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\begin{document}

\title{Oxidative stress-related effects on various aspects of endometriosis}



\author[1]{Hossin Ansariniya}%
\author[1]{Abolfazl Yavari}%
\author[1]{Fateme Zare}%
\author[1]{Atiyeh  Javaheri}%
\affil[1]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 28, 2024}


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\selectlanguage{english}
\begin{abstract}
Endometriosis is a chronic and relatively common disease in women of
childbearing age. Complications of this disease include a wide range of
disorders. The cause of this disease is not known for sure, but several
hypotheses have been proposed for it. In this disease, the entry of
endometrial tissues into the peritoneal cavity causes oxidative stress
through the Fenton reaction and inflammation in this site. Oxidative
stress can be associated with many complications of endometriosis. In
this review, an attempt has been made to discuss the effects of
oxidative stress on various complications of this disease.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Endometriosis is a hormone-inflammatory disease described by the
presence of endometrial tissue outside the uterine cavity, with a
prevalence of 6--10\% in reproductive-age women, but as high as half
when associated with chronic pelvic pain and infertility(1, 2). Several
theories have been suggested to clarify the pathogenicity of
endometriosis, which is delineated in Figure 1; the Sampson hypothesis
presented in 1920 showed the retrograde menstruation through the
fallopian tube into the peritoneal cavity principal reason for
endometriosis(3, 4).

Some studies have shown endometriosis has an association with oxidative
stress, characterized by a balance between the production of reactive
oxygen species (ROS) and their neutralization by the antioxidant
system(5-8). Oxidative stress has an essential role in the cell
proliferation, inflammatory process, and the apoptosis prevention of the
endometriotic cell(3, 9). Well-known inducers of oxidative stress are
macrophages, erythrocytes, and apoptotic endometrial tissue,
transplanted to the peritoneal cavity through retrograde
menstruation(10). Fenton reaction can produce ROS through a catalytic
form of iron. This process can provoke inflammatory responses and
oxidative injury. As a result, the activity of macrophages and
expression of nuclear factor-kappa B increase. All of these processes
result in the upregulation of the expression of multiple proinflammatory
genes such as cytokines, chemokines, adhesion molecules, growth, and
angiogenic factors(8). Enzymatic and non-enzymatic antioxidant defenses
and permitting an overall assessment of this process(11). The present
study attempts to evaluate oxidative stress's role in the complications
of endometriosis.

\textbf{Physiology of reactive oxygen species}

ROS are considered to be byproducts of cellular metabolism and normal
physiologic processes. Some studies have shown that normal levels of ROS
for sperm maturation, chemotaxis, acrosome reaction, zona pellucida
binding, hyperactivation, capacitation, and sperm-oocyte fusion are
needed. Additionally, ROS are crucial intermediaries that have some
roles in gene regulation and vascular tone within the testis(12).

\textbf{Oxidative stress and transcription factor}

Intercellular ROS in the peritoneal activated macrophages can be
generated due to proinflammatory molecules such as heme and iron. As a
result of this phenomenon, transcription factors such as activator
protein-1 (AP-1), CCAAT/enhancer-binding protein (C/EBP), signal
transducer, and activator of transcription (STAT), hypoxia-inducible
factor-1 (HIF-1), and CCAAT/enhancer-binding protein (C/EBP), and
nuclear factor kappa B (NF-kB) but not HNF can be activated. The
transcription factor NF-kB activates proliferative, antiapoptotic,
chemokines, growth and angiogenic factors, proinflammatory, adhesion
molecules (such as VCAM-1, ICAM-1, and selectin E), and induction
enzymes (iNOS and COX-2) genes in many cell types(13, 14). Agents that
are induced in endometriosis by NF-kB and their function is shown in the
table I.

\textbf{Oxidative stress and VEGF}

Some studies have reported endometriosis as an angiogenesis-dependent
disease. Vascular endothelial growth factor (VEGF) as a mitogen has a
crucial role in promoting angiogenesis in physiological and pathological
conditions(8). In the endometrium, oxidative stress can enhance VEGF
production, which by itself can promote the growth of endometrial
implants and stimulate angiogenesis. Glycodelin has a crucial role in
this process. Expression of glycodelin can be stimulated by oxidative
stress, and it can enhance the expression of VEGF in the ectopic
endometrial tissue(15).

\textbf{Oxidative stress and autoantibody}

Some studies have shown enhancement of autoantibody titers because of
oxidative stress in the peritoneal fluid of endometriosis patients.
Evidence suggested the presence of oxidative stress in the peritoneal
cavity, and markers of increased lipid peroxidation, e.g., antibodies to
the oxidized low-density lipoproteins, have been proposed to be
increased in the endometriosis' patients(15). Evidence suggests the
enhancement of titers of autoantibodies in women with endometriosis
which results in an increase in serum autoantibody titers to oxidatively
modified low-density lipoproteins(16). Oxidative stress products, such
as lipid peroxides, can be generated from activated macrophages in the
peritoneal cavity. Oxidized LDL and the peritoneal fluid of
endometriosis patients can be involved in MCP-1 production by
endometrial cells and peritoneal mesothelial cells. Accordingly, the
growth of ectopic endometrium can be the result of the pre-oxidant
environment in the peritoneal fluid and activated macrophages(17).

\textbf{The role of nitric oxide (NO) induced by ROS}

Oxygen free radicals have the ability to induce nitric oxide. Different
studies show that No has different effects on implantation and ovarian
function(17). Harmful effects on sperm motility, toxicity to embryos,
and inhibition of implantation can be expected from high NO levels(18,
19). As a free radical agent, No has a significant role in regulating
apoptosis(20). Additionally, the enhancement of activity and number of
macrophages is related to releasing more cytokines and other immune
mediators, such as NO. For the first time, it was reported that NO
enhancement is accompanied by the augmentation of activity and the
number of macrophages in low-grade inflammation(21). mRNA expression of
nitric oxide synthase (NOS) in the epithelial glands of the human
endometrium is periodic. The level of NO and NOS in the endometrium of
endometriosis' patients are higher than the endometrium of ordinary
women(22-24).

A study has reported the higher NOS activity of peritoneal macrophages,
higher peritoneal fluid NO levels, and higher protein expression of
peritoneal macrophage inducible NOS in infertile women with
endometriosis. This study shows that peritoneal macrophages produce more
NO in response to immune stimulation in vitro express higher levels of
NOS. Moreover, this kind of macrophage has more NOS enzyme activity.
Additionally, enhancement of expression of endothelial NOS in the
glandular endometrium of patients with endometriosis has been(22, 23).
The iNOS isoforms in tissues of patients with endometriosis is also
reported(24). There are studies that show abnormal stimulation of
endothelial NO synthase can be the result of different cytokines
secreted from immune cells, endometrial cells, or macrophages stimulate
endothelial NO synthase to release NO(10, 22, 25). This abnormal
stimulation can release a high level of NO, resulting in inhibition of
implantation(26).

Moreover, during the menstrual cycle of endometriosis' patients, the
expression of endothelial NO synthase in their endometrium will
increase(27). NO is an essential molecule for normal reproductive
biological processes like sustaining pregnancy at physiological
levels(28). According to a hypothesis in endometriosis patients,
stimulation of macrophages for releasing NO can be the result of IL-10,
which is augmented within earlier stages of endometriosis(29). Three
types of NO synthase produce NO from the conversion of L-arginine to
L-citrulline. NOS1, neuronal form, NOS2, the inducible form, and NOS3,
the endothelial form(30).

The peritoneal macrophages can move to different parts of the female
reproductive system, including fallopian tubes in which fertilization
happens. Regarding this subject, these macrophages can cause a more
significant risk of infertility because of the increased capacity of
macrophages for producing NO(31). It has also been reported that in
women with endometriosis-associated infertility, peritoneal macrophages
express higher NO synthase2. Additionally, they have higher NO-synthase
enzyme activity, and they can produce more NO in response to immune
stimulation in vitro(32).

\textbf{Oxidative stress and cancer}

There is a link between the increased ROS and almost all cancers(33).
This link is the result of ROS's effect on MAPK signaling pathways which
can cause cell proliferation. According to the linkage between the
proliferation of cancer cells and ROS and regarding increased ROS
production in endometriosis, we can conclude that ROS has an outstanding
role in regulating cell proliferation in endometriosis(34-36).

\textbf{Oxidative stress and fibrosis}

There is a linkage between the enhancement of expression of genes
encoding profibrotic such as TGF-1\selectlanguage{greek}β \selectlanguage{english}and iron and the iron-mediated
generation of ROS(37, 38). TGF-\selectlanguage{greek}β, \selectlanguage{english}as an inflammatory cytokine, can
induce inflammatory changes and fibrotic in different organs(39).
Changes in iron metabolism have some roles in developing fibrosis and
chronic inflammation(40). Liver in the humans and animal models are
great examples of the linkages between tissue fibrosis and upregulation
of TGF-\selectlanguage{greek}β \selectlanguage{english}and iron(41). The kidney and the heart are other possible
organs that iron may play a role in tissue fibrosis and TGF-\selectlanguage{greek}β
\selectlanguage{english}upregulation(42, 43). Additionally, the vital effect of TGF-\selectlanguage{greek}β \selectlanguage{english}in the
growth of endometriosis has been found in both in vivo and in vitro
studies(44).

\textbf{Oxidative stress and infertility}

Infertile women with endometriosis have some macrophages that had more
inflammatory mediators and iNOS activity. These features of this kind of
macrophages can have some roles in infertility related to
endometriosis(31). These kinds of macrophages can produce high levels of
NO, which can have some deleterious effects on fertility in different
ways. A study shows that changes in peritoneal fluid might influence all
these reproduction steps(21, 45, 46). According to the deleterious
effects of high levels of NO, fertility of women with endometriosis can
be improved by either blocking NO effects or reducing the peritoneal
fluid NO production(31).

\textbf{Conclusion}

It has been reported that in the peritoneal fluid of endometriosis'
patients, there are activated macrophages and growth factors and high
concentrations of cytokines. These conditions have been toxic to embryo
survival and sperm function. ROS can mediate these conditions. Moreover,
it can have some relations with iron concentrations in peritoneal fluid.
Novel therapeutic strategies must regulate intracellular ROS signaling
to inhibit the adverse effects of ROS-induced endometriosis-promoting
events. According to features of antioxidants, they may inhibit early
events of the development of endometriosis.

\textbf{Conflict of Interests}

The authors declare that they have no competing interests.

\textbf{Data Availability Statement}

The data used to support the findings of this study are available from
the corresponding author upon request.

\textbf{Acknowledgments}

No.

\textbf{Author contribution}

H.A. writing manuscript A.Y. data collection F.Z. and A.J. editing. All
authors read and approved the final manuscript.

Figure 1. Theories as to how endometriosis develops

Table 1. Molecules that are induced in endometriosis by NF-kB factor and
their function

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