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GUEST
EDITORIAL
Potential involvement of iron in the pathogenesis
of peritoneal endometriosis |
Defrère
S, Van Langendonckt A, González-Ramos R,
Vaesen S, Jouret M, Lousse J-C, Donnez J
Department of Gynaecology, Université Catholique
de Louvain, Bruxelles, Belgium.
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Despite
an increasing number of studies on endometriosis,
its aetiology remains elusive, partly due to its
multi-factorial characteristics. Indeed, a growing
body of evidence suggests that a combination of
genetic, hormonal, environmental, immunological
and anatomical factors may play a role in the pathogenesis
of this disorder (Giudice and Kao, 2004).
Our hypothesis
is that iron may be involved in the pathogenesis
of endometriosis.
Iron overload in endometriosis patients
Several studies have demonstrated the presence of
iron overload in the different compartments of the
peritoneal cavity of endometriosis patients (peritoneal
fluid, ectopic endometrial tissue, peritoneum adjacent
to lesions and macrophages) (Van Langendonckt et
al., 2002b, c). In the peritoneum and stroma of
endometriotic lesions, cytologic and histochemical
data revealed the presence of iron conglomerates
(Moen and Halvorsen, 1992; Petrozza et al., 1993;
Van Langendonckt et al., 2002c) and macrophages
heavily laden with ferric pigment (Gaulier et al.,
1983; Stowell et al., 1997). In endometriotic cysts
too, iron concentrations in cystic fluid were shown
to be an indicator of endometriosis (Sugimura et
al., 1992; Takahashi et al., 1996; Iizuka et al.,
1998). In the peritoneal fluid of patients with
endometriosis, higher levels of iron were detected
(Arumugam, 1994; Arumugam and Yip, 1995; Van Langendonckt
et al. 2002c; Polak et al., 2006).
Origin of iron
A potential source of iron in body fluids is haemoglobin.
In case of endometriosis, the iron could originate
from lysis of erythrocytes carried into the pelvic
cavity by retrograde menstruation or hemorrhaging
foci of ectopic endometrium (Van Langendonckt et
al., 2004).
Retrograde
menstruation, transporting menstrual reflux through
the fallopian tubes into the peritoneal cavity and
preserving body iron content in women, is a common
physiologic event in all menstruating women with
patent tubes (Halme et al., 1984) and an essential
step in the pathogenesis of peritoneal endometriosis
(Sampson, 1927). However, this phenomenon is often
amplified in endometriosis patients. Indeed, menstruation
is often longer and heavier in women with endometriosis
(Sanfilippo et al., 1986; Darrow et al., 1993; Vercellini
et al., 1997; Vinatier et al., 2001) and cycles
tend to be shorter (Arumugam and Lim, 1997). Moreover,
increased menstrual reflux may be due to certain
anatomical dispositions often encountered in endometriosis
patients (Sanfilippo et al., 1986; Salamanca and
Beltran, 1995; Barbieri, 1998; Vinatier et al.,
2001).
While red blood
cells are frequently present in the peritoneal fluid
of most women, increased concentrations of erythrocytes
have been reported in the peritoneal cavity of women
with endometriosis during menstruation (D’Hooghe
and Debrock, 2002). Halme et al. (1984) demonstrated
that women with endometriosis have a greater number
of erythrocytes, even during the non-menstrual phase,
suggesting that processes other than menstrual reflux,
such as lesion bleeding (which is not under hormonal
control), may contribute to the accumulation of
erythrocytes in peritoneal fluid (Van Langendonckt
et al., 2002).
Iron metabolism in the pelvic cavity in
case of endometriosis
Our studies, mimicking conditions of retrograde
menstrual discharge, allowed us to gather further
data on the metabolism of iron in the pelvic cavity
in the context of endometriosis pathology (see Figure
1). Our work clearly suggests that peritoneal iron
overload encountered in the different compartments
of the peritoneal cavity (lesions, peritoneal fluid
and peritoneal macrophages) of endometriosis patients
may well originate from the lysis of erythrocytes,
which have been carried into the pelvic cavity by
retrograde menstruation or hemorrhaging foci of
ectopic endometrium (Van Langendonckt et al., 2004;
Defrère et al., 2006).
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Figure
1: Origin of iron overload in the pelvic cavity
of endometriosis patients
Erythrocytes are carried into the pelvic cavity
by retrograde menstruation and haemorrhaging foci
of ectopic endometrium. A proportion of them are
phagocytosed by peritoneal macrophages. Macrophages
store some iron in the form of ferritin or haemosiderin,
and release some that binds to transferrin. Lysis
of erythrocytes also releases haemoglobin into
peritoneal fluid. Transferrin and haemoglobin
cause increased pelvic iron concentrations and
may be assimilated by ectopic endometrial cells,
resulting in the formation of iron deposits (ferritin
or haemosiderin).
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As in most tissue, activated macrophages recruited
within the pelvic cavity of women probably play
an important role in the degradation of erythrocytes,
as suggested by the presence of numerous siderophages,
known as iron-storing macrophages, in the peritoneal
fluid of patients with endometriosis (unpublished
data) and mice injected with erythrocytes (Defrère
et al., 2006). Macrophages usually internalize
and lyse senescent erythrocytes, releasing hemoglobin
and ensuring its degradation by heme oxygenase.
The iron released is then returned to the iron
transporter transferrin (Van Langendonckt et al.,
2002b), resulting in increased peritoneal fluid
iron concentrations in both women (Van Langendonckt
et al., 2002c) and our murine model (Defrère
et al., 2006). In vivo, iron in serum is predominantly
bound to apotransferrin, preventing endothelial
damage and favoring iron uptake by cells. Iron
uptake in mammalian cells is mediated by transferrin
receptors. One of our recent in vitro studies
has shown that endometrial stromal and epithelial
cells are able to incorporate transferrin and
metabolize it into ferritin (Mizuuchi et al.,
1988; Defrère et al., submitted).
Metabolisation
of haemoglobin, a by-product of erythrocyte lysis,
also occurs within endometrial implants. Indeed,
heme oxygenase, the enzyme catalyzing degradation
of the heme moiety of haemoglobin into iron, carbon
monoxide and biliverdin, is strongly expressed
in active red endometrial lesions (Van Langendonckt
et al., 2002a; Casanas-Roux et al., 2002). Iron
is sequestrated within tissue and bound to proteins
such as ferritin in a soluble, non-toxic and bioavailable
form (Crichton, 2001). Iron conglomerates have
also been observed in endometriotic lesions in
patients and our experimental model (Van Langendonckt
et al., 2004; Defrère et al., 2006). These
conglomerates consist of haemosiderin, another
iron storage form, which is found in conditions
of iron overload usually associated with toxic
pathological states in humans (Crichton, 2001).
Effect of iron overload on endometriosis
development
The objective of our study was to investigate
the effect of iron overload and iron chelation
on endometriosis development induced in a murine
model (Defrère et al., 2006). For this
purpose, endometriosis was induced by injection
of human menstrual endometrium alone, or supplemented
with erythrocytes or desferrioxamine (DFO), a
current iron chelator, into the pelvic cavity
of nude mice. After five days, endometriosis-like
lesions, peritoneal fluid and macrophages were
recovered. The iron load of different pelvic compartments
was assessed. The occurrence, size and proliferative
activity of lesions were evaluated.
• Effect
of iron overload on endometrial tissue adhesion
Some studies
have shown that an intact mesothelial lining might
serve as a barrier to prevent adhesion of menstrual
endometrial fragments to the peritoneum (Dunselman
et al., 2001). Others have demonstrated that endometrial
cells can adhere to intact mesothelium (Nisolle
et al., 2000a and 2000b). This may be explained
by the fact that the mesothelium is a fragile
surface, which can be damaged by ectopic menstrual
endometrium or inflammatory cells, creating adhesion
sites on the mesothelial lining and facilitating
the development of endometriosis (Demir et al.,
2004).
Iron from menstrual
endometrium could be one of the factors harmful
to mesothelium, since haemoglobin appears to alter
mesothelium (Demir et al., 2004). Indeed, iron
is known to induce oxidative stress, leading to
macromolecular oxidative damage, tissue injury
and chronic inflammation (Hippeli and Elstner,
1999). Oxidative stress was suggested to be responsible
for local destruction of the peritoneal mesothelium
and the development of adhesion sites for ectopic
endometrial cells (Arumugam and Yip, 1995).
Our model effectively
shows that iron overload does not alter the initial
steps of lesion formation since, on day five,
we did not observe any significant effect of iron
overload or iron chelation on the number or surface
area of lesions (Defrère et al., 2006).
Whether this is due to the fact that iron does
not alter peritoneal mesothelium, or that morphological
changes in the mesothelial layer are not sufficient
to influence adhesion of endometrial cells, remains
to be seen.
• Effect
of iron on endometriotic lesion proliferation
Our in vivo study
demonstrates that erythrocyte injection increases
the proliferative activity of epithelial cells
in endometriotic lesions, while DFO administration
significantly decreases it, suggesting that iron
overload may contribute to the further growth
of endometriosis by promoting epithelial cell
proliferation (Defrère et al., 2006).
Iron is an absolute
requirement for proliferation, as iron-containing
proteins catalyze key reactions involved in oxygen
sensing, energy metabolism, respiration, folate
metabolism and DNA synthesis (e.g. ribonucleotide
reductase that catalyzes the conversion of ribonucleotides
into deoxyribonucleotides for DNA synthesis).
In fact, deprived of iron, cells are unable to
proceed from the G1 to the S phase of the cell
cycle (Le and Richardson, 2002). Iron chelators
have proved to be efficient anti-proliferative
agents for the treatment of cancer (Richardson,
2005; Simonart et al., 2002; Pahl and Horwitz,
2005; Brard et al., 2006) but, to our knowledge,
this is the first time that the impact of iron
overload and iron chelation have been evaluated
with respect to endometriotic lesion proliferation.
After implantation
onto the mesothelium, proliferation of lesions
promotes the further development of endometriosis
(Nisolle et al., 2000a). Proliferation of epithelial
cells and their differentiation into glandular
structures are key events, likely to be under
the control of factors in the local environment.
Mitogens produced by stromal cells, like hepatocyte
growth factor and oestradiol (Giudice and Kao,
2004), or growth factors and inflammatory cytokines
present in peritoneal fluid, have indeed been
shown to promote epithelial cell proliferation
and ectopic endometrial cell growth. Iron could
be one of the factors promoting further growth
of implanted ectopic endometrial tissue (Defrère
et al., 2006).
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Professor
Ali Akoum
Editor WES e-journal
Faculty of Medicine
Laval University Research Centre
St-Francis of Assisi Hospital
DO-708B, 10 Rue de L'Espinay
Québec, GIL 3L5, Canada
ali.akoum@crsfa.ulaval.ca
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