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VIEWS AND REVIEWS

Oxidative stress in the pelvic cavity


and its role in the pathogenesis
of endometriosis
Jacques Donnez, M.D., Ph.D.,a Maria Mercedes Binda, Ph.D.,b Olivier Donnez, M.D., Ph.D.,b,c
and Marie-Madeleine Dolmans, M.D., Ph.D.b,d
a
 te
 de Recherche pour lInfertilite
, Brussels, Belgium; b Po
^ le de Recherche en Gyne
 cologie, Institut de Recherche
Socie
rimentale et Clinique, Universite
 Catholique de Louvain, Brussels, Belgium; c Institut du Sein et de Chirurgie
Expe
 cologique d'Avignon, Polyclinique Urbain V, Avignon, France; and d Gynecology Department, Cliniques
Gyne
Universitaires Saint Luc, Brussels, Belgium

Endometriosis is a disorder associated with a general inammatory response in the peritoneal cavity. Oxidative stress is a potential factor involved in the pathophysiology of this disease, and reactive oxygen species (ROS) are implicated in this process. Indeed, in healthy
individuals, ROS and antioxidants are in balance, but when balance is tipped toward an overabundance of ROS, oxidative stress occurs
and can impact the entire reproductive lifespan of a woman. Reactive oxygen species are intermediaries produced by normal oxygen
metabolism but are known to have deleterious effects. Excessive release of ROS induces cellular damage and alters cellular function by
regulating protein activity and gene expression, leading to harmful effects. To protect themselves, cells have developed antioxidant
systems to limit production of ROS, inactivate them, and repair cell damage. Understanding of the control of hemoglobin, heme,
and iron-induced redox balance in endometriosis led us to propose a number of hypotheses to explain why oxidative stress is induced
in case of pelvic endometriosis. Erythrocytes, apoptotic endometrial tissue, and cell debris transplanted into the peritoneal cavity by
menstrual reux and macrophages have all been cited as potential inducers of oxidative stress. Erythrocytes are likely to release
pro-oxidant and proinammatory factors, such as hemoglobin and its highly toxic by-products heme and iron, into the peritoneal environment. Iron and heme are essential to living cells, but unless appropriately chelated, free iron, and to a lesser extent heme, play a key
role in the formation of deleterious ROS. (Fertil Steril 2016;-:--. 2016 by American Society for Reproductive Medicine.)
Key Words: Endometriosis, oxidative stress, reactive oxygen species (ROS)
Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110fertility-and-sterility/posts/11253-oxidative-stress-in-the-pelvic-cavity-and-its-role-in-the-pathogenesis-of-endometriosis

ndometriosis is characterized by
implantation and growth of
endometrial tissue outside the
uterine cavity, and most studies investigating peritoneal endometriosis
adhere to the implantation theory of
Sampson (1), according to which
desquamated endometrial cells are
transported into the peritoneal cavity
after retrograde menstruation.
Already in the late 1990s, studies
suggested that menstrual efuent
contains factors that induce alterations

in
the
morphology
of
the
peritoneal mesothelium (2), which
may create adhesion sites for endometrial cells. Attachment of endometrial
cells seems to be enhanced by induction
of adhesion molecules and their receptors (35), as well as overexpression of
matrix metalloproteinases (6) and
plasminogen activators (7), which
ensure local destruction of the
extracellular matrix in endometriosis.
After adhesion, endometrial cells
proliferate and gradually invade the peri-

Received May 27, 2016; revised July 13, 2016; accepted July 14, 2016.
J.D. is a member of the Scientic Advisory Board of PregLem S.A. M.M.B. has nothing to disclose. O.D.
has nothing to disclose. M.-M.D. has nothing to disclose.
Supported by grants from the Fonds National de la Recherche Scientique de Belgique (grant 5/4/150/
5, to M.-M.D.; grant W.0056.15 to M.M.B.).
 Catholique de Louvain, Institut
Reprint requests: Marie-Madeleine Dolmans, M.D., Ph.D., Universite
rimentale et Clinique, Po
^ le de Recherche en Gyne
cologie, Avenue Mounier
de Recherche Expe
52 - B1.52.02, Brussels 1200, Belgium (E-mail: marie-madeleine.dolmans@uclouvain.be).
Fertility and Sterility Vol. -, No. -, - 2016 0015-0282/$36.00
Copyright 2016 American Society for Reproductive Medicine, Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.fertnstert.2016.07.1075

toneal tissue (4). Vascularization of


endometriotic implants, allowing their
further
development
(812),
is
inuenced by cytokines and growth
factors, such as transforming growth
factor, interleukin-8, interleukin-1, tumor necrosis factor, and interferon-g
(13). All these factors were extensively
studied and described almost 15 years
ago (14, 15) and recently reviewed
(1618).
It is now widely accepted that
endometriosis is a disease associated
with
a
general
inammatory
response in the peritoneal cavity
(14, 19). Oxidative stress has been
proposed as a potential factor
involved in the pathophysiology of
the disease, with reactive oxygen
species (ROS) implicated in the
pathogenesis of many human
diseases and aging (14, 20).

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VIEWS AND REVIEWS

OXYGEN ON EARTH
The rise of oxygen changed the course of evolution.
David Catling, University of Bristol,
United Kingdom (21)
In the beginning there was no oxygen on Earth, but
somehow life arose from nonlife. Without free oxygen, the
rst life to appear by perhaps 3.5 billion years ago had to
breathe elements such as iron, processing them to gain
the merest pittance of energy (Fig. 1) (21). Gradually, bacteria and other cells developed systems for energy metabolism
under anoxic conditions. These systems were based on anoxygenic photosynthesis, which used hydrogen or sulfur
as an electron donor instead of water (22). In time,
oxygen-generating cyanobacteria emerged (2.7 billion years
ago or even earlier [(21)]), which in the presence of sunlight
were able to use chlorophyll and photosynthesis to trap the
sun's energy into carbohydrate form. This process, called
oxygenic photosynthesis, produces oxygen as a waste product of the splitting of water (22). The permanent rise in oxygen to detectable atmospheric levels seems to have
spurred evolution, occurring sometime between 2.4 and
2.1 billion years ago, now popularly known as the Great
Oxidation Event (23). Concentrations of oxygen rose only
modestly until that point, then remained on hold for almost
2 billion years before climbing higher.
The earliest known fossil of a eukaryote with a cell nucleus (Grypania spiralis) that generally requires oxygen is
from approximately 2 billion years ago (21). Our planet's atmosphere was thus transformed from an anoxic state to present oxygen concentrations of 20%21%, oxygenic
photosynthesis being the only signicant source of free oxygen on the Earth's surface (23).

THE DARK SIDE OF OXYGEN


Although oxygen has been known to be toxic for more than
200 years, the clinical importance of oxygen toxicity was
not fully appreciated until an epidemic of retrolental broplasia (severe retinopathy) occurred in the early 1950s (24).

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FIGURE 1

Oxygen at high partial pressures is toxic to the respiratory,


cardiovascular, nervous, and gastrointestinal systems.
Toxicity results from the formation of ROS, which are chemically reactive molecules naturally produced within biological
systems. They arise within mitochondria as byproducts of
prostaglandin and thromboxane synthesis when oxygen is
reduced to water, and by xanthine oxidasecatalyzed reduction of xanthine or hypoxanthine.

ROS, THEIR SCAVENGERS, AND THEIR


MARKERS
Reactive oxygen species are intermediaries produced by
normal oxygen metabolism but are known to have deleterious
effects. To protect themselves, cells have developed a wide
range of antioxidant systems to limit production of ROS,
inactivate them, and repair cell damage (14, 20, 2527).
In healthy individuals, ROS and antioxidants are in balance, but when the balance is tipped toward an overabundance of ROS, oxidative stress occurs and can impact the
entire reproductive lifespan of a woman, as reported by Ruder
et al (20).
The increasing number of diseases associated with
oxidative stress suggests that the oxidative balance may
be precarious (20) and that ROS can damage proteins,
lipids, and DNA structure. Almost all major classes of biomolecules are potential targets for ROS (14, 25). Oxidative
destruction of polyunsaturated fatty acids, known as lipid
peroxidation, is particularly damaging because it is a
self-perpetuating chain reaction that may alter the integrity of cell membranes (25).
Hydroxyl radicals are the most reactive free radical species identied so far and have the ability to react with a
wide range of cellular constituents, including amino acid residues and purine and pyrimidine bases of DNA, as well as attacking membrane lipids to initiate a free radical chain
reaction known as lipid peroxidation. It is clear that ROS
are generated within the cell in the course of normal cellular
mechanisms and that the cell is adequately supplied with a
range of cytoprotective enzymes and antioxidants to combat
their toxicity (14, 20, 25, 26).
Excessive release of ROS not only induces cellular damage but may also alter cellular function by regulating protein
activity and gene expression. Indeed, ROS play an essential
role in the regulation of the transcription factor nuclear factor
kB, which has been implicated in endometriosis (28, 29). This
transcription factor induces expression of multiple genes
encoding proinammatory cytokines, growth and
angiogenic factors, adhesion molecules, and inducible
enzymes nitric oxide synthase and cycloxygenase (19, 29).
All these products are expressed by activated peritoneal
macrophages and are involved in the pathogenesis of endometriosis by inducing endometrial fragment adhesion,
proliferation, and neovascularization (29, 30).

Antioxidant Agents
Evolution of the Earth's atmospheric oxygen content through time.
Donnez. Oxidative stress in the pelvic cavity. Fertil Steril 2016.

In 2006, in a review of the role of antioxidants and immunomodulators, Gupta et al (31) concluded that there was not
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Are There Serum Markers of ROS in


Endometriosis?
In a review by Carvalho et al (33) 19 articles were selected,
and a total of 36 oxidative stress biomarkers (20 different
ones) were evaluated in women with endometriosis. Of
these 36 markers (classied into ve categories: enzymatic
activity, anions/free radicals, lipoperoxidation markers,
DNA damage markers, and protein oxidation), 23 were
found to show signicantly higher expression in endometriosis patients than in control patients, demonstrating
that endometriosis is associated with increased levels of
systemic oxidative stress. Nevertheless, its involvement in
endometriosis progression needs to be investigated in
greater depth.
Heat shock proteins (HSPs) are intracellular proteins
induced to protect cells from various insults during periods
of stress (34). HSP70 and 70b, and thioredoxin, which is a
thiol oxidoreductase, can protect against oxidative stress
induced cell injury or inammation directly via antioxidant
effects and indirectly by proteinprotein interaction with
signaling molecules (35). Women with endometriosis show
evidence of increased systemic oxidative stress expressed by
higher HSP70b levels, but whether this affects endometriosis
progression remains to be elucidated.
In a large study by Santulli et al (36), protein oxidative
stress markers (thiols, advanced oxidation protein products,
protein carbonyl, and nitrates/nitrites) were evaluated in
peritoneal uid according to the surgical classication.
The markers were signicantly increased only in women
with deep endometriosis compared with controls (P .001
and P .05, respectively), whereas other forms of endometriosis (peritoneal and ovarian) showed nonstatistically signicant increases. These authors failed to nd any
difference in protein oxidative stress markers between
women with peritoneal or ovarian endometriosis and control
subjects. Moreover, the fact that the control group included
women operated on for benign gynecologic conditions,
which might be associated with altered peritoneal protein
oxidative stress markers, is also one of the limitations of
the study that may lead to bias, as acknowledged by the authors themselves. Indeed, most published studies on oxidative stress are either observational or casecontrol studies.
Measurement of biomarkers of oxidative stress is subject
to interlaboratory variations and interobserver differences.
A uniform method should be applied, with comprehensive
assessment of these markers, so that the results can be
compared across studies.

ORIGIN OF OXIDATIVE STRESS IN THE


PERITONEAL CAVITY
Erythrocytes and Hemoglobin
Understanding of the control of the hemoglobin (Hb),
heme, and iron-induced redox balance in endometriosis
led us to propose several hypotheses to explain why
oxidative stress is induced in case of pelvic endometriosis
(14) and is a potential factor involved in endometriosis
pathophysiology (Fig. 2). Erythrocytes, apoptotic endometrial tissue, and cell debris carried into the peritoneal cavity by menstrual reux and macrophages have all been
implicated as potential inducers of oxidative stress
(Fig. 2) (14, 3237).
Erythrocytes are likely to release pro-oxidant and
proinammatory factors, such as Hb and its highly toxic
by-products heme and iron, into the peritoneal environment. Iron and heme are essential to living cells, but unless
they are appropriately chelated, free iron and (to a lesser
extent) heme play a key role in the formation of deleterious
ROS (3740).
However, erythrocytes are found in the peritoneal cavity
of 90% of menstruating women (41), so why do some patients develop macroscopically visible peritoneal endometriotic lesions, whereas others do not (42)? One hypothesis is
that in some patients, peritoneal protective mechanisms
are swamped by menstrual reux, either because of the
abundance of the reux or because of defective scavenging
systems (12, 3740). A number of studies have suggested
that the amount of retrograde menstruation may be
related to endometriosis (2, 4, 38, 41). Indeed, shorter
cycles and heavier and longer menstrual ow have been
reported in women with endometriosis. Moreover, in
patients developing the disease, bleeding from red
endometrial lesions may further increase the number of
erythrocytes (18).

Iron Metabolism in the Pelvic Cavity


In case of hemorrhage, lysis of erythrocytes leads to iron
overload, provoking iron-mediated damage, oxidative

FIGURE 2

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enough evidence of the benets of various tested modalities.


More recently, Harlev et al (32) investigated the effect of
different antioxidant agents, including vitamins C and E,
melatonin, resveratrol, xanthohumol, and epigallocatechin3-gallate, specically on endometriosis patients. Although a
signicant impact was reported, it should be noted that
most of these studies are either in vitro or animal-based.
Harlev et al (25) thus concluded that further studies are
required to elucidate the potential role of antioxidant agents
in endometriosis.

Hypotheses explaining oxidative stress in the peritoneal cavity of


women with endometriosis. Bold type indicates factors that have
been studied specically in relation to pelvic endometriosis. NOS
nitric oxide synthase.
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injury, and inammation (4345). Iron may also be
involved in endometriosis development (27, 40, 43, 45).
An important defense mechanism to counteract the
effects of hemorrhage is mediated by haptoglobin (Hp),
which binds extracellular Hb, thereby attenuating its
oxidative and inammatory potential. Haptoglobin also
promotes clearance of Hb via the CD163 scavenger
receptor present on macrophages (44).
Postulated iron metabolism in the pelvic cavity in the
context of endometriosis pathology is illustrated in
Figure 3. As in most tissue, activated macrophages recruited within the pelvic cavity of women play an important role in the degradation of erythrocytes, as suggested
by the presence of numerous iron-loaded macrophages in
the peritoneal uid of endometriosis patients (19, 30) and
mice intraperitoneally injected with erythrocytes (37).
Macrophages usually phagocytose senescent erythrocytes
or endocytose the HbHp complex (44). Metabolism of
Hb and heme by heme oxygenase (HO) releases iron,
which is then incorporated into ferritin in macrophages
or returned to the iron transporter transferrin (Tf) via the
peritoneal uid (46).
Iron conglomerates have also been observed in endometriotic lesions in patients (34, 40). These conglomerates
consist of hemosiderin, another iron storage form found

in conditions of iron overload, usually associated with


toxic pathologic states in humans.

Increased Iron Storage in Peritoneal Macrophages


Iron storage is statistically signicantly increased in peritoneal macrophages of endometriosis patients compared
with controls (40). Different studies (14, 19, 37, 38, 44,
47) highlighted the involvement of peritoneal
macrophages in iron metabolism. Cellular iron storage
within ferritin limits the capacity of iron to generate
free radicals and confers an antioxidant effect (40).
However, continued delivery of iron to macrophages can
overwhelm the capacity of ferritin to store and sequester
the metal, inducing oxidative injury to cells. These
authors also suggested that the iron detoxication
system could be progressively overwhelmed during the
menstrual cycle in endometriosis patients, leading to
abnormal macrophage activation (34). Hence, iron
overload observed in the different compartments of the
peritoneal cavity of endometriosis patients, particularly
macrophages, may be involved in the pathogenesis of
endometriosis by inducing oxidative stress (14, 19, 37,
38, 44, 47).

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FIGURE 3

Origin of iron overload in the pelvic cavity of endometriosis patients. Erythrocytes are carried into the pelvic cavity by retrograde menstruation and
hemorrhaging foci of ectopic endometrium. A proportion of them are phagocytosed by peritoneal macrophages. Metabolism of Hb by HO-1 (HO)
releases iron. Macrophages store some iron in the form of ferritin or hemosiderin, and release some that binds to Tf. Macrophages are also able to
release ferritin into peritoneal uid, whereas lysis of erythrocytes releases Hb. Hemoglobin forms a complex with Hp, which is in part secreted by
ectopic lesions. The HbHp complex is then endocytosed by macrophages. Increased pelvic iron concentrations result from Tf, ferritin, and Hb
accumulation in peritoneal uid. Transferrin and Hb may be assimilated by ectopic endometrial cells, resulting in the formation of iron deposits
(ferritin or hemosiderin) inside lesions.
Donnez. Oxidative stress in the pelvic cavity. Fertil Steril 2016.

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CONSEQUENCES OF OXIDATIVE STRESS IN


THE PERITONEAL CAVITY
Induction of Cellular Damage and Adhesion and
Growth of Ectopic Endometrial Tissue
In other tissues, iron is known to induce oxidative stress, leading to macromolecular oxidative damage, tissue injury and
chronic inammation (36, 45, 48). Oxidative stress was
suggested to be responsible for local destruction of the
peritoneal mesothelium, thereby creating adhesion sites for
ectopic endometrial cells (14, 19, 49) and for promoting
apoptosis (5052). Figure 4 shows the link between iron,
different types of cells involved in endometriosis
development, and processes implicated in the evolution of
the disease.
In the pelvic cavity, there are many other instances in
which the normal balance of oxygen pressure is disrupted, resulting in oxidative stress. During open surgery, there is an increase in ROS production, namely in superoxide anions (53),
xanthine oxidase, an enzyme involved in ROS formation
(54), and malondialdehyde, a marker of ROS production
(55). This is because during open surgery the peritoneal layer
is exposed to high concentrations of oxygen (150 mm Hg or
20.9%), constituting a hyperoxic environment (56). During
laparoscopic surgery the pelvic cavity is in contact with
insufation gas (100% CO2), a hypoxic environment (57,
58). Moreover, during laparoscopic surgery, high
pneumoperitoneum pressure (1015 mm Hg) compresses the
peritoneum, inducing ischemia, leaving the peritoneal layer
to undergo a period of hypoxia followed by a period of
hyperoxia, during which oxygen toxicity can result from
reperfusion of ischemic tissue. Indeed, during laparoscopic
surgery, ROS are known to multiply. An increase in ROS

production has been shown in human peritoneum in a


time- and CO2 volumedependent manner (55), as well as in
the intestine, liver, and lungs of rats (59). In addition, a
negative correlation was noted between ROS scavengers
and the duration/amount of CO2 exposure (59, 60).

HO-1 Detoxication System


Heme oxygenase-1 is a heme-degrading enzyme strongly upregulated by heme. Heme oxygenase protects cells from
heme-induced oxidative stress by generating benecial molecules like carbon monoxide (CO), bilirubin, and ferritin.
Indeed, HO-1 induction is accompanied by increased ferritin
synthesis, scavenging of free iron and, subsequently, protection against its adverse effects (61). Bilirubin is an important
antioxidant, providing potent protection against oxidative
injury and inammation (62), whereas CO is a soluble gas
acting as a signal molecule. Numerous functions have been
ascribed to the HOCO system, including regulation of neuroendocrine response, action as a vasodilator, and inhibition of
muscle cell contractility (25).
Moreover, heme has been shown to bind to several transcription factors, including BACH1 (BTB domain and CNC homolog 1, basic leucine zipper transcription factor 1) and
BACH2, inhibiting BACH1-induced repression of HO-1 gene
expression by directly binding to BACH1 (27).
In addition, HO-1 is strongly induced by a variety of stimuli, including oxidative stress, ROS, free heme, heavy metals,
cytokines, some hormones, and ultraviolet light, through the
major transcription factor nuclear factor-E2-related factor 2
(27, 63).
Finally, free iron is released from heme through HO-1
activity after Hb breakdown. This enzyme degrades the

FIGURE 4

Cells and processes involved in endometriosis development. Iron overload may affect a wide range of cell types, modulating multiple mechanisms
involved in endometriosis development. NF-kB nuclear factor kB.
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heme moiety and liberates biologically active products, like
inorganic ferrous iron, CO, and biliverdin, which play a
unique protective and antioxidant role, as well as having
anti-inammatory and antiapoptotic properties. Heme oxygenase-1induced cytoprotective effects require coexpression of ferritin, whereas CO has been shown to possess
signicant cytoprotective, anti-inammatory, and antiapoptotic properties (27, 33).
In endometriosis patients, Hb concentrations were
found to be increased in peritoneal uid, and higher HO
expression was observed in ectopic endometrium, especially red lesions, compared with eutopic endometrial and
mesothelial cells (14, 33). However, because inducible
HO-1 was poorly expressed by macrophages and mesothelial cells, constituting the majority of cells in the peritoneal
cavity, and because there was no concomitant increase in
peritoneal uid levels of bilirubin, its nal byproduct, it
strongly suggests that detoxifying systems, although present, might be insufcient to metabolize Hb in case of
endometriosis (34, 40).
In conclusion, oxidative stress occurs when the balance
between ROS production and antioxidant defense is disrupted
(14, 25, 32, 52, 53). It may be due to either inadequate
antioxidant protection or excess production of ROS.
Oxidative stress also plays a role in multiple physiologic
processes, from oocyte maturation to fertilization and
embryo development. There is burgeoning literature on the
involvement of oxidative stress in the pathophysiology of
infertility, assisted fertility, and female reproduction.
Various lines of evidence support the role of oxidants in
the development of endometriosis, a benign metastasizing pathology (14, 19, 64), because endometriotic cells show higher
endogenous oxidative stress levels, with increased ROS
production and alterations in ROS detoxication pathways
(65, 66).
First, in endometriosis, Hb, heme, and iron derivatives are
generated from hemolysis of erythrocytes and abnormally
accumulate in endometriotic cysts or the peritoneal cavity
(14). Endometriotic cells are especially prone to DNA damage
owing to direct exposure to these derivatives, promoting ROS
generation.
Second, the ability to survive the oxidative action of these
derivatives seems to be advantageous for endometriotic cell
growth.
Finally, endometriotic lesions may display signicant individual differences with regard to the degree of responsiveness to free radicals or antioxidant defense. Their unique
microenvironment inuences cell survival through binding
of membrane receptors and subsequent cascading activation
of intracellular kinases that stimulate a cellular response
(for review, see McKinnon et al [(67)]).
Investigating the mechanisms underlying oxidative stress
associated with endometriosis may well prove useful for
determining its specic pathways and attempting to channel
them accordingly.
Acknowledgment: The authors thank Deborah Godefroidt
for her administrative support and Mira Hryniuk, B.A., for
revising the English language of the manuscript.

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