FERTILITY AND STERILITY威

VOL. 77, NO. 5, MAY 2002

Copyright ©2002 American Society for Reproductive Medicine
Published by Elsevier Science Inc.
MODERN TRENDS
Printed on acid-free paper in U.S.A. Edward E. Wallach, M.D.
Associate Editor

Oxidative stress and peritoneal

endometriosis
Anne Van Langendonckt, Ph.D., Françoise Casanas-Roux, Ph.D., and
Jacques Donnez, M.D., Ph.D.
Department of Gynecology, Université Catholique de Louvain, Brussels, Belgium

Objective: To review the literature associating pelvic endometriosis with oxidative stress and to discuss the
potential causes and consequences of a pro-oxidant environment in the peritoneal cavity.
Design: Literature survey.
Result(s): Several studies suggest that oxidative stress is a component of the inflammatory reaction associated
with endometriosis. Evidence includes the prevention of endometriosis induction in rabbits by the addition of
antioxidants, an increase in reactive oxygen species release by macrophages, increased peritoneal levels of
oxidized low-density lipoproteins and their by-products, altered expression of endometrial pro-oxidant and
antioxidant enzymes, and consumption of peritoneal fluid vitamin E. Retrograde menstruation is likely to carry
highly pro-oxidant factors, such as heme and iron, into the peritoneal cavity, as well as apoptotic endometrial
cells, which are well-known inducers of oxidative stress. Reactive oxygen species may be involved in
endometriosis-associated infertility and may play a role in the regulation of the expression of genes encoding
immunoregulators, cytokines and cell adhesion molecules implicated in the pathogenesis of endometriosis.
Conclusion(s): Better understanding of the mechanisms of reactive oxygen species production and detoxi-
fication and further investigation of their effect on the peritoneal environment are essential to obtain new
insight into this disease and eventually develop new diagnostic and therapeutic strategies. (Fertil Steril威 2002;
77:861–70. ©2002 by American Society for Reproductive Medicine.)
Key Words: Pelvic endometriosis, hemoglobin, iron, antioxidant, reactive oxygen species, NF-␬ B

Received August 29, 2001;
revised and accepted
November 14, 2001.
Supported by a grant from
the Fonds National de la
Recherche Scientifique de
Belgique. Dr. Van
Langendonckt is a
scientific collaborator of
the Fonds National de la
Recherche Scientifique de
Belgique.
Reprint requests: Jacques
Donnez, M.D., Ph.D.,
Department of Gynecology,
Université Catholique de
Louvain, Cliniques
Universitaires St Luc,
Avenue Hippocrate 10,
1200 Brussels, Belgium
(FAX: 32-2-764-95-07;
E-mail: donnez@gyne.
ucl.ac.be).
0015-0282/02/$22.00
PII S0015-0282(02)02959-X
Endometriosis is characterized by the im-
plantation and growth of endometrial tissue
outside the uterine cavity. Most studies of pel-
vic endometriosis are based on the implanta-
tion theory of Sampson (1). According to this
theory, desquamated endometrial cells are
transported into the peritoneal cavity after ret-
rograde menstruation, and the still-viable cells
subsequently implant and grow.
Recent studies suggest that menstrual efflu-
ent contains factors that induce alterations in
the morphology of the peritoneal mesothelium
(2), which may create adhesion sites for endo-
metrial cells. Attachment of endometrial cells
appears to be enhanced by induction of adhe-
sion molecules and their receptors (3–5) and
overexpression of matrix metalloproteinases
(6) and plasminogen activators (7), which en-
sure local destruction of the extracellular ma-
trix in endometriosis.
After adhesion, endometrial cells proliferate
and gradually invade the peritoneal tissue.
Some factors induce vascularization of endo-
metriotic implants, allowing their further de-
velopment (8 –12). It has been suggested that
this process leads to the formation of red,
flame-like lesions with high vascular and met-
abolic activity. Cytokines and growth factors,
such as transforming growth factor-␤, interleu-
kin-8, interleukin-1, tumor necrosis factor-␣,
interferon-␥ (13), and vascular endothelial
growth factor (11), have been implicated as
inducers of attachment, proliferation, and neo-
vascularization. Endometriosis also seems to
be associated with increased recruitment and
activation of macrophages, which are thought
to play an important role in the development of
the disease (14).
Red lesions regrow constantly after partial
shedding. A scarification process is then initi-
ated, and lesions appear as black and, later,
white quiescent or latent lesions (8, 9, 15).
Endometriosis is a multifactorial disease as-
sociated with a general inflammatory response
in the peritoneal cavity. Oxidative stress has
been proposed as a potential factor involved in

861
the pathophysiology of the disease. Reactive oxygen species
have been implicated in the pathogenesis of many human
diseases and aging (16, 17).
We provide an overview of studies associating oxidative
stress with peritoneal endometriosis. The possible causes and
consequences of an oxidant environment in the peritoneal
cavity are discussed in the light of recent advances in this
field.
REACTIVE OXYGEN SPECIES
Many comprehensive reviews have discussed production
of reactive oxygen species and cellular response to oxidative
stress (16 –18); we therefore cover these topics only briefly.
Reactive oxygen species are intermediaries produced by
normal oxygen metabolism. To protect themselves from the
deleterious effects of reactive oxygen species, cells have
developed a wide range of antioxidant systems to limit
production of reactive oxygen species, inactivate them, and
repair cell damage. However, oxidative stress may occur
when the balance between reactive oxygen species produc-
tion and antioxidant defense is disrupted. The increasing
number of diseases associated with oxidative stress suggests
that oxidative balance may be precarious (17).
Univalent reduction in oxygen results in production of the
superoxide anion. The dismutation of two superoxide anions,
catalyzed by superoxide dismutase, leads to the formation of
hydrogen peroxide. Hydrogen peroxide is detoxified by glu-
tathione peroxidase or inactivated to H2O and O2, a reaction
catalyzed by catalase. Optimal protection is achieved only
when an appropriate balance among superoxide dismutase,
glutathione peroxidase, and catalase is maintained (19). Al-
ternatively, in the presence of transition metals such as iron,
hydrogen peroxide produces the highly reactive hydroxyl
radical. The hydroxyl radical is highly toxic to cells because
it reacts instantaneously with all cellular components.
Almost all major classes of biomolecules, including lip-
ids, proteins, and nucleic acids, are potential targets for
reactive oxygen species. The oxidative destruction of poly-
unsaturated fatty acids, known as lipid peroxidation, is par-
ticularly damaging because it is a self-perpetuating chain-
reaction that may alter the integrity of cell membranes.
These reactions often involve transition-metal ion catalysis
(16). The sequestration of iron by iron-binding proteins
seems to be crucial in protecting cells from damage by
reactive oxygen species and lipid peroxidation. Cells have
evolved enzymatic antioxidants, such as superoxide dis-
mutase, catalase, and glutathione peroxidase, and nonenzy-
matic antioxidants, including vitamin E, vitamin C, taurine,
and glutathione (18).
Nitric oxide (NO), another oxygen-containing radical, is
of growing interest in biology and medicine. Nitric oxide
synthase is involved in the production of NO. Nitric oxide
plays an important role as a mediator of paracrine interac-
862 Van Langendonckt et al. Oxidative stress and endometriosis
tions, as seen in the vascular system (20). However, as a free
radical with an unpaired electron, NO also reacts with a wide
range of cellular molecules. In pathophysiologic conditions,
NO may be overproduced and the highly toxic radical per-
oxynitrite, which is formed from NO and superoxide, may
accumulate. Peroxynitrite is considered to be a strong pro-
oxidant similar to the hydroxyl radical (17).
EVIDENCE OF INCREASED OXIDATIVE
STRESS IN ENDOMETRIOSIS
Generation of Reactive Oxygen Species
In 1987, Zeller et al. (21) showed that production of
reactive oxygen species by peritoneal fluid mononuclear
cells was increased in endometriosis. They concluded that
large amounts of reactive oxygen species were released after
chronic stimulation of peritoneal fluid macrophages in
women with endometriosis. Production of reactive oxygen
species is known to increase after activation of immune cells,
especially polymorphonuclear leukocytes and macrophages.
However, further studies based on direct measurement of
reactive oxygen species production failed to show an obvi-
ous oxidant or antioxidant imbalance in the peritoneal cavity
of patients with endometriosis. Wang et al. (22) found sim-
ilar levels of reactive oxygen species (detected by a chemi-
luminescent method) in the peritoneal fluid of patients with
endometriosis and disease-free controls. Furthermore, Ho et
al. (23) showed that total antioxidant status, as assessed by
spectrophotometry, was not increased in endometriosis; Po-
lak et al. (24) recently confirmed this finding.
Ota et al. (25) also found evidence that oxidative stress
occurs in endometriosis. Expression of xanthine oxidase, an
enzyme which produces reactive oxygen species, in ectopic
and eutopic endometrium remained high throughout the
menstrual cycle in women with endometriosis; in contrast,
cyclic variations in its expression were seen in controls.
This apparent discrepancy between results may be due to
the fact that only persistent markers of oxidative stress, such
as enzymes or stable by-products of oxidative reactions, can
still be detected when endometriosis is diagnosed. Another
possible explanation is that oxidative stress occurs only
locally—for example, at the site of bleeding—and does not
result in an increase in total peritoneal fluid concentrations.
Generation of the NO. Radical
Endothelial nitric oxide synthase, an enzyme that gener-
ates NO, is also overexpressed in endometriosis and adeno-
myosis (26). Three isoforms of nitric oxide synthases have
been identified to date: inducible, endothelial , and neuronal.
Expression of endothelial and inducible nitric oxide syn-
thases has been demonstrated in the endometrium (20), and
increased expression of endothelial nitric oxide synthase was
observed throughout the cycle in the endometrium of women
with endometriosis and adenomyosis (26, 27). However, no
evidence of increased NO metabolism was found in the
Vol. 77, No. 5, May 2002
peritoneal fluid of women with and without endometriosis
(23). Of note, generation of peroxynitrite by ectopic endo-
metrium was recently demonstrated in patients with adeno-
myosis (28). Expression of endothelial and inducible nitric
oxide synthase and peroxynitrite generation were markedly
reduced after GnRH agonist therapy, supporting their poten-
tial role in the pathophysiology of adenomyosis (28).
Animal Models
A study by Portz et al. (29) supports the hypothesis that
oxidative stress is involved in endometriosis. They found
that injection of the antioxidant enzymes superoxide dis-
mutase and catalase into the peritoneal cavity prevented
formation of intraperitoneal adhesions at endometriosis sites
in the rabbit.
Oxidation of Low-Density Lipoproteins
In contrast, Murphy et al. (30) found increased oxidation
of low-density lipoprotein in patients with pelvic endome-
triosis and increased concentrations of oxidized low-density
lipoproteins in the peritoneal fluid of women in whom the
disease was developing (30, 31). Oxidative modification of
these molecules involves peroxidation of the lipid compo-
nent, which leads to release of aldehydes, such as malondi-
aldehyde, and reaction with lysine residues of proteins.
However, Arumugam and Yip (32) found no relation be-
tween levels of malondialdehyde in peritoneal fluid and
severity of endometriosis. Higher levels of lysophosphatidyl
choline, another indicator of lipoprotein peroxidation, were
found in the peritoneal fluid of patients with endometriosis
(30, 33).
Murphy et al. (34) demonstrated increased modified lipid-
protein complexes at the level of the endometrium. Ectopic
endometrial cells were also immunostained with antibodies
to oxidatively modified proteins. The occurrence of oxida-
tively modified lipid-protein complexes was further ascer-
tained by an increase in serum autoantibodies to three mark-
ers of oxidative stress: lipid-peroxide–modified serum
albumin, malondialdehyde-modified low-density lipopro-
tein, and oxidized low-density lipoprotein (35). The latter
two molecules are examples of terminal decomposition of
proteins damaged by peroxidized lipids.
Antioxidant Enzymes
Several recent studies appear to show that in women with
endometriosis, the endometrium shows altered expression of
enzymes involved in defense against oxidative stress. Ota et
al. (36) found that manganese and copper/zinc superoxide
dismutase (37) and glutathione peroxidase (38) are overex-
pressed in the eutopic endometrium of patients with endo-
metriosis or adenomyosis. Expression of both superoxide
dismutases remains high throughout the cycle (37), unlike in
patients without disease, who have cyclic variations in their
levels of expression (37, 39).
Expression of manganese superoxide dismutase (40) and
glutathione peroxidase (38) has been demonstrated in ec-
FERTILITY & STERILITY威
topic endometrium of women with adenomyosis. Expression
of these enzymes, which are induced during increased re-
lease of reactive oxygen species, can be considered as an
indicator of oxidative stress (36). It has been suggested that
eutopic endometrium undergoes oxidative stress even in
patients who do not develop endometriosis (30), but proba-
bly to a lesser extent.
Heat-Shock Proteins
Abnormal expression of heat-shock proteins 27 and 70
has been reported in the eutopic endometrium of women
with endometriosis (13). These stress response proteins are
induced by numerous stimuli, including oxidative stress, and
can also be considered as indicators of an atypical stress
response (13).
Vitamin E
Vitamin E levels are significantly lower in the peritoneal
fluid of women with endometriosis, perhaps because anti-
oxidants in peritoneal fluid are consumed during oxidation
reactions (30, 33). Vitamin E plays an important role in
protecting biological membranes by preventing peroxida-
tion. It may also play a role in preventing activation of
redox-sensitive pathways, which have been implicated in
abnormal cell proliferation and inflammatory response.
A decrease in antioxidant capacity may explain why
low-density lipoproteins in the peritoneal fluid of patients
with endometriosis are more readily oxidized than are low-
density lipoproteins from control patients (33). As far as we
know, apart from this study of vitamin E, the antioxidant
response of the peritoneal environment has not been examined.
Taken together, the data strongly indicate the occurrence
of oxidative stress in the peritoneal cavity of women with
endometriosis and, to a lesser extent, in those without disease.
ORIGIN OF OXIDATIVE STRESS IN
THE PERITONEAL CAVITY
Several hypotheses have been proposed to explain why
oxidative stress is induced in cases of pelvic endometriosis.
Erythrocytes (41), apoptotic endometrial tissue and cell
debris (30) transplanted into the peritoneal cavity by men-
strual reflux and macrophages (30) have been implicated as
potential inducers of oxidative stress (Fig. 1). Excessive
production of reactive oxygen species may also result from
exposure to environmental toxicants and heavy metals,
which may disrupt the balance of pro-oxidants and antioxi-
dants.
Erythrocytes and Their Pro-oxidant By-
Products
Erythrocytes are likely to release pro-oxidant and pro-
inflammatory factors, such as hemoglobin and its highly
toxic by-products heme and iron, into the peritoneal envi-
ronment. Iron and heme are essential to living cells (42).
However, unless they are appropriately chelated, free iron
863
 FIGURE 1

Hypotheses explaining oxidative stress in the peritoneal cavity of women with endometriosis. Bold type indicates factors that
have been studied specifically in relation to pelvic endometriosis. CO ⫽ carbon dioxide; HO ⫽ heme oxygenase; NO ⫽ nitric
oxide; NOS ⫽ nitric oxide synthase.

Van Langendonckt. Oxidative stress and endometriosis. Fertil Steril 2002.

(16) and, to a lesser extent, heme (43, 44) play a key role in
the formation of deleterious reactive oxygen species. Iron-
induced oxidative stress has been implicated in numerous
pathologic processes (16, 17).
However, erythrocytes are found in the peritoneal cavity
of 90% of menstruating women (45). Thus, why do some
patients develop macroscopically visible peritoneal endo-
metriotic lesions but others do not? One hypothesis is that in
some patients, peritoneal protective mechanisms are
swamped by menstrual reflux, either because of the abun-
dance of the reflux or because of defective scavenging sys-
tems (13).
Several studies have suggested that the amount of retro-
grade menstruation may be related to endometriosis (13).
Shorter cycles (46) and heavier and longer menstrual flow
have been reported in women with endometriosis (47).
Moreover, in patients in whom the disease develops, bleed-
ing from red endometrial lesions may further increase the
number of erythrocytes.
Data are lacking on how the peritoneal environment copes
with the presence of erythrocytes. However, cellular re-
sponse is probably similar to that observed in most tissues
during hemorrhage. Some studies indicate that amounts of
hemoglobin and its by-products, as well as proteins involved
in their scavenging or catabolism, are increased in patients
with endometriosis.
Increased levels of hemoglobin have been found in the
peritoneal fluid of patients with pelvic endometriosis com-
pared with disease-free controls (48). Studies by Piva and
Sharpe-Timms (49) and Sharpe-Timms et al. (50) suggested

864 Van Langendonckt et al. Oxidative stress and endometriosis Vol. 77, No. 5, May 2002
that ectopic endometrial cells react by synthesizing and
secreting endo-1, a haptoglobin-like protein that is closely
related to the hemoglobin scavenger haptoglobin. These
investigators recently confirmed that more endo-1 protein is
localized in endometriotic lesions and eutopic endometrium
of women with endometriosis than in eutopic endometrium
of controls (51). The fact that infertile patients with or
without endometriosis have reduced serum levels of antibod-
ies against a haptoglobin-like protein corroborates these
findings (52). These articles discuss the potential role of
haptoglobin as an angiogenic or immunomodulatory factor.
Further studies are needed to assess whether endo-1 binds
hemoglobin. In contrast, Dunselman et al. (53) found no
increase in haptoglobin in the peritoneal fluid of women with
endometriosis.
Catabolism of hemoglobin involves its degradation into
its protein component and nonprotein core, heme. Most cells
protect themselves from heme toxicity by rapid expression
of scavenger proteins, such as hemopexin, and by induction
of heme oxygenase-1, which catalyzes heme degradation
(54).
All products of heme catabolism are biologically active.
These products include iron; carbon monoxide acting as a
signal molecule; and biliverdin, which is further converted
into bilirubin, both biliverdin and bilirubin acting as antioxi-
dants. Van Langendonckt et al. (55) showed that endometrial
cells express constitutive heme oxygenase-2 and inducible
heme oxygenase-1 and that endometrial lesions, especially
red lesions, strongly express inducible heme oxygenase-1
(48). However, the fact that heme oxygenase-1 was poorly
expressed in macrophages and mesothelial cells and that
levels of bilirubin, the final by-product of hemoglobin ca-
tabolism, in peritoneal fluid were not increased may suggest
that detoxifying systems are overwhelmed by excess hemo-
globin in endometriosis (48). This idea is in accordance with
the findings of Gaulier et al. (56), who reported the presence
of bilirubin deposits around endometriotic lesions and an
absence of deposits in the mesothelium in a patient with
endometriosis.
Evidence suggests that iron overload occurs in the peri-
toneal cavity of patients with peritoneal endometriosis.
Higher levels of iron are found in the peritoneal fluid of
patients with endometriosis; concentrations are related to the
severity of the disease (41, 57). Moreover, iron pigment is
more frequently found in endometriotic than in nonendo-
metriotic lesions (58). Most iron is likely to be stored bound
to proteins in a soluble nontoxic form. Levels of ferritin, the
major iron-storing molecule (59), and transferrin, which
ensures iron transport (60), were found to be increased in the
peritoneal fluid of women with endometriosis. This is con-
sistent with the finding that patients with endometriosis have
higher serum levels of antibodies to transferrin (61).
As in most tissue, activated macrophages probably play
an important role in the degradation of erythrocytes. The
FERTILITY & STERILITY威
presence of siderophages, known as iron-storing macro-
phages, is considered to indicate endometriosis (56, 62).
Macrophages usually internalize and lyse senescent erythro-
cytes, releasing hemoglobin and ensuring its degradation by
heme oxygenase. The iron released is then returned to the
iron transporter, transferrin (42).
Martinez-Roman et al. (63) found increased transferrin
receptor expression in peritoneal macrophages of patients
with endometriosis compared with fertile and infertile con-
trols. This further supports the hypothesis of increased iron
metabolism by macrophages in endometriosis. However,
Becker et al. (64) found no increase in transferrin receptor
expression (CD71) in macrophages of patients with endo-
metriosis.
Macrophages, endometriotic lesions, and peritoneal cells
of patients with endometriosis show typical features of iron-
overloaded tissue; specifically, they are heavily laden with
hemosiderin (56, 58, 62). Several authors have suggested
that “hemosiderin is formed when abundant ferritin cores
come into close contact after partial digestion of their protein
coat by lysosomal-siderosome enzymes” (42, 65). In patients
with endometriosis, the presence of tissue iron deposits in
the peritoneum appears to be related to the presence of
endometriotic lesions, since the rate of deposits encountered
was higher in peritoneum close to a lesion than in normal-
looking peritoneum (59).
Taken together, these studies suggest that iron homeosta-
sis in the peritoneal cavity may be disrupted in women with
endometriosis.
Recruitment and Activation of Macrophages
Murphy et al. (30) proposed a hypothesis based on anal-
ogies between endometriosis and arteriosclerosis to explain
the occurrence of oxidative stress in the peritoneal cavity of
patients with endometriosis. Both diseases share common
features, including the presence of tissue macrophages that
express scavenger receptors, increased levels of oxidized
lipoproteins, and the presence of inflammatory cytokines and
growth factors. Murphy et al. (30) suggested that senescent
erythrocytes and apoptotic endometrial cells may be respon-
sible for recruitment and activation of mononuclear phago-
cytes in the peritoneal cavity.
These investigators also showed that the activation of
macrophages in endometriosis patients is associated with an
increase in scavenger receptor activity (31). The presence of
scavenger receptors seems to be essential for clearance of
oxidized low-density lipoproteins. Scavenger receptor activ-
ity appears to be induced in adherent macrophages only, as
suggested by data showing the uncommon occurrence of
such receptors in nonadherent macrophages (66). Nonadher-
ent macrophages would generate oxidative stress; as a con-
sequence, levels of lipid peroxides and oxidatively modified
lipoproteins would further increase, triggering a cascade of
865
proinflammatory reactions involving recruitment of macro-
phages and secretion of proinflammatory cytokines (30).
This hypothesis is supported by the fact that derivatives of
low-density lipoprotein oxidation, such as lysophosphatidyl-
choline (levels of which are increased in patients with en-
dometriosis), may act as a chemotactant for monocytes and
induce secretion of cytokines (30, 33).
Exposure to Toxicants
Exposure to environmental toxicants, such as 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD), may also promote ox-
idative stress in patients with developing endometriosis.
Inhalation of airborne particles or ingestion of toxicants and
heavy metals has been shown to induce oxidative stress and
has been suggested as a contributory factor in the pathogen-
esis of several diseases (17, 67).
Studies indicate that toxicants such as TCDD may also
contribute to the development of endometriosis (67, 68). The
potential role of TCDD in the pathophysiology of endome-
triosis may be based on its role as a disrupter of steroid
action. However, other adverse effects of TCDD, including
induction of oxidative stress (69), may also be involved.
CONSEQUENCES OF INCREASED
OXIDATIVE STRESS IN THE
PERITONEAL CAVITY
Decreased Fertility
Most reports discuss the potential consequences of in-
creased oxidative stress in endometriosis relative to de-
creased fertility. However, the association between endome-
triosis and infertility, especially in patients with mild
disease, is still a matter of debate (70). Oxidative stress is
thought to be one of the factors responsible for impaired
fertility in patients with endometriosis (36).
The peritoneal fluid of patients with endometriosis is
toxic to sperm (57). This effect may be mediated by reactive
oxygen species (71). This detrimental effect appears to be
associated with concentrations of iron in peritoneal fluid
(57).
Reactive oxygen species and NO may also play a role in
ovulation (72–75). Studies have shown that inhibition of
reactive oxygen species (73) and NO production may impair
ovulation (74, 75). The effects of oxidative stress on fertil-
ization, preimplantation embryo development (76), and im-
plantation (20) are well documented.
Induction of Cellular Damage
In other tissues, iron is known to induce oxidative stress,
leading to macromolecular oxidative damage, tissue injury,
and chronic inflammation (17). Oxidative stress was sug-
gested to be responsible for local destruction of the perito-
neal mesothelium, thereby creating adhesion sites for ectopic
endometrial cells (41). It may also promote apoptosis (30);
some studies indicate that apoptosis and oxidative stress are
866 Van Langendonckt et al. Oxidative stress and endometriosis
related (77). However, a recent study appears to show that
morphologic changes in mesothelial cells induced by men-
strual effluent are not due to necrosis or apoptosis (78).
Induction of Adhesion and Growth of Ectopic
Endometrial Cells
Reactive oxygen species can also alter cell function by
regulating protein activity and gene expression. In particular,
reactive oxygen species seem to play an essential role in the
regulation of the transcription factors NF-␬B and AP-1,
which control genes involved in immunologic response,
cellular defense, and expression of cytokines and cell adhe-
sion molecules (79). Of note, many factors that are overex-
pressed in patients with endometriosis have NF-␬B– binding
sites in their genes (30) (Table 1). NF-␬B is a cytoplasmic
protein that, when activated, is translocated into the nucleus,
where it binds to ␬B sequences of DNA and activates target
genes (Fig. 2). Activation of NF-␬B involves release of its
I␬B subunit, which is induced by cytokines, such as tumor
necrosis factor-␣ and interleukin-1; proinflammatory factors,
such as heme; toxicants, such as dioxin; and factors that
induce oxidative stress (Table 1). The potential activation of
NF-␬B by oxidative stress is supported by many studies
demonstrating that the addition of antioxidant prevents
NF-␬B activation (79).
Endometrial cells have been found to express NF-␬B and
its activating kinases (80). Progesterone has been shown to
increase levels of I-␬B and thereby inhibit NF-␬B activation
(81). Thus, altered expression and lower biological activity
of the progesterone receptor in ectopic endometrial cells
(82– 84) may result in NF-␬B activation.
Expression of adhesion molecules, such as intercellular
adhesion molecule-1, vascular cell adhesion molecule-1, and
E-selectin, in endometrial and peritoneal cells may also be
induced by heme (44) and lysophosphatidyl choline, a by-
product of lipoprotein peroxidation (33). Ectopic endome-
trial cells have been shown to overexpress intercellular ad-
hesion molecule-1 (4).
Moreover, heme has been reported to induce activated
macrophages of patients with endometriosis to produce cy-
tokines, such as tumor necrosis factor-␣, interleukin-1, and
interleukin-6 (85). Similarly, oxidized lipids and modified
proteins might induce interleukin-1 and colony-stimulating
factor-1 synthesis by macrophages and promote endometrial
cell growth as pointed out by Murphy et al (33).
CONCLUSIONS
Compelling evidence suggests that oxidative stress is
increased in women with pelvic endometriosis. Oxidative
stress occurs when there is an imbalance between production
of reactive oxygen species, which are intermediaries released
by normal oxygen metabolism, and antioxidant systems,
which are designed to control production of reactive oxygen
species, inactivate reactive oxygen species, and repair cell
Vol. 77, No. 5, May 2002
 TABLE 1

Molecules that are induced in endometriosis and contain an NF-␬B–responsive sequence in their genes or are involved in
NF-␬B activation.

Regulation Link with

Molecule by NF-␬B Function endometriosisa

RANTES 87 Monocytes chemotactant 88

Monocyte chemoattractant protein 89 Monocytes chemotactant 90
Intercellular adhesion molecule 91 Adhesion 4
Vascular cell adhesion molecule 44 Adhesion 92
Heme oxygenase-1 93 Heme degradation 48
Urokinase plasminogen activator 94 Fibrinolysis 95
Inducible nitric oxide synthase 96 Nitric oxide production 28
Cyclooxygenase-2 97 Prostaglandin synthesis 98
Activators of NF-␬B
Tumor necrosis factor-␣ 88 Cytokine 99
Interleukin-1 100 Cytokine 101
Integrin 102 Cell adhesion 3
Fibronectin 103 Cell adhesion 3
Dioxin 104 Toxicant 68
a
Columns show reference numbers.
Van Langendonckt. Oxidative stress and endometriosis. Fertil Steril 2002.

FIGURE 2

Mechanism of NF-␬B activation by factors that have been implicated in the pathogenesis of endometriosis and induction of
target genes. COX ⫽ cyclooxygenase; IL ⫽ interleukin; i-NOS ⫽ inducible nitric oxide synthase; TNF ⫽ tumor necrosis factor.

Van Langendonckt. Oxidative stress and endometriosis. Fertil Steril 2002.

FERTILITY & STERILITY威 867

damage. Production of reactive oxygen species appears to be
increased in women in whom endometriosis is developing,
as indicated by increased release of reactive oxygen species
by macrophages; higher levels of oxidized low-density li-
poproteins and their by-products in peritoneal fluid; and
overexpression by endometrial cells of enzymes that produce
reactive oxygen species, such as xanthine oxidase and nitric
oxide synthase. Several studies indicate that antioxidant de-
fenses may be altered in endometriosis, as suggested by
aberrant expression of endometrial antioxidant enzymes and
lower levels of the antioxidant vitamin E in peritoneal fluid.
Further studies are warranted to assess the contribution of
oxidative stress to the physiopathology of endometriosis. It
would be particularly valuable to determine whether antiox-
idant treatment of endometriosis is effective. Use of mife-
pristone to treat endometriosis has had promising results
(86). This agent has been shown to inhibit endometrial cell
growth, an effect which appears to be due to its antioxidant
properties.
The data do not clearly indicate whether oxidative stress
associated with pelvic endometriosis results from increased
production of reactive oxygen species, defective antioxidant
defense, or both conditions. Information is lacking on how
the peritoneal environment, and particularly mesothelial
cells, respond to the presence of blood, which repeatedly
carried into the peritoneal cavity by retrograde menstruation,
ovulation, and bleeding lesions. Expression of antioxidant
enzymes by endometrial cells appears to be enhanced in
patients with developing endometriosis. Some data seem to
indicate that catabolism of hemoglobin by peritoneal mac-
rophages and release of proteins that chelate iron in perito-
neal fluid are also increased in endometriosis. However, the
occurrence of oxidative stress suggests that despite this in-
crease in antioxidant defense, detoxifying mechanisms might
be overloaded in endometriosis.
Reactive oxygen species have also been increasingly
studied as regulators of protein activity and inducers of gene
expression (76). As a potential inducer of NF-␬B, which
activates genes involved in cell adhesion, secretion of in-
flammatory cytokines, and recruitment of macrophages, ox-
idative stress may help to trigger the chain of events that
leads to the development of endometriotic lesions. Further
studies are needed to examine the potential involvement of
oxidative stress in the pathophysiology of endometriosis.
References
1. Sampson JA. Peritoneal endometriosis due to the menstrual dissemi-
nation of endometrial tissue into the peritoneal cavity. Am J Obstet
Gynecol 1927;14:422– 69.
2. Koks CAM, Demir-Weusten AY, Groothuis PG, Dunselman GAJ, de
Goeij AFPM, Evers JLH. Menstruum induces changes in mesothelial
cell morphology. Gynecol Obstet Invest 2000;50:13– 8.
3. Béliard A, Donnez J, Nisolle M, Foidart JM. Localization of laminin,
fibronectin, E-cadherin and integrins in endometrium and endometri-
osis. Fertil Steril 1997;67:266 –72.
4. Somigliana E, Vigano P, Gaffuri B, Guarneri D, Busacca M, Vignali
M. Human endometrial stromal cells as a source of soluble intercel-
lular adhesion molecule (ICAM)-1 molecules. Hum Reprod 1996;11:
1190 – 4.
868 Van Langendonckt et al. Oxidative stress and endometriosis
5. Selam B, Arici A. Implantation defect in endometriosis: endometrium
or peritoneal fluid. J Reprod Fertil 2000;55:121– 8.
6. 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;68:246 –51.
7. 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;4:730 –5.
8. Donnez J, Nisolle M, Casanas-Roux F. Three-dimensional architec-
tures of peritoneal endometriosis. Fertil Steril 1992;57:980 –3.
9. Nisolle M, Donnez J. Peritoneal endometriosis, ovarian endometriosis,
and adenomyotic nodules of the rectovaginal septum are three differ-
ent entities. Fertil Steril 1997;68:585–96.
10. Nisolle M, Casanas-Roux F, Donnez J. Immunohistochemical analysis
of proliferative activity and steroid receptor expression in peritoneal
and ovarian endometriosis. Fertil Steril 1997;68:912–9.
11. Donnez J, Smoes P, Gillerot S, Casanas-Roux F, Nisolle M. Vascular
endothelial growth factor (VEGF) in endometriosis. Hum Reprod
1998;13:1686 –90.
12. Healy DL, Rogers PA, Hii L, Wingfield M. Angiogenesis: a new
theory for endometriosis. Hum Reprod Update 1998;4:736 – 40.
13. Vinatier D, Cosson M, Dufour P. Is endometriosis an endometrial
disease ? Eur J Obstet Gynecol Reprod Biol 2000;91:113–25.
14. Halme J, Becker S, Wing R. Accentuated cyclic activation of perito-
neal macrophages in patients with endometriosis. Am J Obstet Gy-
necol 1984;148:85–90.
15. Donnez J, Nisolle M, Casanas-Roux F. Peritoneal endometriosis:
two-dimensional and three-dimensional evaluation of typical and sub-
tle lesions. Ann N Y Acad Sci 1994;734:342–51.
16. Halliwell B, Gutteridge JM. Role of free radicals and catalytic metal
ions in human disease: an overview. Methods Enzymol 1990;186:1–
85.
17. Hippeli S, Elstner EF. Transitional metal ion-catalyzed oxygen acti-
vation during pathogenic processes. FEBS Lett 1999;443:1–7.
18. Yu BP. Cellular defenses against damage from reactive oxygen spe-
cies. Physiol Rev 1994;74:139 –59.
19. Michiels C, Raes M, Toussaint O, Remacle J. Importance of Se-
glutathione peroxidase, catalase, and Cu/Zn SOD for cell survival
against oxidative stress. Free Radic Biol Med 1994;17:235– 48.
20. Cameron IT, Campbell S. Nitric oxide in the endometrium. Hum
Reprod Update 1998;4:565–9.
21. Zeller JM, Henig I, Radwanska E, Dmowski WP. Enhancement of
human monocyte and peritoneal macrophage chemiluminescence ac-
tivities in women with endometriosis. Am J Reprod Immunol Micro-
biol 1987;13:78 – 82.
22. Wang Y, Sharma RK, Falcone T, Goldberg J, Agarwal A. Importance
of reactive oxygen species in the peritoneal fluid of women with
endometriosis or idiopathic infertility. Fertil Steril 1997;68:826 –30.
23. Ho HN, Wu MY, Chen SU, Chao KH, Chen CD, Yang YS. Total
antioxidant status and nitric oxide do not increase in peritoneal fluids
from women with endometriosis. Hum Reprod 1997;12:2810 –5.
24. Polak G, Koziol-Montewka M, Gogacz M, Blaszkowska I, Kotarski J.
Total antioxidant status of the peritoneal fluid in infertile women. Eur
J Obstet Gynecol Reprod Biol 2001;94:261–3.
25. Ota H, Igarashi S, Tanaka T. Xanthine oxidase in eutopic and ectopic
endometrium in endometriosis and adenomyosis. Fertil Steril 2001;
75:785–90.
26. Ota H, Igarashi S, Hatazawa J, Tanaka T. Endothelial nitric oxide
synthase in the endometrium during the menstrual cycle in patients
with endometriosis and adenomyosis. Fertil Steril 1998;69:303– 8.
27. Song IO, Huh Y, Yoo KJ, Choi BC, Paik EC, Son IP, et al. Increased
expression of endothelial nitric oxide synthase in endometrium of
infertile women with endometriosis or hydrosalpinx during the win-
dow of implantation [abstract no. O-035]. In: Abstracts of the 15th
Annual Meeting of the ESHRE. Tours, France, June 14 –17, 2000.
28. Kamada Y, Nakatsuka M, Asagari K, Noguchi S, Habara T, Takata M,
et al. GnRH agonist-suppressed expression of nitric oxide synthases
and generation of peroxynitrite in adenomyosis. Hum Reprod 2000;
15:2512–9.
29. Portz DM, Elkins TE, White R, Warren J, Adadevoh S, Randolph J.
Oxygen free radicals and pelvic adhesion formation: blocking oxygen
free radical toxicity to prevent adhesion formation in an endometriosis
model. Int J Fertil 1991;36:39 – 42.
30. Murphy AA, Santanam N, Parthasarathy S. Endometriosis: a disease
of oxidative stress? Semin Reprod Endocrinol 1998;16:263–73.
31. Murphy AA, Palinski W, Rankin S, Morales AJ, Parthasarathy S.
Macrophage scavenger receptor(s) and oxidatively modified proteins
in endometriosis. Fertil Steril 1998;69:1085–94.
32. Arumugam K, Yip Dip YC. Endometriosis and infertility: the role of
exogenous lipid peroxides in the peritoneal fluid. Fertil Steril 1995;
63:198 –9.
Vol. 77, No. 5, May 2002
33. Murphy AA, Santanam N, Morales AJ, Parthasarathy S. Lysophos-
phatidyl-choline, a chemotactic factor for monocytes/T-lymphocytes
is elevated in endometriosis. J Clin Endocrinol Metab
1998;83:2110 –3.
34. Murphy AA, Palinski W, Rankin S, Morales AJ, Parthasarathy S.
Evidence for oxidatively modified lipid-protein complexes in endo-
metrium and endometriosis. Fertil Steril 1998;69:1092– 4.
35. Shanti A, Santanam N, Morales AJ, Parthasarathy S, Murphy AA.
Autoantibodies to markers of oxidative stress are elevated in women
with endometriosis. Fertil Steril 1999;71:1115– 8.
36. Ota H, Igarashi S, Hatazawa J, Tanaka T. Endometriosis and free
radicals. Gynecol Obstet Invest 1999;48:29 –35.
37. Ota H, Igarashi S, Hatazawa J, Tanaka T. Immunohistochemical
assessment of superoxide dismutase expression in the endometrium in
endometriosis and adenomyosis. Fertil Steril 1999;72:129 –34.
38. Ota H, Igarashi S, Kato N, Tanaka T. Aberrant expression of gluta-
thione peroxidase in eutopic and ectopic endometrium in endometri-
osis and adenomyosis. Fertil Steril 2000;74:313– 8.
39. Sugino N, Shimamura K, Takiguchi S, Tamura H, Ono M, Nakata M,
et al. Changes in activity of superoxide dismutase in the human
endometrium throughout the menstrual cycle and in early pregnancy.
Hum Reprod 1996;11:1073– 8.
40. Ishikawa M, Nakata T, Yaginuma Y, Nishiwaki K, Goishi K, Saitoh
S. Expression of superoxide dismutase (SOD) in adenomyosis. Am J
Obstet Gynecol 1993;169:730 – 4.
41. Arumugam K, Yip YC. De novo formation of adhesions in endome-
triosis. The role of iron and free radical reactions. Fertil Steril 1995;
64:62– 4.
42. Ponka P, Beaumont C, Richardson DR. Function and regulation of
transferrin and ferritin. Semin Hematol 1998;35:35–54.
43. Balla J, Jacob HS, Balla G, Nath K, Eaton JW, Vercellotti GM.
Endothelial-cell heme uptake from heme proteins: induction of sensi-
tization and desensitization to oxidant damage. Proc Natl Acad Sci U
S A 1993;90:9285–9.
44. Wagener FA, Feldman E, De Witte T, Abraham NG. Heme induces
the expression of adhesion molecule ICAM-1, VCAM-1 and E Selec-
tin in vascular endothelial cells. Proc Soc Exp Biol Med 1997;216:
456 – 63.
45. Halme J, Hammond MG, Hulka JF, Raj SG, Talbert LM. Retrograde
menstruation in healthy women and in patients with endometriosis.
Obstet Gynecol 1984;64:151– 4.
46. Arumugam K, Lim JM. Menstrual characteristics associated with
endometriosis. Br J Obstet Gynaecol 1997;104:948 –50.
47. Vercellini P, De Giorgi O, Aimi G, Panazza S, Uglietti A, Crosignani
PG. Menstrual characteristics in women with and without endometri-
osis. Obstet Gynecol 1997;90:264 – 8.
48. Van Langendonckt A, Casanas-Roux F, Dolmans MM, Nisolle M,
Donnez J. Hemoglobin and heme: a potential implication in the
pathogenesis of peritoneal endometriosis? Fertil Steril [In press].
49. Piva M, Sharpe-Timms KL. Peritoneal endometriotic lesions differ-
entially express a haptoglobin-like gene. Mol Hum Reprod 1999;5:
71– 8.
50. Sharpe-Timms KL, Piva M, Ricke EA, Surewicz K, Zhang YL,
Zimmer RL. Endometriotic lesions synthesize and secrete a haptoglo-
bin-like protein. Biol Reprod 1998;58:988 –94.
51. Sharpe-Timms KL, Ricke EA, Piva M, Horowitz GM. Differential
expression and localization of de-novo synthesized endometriotic hap-
toglobin in endometrium and endometriotic lesions. Hum Reprod
2000;15:2180 –5.
52. Berkova N, Lemay A, De Grandpré P, Goupil S, Maheux R. Immu-
noblot detection of decreased antibodies to haptoglobin-like protein in
the serum of infertile women with or without endometriosis. Biol
Reprod 1997;57:178 – 85.
53. Dunselman GAJ, Bouckaert PXJM, Evers JLH. The acute-phase re-
sponse in endometriosis of women. J Reprod Fertil 1988;83:803– 8.
54. Maines MD. The heme oxygenase system: a regulator of second
messenger gases. Annu Rev Pharmacol Toxicol 1997;37:517–54.
55. Van Langendonckt A, Casanas-Roux F, Nisolle M, Donnez J. Poten-
tial implication of haemoglobin and its derivatives in pelvic adhesion
formation [abstract no.18]. In: Abstracts of the Endometriosis 7th
Biennial World Congress, London, May 14 –17, 2000.
56. Gaulier A, Jouret-Mourin A, Marsan C. Peritoneal endometriosis.
Report of a case with cytologic, cytochemical and histopathologic
study. Acta Cytol 1983;27:446 –9.
57. Arumugam K. Endometriosis and infertility: raised iron concentration
in the peritoneal fluid and its effect on the acrosome reaction. Hum
Reprod 1994;9:1153–7.
58. Moen MH, Halvorsen TB. Histologic confirmation of endometriosis in
different peritoneal lesions. Acta Obstet Gynecol Scand 1992;71:337–
42.
59. Casanas-Roux F, Van Langendonckt A, Nisolle M, Donnez J. Iron
deposits and oxidative stress in the peritoneal cavity of patients with
FERTILITY & STERILITY威
endometriosis [abstract no. 10]. In: Abstracts of the Endometriosis 7th
Biennial World Congress. London, 2000.
60. Mathur SP, Lee JH, Jiang H, Arnaud P, Rust PF. Levels of transferrin
and alpha 2-HS glycoprotein in women with and without endometri-
osis. Autoimmunity 1999;29:121–7.
61. Mathur SP, Holt VL, Lee JH, Jiang H, Rust PF. Levels of antibodies
to transferrin and alpha 2-HS glycoprotein in women with and without
endometriosis. Am J Reprod Immunol 1998;40:69 –73.
62. Stowell SB, Wiley CM, Perez-Reyes N, Powers CN. Cytologic diag-
nosis of peritoneal fluids. Applicability to the laparoscopic diagnosis
of endometriosis. Acta Cytol 1997;41:817–22.
63. Martinez-Roman S, Balasch J, Creus M, Fabregues F, Carmona F,
Vilella R, et al. Transferrin receptor (CD71) expression in peritoneal
macrophages from fertile and infertile women with and without en-
dometriosis. Am J Reprod Immunol 1997;38:413–7.
64. Becker JL, Widen RH, Mahan CS, Yeko TR, Parsons AK, Spellacy
WN. Human peritoneal macrophage and T lymphocyte populations in
mild and severe endometriosis. Am J Reprod Immunol 1995;34:179 –
87.
65. Fischbach FA, Gregory DW, Harrison PM, Hoy TG, Williams JM. On
the structure of hemosiderin and its relationship to ferritin. J Ultra-
struct Res 1971;37:495–503.
66. Kim JC, Keshava C, Murphy AA, Pitas RE, Pathasarathy S. Fresh
mouse peritoneal macrophages have low scavenger receptor activity. J
Lipid Res 1997;38:2207–15.
67. Donnez J, Nisolle M. Environmental toxins, reproduction and endo-
metriosis. Ref Gynecol Obstet 1999;6:191– 8.
68. Mayani A, Barel S, Soback S, Almagor M. Dioxin concentrations in
women with endometriosis. Hum Reprod 1997;12:373–5.
69. Shertzer HG, Nebert DW, Puga A, Ary M, Sonntag D, Dixon K, et al.
Dioxin causes a sustained oxidative stress response in the mouse.
Biochem Biophys Res Commun 1998;253:44 – 8.
70. Haney AF. Endometriosis-associated infertility. Baillieres Clin Obstet
Gynaecol 1993;7:791– 812.
71. de Lamirande E, Gagnon C. Impact of reactive oxygen species on
spermatozoa: a balancing act between beneficial and detrimental ef-
fects. Hum Reprod 1995;10 Suppl:115–21.
72. Ellman C, Corbett JA, Misko TP, McDaniel M, Beckerman KP. Nitric
oxide mediates interleukin-1-induced cellular cytotoxicity in the rat
ovary. A potential role for nitric oxide in the ovulatory process. J Clin
Invest 1993;92:3053– 6.
73. Miyazaki T, Sueoka K, Dharmarajan AM, Atlas SJ, Bulkley GB,
Wallach EE. Effect of inhibition of oxygen free radical on ovulation
and progesterone production by the in-vitro perfused rabbit ovary. J
Reprod Fertil 1991;91:207–12.
74. Hesla JS, Preutthipan S, Maguire MP, Chang TSK, Wallach EE,
Dharmarajan AM. Nitric oxide modulates human chorionic gonado-
tropin-induced ovulation in the rabbit. Fertil Steril 1997;67:548 –52.
75. Klein SL, Carnovale D, Burnett AL, Wallach EE, Zacur HA, Crone
JK, et al. Impaired ovulation in mice with targeted deletion of the
neuronal isoform of nitric oxide synthase. Mol Med 1998;4:658 – 64.
76. Guérin P, El Mouatassim S, Ménézo Y. Oxidative stress and protec-
tion against reactive oxygen species in the pre-implantation embryo
and its surroundings. Hum Reprod Update 2001;7:175– 89.
77. Buttke TM, Sandstrom PA. Oxidative stress as a mediator of apopto-
sis. Immunol Today 1994;15:7–10.
78. Demir-Weusten AY, Groothuis PG, Dunselman GAJ, de Goeij AF,
Arends JW, Evers JL. Morphological changes in mesothelial cells
induced by shed menstrual endometrium in vitro are not primarily due
to apoptosis or necrosis. Hum Reprod 2000;15:1462– 8.
79. Dalton TP, Shertzer HG, Puga A. Regulation of gene expression by
reactive oxygen. Annu Rev Pharmacol Toxicol 1999;39:67–101.
80. King AE, Critchley HOD, Kelly RW. The NF-␬B pathway in human
endometrium and first trimester decidua. Mol Hum Reprod 2001;7:
175– 83.
81. Wissink S, Van Heerde EC, Van der Burg B, Van der Saag PT. A dual
mechanism mediates repression of NF-kappa B activity by glucocor-
ticoids. Mol Endocrinol 1998;12:355– 63.
82. Nisolle M, Casanas-Roux F, Wyns C, de Menten Y, Mathieu PE,
Donnez J. Immunohistochemical analysis of estrogen and progester-
one receptors in endometrium and peritoneal endometriosis: a new
quantitative method. Fertil Steril 1994;62:751–9.
83. Nisolle M. [Peritoneal, ovarian and rectovaginal endometriosis are
three distinct entities]. In: Thèse d’Agrégation de l’Enseignement
Supérieur. Louvain (Belgium): Université Catholique de Louvain,
1996.
84. Bergqvist A, Ferno M. Oestrogen and progesterone receptors in en-
dometriotic tissue and endometrium: comparison of different cycle
phases and ages. Hum Reprod 1993;8:2211–7.
85. Simoni J, Simoni G, Lox CD, McGunegle DE, Feola M. Cytokines
and PAF release from human monocytes and macrophages: effect of
869
 hemoglobin and contaminants. Artif Cells Blood Subs Immob Biotech
1994;22:525–34.
86. Murphy AA, Zhou MH, Malkapuram S, Santanam N, Parthasarathy S,
Sidell N. RU486-induced growth inhibition of human endometrial
cells. Fertil Steril 2000;74:1014 –9.
87. Hiura TS, Kempiak SJ, Nel AE. Activation of the human RANTES
gene promoter in a macrophage cell line by lipopolysaccharide is
dependent on stress-activated protein kinases and the I kappaB kinase
cascade: implications for exacerbation of allergic inflammation by
environmental pollutants. Clin Immunol 1999;90:287–301.
88. Khorram O, Taylor RN, Ryan IP, Schall TJ, Landers DV. Peritoneal
fluid concentrations of the cytokine RANTES correlate with the se-
verity of endometriosis. Am J Obstet Gynecol 1993;169:1545–9.
89. Martin T, Cardarelli PM, Parry GC, Felts KA, Cobb RR. Cytokine
induction of monocyte chemoattractant protein-1 gene expression in
human endothelial cells depends on the cooperative action of NF-
kappa B and AP-1. Eur J Immunol 1997;27:1091–7.
90. Akoum A, Lemay A, McColl S, Turcot-Lemay L, Maheux R. Elevated
concentration and biologic activity of monocyte chemotactic protein-1
in the peritoneal fluid of patients with endometriosis. Fertil Steril
1996;66:17–23.
91. Ledebur HC, Parks TP. Transcriptional regulation of the intercellular
adhesion molecule-1 gene by inflammatory cytokines in human endo-
thelial cells. Essential roles of a variant NF-kappa B site and p65
homodimers. J Biol Chem 1995;270:933– 43.
92. Daniel Y, Geva E, Amit A, Eshed-Englender T, Baram A, Fait G, et
al. Do soluble adhesion molecules play a role in endometriosis? Am J
Reprod Immunol 2000;43:160 – 6.
93. Lavrovsky Y, Schwartzman ML, Levere RD, Kappas A, Abraham
NG. Identification of binding sites for transcription factors NF-kappa
B and AP-2 in the promoter region of the human heme oxygenase 1
gene. Proc Natl Acad Sci U S A 1994;91:5987–91.
94. Guerrini L, Casalino L, Corti A, Blasi F. NF-kappa B-mediated
regulation of urokinase gene expression by PMA and TNF-alpha in
human A549 cells. FEBS Lett 1996;393:69 –73.
95. Bruse C, Bergqvist A, Carlstrom K, Fianu-Jonasson A, Lecander I,
Astedt B. Fibrinolytic factors in endometriotic tissue, endometrium,
870 Van Langendonckt et al. Oxidative stress and endometriosis
peritoneal fluid, and plasma from women with endometriosis and in
endometrium and peritoneal fluid from healthy women. Fertil Steril
1998;70:821– 6.
96. Chu SC, Marks-Konczalik J, Wu HP, Banks TC, Moss J. Analysis of
the cytokine-stimulated human inducible nitric oxide synthase (iNOS)
gene: characterization of differences between human and mouse iNOS
promoters. Biochem Biophys Res Commun 1998;248:871– 8.
97. Nakao S, Ogata Y, Shimizu-Sasaki E, Yamazaki M, Furuyama S,
Sugiya H. Activation of NFkappaB is necessary for IL-1beta-induced
cyclooxygenase-2 (COX-2) expression in human gingival fibroblasts.
Mol Cell Biochem 2000;209:113– 8.
98. Ota H, Igarashi S, Sasaki M, Tanaka T. Distribution of cyclooxygen-
ase-2 in eutopic and ectopic endometrium in endometriosis and ade-
nomyosis. Hum Reprod 2001;16:561– 6.
99. Eisermann J, Gast MJ, Pineda J, Odem RR, Collins JL. Tumor
necrosis factor in peritoneal fluid of women undergoing laparoscopic
surgery. Fertil Steril 1988;50:573–9.
100. Joshi-Barve SS, Rangnekar VV, Sells SF, Rangnekar VM. Interleu-
kin-1-inducible expression of gro-beta via NF-kappa B activation is
dependent upon tyrosine kinase signaling. J Biol Chem 1993;268:
18018 –29.
101. Fakih H, Baggett B, Holtz G, Tsang KY, Lee JC, Williamson HO.
Interleukin-1: a possible role in the infertility associated with endo-
metriosis. Fertil Steril 1987;47:213–7.
102. Lin TH, Rosales C, Mondal K, Bolen JB, Haskill S, Juliano RL.
Integrin-mediated tyrosine phosphorylation and cytokine message in-
duction in monocytic cells. A possible signaling role for the Syk
tyrosine kinase. J Biol Chem 1995;270:16189 –97.
103. Qwarnstrom EE, Ostberg CO, Turk GL, Richardson CA, Bomsztyk K.
Fibronectin attachment activates the NF-kappa B p50/p65 heterodimer
in fibroblasts and smooth muscle cells. J Biol Chem 1994;269:
30765– 8.
104. Puga A, Barnes SJ, Chang C, Zhu H, Nephew KP, Khan SA, et al.
Activation of transcription factors activator protein-1 and nuclear
factor-kappaB by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochem Phar-
macol 2000;59:997–1005.
Vol. 77, No. 5, May 2002