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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
 de Recherche pour lInfertilite
, Brussels, Belgium; b Po
^ le de Recherche en Gyne
 cologie, Institut de Recherche
rimentale et Clinique, Universite
 Catholique de Louvain, Brussels, Belgium; c Institut du Sein et de Chirurgie
 cologique d'Avignon, Polyclinique Urbain V, Avignon, France; and d Gynecology Department, Cliniques
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

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

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:
Fertility and Sterility Vol. -, No. -, - 2016 0015-0282/$36.00
Copyright 2016 American Society for Reproductive Medicine, Published by Elsevier Inc.

toneal tissue (4). Vascularization of

endometriotic implants, allowing their
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
It is now widely accepted that
endometriosis is a disease associated
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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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).


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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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.


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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Fertility and Sterility

Are There Serum Markers of ROS in

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.


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


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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.
Donnez. Oxidative stress in the pelvic cavity. Fertil Steril 2016.

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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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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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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


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
Second, the ability to survive the oxidative action of these
derivatives seems to be advantageous for endometriotic cell
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.















Sampson JA. Peritoneal endometriosis due to the menstrual dissemination

of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol
Koks CA, Demir-Weusten AY, Groothuis PG, Dunselman GA, de Goeij AF,
Evers JL. Menstruum induces changes in mesothelial cell morphology. Gynecol Obstet Invest 2000;50:138.
Beliard A, Donnez J, Nisolle M, Foidart JM. Localization of laminin, bronectin, E-cadherin and integrins in endometrium and endometriosis. Fertil
Steril 1997;67:26672.
Somigliana E, Vigano P, Gaffuri B, Guarneri D, Busacca M, Vignali M. Human
endometrial stromal cells as a source of soluble intercellular adhesion molecule (ICAM)-1 molecules. Hum Reprod 1996;11:11904.
Selam B, Arici A. Implantation defect in endometriosis: endometrium or peritoneal uid. J Reprod Fertil 2000;55:1218.
Kokorine I, Nisolle M, Donnez J, Eeckhout Y, Courtoy PJ, Marbaix E. Expression of interstitial collagenase (matrix metalloproteinase-1) is related to the
activity of human endometriotic lesions. Fertil Steril 1997;68:24651.
Sillem M, Prifti S, Neher M, Runnebaum B. Extracellular matrix remodelling in
the endometrium and its possible relevance to the pathogenesis of endometriosis. Hum Reprod Update 1998;4:7305.
Donnez J, Nisolle M, Casanas-Roux F. Three-dimensional architectures of
peritoneal endometriosis. Fertil Steril 1992;57:9803.
Donnez J, Smoes P, Gillerot S, Casanas-Roux F, Nisolle M. Vascular endothelial growth factor (VEGF) in endometriosis. Hum Reprod 1998;13:168690.
Nisolle M, Casanas-Roux F, Donnez J. Early-stage endometriosis: adhesion
and growth of human menstrual endometrium in nude mice. Fertil Steril
Donnez J, Nisolle M, Casanas-Roux F, Brion P, Da Costa Ferreira N. Stereometric evaluation of peritoneal endometriosis and endometriotic nodules
of the rectovaginal septum. Hum Reprod 1996;11:2248.
Healy DL, Rogers PA, Hii L, Wingeld M. Angiogenesis: a new theory for
endometriosis. Hum Reprod Update 1998;4:73640.
Vinatier D, Cosson M, Dufour P. Is endometriosis an endometrial disease?
Eur J Obstet Gynecol Reprod Biol 2000;91:11325.
Van Langendonckt A, Casanas-Roux F, Donnez J. Oxidative stress and peritoneal endometriosis. Fertil Steril 2000;77:86170.
Giudice LC, Kao LC. Endometriosis. Lancet 2004;364:178999.
Bulun SE. Endometriosis. N Engl J Med 2009;360:26879.
de Ziegler D, Borghese B, Chapron C. Endometriosis and infertility: pathophysiology and management. Lancet 2010;376:7308.
Donnez J, Donnez O, Orellana R, Binda MM, Dolmans MM. Endometriosis
and infertility. Panminerva Med 2016;58:14350.
Lousse JC, Van Langendonckt A, Defrere S, Gonzalez Ramos R, Colette S,
Donnez J. Peritoneal endometriosis is an inammatory disease. Front Biosci
Ruder EH, Hartman TJ, Blumberd J, Goldman MB. Oxidative stress and antioxidants: exposure and impact on female fertility. Hum Reprod Update
Kerr RA. Earth science. The story of O2. Science 2005;308:17302.
Lindahl SGE. Oxygen and life on Earth an anesthesiologists views on oxygen
evolution, discovery, sensing, and utilization. Anesthesiology 2008;109:
Lyons TW, Reinhard CT, Planavsky NJ. The rise of oxygen in Earths early
ocean and atmosphere. Nature 2014;506:30715.
Bostek CC. Oxygen toxicity: an introduction. AANA J 1989;57:2317.
Agarwal A, Aponte-Mellado A, Premkumar BJ, Shaman A, Gupta S. The effects of oxidative stress on female reproduction: a review. Reprod Biol Endocrinol 2012;10:49.
Aon MA, Cortassa S, ORourke B. Redox-optimized ROS balance: a unifying
hypothesis. Biochim Biophys Acta 2010;1797:86577.
Iwabuchi T, Yoshimoto C, Shigetomi H, Kobayashi H. Oxidative stress and
antioxidant defense in endometriosis and its malignant transformation.
Oxid Med Cell Longev 2015;2015:848595.
Guo SW. Nuclear factor-kB (NF-kB): an unsuspected major culprit in the
pathogenesis of endometriosis that is still at large? Gynecol Obstet Invest
VOL. - NO. - / - 2016

REV 5.4.0 DTD  FNS30415_proof  16 August 2016  12:28 pm  ce JS

Fertility and Sterility

















Gonzalez-Ramos R, Donnez J, Defrere S, Leclercq I, Squifet J, Lousse JC,

et al. Nuclear factor-kappa B (NF-kB) is constitutively activated in peritoneal
endometriosis. Mol Hum Reprod 2007;13:5039.
Lousse JC, Van Langendonckt A, Gonzalez-Ramos R, Defrere S, Renkin E,
Donnez J. Increased activation of nuclear factor-kappa B (NF-kappaB) in isolated peritoneal macrophages of patients with endometriosis. Fertil Steril
Gupta S, Agarwal A, Agarwal R, Loret de Mola JR. Impact of ovarian endometrioma on assisted reproduction outcomes. Reprod Biomed Online 2006;
Harlev A, Gupta S, Agarwal A. Targeting oxidative stress to treat endometriosis. Expert Opin Ther Targets 2015;19:144764.
Carvalho LF, Samadder AN, Agarwal A, Fernandes LF, Abr~ao MS. Oxidative
stress biomarkers in patients with endometriosis: systematic review. Arch
Gynecol Obstet 2012;286:103340.
Lambrinoudaki IV, Augoulea A, Christodoulakos GE, Economou EV,
Kaparos G, Kontoravdis A, et al. Measurable serum markers of oxidative stress response in women with endometriosis. Fertil Steril 2009;91:
Yamawaki H, Pan S, Lee RT, Berk BC. Fluid shear stress inhibits vascular
inammation by decreasing thioredoxin-interacting protein in endothelial
cells. J Clin Invest 2005;115:7338.
Santulli P, Chouzenoux S, Fiorese M, Marcellin L, Lemarechal H,
Millischer AE, et al. Protein oxidative stress markers in peritoneal uids of
women with deep inltrating endometriosis are increased. Hum Reprod
ere S, Van Langendonckt A, Vaesen S, Jouret M, Gonzalez Ramos R,
Gonzalez D, et al. Iron overload enhances epithelial cell proliferation in endometriotic lesions induced in a murine model. Hum Reprod 2006;21:
Van Langendonckt A, Casanas-Roux F, Dolmans MM, Donnez J. Potential
involvement of hemoglobin and heme in the pathogenesis of peritoneal
endometriosis. Fertil Steril 2002;77:56170.
Van Langendonckt A, Casanas-Roux F, Donnez J. Iron overload in the peritoneal cavity of women with pelvic endometriosis. Fertil Steril 2002;78:
Van Langendonckt A, Casanas-Roux F, Eggermont J, Donnez J. Characterization of iron deposition in endometriotic lesions induced in the nude
mouse model. Hum Reprod 2004;19:126571.
Nisolle M, Donnez J. Peritoneal endometriosis, ovarian endometriosis, and
adenomyotic nodules of the rectovaginal septum are three different entities.
Fertil Steril 1997;68:58596.
Koninckx PR, Donnez J, Brosens I. Microscopic endometriosis: impact on our
understanding of the disease and its surgery. Fertil Steril 2016;105:3056.
Lousse JC, Defr
ere S, Van Langendonckt A, Gras J, Gonzalez Ramos R,
Colette S, et al. Iron storage is signicantly increased in peritoneal macrophages of patients with endometriosis and correlates with iron overload in
the peritoneal uid. Fertil Steril 2009;91:166875.
Levy AP, Levy JE, Kalet-Litman S, Miller-Lotan R, Levy NS, Asaf R, et al. Haptoglobin genotype is a determinant of iron, lipid peroxidation, and macrophage accumulation in the atherosclerotic plaque. Arterioscler Thromb
Vasc Biol 2007;27:13440.
ere S, Lousse JC, Gonzalez-Ramos R, Colette S, Donnez J, Van
Langendonckt A. Potential involvement of iron in the pathogenesis of peritoneal endometriosis. Mol Hum Reprod 2008;14:37785.
Balla G, Jacob HS, Balla J, Rosenberg M, Nath K, Apple F, et al. Ferritin: a cytoprotective antioxidant stratagem of endothelium. J Biol Chem 1992;267:















Lousse JC, Defrere S, Colette S, Van Langendonckt A, Donnez J. Expression

of eicosanoid biosynthetic and catabolic enzymes in peritoneal endometriosis. Hum Reprod 2010;25:73441.
Potts MB, Koh SE, Whetstone WD, Walker BA, Yoneyama T, Claus CP, et al.
Traumatic injury to the immature brain: inammation, oxidative injury, and
iron-mediated damage as potential therapeutic targets. NeuroRx 2006;3:
Arumugam K, Yip YC. De novo formation of adhesions in endometriosis: the
role of iron and free radical reactions. Fertil Steril 1995;64:624.
Murphy AA, Santanam N, Parthasarathy S. Endometriosis: a disease of
oxidative stress? Semin Reprod Endocrinol 1998;16:26373.
Buttke TM, Sandstrom PA. Oxidative stress as a mediator of apoptosis. Immunol Today 1994;15:710.
Agarwal A, Gupta S, Sharma R. Role of oxidative stress in female reproduction. Reprod Biol Endocrinol 2005;3:121.
Elkins TE, Warren J, Portz D, McNeeley SG. Oxygen free radicals and pelvic
adhesion formation: II. The interaction of oxygen free radicals and
adhesion-preventing solutions. Int J Fertil 1991;36:2317.
Anup R, Aparna V, Pulimood A, Balasubramanian KA. Surgical stress and the
small intestine: role of oxygen free radicals. Surgery 1999;125:5609.
Bentes de Souza AM, Rogers MS, Wang CC, Yuen PM, Ng PS. Comparison
of peritoneal oxidative stress during laparoscopy and laparotomy. J Am Assoc Gynecol Laparosc 2003;10:6574.
Binda MM, Molinas CR, Koninckx PR. Reactive oxygen species and adhesion
formation: clinical implications in adhesion prevention. Hum Reprod 2003;
Molinas CR, Mynbaev O, Pauwels A, Novak P, Koninckx PR. Peritoneal mesothelial hypoxia during pneumoperitoneum is a cofactor in adhesion formation in a laparoscopic mouse model. Fertil Steril 2001;76:5607.
Elkelani OA, Binda MM, Molinas CR, Koninckx PR. Effect of adding more
than 3% oxygen to carbon dioxide pneumoperitoneum on adhesion formation in a laparoscopic mouse model. Fertil Steril 2004;82:161622.
Eleftheriadis E, Kotzampassi K, Papanotas K, Heliadis N, Sarris K. Gut
ischemia, oxidative stress, and bacterial translocation in elevated abdominal
pressure in rats. World J Surg 1996;20:116.
Taskin O, Buhur A, Birincioglu M, Burak F, Atmaca R, Yilmaz I, et al. The effects of duration of CO2 insufation and irrigation on peritoneal microcirculation assessed by free radical scavengers and total glutathion levels during
operative laparoscopy. J Am Assoc Gynecol Laparosc 1998;5:12933.
Wagener FA, Volk HD, Willis D, Abraham NG, Soares MP, Adema GJ, et al.
Different faces of the heme-heme oxygenase system in inammation. Pharmacol Rev 2003;55:55171.
Stocker R, Glazer AN, Ames BN. Antioxidant activity of albumin-bound bilirubin. Proc Natl Acad Sci U S A 1987;84:591822.
Nakahira K, Takahashi T, Shimizu H, Maeshima K, Uehara K, Fujii H, et al.
Protective role of heme oxygenase-1 induction in carbon tetrachlorideinduced hepatotoxicity. Biochem Pharmacol 2003;15:1091105.
Borghese B, Vaiman D, de Ziegler D, Chapron C. Endometriosis and genetics: what responsibility for the genes? J Gynecol Obstet Biol Reprod
Ngo C, Chereau C, Nicco C, Weill B, Chapron C, Batteux F. Reactive oxygen
species controls endometriosis progression. Am J Pathol 2009;175:22534.
Leconte M, Nicco C, Ngo C, Chereau C, Chouzenoux S, Marut W, et al. The
mTOR/AKT inhibitor temsirolimus prevents deep inltrating endometriosis in
mice. Am J Pathol 2011;179:8809.
McKinnon BD, Kocbek V, Nirgianakis K, Bersinger NA, Mueller MD. Kinase
signalling pathways in endometriosis: potential targets for non-hormonal
therapeutics. Hum Reprod Update 2016;22.

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