| The
natural history and spontaneous evolution of endometriosis
is still shrouded in the mist of intricate puzzle
and the current efforts to study these phenomenons
are staggering to envisage, but an area of great
interest. Although the aetiology is not precisely
known, endometriosis is suggested to result from
refluxed endometrial cells into the peritoneal cavity
during menstruation [Sampson 1927]. However, there
is still limited information available regarding
the early endometrial-peritoneal attachment and
invasion process in the development of peritoneal
endometriosis, mostly from in vitro studies [Witz
et al 1999, Debrock et al 2002,
Debrock et al 2004, Groothuis et al
1999, Debrock et al 2006]. To study how
endometriosis evolves, it is important to understand
the biology of the two tissues involved and how
they interact with each other before the transition
of endometrium to endometriosis occurs.
Endometrium is
a unique adult tissue that undergoes a proliferation
and secretion followed by menstruation [Jabbour
et al 2006, Tabibzadeh 1996, Osteen et
al 2002] leading to re-growth of functional
endometrium during the menstrual cycle. It is not
clear how endometrium has the capacity to survive
outside the uterine cavity and how it can implant
leading to the development of endometriosis. The
peritoneum on the other hand is a single layer of
mesothelial cells underlying extracellular matrix
of connective tissue with fibroblasts, collagen
fibres, adipocytes, leukocytes and blood vessels
[Witz et al 1998].
The current assertion
is that successful development of endometriosis
requires endometrial cells to adhere to mesothelium
and to invade the extracellular matrix. This theory
suggests that the peritoneum may function as a “passive
recipient” for ectopic tissue attachment,
and is supported by previous in vitro studies [Witz
et al 1999, Witz et al 2001].
However, other investigators have reported that
the mesothelium acts as a barrier to the attachment
of endometrial cells and have proposed that trauma
or injury to the peritoneum is required for endometrial-peritoneal
adhesion [Van der Linden et al 1996, Groothuis
et al 1998].
The development of endometriosis is hypothesised
to be a complex process, which may be facilitated
by several factors, including the cytokines, growth
factors and quality of endometrial cells. It has
been suggested that the expression of adhesion molecules
like integrins on the surface of mesothelium may
play a role in the initial attachment of endometrial
cells to peritoneum [Witz et al 1998].
Macrophage derived cytokines may also contribute
to the development of endometriosis by promoting
neovascularisation and attachment of endometrial
cells to the peritoneum [Wieser et al 2002,
Harada et al 2001]. Increased angiogenesis
is reported to be common around the peritoneal explants
and increased angiogenic activity has been observed
in peritoneal fluid (PF) of women with endometriosis
[Nothnick 2001]. It is not clear to which extent
these phenomena are endometrium-dependent or peritoneum-dependent.
An active role
for the endometrium in endometrial-peritoneal attachment
and invasion has been supported by the significant
biological differences in eutopic endometrium between
women with and without endometriosis. However, few
investigators have compared the biological properties
of menstrual endometrium between women with and
without endometriosis.
In a recent study
[Kyama et al 2006a] we reported increased
menstrual endometrial mRNA expression of alphaV
integrin, the combined aVß3 integrins in women
with endometriosis when compared with controls.
During the luteal phase, endometrial mRNA expression
of IL-1-beta and RANTES was increased in women with
endometriosis when compared with controls [Kyama
et al 2006a]. During the menstrual or luteal
phase, endometrial mRNA expression of aromatase
was higher in women with endometriosis when compared
to controls [Kyama et al 2006b].
At present, it
is clear that not only endometrium but also macroscopically
normal peritoneum taken outside the pelvic brim
is an active player and not a passive recipient
in the development of endometriosis, especially
during menstruation [Kyama et al 2006a
and 2006b].
Firstly, during
the menstrual phase, peritoneal expression of IL1-beta,
ICAM-1, TGF-beta and IL-6 mRNA is up-regulated in
women with endometriosis when compared with controls
[Kyama et al 2006a and 2006b].
Secondly, in women
with or without endometriosis, the expression levels
of mRNA for aromatase (luteal phase only) and for
VCAM-1 are lower in endometrium than in peritoneum
[Kyama et al 2006a].
Thirdly, we demonstrated
increased peritoneal mRNA expression of TNF-alpha
and MMP-3 in endometriosis women when compared with
controls during the luteal phase [Kyama et al
2006b].
Fourthly, in women with endometriosis, peritoneal
mRNA expression of RANTES and VCAM-1 are significantly
higher during the menstrual phase when compared
to the luteal phase [Kyama et al 2006a].
These observations
may have important implications regarding endometrial-peritoneal
interactions. In vitro studies have shown increased
endometrial stromal cell adhesion to mesothelial
cells pretreated with TNF-alpha [Zhang et al
1993]. Similarly, in vitro incubation of endometrial
stromal cells with increasing concentrations of
IL-8 has been reported to stimulate their adhesion
to fibronectin [Garcia Velasco et al 1999].
Also in vivo adhesion of human endometrial cells
to mouse peritoneum was moderately increased by
treatment with TNF-alpha and IL-6 [Beliard et
al 2003].
In contrast in
a recent study, TNF-alpha, IL-8 and IL-6 failed
to stimulate, in vitro adhesion between endometrial
epithelial cells and mesothelial cells in a dose
dependent fashion [Debrock et al 2006].
After attachment,
endometrial cells invade the extracellular matrix,
a process influenced by matrix metalloproteinases
(MMPs), a group of enzymes important in the control
of extracellular matrix turnover [Bruner et
al 1999]. MMPs are up-regulated by TNF-alpha
and IL-1, which could partly explain the increased
invasiveness of endometrial fragments in women with
endometriosis [Sillem et al 2001].
In conclusion,
recent evidence has shown increased expression of
inflammatory cytokines, aromatase and adhesion factors
in endometrium and in macroscopically normal peritoneum
from women with endometriosis compared to controls
during the menstrual or luteal phase [Kyama et
al 2006a and 2006b].
Both endometrium
and macroscopically normal peritoneum are affected
by profound biological changes dependent on the
phase of the menstrual cycle and on the presence
or absence of endometriosis. The time has come to
define endometriosis not only as an endometrial
disorder but also as a peritoneal disease.
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