal, growth,
remodelling and angiogenic factors. It is now believed
that these dysfunctions play a central role in the
pathogenesis of endometriosis and the manifestation
of its clinical symptoms. However, further studies
are needed to translate these findings into sustainable
improvements of endometriosis diagnosis and clinical
outcomes.
REFERENCES
1. Endometriosis and infertility.
Fertil Steril 2004; 81: 1441-1446.
2. Sampson J. Peritoneal endometriosis due to menstrual
dissemination of endometrial tissue into the pelvic
cavity Am J Obstet Gynecol 1927; 14: 422-425.
3. Mertens HJ, Heineman MJ, Theunissen PH, de Jong
FH, Evers JL. Androgen, estrogen and progesterone
receptor expression in the human uterus during the
menstrual cycle. Eur J Obstet Gynecol Reprod Biol
2001; 98: 58-65.
4. Attia GR, Zeitoun K, Edwards D, Johns A, Carr
BR, Bulun SE. Progesterone receptor isoform A but
not B is expressed in endometriosis. J Clin Endocrinol
Metab 2000; 85: 2897-2902.
5. Brandenberger AW, Lebovic
DI, Tee MK, Ryan IP, Tseng JF, Jaffe RB, Taylor
RN. Oestrogen receptor (ER)-alpha and ER-beta isoforms
in normal endometrial and endometriosis-derived
stromal cells. Mol Hum Reprod 1999; 5: 651-655.
6. Zeitoun KM, Bulun SE. Aromatase: a key molecule
in the pathophysiology of endometriosis and a therapeutic
target. Fertil Steril 1999; 72: 961-969.
7. Akoum A, Lemay A, Brunet C, Hebert J. Secretion
of monocyte chemotactic protein-1 by cytokine-stimulated
endometrial cells of women with endometriosis. Le
groupe d'investigation en gynecologie. Fertil Steril
1995; 63: 322-328.
8. Jolicoeur C, Boutouil M, Drouin R, Paradis I,
Lemay A, Akoum A. Increased expression of monocyte
chemotactic protein-1 in the endometrium of women
with endometriosis. Am J Pathol 1998; 152: 125-133.
9. Simon C, Pellicer A, Polan ML. Interleukin-1
system crosstalk between embryo and endometrium
in implantation. Hum Reprod 1995; 10 Suppl 2: 43-54.
10. Colotta F, Re F, Muzio M, Bertini R, Polentarutti
N, Sironi M, Giri JG, Dower SK, Sims JE, Mantovani
A. Interleukin-1 type II receptor: a decoy target
for IL-1 that is regulated by IL-4. Science 1993;
261: 472-475.
11. Akoum A, Jolicoeur C, Kharfi A, Aube M. Decreased
expression of the decoy interleukin-1 receptor type
II in human endometriosis. Am J Pathol 2001; 158:
481-489.
12. Kharfi A, Boucher A, Akoum A. Abnormal interleukin-1
receptor type II gene expression in the endometrium
of women with endometriosis. Biol Reprod 2002; 66:
401-406.
13. Noble LS, Takayama K, Zeitoun KM, Putman JM,
Johns DA, Hinshelwood MM, Agarwal VR, Zhao Y, Carr
BR, Bulun SE. Prostaglandin E2 stimulates aromatase
expression in endometriosis-derived stromal cells.
J Clin Endocrinol Metab 1997; 82: 600-606.
14. Rodgers WH, Matrisian LM, Giudice LC, Dsupin
B, Cannon P, Svitek C, Gorstein F, Osteen KG. Patterns
of matrix metalloproteinase expression in cycling
endometrium imply differential functions and regulation
by steroid hormones. J Clin Invest 1994; 94: 946-953.
15. Koks CA, Groothuis PG, Dunselman GA, de Goeij
AF, Evers JL. Adhesion of menstrual endometrium
to extracellular matrix: the possible role of integrin
alpha(6)beta(1) and laminin interaction. Mol Hum
Reprod 2000; 6: 170-177.
16. Osteen KG, Bruner-Tran KL, Eisenberg E. Reduced
progesterone action during endometrial maturation:
a potential risk factor for the development of endometriosis.
Fertil Steril 2005; 83: 529-537.
17. Collette T, Maheux R, Mailloux J, Akoum A. Increased
expression of matrix metalloproteinase-9 in the
eutopic endometrial tissue of women with endometriosis.
Hum Reprod 2006.
18. Griffioen AW, Molema G. Angiogenesis: potentials
for pharmacologic intervention in the treatment
of cancer, cardiovascular diseases, and chronic
inflammation. Pharmacol Rev. 2000; 52: 237-268.
19. Hull ML, Charnock-Jones DS, Chan CL, Bruner-Tran
KL, Osteen KG, Tom BD, Fan TP, Smith SK. Antiangiogenic
agents are effective inhibitors of endometriosis.
J Clin Endocrinol Metab 2003; 88: 2889-2899.
20. Nap AW, Griffioen AW, Dunselman GA, Bouma-Ter
Steege JC, Thijssen VL, Evers JL, Groothuis PG.
Antiangiogenesis therapy for endometriosis. J Clin
Endocrinol Metab 2004; 89: 1089-1095.
21. Donnez J, Smoes P, Gillerot S, Casanas-Roux
F, Nisolle M. Vascular endothelial growth factor
(VEGF) in endometriosis. Hum Reprod 1998; 13: 1686-1690.
22. Chesney J, Metz C, Bacher M, Peng T, Meinhardt
A, Bucala R. An essential role for macrophage migration
inhibitory factor (MIF) in angiogenesis and the
growth of a murine lymphoma. Mol Med. 1999; 5: 181-191.
23. Akoum A, Metz CN, Al-Akoum M, Kats R. Macrophage
migration inhibitory factor expression in the intrauterine
endometrium of women with endometriosis varies with
disease stage, infertility status, and pelvic pain.
Fertil Steril. 2006; 85: 1379-1385. Epub 2006 Apr
1317.
24. Ulukus M, Cakmak H, Arici A. The role of endometrium
in endometriosis. J Soc Gynecol Investig 2006; 13:
467-476.
25. Meresman GF, Vighi S, Buquet RA, Contreras-Ortiz
O, Tesone M, Rumi LS. Apoptosis and expression of
Bcl-2 and Bax in eutopic endometrium from women
with endometriosis. Fertil Steril 2000; 74: 760-766.
26. Tabibzadeh S. Molecular control of the implantation
window. Hum Reprod Update. 1998; 4: 465-471.
27. Lessey BA, Castelbaum AJ, Buck CA, Lei Y, Yowell
CW, Sun J. Further characterization of endometrial
integrins during the menstrual cycle and in pregnancy.
Fertil Steril. 1994; 62: 497-506.
28. Lessey BA, Castelbaum AJ, Sawin SW, Buck CA,
Schinnar R, Bilker W, Strom BL. Aberrant integrin
expression in the endometrium of women with endometriosis.
J Clin Endocrinol Metab. 1994; 79: 643-649.
29. Taylor HS, Bagot C, Kardana A, Olive D, Arici
A. HOX gene expression is altered in the endometrium
of women with endometriosis. Hum Reprod 1999; 14:
1328-1331.
30. Daftary GS, Taylor HS. EMX2 gene expression
in the female reproductive tract and aberrant expression
in the endometrium of patients with endometriosis.
J Clin Endocrinol Metab 2004; 89: 2390-2396.
31. Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi
I, Kontgen F, Abbondanzo SJ. Blastocyst implantation
depends on maternal expression of leukaemia inhibitory
factor. Nature 1992; 359: 76-79.
32. Dimitriadis E, Stoikos C, Stafford-Bell M, Clark
I, Paiva P, Kovacs G, Salamonsen LA. Interleukin-11,
IL-11 receptoralpha and leukemia inhibitory factor
are dysregulated in endometrium of infertile women
with endometriosis during the implantation window.
J Reprod Immunol 2006; 69: 53-64.
Next...
|
