European Journal of Obstetrics & Gynecology and Reproductive Biology 185 (2015) 59–65

Contents lists available at ScienceDirect

European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

Review

Systems genetics view of endometriosis: a common complex disorder

Vladislav S. Baranov a,b,*, Tatyana E. Ivaschenko a, Thomas Liehr c, Maria I. Yarmolinskaya a
a
D.O Ott Research Institute of Obstetrics and Gynecology, Mendeleevskaya line, 3, 199034 St. Petersburg, Russia
b
St Petersburg State University, Universitetskaya nab., 7/9, 199034 St. Petersburg, Russia
c
Jena University Hospital, Friedrich Schiller University, Institute of Human Genetics, Kollegiengasse 10, D-07743 Jena, Germany

A R T I C L E I N F O A B S T R A C T

Article history: Endometriosis is a condition in which cells derived from the endometrium grow outside the uterus, e.g.
Received 1 August 2014 in the peritoneum (external genital endometriosis). As these cells are under the influence of female
Received in revised form 20 November 2014 hormones, major symptoms of endometriosis are pain, especially during the cycle, and infertility.
Accepted 27 November 2014
Numerous hypotheses for the formation of endometriosis can be found in the literature, but there is
growing evidence of serious genetic contributions to endometriosis susceptibility. The involvement of
Keywords: genes, steroid hormone metabolism, immunological reactions, receptor formation, inflammation,
Endometriosis
proliferation, apoptosis, intercellular adhesion, cell invasion and angiogenesis as well as genes regulating
Systems genetics
Genetic network
the activity of aforementioned enzymes have been suggested. Some more recently suggested candidate
Epigenetic regulation genes picked up in genome-wide association studies are involved in oncogenesis, metaplasia of
endometrium cells and pathways of embryonic development of the female reproductive system.
However, gene mutations proven to be causative for endometriosis have not been identified so far, even
though the abnormal expression of candidate genes for endometriosis could be provoked by different
epigenetic modifications including DNA methylation, heterochromatization or introduction of
regulatory miRNA. We hypothesize that endometriosis is induced by a combination of abnormal
genetic and/or epigenetic mutations: the latter pave the way for pathological changes which become
irreversible, and according to the ‘‘epigenetic landscape’’ theory, this proceeds to the typical clinical
manifestations. Two stages in the endometriosis pathway are suggested: (1) induction of primary
endometrial cells toward endometriosis, and (2) implantation and progression of these cells into
endometriosis lesions. The model favors endometriosis as an outgrowth of primary cells different in their
origin, canalization of pathological processes, manifestation diversity provoked by unique genetic
background and epigenetic influences, which result in many different clinical forms of the disease.
ß 2014 Elsevier Ireland Ltd. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Candidate genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Epigenetic mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
DNA methylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
miRNA studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Environmental factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Genetic and epigenetic interactions leading to endometriosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Influence of immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Influence of estrogens and vascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Systems genetics of endometriosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
The origin of PECs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

* Corresponding author at: D.O. Ott Research Institute of Obstetrics and Gynecology, Mendeleevskaya line, 3, 199034 St. Petersburg, Russia.
Tel.: +7 812 328 04 87/+7 921 337 77 96; fax: +7 812 328 04 87.
E-mail addresses: baranov@vb2475.spb.edu, vsbar40@mail.ru (V.S. Baranov).

http://dx.doi.org/10.1016/j.ejogrb.2014.11.036
0301-2115/ß 2014 Elsevier Ireland Ltd. All rights reserved.
60 V.S. Baranov et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 185 (2015) 59–65

The propagation of PEC to EL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Condensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Introduction testing, reliable preclinical diagnostics and/or efficient personalized

treatment.
Endometriosis is a common disorder, affecting 10% of women of
reproductive age. In endometriosis cells derived from endometri-
Candidate genes
um grow outside the uterus, e.g. in the peritoneum. These cells
are under the influence of female hormones, and thus, major
The genes and their variants potentially providing a hereditary
symptoms arise during the woman’s cycle as pain but it also causes
contribution into endometriosis have been widely investigated
infertility. Endometriosis as a complex disease is thought to arise
[14]. Candidate gene association studies, whole genome linkage
from the interplay between multiple genetic and environmental
analysis as well as, more recently, genome-wide association
factors [1,2].
studies (GWAS), have been applied and already yielded over 100
The precise etiology of endometriosis remains unclear, and
candidate genes [2,14]. The utility of the most of these genes for
many different forms of endometriosis can be discriminated
understanding the pathogenesis of endometriosis is still to be
according to variable clinical and pathomorphological criteria. The
proven, but at least some of these genes identified by different
most common classification of endometriosis relies on the number
methods, especially by the GWAS approach, could be already
of endometriotic lesions (EL) and the depth of their outgrowths.
admitted as meaningful entities of endometriosis [18,20]. A recent
The most common form of endometriosis is pelvic endometriosis
meta-analysis narrowed down the earlier findings of GWAS to a
with a number of disseminating EL invasions of the peritoneum
total of seven single nucleotide polymorphisms (SNPs) that passed
(peritoneal endometriosis) and ovary (ovarian endometriosis).
a genome-wide significance (P < 5  10 8); also, at least six
Distinct from peritoneal and ovarian endometriosis, rectovaginal
genes were recognized or suspected as the most plausible
septum adenomyotic nodules should be considered, originating
candidates of endometriosis (WNT4, CDC42, HSPC157, HOX10,
from the Müllerian rests present in the rectovaginal septum [3].
CDKN2BAS and FN1) [19,20].
Deep endometrial invasion in the uterine wall is treated as
What is noteworthy is that a good correlation could be traced
adenomyosis. In 0.5–1% of cases, endometriosis could give rise to
between the spectrum of endometriosis candidate genes and
tumor transformation [1,2].
already postulated mechanisms of endometriosis origin [2,14,19].
Basic concepts of pathophysiology and pathogenesis of endome-
Numerous genes responsible for hormonal imbalance, immuno-
triosis were recently reviewed by Burney and Giudice [4].
logical impairments and neoplastic transformation of endometri-
Tentatively, endometriosis could be attributed to either (i)
um cells (metaplasia) have been implicated in endometriosis
implantation of otherwise normal endometrial cells in the
[2,21–23]. Major pathways and the genes thought to be involved in
peritoneum, or (ii) metaplasia of preexisting undifferentiated
endometriosis due to the aforementioned observations are
epithelium or mesenchymal cells. Scenario (i) would implicate
summarized in Fig. 1, and fall into seven principal groups. These
adhesion, angiogenesis and invasion of vital endometriosis-like
include genes responsible for steroid sex hormones and their
tissue into the peritoneum and the organs of peritoneal cavity, while
receptors, synthesis and metabolism (group 1), genes participating
in scenario (ii) metaplasia could arise either from dedifferentiated
in endometrial cell proliferation and menstrual cycling (group 2),
coelomic cells of the peritoneum, from stem cells of native
tumor suppressor genes and some oncogenes (group 3), the genes
endometrium, from dormant embryonic cells embedded in pelvic
responsible for detoxification e.g. of industrial and agricultural
lining or from mesenchymal progenitor cells of bone marrow. As
pollutants, like benzopyrenes, pesticides, etc. (group 4), abundant
might be inferred from Table 1, a dozen different theories and
and very polymorphic miRNA regulators (group 5), pre-inflamma-
hypotheses are suggested to explain the origin and pathogenesis
tory cytokines (group 6), and a cohort of other genes involved in
of this very common and still rather enigmatic disorder [5–17]. Each
angiogenesis and cell invasion (group 7).
of these ideas from Table 1 could be addressed by solid clinical
Some other regions identified by GWAS also hold promise as
studies, and some by experimental data, though no single one is
candidate loci for endometriosis, but no major candidate genes
sufficient for understanding the molecular pathways of the disease.
specific for EL has been identified so far. However, it is presently
Thus, for endometriosis, one is still far from being able to offer early
assumed that any new endometriosis loci that contribute to the

Table 1
Basic theories/hypotheses of endometriosis origin.

No. Theory/hypothesis Pathophysiology References

1 Transplantation Retrograde menstruation Sampson [5]

2 Immunologic Failure to destroy endometrium cells in peritoneal cavity Tariverdian et al. [6]
3 Toxicologic Pro-inflammation cytokine stimulation Foster et al. [7]
4 Metaplasia Dormant stem-cells in peritoneum epithelium Meyer [9]
5 Dormant embryonic cell Dislocation of endometrium cells outside the uterine cavity Signorile et al. [10]
6 Denervation–reinnervation Abnormal contractility of uteri muscles Quinn [11]
7 Hormonal deregulation of sex hormones balances Dizerega et al. [12]
8 Infection Inflammation of pelvic epithelium caused by microbial infection Chaudhury and Chakravarty [13]
9 Genetic Candidate genes mutations and signaling pathway impairments Rahmioglu et al. [14]; Kim and Yim [15]
10 Epigenetic Impairment of gene regulation Guo [16]
 V.S. Baranov et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 185 (2015) 59–65
Fig. 1. The gene nets associated with pathogenesis of endometriosis [14,20,28].
‘‘missing heritability’’ of endometriosis must be rare, or show
minimal phenotypic effect [19]. Recent whole-exome sequencing
of endometriosis samples supports this statement.
Alterations in multiple endometriosis samples have been
observed as mutations in thousands of different genes [24].
Interestingly, similar to next generation sequencing studies in
tumor cells, endometriosis of individual patients were each shown
to hold unique genetic fingerprints. On the other hand, the
existence of similarities concerning frequently mutated genes in
eutopic or ectopic endometrium might suggest that most of the
mutations present in genomes of endometriosis already existed
in the eutopic endometrium cell that was ‘‘transformed’’ by the
initiating mutation(s). If so, it might be suggested that almost all of
these mutations may be benign and/or irrelevant for pathogenesis
[24]. What these mutations really mean – especially if they can be
addressed to already known candidate genes and if they represent
any functionally unfavorable constellations affecting relevant
metabolic pathways – remains unknown at present and needs
to be clarified. As even sophisticated GWAS technology applied for
genetic analysis of several thousand patients did not pick up all
candidate genes [14] exome, and whole genome NGS are the
forthcoming next steps for identification of candidate genes and
elaboration of practically valuable panels of genetic markers for
endometriosis.
Epigenetic mechanisms
Impairment of gene function may occur at any stages of gene
expression with mutations leading just to genetic polymorphisms
at one end of the scale or really deleterous mutations on the other.
Epigenetic mechanisms such as DNA methylation, specific micro-
RNA or DNA spreading provide basic regulation of gene activity.
The establishment in embryogenesis and further maintenance
of cell type-specific epigenetic patterns are essential to form
adequate gene expression profiles for normal cell functioning,
including cellular differentiation [25,26]. Epigenetic models for
61
formation of or influencing endometriosis were suggested in 2009
by Guo [16]. The following facts are in favor of such a model:
1. abnormal expression profiles of many candidate genes could be
caused by the failure of their proper methylation pattern and/or
imbalance of specific miRNAs [27,28];
2. experimentally endometriosis could be induced by dioxin in
monkeys [29];
3. curative effect of synthetic histone deacetylase inhibitors could
be shown in endometriosis, which stimulates the expression of
epigenetically suppressed genes [6];
4. activation and/or suppression of estrogen receptor genes can
be induced by methylation of progesterone genes and their
receptors [30];
5. endometriosis could be experimentally developed from single
cells with inherited epigenetic changes, which result in prolifera-
tion and invasive capacities of these cells [16].
DNA methylation
Other recent studies give more credit to the epigenetic
hypothesis. Recently, DNA methylation has been shown to affect
a number of endometriosis candidate genes [30]. Abnormal
methylation/hypomethylation has been already shown for the
candidate genes in each of the seven groups indicated in Fig. 1.
Methylation deregulation was especially obvious for the genes
involved in sex-hormone metabolism (groups 1 and 4), cell
proliferation, embryonic development (group 2), tumor suppression
(groups 3 and 4), immunological effects (group 6), vessel growth
and cell interactions (group 7). Hypomethylation of the NF-IL6
site within the promoter of COX-2 gene (1) of endometriosis cells
stimulates the synthesis of prostoglandines associated with
inflammatory response; NF-IL6 site can be induced by growth
factors, oncogenes, and tumor promoters. Hypomethylated, and thus
functionally active in E cells, are the genes of estrogen receptor-beta
(ESR2), steroidogenic factor-1 (NR5A1), and aromatase (CYP19A1)
62 V.S. Baranov et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 185 (2015) 59–65
(group 1). Hypermethylation with inferior activity in endometriosis
cells was reported for progesterone receptor (PGR)-B histone
deacetylase inhibitors genes (HDACi, CDKN2A/B IGFBP-1), leukemia
inhibitory factor (LIF) and DNA methyltransferase (DNMT) [30].
Differential methylation and expression of genes involved in the
regulation of implantation, such as HOXA10 and PR- B, E-cadherin
(CDH1), have also been reported in the eutopic endometrium of
endometriosis patients.
Genome-wide studies for DNA methylation comparing healthy
endometrial and endometriosis cells have recently been reported
[31]. Significant differences in methylation of endometriosis cells
were mapped to 403 genes and included a disproportionally large
number of transcription factors. DNA methylation in endometri-
osis cells correlated with a shift in GATA isoforms (transcription
factors) expression, which facilitates progesterone resistance and
disease progression. Repression through hypermethylation of
GATA2 gene in endometriosis cells with concomitant hypomethy-
lation (activation) of GATA6 isoform blocked hormonal sensitivity
and promoted aberrant expression of many candidate genes seen
in endometriosis [31].
Other even more spectacular data concern an overexpression of
cycloxygenase-2 in eutopic endometrium of endometriosis. Hypo-
methylation within the promoter region of the COX-2 gene
responsible for its overexpression, resulted in the production of
prostaglandins (PGF2) that may be a key mechanism causing severe
endometriosis-related dysmenorrhea and inflammation [30]. Thus
the unique epigenetic fingerprint in endometriosis suggests DNA
methylation is an integral component of the disease. Furthermore,
the influence of epigenetics in endometriosis is also supported
by analysis of the imprinting phenomenon—i.e. uniparental gene
expression caused by differences in DNA methylation of parental
chromosomes during gametogenesis. At least ten imprinted genes
are expressed in endometriosis, of which seven are paternally
expressed, and associated with female reproduction such as normal
endometrial development, decidualization and placentation [32].
Imprinted endometriosis susceptibility genes include growth
factors (DIRAS3, IGF2 and FGFRL1), Wnt signal transduction
(DVL1), metabolism (CYP1B1), and stress response and detoxification
(CYP1B1) [32]. Some biological aspects of endometriosis may
be explained from a deregulation of parentally imprinted genes.
Aberrant epigenetic deregulation of specific imprinting genes may
contribute to endometriosis predisposition. Thus, epigenetic regu-
lation of gene activity makes a substantial contribution to the origin
and pathogenesis of endometriosis.
miRNA studies
miRNA expression regulation is another common epigenetic
mechanism of gene regulation: this is now a hot topic in
endometriosis studies [2,27,29]. Global profiling of more than
1000 miRNAs identified 23 candidate miRNAs, which were
differentially expressed between healthy controls and endometri-
osis patients [33]. As a result of these studies, unique plasma
miRNA expression signatures (upregulation of miR-21, miR-203,
and miR-205) have been identified that distinguish endometriosis
patients from healthy controls, suggesting that circulating miRNAs
may serve as promising biomarkers with high sensitivity and
specificity for early endometriosis detection and diagnosis.
Environmental factors
Besides genetics and epigenetics, environmental factors seem
to play a role in endometriosis susceptibility. Experimentally,
endometriosis can be induced by low doses of dioxine treatment in
monkeys, which gives some credit to an exogenic impact into
endometriosis origin [7,29]. In line with these findings, our earlier
studies suggested involvement of null alleles of detoxification
gene GSTM1 in the development of endometriosis [34–36]. The
association of detoxification gene polymorphisms with endome-
triosis was later confirmed but also partly contradicted by others.
The involvement of environmental genes in endometriosis was
supported by neither meta-analysis of candidate genes nor GWAS
[13,20,27]. Recently, a meta-analysis of 25 case-control studies
provided evidence that null-genotype of GSTM1 and/or GSTT1
contributes to risk of endometriosis [37]. Considering the above
ideas (part 2), epigenetic changes of candidate gene expression
provoked by noxious factors seem to be a reasonable molecular
mechanism in endometriosis development [14,38] (Fig. 2).
Genetic and epigenetic interactions leading to endometriosis
As we have seen, endometriosis as a common disease should be
considered as an outcome of the complex interactions between
abnormal genetic and epigenetic factors augmented by some
environmental toxins. Meanwhile, each factor alone is not sufficient
to launch and support the disease. Not all women subjected to toxic
environmental pollutants suffer from immunological or hormonal
imbalances or even develop endometriosis. It seems most likely
that endometriosis predominantly affects women with some
unfavorable combinations of genetic, hormonal or immunological
factors where detrimental effects are additionally augmented by
some environmental toxins. The complex interaction of noxious
exogenic and endogenetic factors in pathogenesis of endometriosis
is shown in Fig. 2.
Influence of immune system
Severe and rather uniform hormonal and immunological
variations are common for all endometriosis patients. Some of
them are genetically determined, while functional impairments of
most of the candidate genes as indicated in the previous section
(see point 2) are potentiated by some common epigenetic
mechanisms interfering with gene expression. An abundant group
of endometriosis-causing factors is represented by genes control-
ling hormonal and immune systems activity [14]. A very complex
and still poorly understood interaction between them constitutes a
major task of current studies of endometriosis.
Influence of estrogens and vascularization
Estrogens act on various macrophage signaling pathways,
influencing in particular those related to the ability to sustain the
recruitment of inflammatory cells, such as mitogen-activated
Fig. 2. Complex interaction of noxious environmental and internal factors in
pathogenesis of endometriosis [16,21].
 V.S. Baranov et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 185 (2015) 59–65
protein kinase (MAPK), phosphatidylinositide-3-kinase/protein
kinase B (PI3K/AKT), and nuclear factor-kappa B (NF-kB). As a
consequence, a deregulated response to steroids might influence
the survival of ectopic endometrial cells and promote the
vascularization of the lesions [2,39]. Angiogenesis is a prerequisite
for EL to establish and to grow in-vivo. EL neovascularization
involves both conventional sprouting angiogenesis and actual
vasculogenesis [42]. Microbial components such as lipopolysac-
charide and/or cytokines such as IFN-g or GM-CSF elicit
conventionally activated macrophages. The recruitment of macro-
phages at the site of endometrial cell engraftment is a limiting step
for the lesion to organize and to grow. Local hypoxia and the
production of chemokines play a major role in the recruitment of
macrophages. Once endometriosis is established, the cyclic death
of endometrial cells, as a consequence of progesterone withdrawal,
leads to the release of cell debris, erythrocytes, and heme-bound
iron in the peritoneal fluid. They activate a reparative/regenera-
tive/angiogenic programme that is required for lesion mainte-
nance, growth and spreading. In the absence of macrophages,
syngeneic endometrium retains the ability to adhere to the
peritoneal layer and to infiltrate the serosal membrane. However,
ectopic lesions fail to grow in these conditions.
Vessels do not extend to the lesions’ core, which stop growing
and do not develop a well-organized glandular and stromal
architecture of EL. The data suggest that the recruitment of
macrophages into the lesions is not only an early event in the
lesion development, but a necessary step for the successful
establishment of EL. The molecular bases of the association are
not completely defined.
The prominent impact of the macrophage cytokine system,
interleukins and their receptors as well as tumor necrosis factor
alpha (TNFa) and endothelial vessel factor growth (VEGF2), has
been repeatedly shown [6,14,39]. The immunological changes in
the relevant gene products in blood serum as well as in peritoneal
fluid are in line with major and minor alleles of relevant genes
controlling the synthesis of these proteins. The same correlation
is true for the genes responsible for sex hormones and their
receptors.
Candidate genes of endometriosis controlling over 39 different
metabolic pathways and epigenetic mechanisms of their regula-
tion are now an area of hot scientific interest [2,14,15]. Three major
signaling pathways studied in endometriosis are MAPK (mitogen-
activated protein kinase-cellular response to external stimuli),
P13K/AKT (phosphoinositid-3-kinase—promoting cell survival and
proliferation), and cAMP-PKA (protein signaling A—regulating cell
proliferation, glycogen metabolism, cortisol secretion) [2,15].
Microarray studies identified genes associated with these path-
ways to be aberrantly expressed in endometriosis MAPK, and AKT
pathways are overactive in endometriosis most probably due to
their abnormal epigenetic regulation.
Systems genetics of endometriosis
Gene interactions through their RNA and protein moieties,
functional epistasis, contributing to suppression and induction of
the genes participating in the relevant gene-networks, their protein
products and related metabolic pathways should be addressed by
systems genetics. This is a novel integrative genome approach
directed to determine genetic architecture of complex traits,
including common diseases [40].
Taking into account the partially epigenetic nature of endome-
triosis, the following pathway of this disorder could be tentatively
suggested: local pelvic inflammation induced by some infectious
agents or by endometrial fragments leaking into peritoneal cavity
with menstrual blood might serve as primary triggers of epithelium
cell injuries in the peritoneum lining. These inflammation foci
63
infested with macrophages activate a developmental programme
leading to ectopic cell survival, vascularization and invasion of
outgrowths with subsequent similar clinical manifestations.
Pathological development in endometriosis is in a good
agreement with ‘‘equifinality’’ of epigenetic processes postulated
by the founder of epigenetic science, Prof. Conrad Waddington [41].
To understand the epigenetic landscape of endometriosis, three
basic questions should be addressed: (i) What are the primary
endometriotic cells (PECs)? (ii) What are the intrinsic mechanisms
supporting their survival? (iii) Why are there so many different
clinical forms of endometriosis? The hypothesis suggested here
provides tentative clues to these puzzles and postulates the
existence of two basic successive stages in development of
endometriosis: (1) the origin of PECs, and (2) the propagation
of PEC to EL. A more general scheme of this hypothesis is shown in
Fig. 3 and outlined below.
The origin of PECs
PECs could be generated by metaplasia and/or transformation
of already existing differentiated cells, or by abnormal differentia-
tion of preexisting stem cells of reproductive tissues. Functional
endometrium cells delivered into the pelvic cavity with a stream of
menstrual blood suffer the shortage of nourishment which is
known from mammalian cloning experiments [42] as an important
prerequisite for switching on ‘‘early’’ genes. In the case of
endometriosis these could be WNT4, HOXA, HOXB, GALT genes
[19,20,43]. These early genes in conjunction with CDKN2BAS –
cycline dependent kinase inhibitor of oncosuppressors (CDKN-2B,
CDKN2A) – have revealed close association with endometriosis
[18,20]. Further development of abnormal endometrial cells is
canalized and becomes irreversible soon after they acquire a
genetic programme similar to that of benign tumor cells. Other
feasible sources of PEC include coelomic cell metaplasia [9,10,12],
circulating bone marrow stem cells or embryonic cells derived
Fig. 3. Two hypothetical stages in pathogenesis of endometriosis. Stage 1 (reverse
epigenetic landscape). Feasible routes of primary endometrioid cells (PECs) origin:
1—dedifferentiation and transformation of otherwise normal cycling endometrium
cells in pelvic cavity; 2—resting embryonic cells of Mullerian duct, 3—stem cells in
menstrual endometrial debris; 4—metaplasia of coelomic epithelium or dormant
stem cells in peritoneal epithelium lining; 5—mesenchymal bone marrow cells.
Stage 2 (direct epigenetic landscape). The feasible routs of abnormal differentiation
and outgrowth of PECs into endometrioid lesions (EL) generating different clinical
forms of endometriosis (I–IV—stages of endometriosis, V—adenomyosis).
Explanation is in the text.
64 V.S. Baranov et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 185 (2015) 59–65
from Mullerian ducts [10]. Thus, both genetic and epigenetic
modifications result in transformation of functionally normal
endometrium cells into benign tumor cells of EL. No chromosome
aberrations have been registered in EL cells, though hypermethy-
lation of chromosome subtelomeres in EL cells were reported [44].
The significance of this finding in metaplasia of endometrium cells
remains problematic and should be proven.
Taking into account the high frequency of endometriosis, it
should be remembered that a significant proportion of dormant
stem cells are dwelling inside the endometrium layer, and thus
could easily flow out cycling endometrial debris in peritoneum
[45]. Irrespective of their origin, however, all types of PEC follow
the same genetic/epigenetic programme in their abnormal
progression to EL. Fig. 3 shows feasible routes contributing to
the origin of PEC. As already mentioned, at least five of them could
be specified at present: (a) dedifferentiation of normal endome-
trial cells, (b) resting embryonic cells, (c) stem cells hidden
in menstrual endometrial debris, or (d) dormant stem cells in
epithelium layer of peritoneal cavity, as well as (e) stromal
mesenchymal cells of bone marrow. Thus, all types of PEC result
from ultimate transformation (genetic or epigenetic reprogram-
ming) of otherwise normal cells into kinds of benign tumor cells of
endometrioid tissue. Identification of PEC by means of specific
molecular and immunological biomarkers, and their complex
analysis both in-vivo and in-vitro might make a substantial
contribution to deciphering endometriosis pathogenesis, its early
diagnoses and efficient treatment.
The propagation of PEC to EL
The second stage of endometriosis development concerns
abnormal differentiation of newly formed PEC in connection with
their capacity for proliferation, implantation, differentiation
and outgrowth into typical EL (Fig. 3). Genetic and epigenetic
deregulation of many already mentioned metabolic pathways,
especially those governed by hormonal and immunological
systems, should be treated as a mandatory prerequisite of PEC
progression at stage 2.
In agreement with the ‘‘epigenetic landscape’’ model of
embryonic cell development [41], endometriosis progression is
also launched by still undifferentiated PECs but with an already
genetically and epigenetically deregulated development pro-
gramme. Because of the unique genetic profile of each endometri-
osis patient based, for example, on specific patterns of individual
genetic polymorphisms, efficiency of individual metabolic path-
ways, differences in types of PEC by origin and endometriosis
provoking triggers, manifestation of endometriosis could vary in a
wide range. The existence of different clinical forms of endometri-
osis in connection with severity, spreading of EL, growth capacity
and depth of invasions is in line with already existing ideas (K.
Zondervan, personal communication, 2013) that endometriosis
actually comprises a group of genetically (epigenetically) different
diseases, but with similar traits and clinical manifestations [3,4].
The pathway of endometriosis suggested here is only one of
many other feasible pathogenic mechanisms of endometriosis
formation, which can vary and be much more complicated in
reality. It cannot be excluded that endometriosis could have its
start from numerous different ‘‘weak’’ points of relevant genetic
and epigenetic networks, which should always include PEC at its
start, and inevitably ends in a clinical manifestation with many
possible fluctuations of its specific traits.
Identification of the molecular mechanisms operating in a
deregulated development programme, and their correction, could
make a substantial contribution in prevention, diagnosis and
treatment of endometriosis [46]. A comparative analysis of allelic
polymorphisms of candidate genes and their expression profiles at
different stages of pathological process, the mechanisms of their
regulation by means of methylation, specific miRNA or DNA
configuration, is a promising field for subsequent studies of
endometriosis. Of special scientific and practical value is the
identification of specific miRNA or other biomarkers that signal the
risk of endometriosis, as well as elaboration of sophisticated
bioinformatic approaches for a more objective evaluation of the
results of complex genetic, immunological and endocrinological
studies.
Condensation
A systems genetics approach to endometriosis is reviewed, and
an epigenetic landscape two-step hypothesis of endometriosis
development is suggested.
Conflict of interest statement
The authors declare that they have no conflict of interests.
Acknowledgements
The authors acknowledge Dr. Anton V. Kiselev and Dr. Olga A.
Efimova for assistance in preparing the paper. This work was
supported by Russian Scientific Foundation (grant number 14-15-
00737).
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