Accepted Manuscript

Pathogenesis of Endometriosis: Interaction between Endocrine and Inflammatory

Pathways

Bansari G. Patel, Emily E. Lenk, Dan I. Lebovic, Yimin Shu, Jie Yu, Robert N. Taylor

PII: S1521-6934(18)30023-3
DOI: 10.1016/j.bpobgyn.2018.01.006
Reference: YBEOG 1782

To appear in: Best Practice & Research Clinical Obstetrics & Gynaecology

Received Date: 23 November 2017

Accepted Date: 23 January 2018

Please cite this article as: Patel BG, Lenk EE, Lebovic DI, Shu Y, Yu J, Taylor RN, Pathogenesis of
Endometriosis: Interaction between Endocrine and Inflammatory Pathways, Best Practice & Research
Clinical Obstetrics & Gynaecology (2018), doi: 10.1016/j.bpobgyn.2018.01.006.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.
 ACCEPTED MANUSCRIPT

Pathogenesis of Endometriosis:

Interaction between Endocrine and Inflammatory Pathways

PT
Bansari G. Patel1, Emily E. Lenk1, Dan I. Lebovic3, Yimin Shu1, Jie Yu1 and Robert N. Taylor1,2

RI
1
Department of Obstetrics and Gynecology and2Molecular Medicine and Translational Sciences,

SC
Wake Forest School of Medicine, Winston-Salem, North Carolina, USA 27157
3
Center for Reproductive Medicine, Minneapolis, Minnesota, USA 55435

U
AN
Corresponding author: Robert N. Taylor, MD PhD
M

Professor and Vice Chair for Research

Department of Obstetrics and Gynecology

D

Wake Forest School of Medicine

TE

1 Medical Center Boulevard

Winston-Salem, North Carolina, USA 27157

EP

email: rtaylor@wakehealth.edu

tel: +1-336-716-5451
C
AC
 ACCEPTED MANUSCRIPT

Abstract

Despite an estimated prevalence of 11% in women and plausible historical descriptions dating

PT
back to the 17th century, the etiology of endometriosis remains poorly understood. Classical

theories of the histological origins of endometriosis are reviewed below. Clinical presentations

RI
are variable and signs and symptoms do not correlate well with the extent of disease. In this

SC
summary we have attempted to synthesize the growing evidence that hormonal and immune

factors conspire to activate a local inflammatory microenvironment that encourages

U
endometriosis to persist and elaborate mediators of its two cardinal symptoms: pain and
AN
infertility. Surprisingly, in the search for novel therapeutics for medical treatment of

endometriosis, some compounds appear to have dual pharmacological functions, simultaneously

M

modifying endocrine and immune system facets of this complex gynecologic syndrome. We
D

predict that these lead drugs will provide more therapeutic choices for patients in the future.
TE
C EP

Key words: endometriosis, estrogen, progesterone, GnRH (gonadotropin releasing hormone) ,

AC

SERM (selective estrogen receptor modulator)

 ACCEPTED MANUSCRIPT

Introduction

Endometriosis is a common gynecological disorder defined by the presence of endometrial

PT
implants at extrauterine (ectopic) sites, leading to chronic inflammation, pain and infertility.

Scholars of endometriosis have identified reports consistent with its modern presentations dating

RI
to the 1600s (1). Recent population-based magnetic imaging findings, confirm long-held

SC
epidemiological estimates that the disease affects ~11% of women of reproductive age (2) with

~176 million cases globally (3). In women with pelvic pain, infertility, or both, the frequency

U
approaches 35-50% and is the second commonest indication for surgery in women of
AN
premenopausal age. Three primary forms of endometriosis— peritoneal, ovarian, and deep

infiltrating— are all manifestations of lesions containing endometrial glands and stroma, along
M

with nerves, blood vessels and inflammatory cells. These elements contribute to a variety of
D

symptoms depending on the organs involved, but neither gross, microscopic, nor even molecular
TE

characteristics correlate directly with endometriosis-associated pain or infertility.

EP

Theories of Endometriosis Pathogenesis

C

The histogenesis of endometriosis remains controversial, with three popular theories dominating
AC

the literature: 1) retrograde menstruation, 2) coelomic metaplasia, and 3) vascular and lymphatic

metastatic spread. Genetic susceptibility and altered immunity also are considered to explain the

etiology of endometriosis.

Reflux Menstruation
 ACCEPTED MANUSCRIPT

The most generally accepted theory, retrograde menstruation and transplantation, was proposed

by Sampson in the 1920s. While performing laparotomy during his patients’ menses, this

gynecologic surgeon observed the free flow of blood and shed endometrial tissue from the

fallopian tubes into the peritoneal cavity. He postulated that endometrial cells in the effluent

PT
might adhere to and invade serosal (4) and peritoneal (5) mesothelia, ultimately generating the

RI
pigmented lesions that he noted on the surface of the ovaries and cul-de-sac. This theory is

supported by evidence that affected women have greater volumes of refluxed blood during

SC
menses compared to controls (6). Additionally, endometriosis occurs frequently in baboons when

cervical occlusion is performed to prevent antegrade menstrual flow (7). Indeed, women with

U
outflow tract obstruction have a high incidence of endometriosis (8).
AN
Coelomic Metaplasia
M

The hypothesis that endometriosis may arise from coelomic epithelium was first attributed to
D

Robert Meyer of Berlin in the early 1920s (9) and was further supported by Ferguson and
TE

colleagues (10). “Metaplasia” is the process by which a committed cell type (eg, mesothelium)

transdifferentiates into an alternative cell type (eg, endometrial epithelium). In contemporary

EP

views of metaplasia, re-programming of mesenchymal stem cells may be involved (11). Other

clinical examples of metaplasia include Barrett’s esophagus, where bile acids transform stratified
C

squamous esophageal cells into mucin-containing goblet cells, and in the lung, where columnar
AC

tracheobronchial epithelium can be induced by cigarette smoking to undergo squamous

differentiation (12). In endometriosis, however, precise inflammatory “inducers” of metaplasia

are unknown. Analyses by Matsuzaki argue that metaplasia may explain the genesis of deep

infiltrating endometriosis (DIE) in the rectovaginal septum, but the phenomenon is unlikely to be

a dominant mechanism for superficial peritoneal disease (13).

 ACCEPTED MANUSCRIPT

Lymphatic and Vascular Metastasis

Endometriosis has also been identified in sites distant from the pelvis, including abdominal

PT
lymph nodes, lungs, pleura, spinal cord, and even in the nose (14). The metastasis theory

hypothesizes that menstrual tissue travels from the endometrial cavity to sentinel lymph nodes

RI
and from there through lymphatic channels and veins to distant sites (15). An alternative

SC
“metastatic” mechanism, that bone marrow-derived stem cells can traffic hematogenously to and

seed ectopic sites, has been championed by Hugh Taylor and his group (16) and is discussed in

U
greater detail below (see Fig. 1).
AN
M

Endocrine Factors in Endometriosis

D

Clinical Hormone Effects

TE

Physicians have long recognized menstrual patterns that appear to predispose to endometriosis.

For example, women with incessant ovulation and menstruation are at an increased risk; early
EP

menarche, heavy or extended (>7 days) menstrual flow and late menopause have all been

associated with a greater prevalence of endometriosis (17). Nullipara, never-users of oral

C

contraceptives (OC), and women with genital outflow tract obstruction have more risk, while
AC

prior pregnancy, lactation, and prolonged OC use have been noted as protective factors. The

association of endometriosis with characteristics related to endometrial proliferation and

increased menstrual reflux has been hypothesized (18). Other less intuitive risk factors include a

low body mass index (19), red hair, left-handedness (20) and a history of dysplastic nevi (21).
 ACCEPTED MANUSCRIPT

Aspects of Diet and Nutrition

Consumption of red meats, trans-fats, and one or more alcoholic beverages per week have been

PT
associated with an increased risk of endometriosis. Conversely, eating fruits, green vegetables,

and omega-3 long-chain fatty acids decrease risk in some (18), but not all studies (22). Dietary

RI
carotenoids contribute to another important class of isoprenoid endocrine factors that we will

SC
collectively refer to as retinoids.

Retinol (ROL), the metabolic precursor of retinoic acid (RA), has long been recognized as a

U
necessary vitamin for mammalian endometrial function (23) and nuclear retinoid receptors have
AN
been identified in normal endometrial and endometriotic cells. Several examples of RA-regulated
M

genes, including IL-6 (24), connexin 43 (25) and fas ligand ((26), are aberrantly expressed in

endometriotic lesions (27). Thus, disparate features of endometriosis (reduced apoptosis,

D

increased invasion and exuberant inflammation) might be attributed to impaired RA action.

TE

Serdar Bulun and colleagues have comprehensively investigated the metabolism and action of

retinoids in endometriosis cells (28) discovering that genes regulating RA biosynthesis and
EP

signaling are anomalously expressed in endometriosis. Further work (29) indicated that RA
C

concentrations and the enzymatic oxidation of ROL to RA were consistently reduced in ectopic
AC

endometriotic lesions compared to eutopic tissues. These findings encourage further

investigation of dietary and hormonal influences in endometriosis.

 ACCEPTED MANUSCRIPT

Progesterone deficiency or resistance

Clinicians have suspected for years that progesterone action on uterine function was abnormal in

cases of endometriosis. While progestin therapy, first introduced by Robert Kistner in 1958 (30),

PT
typically suppresses ovarian estradiol production via gonadotropin inhibition and often

ameliorates endometriosis symptoms, a subset of patients do not benefit from progestin

RI
treatments (31). Failure could be due to local endogenous estradiol synthesis by endometriotic

SC
lesions (as mentioned below) or as a result of progesterone deficiency. From the early days of

radioimmunoassay, some studies showed low circulating serum progesterone levels (32), or a

U
delayed rise in luteal concentrations (33) among women with endometriosis, whereas others
AN
reported no differences (34). In recent years, alterations in progesterone receptor isoform

expression are increasingly attributed to aberrant progesterone action (35). Progesterone effects
M

on target genes are conferred primarily by nuclear progesterone receptor B (PR-B) homodimers

acting as transcription factors, whereas the truncated PR-A isoforms repress the actions of PR-B.
D

The two isoforms appear to have converse effects on inflammation, with PR-B opposing and PR-
TE

A promoting a proinflammatory environment (35). The original observation by Attia et al. (36),

that PR-B transcript levels were markedly reduced in endometriosis lesions, anticipated
EP

subsequent findings that progesterone-regulated endometrial genes were generally

C

underexpressed (eg, glycodelin, N-acetylglucosamine-6-O-sulfotransferase, 17β hydroxysteroid

AC

dehydrogenase 2 [17βHSD2], transducer of ErbB-2 [TOB1]) whereas proinflamatory genes are

overexpressed (granzyme A) in cases of endometriosis (37). This concept was further supported

by evidence that the PR-B promoter is hypermethylated in endometriosis (38) and other

chromatin modifications occur that may account for reduced PR-B expression (39). Interaction

of PRs with Hic-5 also is attenuated as a result of reduced expression of the latter in endometrial
 ACCEPTED MANUSCRIPT

tissue derived from women with endometriosis (40). Corroborating these concepts, a state of

transient eutopic endometrial PR resistance can be generated in baboons with surgically-induced

endometriosis (41).

PT
Enhanced sensitivity to estrogen action

RI
A complementary hypothesis is that estrogen signaling is excessive in cases of endometriosis.

SC
Indeed, almost all the medical therapies that have been promoted to treat endometriosis are

founded on the principle of suppressing estradiol production. Some medications attempt to

U
mimic pregnancy, such as continuous oral contraceptive pills (OCs) (42), depot formulations of
AN
medroxyprogesterone acetate (MPA) or implantable etonogestrel-containing rods. In addition to
M

pituitary suppression, the mechanism of action of these approaches involves decidualization and

subsequent atrophy of endometrial tissue (43). In addition to their efficacious symptom control
D

and long-term safety these treatments have very favorable cost profiles compared to other
TE

methods (44).

GnRH analogues (GnRHa) have been extensively investigated and widely used in endometriosis
EP

(45). These agents induce a menopausal state by down-regulating (superagonists) or directly

C

inhibiting (antagonists) pituitary GnRH receptors, causing decreased gonadotropin secretion,

AC

suppression of ovulation, reduced serum estrogen levels, and resultant endometrial and

endometriosis atrophy (46). Meta-analyses demonstrate that GnRHa improves endometriosis-

related pain by 60-100%, comparable in efficacy to OCs and danazol (47) but their side-effects

include hot flashes, vaginal dryness, loss of libido and emotional lability and long-term use is

associated with loss of bone mineral (3.2% reduction in lumbar spine density after 6 months of
 ACCEPTED MANUSCRIPT

continuous treatment). The USA Food and Drug Administration (FDA) limits therapy with these

agents to a maximum of 6 months duration. To ameliorate these adverse effects, add-back

therapy with norethindrone acetate alone or with low dose ethinyl estradiol has been advocated

in patients undergoing long-term treatment with GnRH analogues (48). Fortunately, add-back

PT
therapy does not appear to exacerbate endometriosis pain, a phenomenon attributed to the

RI
“estrogen threshold” hypothesis, which posits that the plasma concentrations of estradiol

necessary to activate endometriosis pain are significantly greater than the levels needed for bone

SC
protection (49) (50).

U
In the past few years, considerable progress in the development of orally active, non-peptidergic
AN
GnRH antagonists promises to provide a new of class of compounds to partially suppress the

HPO axis and estradiol levels (51). Early experience with one prototype agent, elagolix, showed
M

similar efficacy to leuprolide in terms of serum estradiol suppression, bone density changes and

endometriosis pain relief (52).

D
TE

Increased estrogenic action in these lesions appears to be a consequence of increased expression

of both its receptors, estrogen receptor α (ERα) and ERβ (53) (54) (55) and increased local
EP

hormone biosynthesis by aromatase, the CYP19A1 gene product. Recent pharmaceutical

developments have focused on the important role of estrogen receptor signaling in

C

endometriosis. Two novel ER ligands, which bind preferentially to ERα and ERβ, respectively,
AC

are oxabicycloheptene sulfonate (OBHS) and chloroindazole (CLI). These compounds displayed

dual suppression of proliferative and inflammatory activities and effectively prevented the

establishment and progression of endometriotic lesions in a mouse model (56). The selective

estrogen receptor modulators (SERMs) bazedoxifene (57) and ERB-041 (58), also were shown

to suppress endometriotic lesion growth in rodents. Unfortunately, in the one published

 ACCEPTED MANUSCRIPT

randomized clinical trial of another SERM, raloxifene, for postoperative recurrence of

endometriosis pain, women receiving active treatment experienced a more rapid recrudescence

of pelvic pain than women in the placebo arm, causing the study to be discontinued (59).

PT
Aromatase is the key cytochrome P450 enzyme responsible for estrogen biosynthesis, catalyzing

the conversion of androstenedione and testosterone to estrone and estradiol, respectively. The

RI
important discovery that this enzyme is expressed locally in endometriosis tissue provided a

SC
novel mechanism for lesions to generate their own source of estrogens in situ (60). As noted

above, estradiol is a potent trophic factor for endometriosis implant proliferation and it also

U
directly stimulates angiogenesis (61) (see Fig. 1). Aromatase inhibitors target this enzyme to
AN
decrease local estrogen synthesis and inhibit lesion growth (62) and have proven efficacy in

suppressing pelvic pain and gastrointestinal dysfunction associated with endometriosis (63).
M

However, use of aromatase inhibitors reduces negative feedback and leads to an increase in FSH,

with subsequent ovarian stimulation; hence, agents that suppress follicular activity, such as OCs,
D

progestins or GnRHa, must be utilized in concert with aromatase inhibitors to prevent ovarian
TE

stimulation in premenopausal women.

EP

Due to their hypoestrogenic effects, prolonged use of aromatase inhibitors place women at risk

for developing osteopenia, osteoporosis and bone fractures. In a small, six-month study where
C

women were treated with letrozole (2.5 mg/day), norethindrone acetate (2.5 mg/day), calcium
AC

and vitamin D, laparoscopically visible endometriosis lesions were reduced and pelvic pain

scores were improved without a significant change in bone mineral density (64).
 ACCEPTED MANUSCRIPT

Inflammatory Factors in Endometriosis

Numerous studies now support widespread but subtle immune dysregulation in patients with

moderate to severe endometriosis. Evidence that women with endometriosis have altered

PT
immune parameters, such as reduced T-lymphocyte mediated cytotoxicity to autologous

endometrial cells, has existed for >30 years (65). It was postulated that these subjects have

RI
decreased immunosurveillance and impaired recognition of ectopic endometrial cells secondary

SC
to defective NK-cell activity (66). Furthermore, lesions may escape immune-detection via

secretion of immunomodulatory proteins such as soluble ICAM-1 that prevent recognition and

U
destruction of ectopic endometrium (67).
AN
Women with endometriosis were noted to have augmented production of C-C chemokines,

which may account for increased local macrophage recruitment and activation in ectopic lesions
M

and peritoneal fluid (68) (69). Peritoneal fluid also can promote inflammation around
D

endometrial deposits by increasing oxidant levels and lipid peroxidation (70) (71).
TE

High levels of pelvic fluid interleukin (IL)-1β, IL-6 and IL-8, along with other proinflammatory

cytokines, have been reported in patients with endometriosis compared to controls (68).
EP

Endometriotic lesions may be further potentiated via increased expression of growth factors,

including BDNF, PDGF, TGF-β and VEGF. These proteins facilitate recruitment of nearby
C

nerves and capillaries providing the proliferating implants with a robust neurovascular supply, a
AC

process that we have referred to as “neuroangiogenesis” (72) and is described in more detail

below (see Fig. 1). Down-regulation of pro-apoptotic genes and upregulation of anti-apoptotic

genes from the BCL2, BCL6 and BAX families, have been observed in eutopic endometrium of
 ACCEPTED MANUSCRIPT

women with endometriosis and also in ectopic endometriosis lesions, which recently have been

promoted as a noninvasive diagnostic biomarker of endometriosis (73).

PT
Stem Cells

RI
Pluripotent mesenchymal stem cells, derived from the bone-marrow (74) or emanating from

from a niche within the superficial basalis endometrium (75) have the ability to differentiate cells

SC
into mature endometrial epithelial and stromal cells in ectopic sites. Similarly, somatic stem cells

in ovarian endometriomas have been identified (76). An alternative theory that retrograde

U
seeding of naïve muellerian cells in the immediate postnatal period might contribute to cells that
AN
are hormonally reactivated in adolescence, yielding endometriosis lesions in early reproductive
M

life, has been proposed (77).

D
TE

Cancer Risk and Endometriosis

Endometriosis has been associated with an increased risk of several cancers, most notably
EP

endometrioid and clear cell ovarian cancer, breast cancer, non-Hodgkin lymphoma, and

melanoma (78). Ovarian cancer develops in 1–5% of cases with ovarian endometriosis and in a
C

lower percentage of cases with endometriosis outside the ovary. Ovarian endometrioid
AC

adenocarcinoma and clear cell carcinoma (10–20% and <5%, respectively) are the commonest

types (79). Cervical cancer incidence appears reduced in women with endometriosis, while no

significant differences have been reported for the incidence of endometrial cancer (78). The latter
 ACCEPTED MANUSCRIPT

finding is of some interest, as the estrogen-dominant/progesterone resistant endocrine milieu of

endometriosis would be expected to increase the risk of type I endometrial cancers in particular.

PT
Immune Cells and Immunosurveillance

RI
The accumulation of extravasating immune cells (“endothelial leukocytes”) around

endometriotic lesions was originally described by Meigs in 1922 (80). It is now recognized that

SC
trafficking of innate immune cells into the peritoneal fluid and their recruitment into eutopic and

ectopic endometrial tissue is a dynamic, physiological process mediated via the expression of

U
soluble chemoattractant proteins referred to as chemokines. Neutrophils, natural killer (NK)
AN
cells, and macrophages are the major cells providing innate defense, which is not antigen-
M

specific and has no immunological memory. Given the predominant monocytic inflammatory

response observed in endometriosis, our group has focused on cytokines and chemokines
D

selective for the macrophage lineage. In particular, IL-8, CCL2 (MCP-1, monocyte chemotactic
TE

protein-1), and CCL5 (RANTES, regulated upon activation, normal T cell expressed and

secreted) have been studied extensively (69). Using a non-biased systems biology approach,
EP

Beste et al. (81) found many of these same macrophage-related factors to be upregulated in

pelvic fluid of endometriosis cases. Macrophage polarization is becoming increasingly

C

understood. In the context of endometriosis compared to women without disease, Takebayashi et

AC

al. (82) reported that the ratio of classically activated (M1) to alternatively activated (M2)

macrophages was increased. We made similar observations in endometrial carcinoma (83).

An intriguing concept in the etiology of endometriosis is defective immunosurveillance in

susceptible women. If normal eutopic endometrium elicited an immune response,

 ACCEPTED MANUSCRIPT

antiendometrial autoantibodies would be prevalent in all women, rather than being restricted to a

subset of endometriosis cases (84). Hence, adaptive immunity toward these cells seems to occur

when they are present in ectopic locations.

PT
In normal women, intraperitoneal menstrual debris appears to be eliminated without loss of

immune tolerance, presumably mediated by a balance between regulatory T cells (Tregs) and

RI
effector T cells; CD8+ T cells and immunosuppressive cytokines (e.g., IL-13, IL-1RA) also play

SC
a role. However, as noted in other autoimmune disorders, immune tolerance might break down in

endometriosis, resulting in the recognition of ectopic implants by a chronic inflammatory

U
response. Induction of so-called “blocking antibodies” of endometrial antigens have been
AN
postulated but never confirmed (85). As noted above, ICAM-1 has been reported to interfere

with peritoneal immunosurveillance and may allow refluxed endometrium to escape

M

phagocytosis and clearance (67) (see Fig. 1). Moreover, endometriotic cells are reported to be

inherently resistant to apoptosis and phagocytosis (86) and may inhibit NK cell cytotoxicity (66).
D
TE

Oxidative Stress, Fibrosis and Epithelial-Mesenchymal Transition

EP

Oxygen free radicals have been hypothesized for years as mediators of the cellular pathology
C

associated with endometriosis. Free radicals are highly reactive molecules that can transiently
AC

sustain one or two unpaired electrons. The transfer of these unstable electrons to other structural

or regulatory molecules can cause cell damage. Most free radicals of biologic significance are

reactive oxygen species (ROS), such as hydroxyl (OH•), peroxyl (ROO•) or superoxide (O2•–)

ions. Oxidative stress occurs when the homeostatic balance of antioxidant vitamins and enzymes

are overwhelmed in a pro-oxidant environment of ROS, exceeding the defensive ability of

 ACCEPTED MANUSCRIPT

protective molecular species. Murphy et al. found that peritoneal fluid levels of the antioxidant

vitamin E were consumed and the ratio of lysophosphatidylcholine to phosphatidylcholine

increased in women with endometriosis (87), findings consistent with increased lipid

peroxidation in endometriosis. It has been shown that oxidative stress can mediate a mitogenic

PT
response in endometrial stromal cells in vitro (88); hence a surplus of free radicals, generated in

RI
part via intralesional bleeding, may directly contribute to implant proliferation and invasion (89).

SC
Other classes of biochemical factors secreted by endometriotic lesions or neighboring peritoneal

cells also might contribute to the adhesions that classically surround the implants and adjoining

U
pelvic organs (90) TGF-β, a growth factor associated with intraperitoneal fibrosis, was noted to
AN
be elevated in peritoneal fluid of women with endometriosis (91) and is thought to play a key

role in the pelvic fibrogenesis characteristic of endometriosis.

M

Relevant to the generation of pelvic adhesions associated with endometriosis is the phenomenon
D

of epithelial-mesenchymal transition (EMT). EMT is a phylogenetically conserved mechanism

TE

of embryonic development. For example, in the Müllerian tract, a reciprocal process, called

mesenchymal-epithelial transition (MET) induces the cranial-to-caudal differentiation of

EP

cœlomic urogenital sinus mesoderm to generate the embryonic uterine epithelium. Studies from

the cancer literature indicate that reversible EMT programs are manifested during tumor
C

metastasis (92), and similar transitions have been reviewed in endometriosis (93). Our own
AC

group observed that endometrial stromal cells are highly plastic and reversibly undergo EMT and

MET in response to ovarian hormones (94). If these same phenomena occur in endometriosis,

they could represent another facet of endocrine-inflammation cross-talk in this condition.

 ACCEPTED MANUSCRIPT

Proliferative and Apoptosis Factors

A variety of human growth factors stimulate mitogenic activity in endometriotic and endometrial

cells, many of which have been identified in endometriotic tissues and in the peritoneal fluid of

PT
women with endometriosis. Although their precise roles are not fully characterized, these factors

are potential regulators of endometriosis implant proliferation. Figure 1 summarizes the putative

RI
pathways that are influenced by endcrine and paracrine growth factors.

SC
Contrariwise, factors associated with programmed cell death (apoptosis) have been implicated in

cyclical endometrial remodeling (95). For example, there is considerable current interest in the

U
anti-apoptotic factor BCL6, as a sensitive biomarker for endometriosis (73).
AN
M

Neuroangiogenic Factors
D

Based on the exaggerated vascularity visualized laparoscopically around ectopic implants and
TE

their analogy with tumor metastases(96), the angiogenic hypothesis of endometriosis became

well established by the mid-1990s (97) (98;99). The sprouting of new blood vessels from
EP

preexisting vessels includes the proteolysis of extracellular matrix, proliferation and migration of

endothelial cells, and ultimately the organization of patent capillary tubules. Several growth
C

factors and cytokines exert mitogenic and chemotactic effects on endothelial cells, pericytes and
AC

vascular smooth muscle cells. Increased IL-1β sensitivity increases the angiogenic potential of

endometriosis lesions (100). One interpretation of these findings is that endometriosis cells

manifest an “activated” angiogenic phenotype. In analogy to Knudson’s “two-hit” hypothesis of

oncogenesis (101), women susceptible to the development of endometriosis may carry a “first
 ACCEPTED MANUSCRIPT

hit” genetic trait that increases stem cell viability and a “second hit” that enhances endometrial

cell angiogenic factor production or receptivity.

In addition to increased angiogenesis, endometriotic lesions recruit a nerve supply from the

PT
surrounding peritoneum and these processes appear to be coordinated (72). Many of the growth

factors involved in neuroangiogenesis have bi- or multi-functional activities. For example,

RI
angiopoietin 2 (102), BDNF (103), NGF (104) and VEGF (105) are known to have neurogenic

SC
as well as angiogenic effects.

In an immunocompetent murine model of endometriosis, where syngeneic fragments of uterine

U
tissue were surgically attached to the abdominal peritoneum, the growth of these endometriosis-
AN
like lesions was estrogen dependent. As in women with the disease, proliferation of the lesions

was associated with neurogenesis, angiogenesis, cytokine (IL-6 and TNF-α) chemokine (CCL2
M

and CCL5) secretion and macrophage recruitment (56). Selective estrogen receptor modulators
D

that are specific for ERα (OBHS) and ERβ (CLI) effectively inhibited lesion growth and
TE

inflammation and reduced neuroangiogenic biomarkers. The same effects were observed using

primary cultures of stromal cells derived from human endometriomas (106) treated with estradiol
EP

and TNF-α. Histone phosphorylation, IL-6 and CCL2 were reduced and apoptosis was increased

following OBHS or CLI treatment.

C
AC

Conclusions

Endometriosis is a common disease affecting women in their reproductive years that negatively

impacts their quality of life and impairs their fecundity. The exact etiology of this complex

disease remains a mystery and likely has manifold influences, described elsewhere in this
 ACCEPTED MANUSCRIPT

monograph. Cell biological, transcriptomic and proteomic approaches have been very

informative regarding the pathophysiology of endometriosis, providing substantial evidence that

both the endocrine responsiveness and the inflammatory activation of eutopic and ectopic

endometrium are critically involved. Exciting new observations indicate that these seemingly

PT
distinct pathways engage in intimate cross-talk. Suppression of ovarian estrogen production

RI
results in amelioration of inflammatory responses and symptoms. New, oral GnRH antagonist

preparations are promising additions to our clinical pharmacopeia. Moreover, novel SERMs

SC
exert dual anti-estrogenic and immunosuppressive activities in preclinical models of

endometriosis and we are optimistic that similar compounds will be discovered and developed.

U
Whereas surgical therapy will always be considered as a mainstay for managing endometriosis
AN
related symptoms, the future of medical treatments, some with overlapping hormonal and

inflammation targets, appears auspicious.

M
D
TE

Practice Points

• Surgical excision or obliteration of endometriosis lesions will always be considered as an

EP

option for managing endometriosis related symptoms, but to avoid the long delay from symptom

onset to definitive therapy, more medical options, particularly for younger women, are needed.
C
AC

• Growth factors exert multiple actions on leiomyoma cells through activating multiple

signal transduction pathways.

• Based on our current knowledge of the therapeutic actions of available medical

treatments, clinicians and scientists can collaborate on the discovery of novel pathways and

institute trials of new or repurposed drugs for endometriosis.

 ACCEPTED MANUSCRIPT

Research Agenda

• Development of authentic and reproducible models of endometriosis needs to continue.

PT
Animal models, such as nonhuman primates (where spontaneous endometriosis occurs) and in

transgenic rodents (where molecular modifications can be incorporated) offer important

RI
advantages. Human cell culture systems also have been highly informative.

SC
• In endometriosis, as in a number of immune conditions that disproportionately afflict

women, estrogens exacerbate inflammatory symptoms and SERMs suppress them. Further

U
studies are needed to understand how hormones and inflammatory factors engage in molecular
AN
cross-talk.
M

• High-throughput drug discovery efforts are needed to uncover new biological and small-

molecule compounds, potentially based on the novel SERMs and GnRH antagonists described in
D

this review, that might offer new options for women with endometriosis symptoms.
TE
C EP

Conflicts of interest
AC

The authors have no conflicts of interest.

 ACCEPTED MANUSCRIPT

Figure 1 Legend

Endocrine and inflammatory pathways in endometriosis and their consequences. Abbreviations:

BDNF (brain-derived neurotrophic factor); E2 (estradiol); ICAM-1 (soluble intercellular

PT
adhesion molecule-1); IL (interleukin)-1β, -6, -8; NK cells (natural killer cells); PDGF (platelet-

derived growth factor); P4 (progesterone) resistance; RANTES (regulated on activation, normal

RI
T cell expressed and secreted, CCL5); T & B (thymus and bursa) lymphocytes; Tregs (regulatory

SC
T cells); TNF (tumor necrosis factor)-α; VEGF (vascular endothelial growth factor)..

U
References (* indicates 10 highlighted references)
AN
1. Knapp VJ 1999 How old is endometriosis? Late 17th- and 18th-century European
M

descriptions of the disease. Fertil Steril 72:10-14

2. Buck Louis GM, Hediger ML, Peterson CM, Croughan M, Sundaram R, Stanford
D

J, et al. 2011 Incidence of endometriosis by study population and diagnostic method: the
TE

ENDO study. Fertil Steril 96:360-365

EP

3. Adamson GD, Kennedy SH, Hummelshoj L 2010 Creating solutions in endometriosis:

global collaboration through the World Endometriosis Research Foundation. J

C

Endometriosis 2:3-6
AC

4. Sampson JA 1921 Perforating hemorrhagic (chocolate) cysts of the ovary: their

importance and especially their relation to pelvic adenomyomas of endometrial type. 3

ed.; 245-323
 ACCEPTED MANUSCRIPT

5. Sampson JA 1927 Peritoneal endometriosis due to menstrual dissemination of

endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 14:442-469

6. Halme J, Hammond MG, Hulka JF, Raj SG, Talbert LM 1984 Retrograde

PT
menstruation in healthy women and in patients with endometriosis. Obstet Gynecol

64:151-154

RI
7*. D'Hooghe TM 1997 Clinical relevance of the baboon as a model for the study of

SC
endometriosis. Fertil Steril 68:613-625

U
8. Nunley WC, Jr., Kitchin JD, III 1980 Congenital atresia of the uterine cervix with
AN
pelvic endometriosis. Arch Surg 115:757-758

9. Meyer R 1924 Zur Frage der heterotopen Epithelwucherung, insbesondere des

M

Peritonealepithels und in die Ovarien. Virch Arch Path Anat Phys 250:595-610
D

10. Ferguson BR, Bennington JL, Haber SL 1969 Histochemistry of mucosubstances and
TE

histology of mixed mullerian pelvic lymph node glandular inclusions. Evidence for

histogenesis by mullerian metaplasia of coelomic epithelium. Obstet Gynecol 33:617-625

EP

11*. Figueira PG, Abrao MS, Krikun G, Taylor HS 2011 Stem cells in endometrium and
C

their role in the pathogenesis of endometriosis. Ann N Y Acad Sci 1221:10-7. doi:
AC

10.1111/j.1749-6632.2011.05969.x.:10-17

12*. Taylor RN, Kane MA, Sidell N 2015 Pathogenesis of endometriosis: Roles of retinoids

and inflammatory pathways. Semin Reprod Med 33:246-256

 ACCEPTED MANUSCRIPT

13. Matsuzaki S, Darcha C 2012 Epithelial to mesenchymal transition-like and

mesenchymal to epithelial transition-like processes might be involved in the pathogenesis

of pelvic endometriosis. Hum Reprod 27:712-721

PT
14. Laghzaoui O, Laghzaoui M 2001 [Nasal endometriosis: apropos of 1 case]. J Gynecol

Obstet Biol Reprod (Paris) 30:786-788

RI
15. Mechsner S, Weichbrodt M, Riedlinger WF, Bartley J, Kaufmann AM, Schneider

SC
A, et al. 2008 Estrogen and progestogen receptor positive endometriotic lesions and

disseminated cells in pelvic sentinel lymph nodes of patients with deep infiltrating

U
rectovaginal endometriosis: a pilot study. Hum Reprod 23:2202-2209
AN
16. Pluchino N, Taylor HS 2016 Endometriosis and Stem Cell Trafficking. Reprod Sci
M

23:1616-1619
D

17. Treloar SA, Bell TA, Nagle CM, Purdie DM, Green AC 2010 Early menstrual
TE

characteristics associated with subsequent diagnosis of endometriosis. Am J Obstet

Gynecol 202:534-536
EP

18*. Giudice LC 2010 Clinical practice. Endometriosis. N Engl J Med 362:2389-2398

C

19. Shah DK 2013 Diminished ovarian reserve and endometriosis: insult upon injury. Semin
AC

Reprod Med 31:144-149

20. Audebert A, Akladios CY, Lefebvre F, Wattiez A 2013 Are left-handed women at

increased risk of endometriosis? Acta Obstet Gynecol Scand 92:607

 ACCEPTED MANUSCRIPT

21. Hornstein MD, Thomas PP, Sober AJ, Wyshak G, Albright NL, Frisch RE 1997

Association between endometriosis, dysplastic naevi and history of melanoma in women

of reproductive age. Hum Reprod 12:143-145

PT
22. Trabert B, Peters U, De Roos AJ, Scholes D, Holt VL 2011 Diet and risk of

endometriosis in a population-based case-control study. Br J Nutr 105:459-467

RI
23. Bo WJ, Smith MS 1966 The effect of retinol and retinoic acid on the morphology of the

SC
rat uterus. Anat Rec 156:5-9

U
24. Sawatsri S, Desai N, Rock JA, Sidell N 2000 Retinoic acid suppresses interleukin-6
AN
production in human endometrial cells. Fertil Steril 73:1012-1019

25. Wu J, Taylor RN, Sidell N 2013 Retinoic acid regulates gap junction intercellular
M

communication in human endometrial stromal cells through modulation of the

D

phosphorylation status of connexin 43. J Cell Physiol 228:903-910

TE

26. Xia HF, Ma JJ, Sun J, Yang Y, Peng JP 2010 Retinoic acid metabolizing enzyme

CYP26A1 is implicated in rat embryo implantation. Hum Reprod 25:2985-2998

EP

27. Sharpe-Timms KL 2001 Endometrial anomalies in women with endometriosis. Ann N

C

Y Acad Sci 943:131-147

AC

28*. Pavone ME, Reierstad S, Sun H, Milad M, Bulun SE, Cheng YH 2010 Altered

retinoid uptake and action contributes to cell survival in endometriosis. J Clin Endocrinol

Metab 95:E300-E309
 ACCEPTED MANUSCRIPT

29. Pierzchalski K, Taylor RN, Nezhat C, Jones JW, Napoli JL, Yang G, et al. 2014

Retinoic acid biosynthesis is impaired in human and murine endometriosis. Biol Reprod

91:84

PT
30. Kistner RW 1958 The use of newer progestins in the treatment of endometriosis. Am J

Obstet Gynecol 75:264-278

RI
31. Lessey BA 2000 Medical management of endometriosis and infertility. Fertil Steril

SC
73:1089-1096

U
32. Barry-Kinsella C, Sharma SC, Cottell E, Harrison RF 1994 Mid to late luteal phase
AN
steroids in minimal stage endometriosis and unexplained infertility. Eur J Obstet Gynecol

Reprod Biol 54:113-118

M

33. Pittaway DE, Maxson W, Daniell J, Herbert C, Wentz AC 1983 Luteal phase defects
D

in infertility patients with endometriosis. Fertil Steril 39:712-713

TE

34. Kusuhara K 1992 Luteal function in infertile patients with endometriosis. Am J Obstet

Gynecol 167:274-277
EP

35. Patel B, Elguero S, Thakore S, Dahoud W, Bedaiwy M, Mesiano S 2014 Role of

C

nuclear progesterone receptor isoforms in uterine pathophysiology. Hum Reprod Update

AC

21:155-73

36*. Attia GR, Zeitoun K, Edwards D, Johns A, Carr BR, Bulun SE 2000 Progesterone

receptor isoform A but not B is expressed in endometriosis. J Clin Endocrinol Metab

85:2897-2902
 ACCEPTED MANUSCRIPT

37. Burney RO, Talbi S, Hamilton AE, Vo KC, Nyegaard M, Nezhat CR, et al. 2007

Gene expression analysis of endometrium reveals progesterone resistance and candidate

susceptibility genes in women with endometriosis. Endocrinology 148:3814-3826

PT
38. Wu Y, Strawn E, Basir Z, Halverson G, Guo SW 2006 Promoter hypermethylation of

progesterone receptor isoform B (PR-B) in endometriosis. Epigenetics 1:106-111

RI
39. Al-Sabbagh M, Lam EW, Brosens JJ 2012 Mechanisms of endometrial progesterone

SC
resistance. Mol Cell Endocrinol 358:208-215

U
40. Aghajanova L, Hamilton A, Kwintkiewicz J, Vo KC, Giudice LC 2009 Steroidogenic
AN
enzyme and key decidualization marker dysregulation in endometrial stromal cells from

women with versus without endometriosis. Biol Reprod 80:105-114

M

41. Fazleabas AT 2010 Progesterone resistance in a baboon model of endometriosis. Semin

D

Reprod Med 28:75-80

TE

42. Vercellini P, Frontino G, De Giorgi O, Pietropaolo G, Pasin R, Crosignani PG 2003

Continuous use of an oral contraceptive for endometriosis-associated recurrent

EP

dysmenorrhea that does not respond to a cyclic pill regimen. Fertil Steril 80:560-563
C

43. Endometriosis and infertility: a committee opinion 2012 Fertil Steril 98:591-598
AC

44*. Berlanda N, Somigliana E, Vigano P, Vercellini P 2016 Safety of medical treatments

for endometriosis. Expert Opin Drug Saf 15:21-30

45. Valle RF, Sciarra JJ 2003 Endometriosis: treatment strategies. Ann N Y Acad Sci

997:229-39.:229-239
 ACCEPTED MANUSCRIPT

46. Crosignani P, Olive D, Bergqvist A, Luciano A 2006 Advances in the management of

endometriosis: an update for clinicians. Hum Reprod Update 12:179-189

47. Prentice A, Deary AJ, Goldbeck-Wood S, Farquhar C, Smith SK 2000

PT
Gonadotrophin-releasing hormone analogues for pain associated with endometriosis.

Cochrane Database Syst RevCD000346

RI
48. Surrey ES, Hornstein MD 2002 Prolonged GnRH agonist and add-back therapy for

SC
symptomatic endometriosis: long-term follow-up. Obstet Gynecol 99:709-719

U
49. Barbieri RL 1998 Endometriosis and the estrogen threshold theory. Relation to surgical
AN
and medical treatment. J Reprod Med 43:287-292

50. Riggs MM, Bennetts M, van der Graaf PH, Martin SW 2012 Integrated
M

pharmacometrics and systems pharmacology model-based analyses to guide GnRH

D

receptor modulator development for management of endometriosis. CPT

TE

Pharmacometrics Syst Pharmacol 1:e11. doi: 10.1038/psp.2012.10.:e11

51. Donnez J, Taylor RN, Taylor HS 2017 Partial suppression of estradiol: a new strategy
EP

in endometriosis management? Fertil Steril 107:568-570

C

52*. Taylor HS, Giudice LC, Lessey BA, Abrao MS, Kotarski J, Archer DF, et al. 2017
AC

Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N

Engl J Med 377:28-40

 ACCEPTED MANUSCRIPT

53. Brandenberger AW, Lebovic DI, Tee MK, Ryan IP, Tseng JF, Jaffe RB, et al. 1999

Oestrogen receptor (ER)-alpha and ER-beta isoforms in normal endometrial and

endometriosis-derived stromal cells. Mol Hum Reprod 5:651-655

PT
54. Bulun SE, Cheng YH, Pavone ME, Xue Q, Attar E, Trukhacheva E, et al. 2010

Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in

RI
endometriosis. Semin Reprod Med 28:36-43

SC
55. Pellegrini C, Gori I, Achtari C, Hornung D, Chardonnens E, Wunder D, et al. 2012

The expression of estrogen receptors as well as GREB1, c-MYC, and cyclin D1,

U
estrogen-regulated genes implicated in proliferation, is increased in peritoneal
AN
endometriosis. Fertil Steril 98:1200-1208
M

56*. Zhao Y, Gong P, Chen Y, Nwachukwu JC, Srinivasan S, Ko C, et al. Dual

suppression of estrogenic and inflammatory activities for targeting of endometriosis. Sci

D

Transl Med 7(271):271ra9

TE

57. Kulak J, Jr., Fischer C, Komm B, Taylor HS 2011 Treatment with bazedoxifene, a
EP

selective estrogen receptor modulator, causes regression of endometriosis in a mouse

model. Endocrinology 152:3226-3232

C

58. Harris HA, Bruner-Tran KL, Zhang X, Osteen KG, Lyttle CR 2005 A selective
AC

estrogen receptor-beta agonist causes lesion regression in an experimentally induced

model of endometriosis. Hum Reprod 20:936-941

 ACCEPTED MANUSCRIPT

59. Stratton P, Sinaii N, Segars J, Koziol D, Wesley R, Zimmer C, et al. 2008 Return of

chronic pelvic pain from endometriosis after raloxifene treatment: a randomized

controlled trial. Obstet Gynecol 111:88-96

PT
60. Zeitoun KM, Bulun SE 1999 Aromatase: a key molecule in the pathophysiology of

endometriosis and a therapeutic target. Fertil Steril 72:961-969

RI
61. Mueller MD, Vigne JL, Minchenko A, Lebovic DI, Leitman DC, Taylor RN 2000

SC
Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen

receptors alpha and beta. Proc Natl Acad Sci U S A 97:10972-10977

U
AN
62. Bulun SE, Fang Z, Imir G, Gurates B, Tamura M, Yilmaz B, et al. 2004 Aromatase

and endometriosis. Semin Reprod Med 22:45-50

M

63. Pavone ME, Bulun SE 2012 Aromatase inhibitors for the treatment of endometriosis.
D

Fertil Steril 98:1370-1379

TE

64. Ailawadi RK, Jobanputra S, Kataria M, Gurates B, Bulun SE 2004 Treatment of

endometriosis and chronic pelvic pain with letrozole and norethindrone acetate: a pilot
EP

study. Fertil Steril 81:290-296

C

65. Steele RW, Dmowski WP, Marmer DJ 1984 Immunologic aspects of human
AC

endometriosis. Am J Reprod Immunol 6:33-36

66. Oosterlynck DJ, Meuleman C, Waer M, Vandeputte M, Koninckx PR 1992 The

natural killer activity of peritoneal fluid lymphocytes is decreased in women with

endometriosis. Fertil Steril 58:290-295

 ACCEPTED MANUSCRIPT

67. Vigano P, Gaffuri B, Somigliana E, Busacca M, Di Blasio AM, Vignali M 1998

Expression of intercellular adhesion molecule (ICAM)-1 mRNA and protein is enhanced

in endometriosis versus endometrial stromal cells in culture. Mol Hum Reprod 4:1150-

1156

PT
68*. Lebovic DI, Mueller MD, Taylor RN 2001 Immunobiology of endometriosis. Fertil

RI
Steril 75:1-10

SC
69. Reis FM, Petraglia F, Taylor RN 2013 Endometriosis: hormone regulation and clinical

consequences of chemotaxis and apoptosis. Hum Reprod Update 19:406-18

U
AN
70. Santanam N, Murphy AA, Parthasarathy S 2002 Macrophages, oxidation, and

endometriosis. Ann N Y Acad Sci 955:183-198

M

71. Van LA, Casanas-Roux F, Donnez J 2002 Oxidative stress and peritoneal
D

endometriosis. Fertil Steril 77:861-870

TE

72. Asante A, Taylor RN 2011 Endometriosis: the role of neuroangiogenesis. Annu Rev

Physiol 73:163-182
EP

73. Evans-Hoeker E, Lessey BA, Jeong JW, Savaris RF, Palomino WA, Yuan L, et al.
C

2016 Endometrial BCL6 Overexpression in Eutopic Endometrium of Women With

AC

Endometriosis. Reprod Sci 23:1234-1241

74. Taylor HS 2004 Endometrial cells derived from donor stem cells in bone marrow

transplant recipients. JAMA 292:81-85

 ACCEPTED MANUSCRIPT

75. Gargett CE, Masuda H 2010 Adult stem cells in the endometrium. Mol Hum Reprod

16:818-834

76. Chan RW, Ng EH, Yeung WS 2011 Identification of cells with colony-forming activity,

PT
self-renewal capacity, and multipotency in ovarian endometriosis. Am J Pathol 178:2832-

2844

RI
77. Brosens I, Gargett CE, Guo SW, Puttemans P, Gordts S, Brosens JJ, et al. 2016

SC
Origins and Progression of Adolescent Endometriosis. Reprod Sci 23:1282-1288

U
78. Kokcu A 2011 Relationship between endometriosis and cancer from current perspective.
AN
Arch Gynecol Obstet 284:1473-1479

79. Nagle CM, Olsen CM, Webb PM, Jordan SJ, Whiteman DC, Green AC 2008
M

Endometrioid and clear cell ovarian cancers: a comparative analysis of risk factors. Eur J
D

Cancer 44:2477-2484
TE

80. Meigs JV 1922 Endometrial hematomas of the ovary. Boston Med Surg J 187:1-13
EP

81. Beste MT, Pfaffle-Doyle N, Prentice EA, Morris SN, Lauffenburger DA, Isaacson

KB, et al. 2014 Molecular network analysis of endometriosis reveals a role for c-Jun-
C

regulated macrophage activation. Sci Transl Med 6:222ra16

AC

82. Takebayashi A, Kimura F, Kishi Y, Ishida M, Takahashi A, Yamanaka A, et al.

2015 Subpopulations of macrophages within eutopic endometrium of endometriosis

patients. Am J Reprod Immunol 73:221-231

 ACCEPTED MANUSCRIPT

83. Kelly MG, Francisco AM, Cimic A, Wofford A, Fitzgerald NC, Yu J, et al. 2015

Type 2 Endometrial Cancer is Associated With a High Density of Tumor-Associated

Macrophages in the Stromal Compartment. Reprod Sci 22:948-53

PT
84. Mathur SP 2000 Autoimmunity in endometriosis: relevance to infertility. Am J Reprod

Immunol 44:89-95

RI
85. Grosskinsky CM, Halme J 1993 Endometriosis: the host response. Baillieres Clin

SC
Obstet Gynaecol 7:701-713

U
86. Dmowski WP, Ding J, Shen J, Rana N, Fernandez BB, Braun DP 2001 Apoptosis in
AN
endometrial glandular and stromal cells in women with and without endometriosis. Hum

Reprod 16:1802-1808
M

87. Murphy AA, Santanam N, Morales AJ, Parthasarathy S 1998 Lysophosphatidyl

D

choline, a chemotactic factor for monocytes/T-lymphocytes is elevated in endometriosis.

TE

J Clin Endocrinol Metab 83:2110-2113

88. Foyouzi N, Berkkanoglu M, Arici A, Kwintkiewicz J, Izquierdo D, Duleba AJ 2004

EP

Effects of oxidants and antioxidants on proliferation of endometrial stromal cells. Fertil

Steril 82 Suppl 3:1019-22.:1019-1022

C
AC

89. Donnez J, Binda MM, Donnez O, Dolmans MM 2016 Oxidative stress in the pelvic

cavity and its role in the pathogenesis of endometriosis. Fertil Steril 106:1011-1017
 ACCEPTED MANUSCRIPT

90. Matsuzaki S, Canis M, Darcha C, Dechelotte P, Pouly JL, Bruhat MA 1999

Fibrogenesis in peritoneal endometriosis. A semi-quantitative analysis of type-I collagen.

Gynecol Obstet Invest 47:197-199

PT
91. Oosterlynck DJ, Meuleman C, Waer M, Koninckx PR 1994 Transforming growth

factor-beta activity is increased in peritoneal fluid from women with endometriosis.

RI
Obstet Gynecol 83:287-292

SC
92. Thiery JP 2002 Epithelial-mesenchymal transitions in tumour progression. Nat Rev

Cancer 2:442-454

U
AN
93. Yang YM, Yang WX 2017 Epithelial-to-mesenchymal transition in the development of

endometriosis. Oncotarget %20;8:41679-41689

M

94. Yu J, Berga SL, Johnston-MacAnanny EB, Sidell N, Bagchi IC, Bagchi MK, et al.
D

2016 Endometrial stromal decidualization responds reversibly to hormone stimulation

TE

and withdrawal. Endocrinology 157:2432-2446

95. Vaskivuo TE, Stenback F, Tapanainen JS 2002 Apoptosis and apoptosis-related

EP

factors Bcl-2, Bax, tumor necrosis factor-alpha, and NF-kappaB in human endometrial

hyperplasia and carcinoma. Cancer 95:1463-1471

C
AC

96. Folkman J 1992 The role of angiogenesis in tumor growth. Semin Cancer Biol 3:65-71

97. Shifren JL, Tseng JF, Zaloudek CJ, Ryan IP, Meng YG, Ferrara N, et al. 1996

Ovarian steroid regulation of vascular endothelial growth factor in the human

 ACCEPTED MANUSCRIPT

endometrium: implications for angiogenesis during the menstrual cycle and in the

pathogenesis of endometriosis. J Clin Endocrinol Metab 81:3112-3118

98. McLaren J, Prentice A, Charnock-Jones DS, Millican SA, Muller KH, Sharkey AM,

PT
et al. 1996 Vascular endothelial growth factor is produced by peritoneal fluid

macrophages in endometriosis and is regulated by ovarian steroids. J Clin Invest 98:482-

RI
489

SC
99. Donnez J, Smoes P, Gillerot S, Casanas-Roux F, Nisolle M 1998 Vascular endothelial

growth factor (VEGF) in endometriosis. Hum Reprod 13:1686-1690

U
AN
100. Lebovic DI, Bentzien F, Chao VA, Garrett EN, Meng YG, Taylor RN 2000 Induction

of an angiogenic phenotype in endometriotic stromal cell cultures by interleukin-1beta.

M

Mol Hum Reprod 6:269-275

D

101. Knudson AG, Jr. 1977 Genetics and etiology of human cancer. Adv Hum Genet 8:1-
TE

66.:1-66

102. Hansen TM, Moss AJ, Brindle NP 2008 Vascular endothelial growth factor and
EP

angiopoietins in neurovascular regeneration and protection following stroke. Curr

Neurovasc Res 5:236-245

C
AC

103. Browne AS, Yu J, Huang RP, Francisco AM, Sidell N, Taylor RN 2012 Proteomic

identification of neurotrophins in the eutopic endometrium of women with endometriosis.

Fertil Steril 98:713-719

 ACCEPTED MANUSCRIPT

104. Barcena de Arellano ML, Arnold J, Lang H, Vercellino GF, Chiantera V, Schneider

A, et al. 2013 Evidence of neurotrophic events due to peritoneal endometriotic lesions.

Cytokine 62:253-261

PT
105. Hey-Cunningham AJ, Markham R, Fraser IS, Berbic M 2013 Dysregulation of

vascular endothelial growth factors and their neuropilin receptors in the eutopic

RI
endometrium of women with endometriosis. Reprod Sci 20:1382-1389

SC
106. Ryan IP, Schriock ED, Taylor RN 1994 Isolation, characterization, and comparison of

human endometrial and endometriosis cells in vitro. J Clin Endocrinol Metab 78:642-649

U
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
TE
EP
C
AC