Endometriosis is a disorder associated with a general inammatory response in the peritoneal cavity. Oxidative stress is a potential factor involved in the pathophysiology of this disease, and reactive oxygen species (ROS) are implicated in this process. Indeed, in healthy
individuals, ROS and antioxidants are in balance, but when balance is tipped toward an overabundance of ROS, oxidative stress occurs
and can impact the entire reproductive lifespan of a woman. Reactive oxygen species are intermediaries produced by normal oxygen
metabolism but are known to have deleterious effects. Excessive release of ROS induces cellular damage and alters cellular function by
regulating protein activity and gene expression, leading to harmful effects. To protect themselves, cells have developed antioxidant
systems to limit production of ROS, inactivate them, and repair cell damage. Understanding of the control of hemoglobin, heme,
and iron-induced redox balance in endometriosis led us to propose a number of hypotheses to explain why oxidative stress is induced
in case of pelvic endometriosis. Erythrocytes, apoptotic endometrial tissue, and cell debris transplanted into the peritoneal cavity by
menstrual reux and macrophages have all been cited as potential inducers of oxidative stress. Erythrocytes are likely to release
pro-oxidant and proinammatory factors, such as hemoglobin and its highly toxic by-products heme and iron, into the peritoneal environment. Iron and heme are essential to living cells, but unless appropriately chelated, free iron, and to a lesser extent heme, play a key
role in the formation of deleterious ROS. (Fertil Steril 2016;-:--. 2016 by American Society for Reproductive Medicine.)
Key Words: Endometriosis, oxidative stress, reactive oxygen species (ROS)
Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110fertility-and-sterility/posts/11253-oxidative-stress-in-the-pelvic-cavity-and-its-role-in-the-pathogenesis-of-endometriosis
ndometriosis is characterized by
implantation and growth of
endometrial tissue outside the
uterine cavity, and most studies investigating peritoneal endometriosis
adhere to the implantation theory of
Sampson (1), according to which
desquamated endometrial cells are
transported into the peritoneal cavity
after retrograde menstruation.
Already in the late 1990s, studies
suggested that menstrual efuent
contains factors that induce alterations
in
the
morphology
of
the
peritoneal mesothelium (2), which
may create adhesion sites for endometrial cells. Attachment of endometrial
cells seems to be enhanced by induction
of adhesion molecules and their receptors (35), as well as overexpression of
matrix metalloproteinases (6) and
plasminogen activators (7), which
ensure local destruction of the
extracellular matrix in endometriosis.
After adhesion, endometrial cells
proliferate and gradually invade the peri-
Received May 27, 2016; revised July 13, 2016; accepted July 14, 2016.
J.D. is a member of the Scientic Advisory Board of PregLem S.A. M.M.B. has nothing to disclose. O.D.
has nothing to disclose. M.-M.D. has nothing to disclose.
Supported by grants from the Fonds National de la Recherche Scientique de Belgique (grant 5/4/150/
5, to M.-M.D.; grant W.0056.15 to M.M.B.).
Catholique de Louvain, Institut
Reprint requests: Marie-Madeleine Dolmans, M.D., Ph.D., Universite
rimentale et Clinique, Po
^ le de Recherche en Gyne
cologie, Avenue Mounier
de Recherche Expe
52 - B1.52.02, Brussels 1200, Belgium (E-mail: marie-madeleine.dolmans@uclouvain.be).
Fertility and Sterility Vol. -, No. -, - 2016 0015-0282/$36.00
Copyright 2016 American Society for Reproductive Medicine, Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.fertnstert.2016.07.1075
OXYGEN ON EARTH
The rise of oxygen changed the course of evolution.
David Catling, University of Bristol,
United Kingdom (21)
In the beginning there was no oxygen on Earth, but
somehow life arose from nonlife. Without free oxygen, the
rst life to appear by perhaps 3.5 billion years ago had to
breathe elements such as iron, processing them to gain
the merest pittance of energy (Fig. 1) (21). Gradually, bacteria and other cells developed systems for energy metabolism
under anoxic conditions. These systems were based on anoxygenic photosynthesis, which used hydrogen or sulfur
as an electron donor instead of water (22). In time,
oxygen-generating cyanobacteria emerged (2.7 billion years
ago or even earlier [(21)]), which in the presence of sunlight
were able to use chlorophyll and photosynthesis to trap the
sun's energy into carbohydrate form. This process, called
oxygenic photosynthesis, produces oxygen as a waste product of the splitting of water (22). The permanent rise in oxygen to detectable atmospheric levels seems to have
spurred evolution, occurring sometime between 2.4 and
2.1 billion years ago, now popularly known as the Great
Oxidation Event (23). Concentrations of oxygen rose only
modestly until that point, then remained on hold for almost
2 billion years before climbing higher.
The earliest known fossil of a eukaryote with a cell nucleus (Grypania spiralis) that generally requires oxygen is
from approximately 2 billion years ago (21). Our planet's atmosphere was thus transformed from an anoxic state to present oxygen concentrations of 20%21%, oxygenic
photosynthesis being the only signicant source of free oxygen on the Earth's surface (23).
FIGURE 1
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
VOL. - NO. - / - 2016
FIGURE 2
FIGURE 3
Origin of iron overload in the pelvic cavity of endometriosis patients. Erythrocytes are carried into the pelvic cavity by retrograde menstruation and
hemorrhaging foci of ectopic endometrium. A proportion of them are phagocytosed by peritoneal macrophages. Metabolism of Hb by HO-1 (HO)
releases iron. Macrophages store some iron in the form of ferritin or hemosiderin, and release some that binds to Tf. Macrophages are also able to
release ferritin into peritoneal uid, whereas lysis of erythrocytes releases Hb. Hemoglobin forms a complex with Hp, which is in part secreted by
ectopic lesions. The HbHp complex is then endocytosed by macrophages. Increased pelvic iron concentrations result from Tf, ferritin, and Hb
accumulation in peritoneal uid. Transferrin and Hb may be assimilated by ectopic endometrial cells, resulting in the formation of iron deposits
(ferritin or hemosiderin) inside lesions.
Donnez. Oxidative stress in the pelvic cavity. Fertil Steril 2016.
FIGURE 4
Cells and processes involved in endometriosis development. Iron overload may affect a wide range of cell types, modulating multiple mechanisms
involved in endometriosis development. NF-kB nuclear factor kB.
Donnez. Oxidative stress in the pelvic cavity. Fertil Steril 2016.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.