Pathogenesis and pathophysiology

of endometriosis
Richard O. Burney, M.D., M.Sc.,a and Linda C. Giudice, M.D., Ph.D.b
a
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Madigan Healthcare
System, Tacoma, Washington; and b Department of Obstetrics, Gynecology and Reproductive Sciences, University of
California, San Francisco, California

Originally described over three hundred years ago, endometriosis is classically dened by the presence of endometrial glands and stroma
in extrauterine locations. Endometriosis is an inammatory, estrogen-dependent condition associated with pelvic pain and infertility.
This work reviews the disease process from theories regarding origin to the molecular basis for disease sequelae. A thorough understand-
ing of the histopathogenesis and pathophysiology of endometriosis is essential to the develop-
ment of novel diagnostic and treatment approaches for this debilitating condition. (Fertil Steril Use your smartphone
2012;98:5119. 2012 by American Society for Reproductive Medicine.) to scan this QR code
Key Words: Endometriosis, pathogenesis, pathophysiology, lesion biology and connect to the
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E
ndometriosis is classically de- United States, with total annual socie- the disparate observations regarding
ned as the presence of endome- tal costs estimated at $69.4 billion in pathogenesis, and these can generally
trial glands and stroma in 2009 (5). The signicant individual be categorized as those proposing that
ectopic locations, primarily the pelvic and public health concerns associated implants originate from uterine endo-
peritoneum, ovaries, and rectovaginal with endometriosis underscore the im- metrium and those proposing that im-
septum. Affecting 6%10% of women portance of understanding its patho- plants arise from tissues other than
of reproductive age, the stigmata of en- genesis and pathophysiology toward the uterus. Intrinsic to these theories
dometriosis include dysmenorrhea, prevention and the development of are inciting factors and genetic suscep-
dyspareunia, chronic pelvic pain, irreg- sensitive nonsurgical diagnostic assays tibilities whose roles are beginning to
ular uterine bleeding, and/or infertility and effective treatments. The past sev- be delineated, although they are insuf-
(1). The prevalence of this condition in eral decades have witnessed substantial ciently established to conrm cause
women experiencing pain, infertility, progress toward unraveling the enigma and effect and subsequent development
or both is as high as 35%50% (2). associated with this disorder. Herein we of endometriosis. For example, reports
Yet endometriosis is underdiagnosed outline the current understanding of linking endocrine disrupting chemicals
and associated with a 6.7-year mean la- the pathogenesis and pathophysiology (EDCs) with endometriosis (6) suggest
tency from onset of symptoms to den- of endometriosis. these, and endogenous/exogenous
itive diagnosis (3), in part owing to the estrogens, as potential transforming/
requirement for surgical diagnosis. En- inductive/stimulant candidates in the-
dometriosis is a debilitating condition, HISTOPATHOGENESIS ories of endometriosis pathogenesis.
posing signicant quality-of-life issues A unifying theory regarding the origin The developmental timing of action of
for the individual patient (4). The disor- of endometriosis has remained mysti- such agents and their roles in inuenc-
der represents a major cause of hyster- fyingly elusive. Instead, several theo- ing other systems that predispose to
ectomy and hospitalization in the ries (Fig. 1) have arisen to account for endometriosis (endocrine, immune,
stem/progenitor cells, epigenetic modi-
Received June 4, 2012; revised and accepted June 19, 2012; published online July 20, 2012.
R.O.B. has nothing to disclose. L.C.G. has nothing to disclose. cations) must be considered in the
Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human context of genetic background as well
Development/National Institutes of Health (NICHD/NIH) through cooperative agreement
U54HD055764-06 as part of the Specialized Cooperative Centers Program in Reproduction and
as stimulus-driven reprogramming of
Infertility Research (L.C.G.). the female reproductive tract (7).
Reprint requests: Linda C. Giudice, M.D., Ph.D., Department of Obstetrics, Gynecology and Reproduc- Among theories proposing a nonu-
tive Sciences, University of California, San Francisco, California 94143-0138 (E-mail: giudice@
obgyn.ucsf.edu). terine origin of disease, coelomic meta-
plasia involves the transformation of
Fertility and Sterility Vol. 98, No. 3, September 2012 0015-0282/$36.00
Copyright 2012 American Society for Reproductive Medicine, Published by Elsevier Inc.
normal peritoneal tissue to ectopic en-
http://dx.doi.org/10.1016/j.fertnstert.2012.06.029 dometrial tissue (8). Agents responsible

VOL. 98 NO. 3 / SEPTEMBER 2012 511

VIEWS AND REVIEWS

FIGURE 1

Theories regarding endometriosis pathogenesis.

Burney. Pathogenesis and pathophysiology of endometriosis. Fertil Steril 2012.

for such transformation remain poorly dened, although a baboon model of induced endometriosis (18) and in 6%
EDCs may be candidates. The closely related induction theory 7% of women at lymphadenectomy (19). The strongest
holds that an endogenous inductive stimulus, such as a hor- evidence for the theory of benign metastasis is derived from
monal or immunologic factor, promotes the differentiation reports of histologically proven endometriotic lesions
of cells in the peritoneal lining to endometrial cells (9, 10). occurring in sites distant from the uterus, including bone,
Finally, the theory of embryonic M ullerian rests, or lung, and brain (20).
m ullerianosis, purports that cells residual from embryologic Initially proposed by Sampson in the 1920s, the theory of
M ullerian duct migration maintain the capacity to develop retrograde menstruation is both intuitively attractive and
into endometriotic lesions under the inuence of estrogen supported by multiple lines of scientic evidence (21). Ac-
beginning at puberty (11) or perhaps in response to estrogen cording to this theory, eutopic endometrium is sloughed via
mimetics. These theories nd support in epidemiological patent fallopian tubes into the peritoneal cavity during men-
studies reporting a twofold increased risk of endometriosis struation. Indeed, the universality of this phenomenon is sup-
in women exposed to diethylstilbestrol in utero (12). ported by the nding of menstrual blood in the peritoneal
A more recent proposal suggests that extrauterine stem/ uid of up to 90% of healthy women with patent fallopian
progenitor cells originating from bone marrow may differen- tubes undergoing laparoscopy during the perimenstrual
tiate into endometriotic tissue (13). Candidate cell lineages in- time of the cycle (22).
clude bone marrow mesenchymal stem progenitors and Further support for this etiology is derived from studies of
endothelial progenitors, and this represents an active area of obstructed or compromised outow tracts. In adolescent girls
investigation. Support for theories advocating a nonendome- with congenital outow obstruction, the prevalence of endo-
trial origin for endometriosis is derived from clinical accounts metriosis is high (23). Likewise, iatrogenic obstruction of the
of histologically conrmed endometriotic tissue in patients outow tract in a nonhuman primate model results in endo-
without menstrual endometrium, such as individuals with metriotic lesions within the peritoneal cavity (24). Even subtle
Rokitansky-Kuster-Hauser syndrome (14) and men with pros- compromise of antegrade menstruation may predispose to en-
tate cancer undergoing high-dose estrogen treatment (15). dometriosis, as evidenced by the higher prevalence of endo-
The theory of benign metastasis holds that ectopic endo- metriosis in women with a uterine septum (25) and cervical
metrial implants are the result of lymphatic or hematogenous stenosis (26). The anatomic distribution of endometriotic le-
dissemination of endometrial cells (16, 17). Microvascular sions also favors the retrograde menstruation theory. Super-
studies demonstrated ow of lymph from the uterine body cial implants are more often located in the posterior
into the ovary, rendering possible a role for the lymphatic compartment of the pelvis (27) and in the left hemipelvis
system in the etiology of ovarian endometriosis. (28). The propensity for lesions to implant in the posterior
Endometriosis within lymph nodes has been documented in cul de sac is explained by the accumulation of regurgitated

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 Fertility and Sterility

menstrual efuent in this most dependent portion of the peri- 6 times higher than that for relatives of unaffected women
toneal cavity under the inuence of gravity. In allowing ow (33). Studies of monozygotic twins demonstrate high concor-
from the anterior to posterior compartment in the upright or dance rates for histologically conrmed endometriosis (34).
supine position, a retroverted uterine position is correlated Linkage analysis has elucidated candidate genes with biolog-
with the nding of endometriosis (29). By acting as an obsta- ical plausibility. The largest of these involved over 1,100 fam-
cle to the diffusion of menstrual efuent from the left fallo- ilies with two or more affected sib pairs, and established
pian tube, the sigmoid colon promotes stasis of this signicance for a susceptibility locus in the regions of chro-
efuent, thereby extending the interval for reuxed endome- mosome 10q26 and 7p15 (35, 36).
trial fragments to implant in the left hemipelvis. Acquired genomic alterations represent a potential source
A murine model of endometriosis has provided insight into for a conferred survival advantage to sloughed endometrial
the pathogenesis of peritoneal endometriosis (30). The condi- cells in the establishment of endometriotic implants. The endo-
tional activation of the K-ras oncogene in endometrial cells de- metrium is a setting of extraordinary cell turnover and, conse-
posited into the peritoneum resulted in histologically quently, is vulnerable to errors of genetic recombination. The
conrmed peritoneal endometriotic implants in nearly 50% occurrence of genomic alteration in eutopic endometrium is
of mice within 8 months. On the other hand, similar activation well documented and may be consequent to epigenetic factors
of the K-ras oncogene in peritoneal cells showed no progression or oxidative stress (37). Loss of heterozygosity and somatic
to endometriosis. These preclinical observations favor an endo- mutation of the tumor suppressor gene PTEN has been docu-
metrial origin of the development of peritoneal lesions. mented in 56% and 21% of solitary endometrial cysts of the
Although retrograde menstruation explains the physical ovary, respectively (38). Genomic alterations within endo-
displacement of endometrial fragments into the peritoneal metriotic implants have been described using comparative ge-
cavity, additional steps are necessary for the development nomic hybridization (CGH) microarrays (39). Interestingly, the
of endometriotic implants. Escape from immune clearance, CGH proles (chromosome loss or gain) clustered by anatomic
attachment to peritoneal epithelium, invasion of the epithe- location of the implant as peritoneal or ovarian.
lium, establishment of local neurovascularity, and continued Finally, increasing evidence supports epigenetic regula-
growth and survival are necessary if endometriosis is to de- tion of steroid hormone action in the endometrium (40) and
velop from retrograde passage of endometrium. Collectively, dysregulation in women with endometriosis (41). In particu-
investigations involving the pathophysiology of endometri- lar, aberrant DNA methylation of promoters of genes whose
osis have revealed several well supported molecular hallmarks products are critical for normal endometrial P response
of this disease: genetic predisposition, estrogen dependence, P have been reported in endometriosis and animal models of
resistance, and inammation. the disease, with resulting P resistance (42). MicroRNAs (miR-
It is the propensity for implantation that best accounts NAs) are short noncoding RNAs that generally repress gene
for the discrepancy between the 90% prevalence of retro- expression through mRNA degradation. Differential and
grade menstruation and the nearly 10% prevalence of the ovarian steroid-dependent expression of miRNAs in eutopic
disease. Hereditary or acquired properties of the endome- endometrium from women with and without endometriosis
trium, hereditary or acquired defects of the peritoneal epi- has been demonstrated (43).
thelium, and/or defective immune clearance of sloughed The search for an innate or acquired survival advantage
endometrium are areas of active investigation in the search of eutopic endometrium toward ectopic implantation has fu-
for the factor or factors that inuence a predisposition to- eled a number of studies comparing eutopic endometrium
ward implantation of the displaced endometrial cellsa nec- from women with and without endometriosis. Collectively,
essary correlate to theories proposing an endometrial origin these studies reveal striking differences in gene and protein
to disease pathogenesis. expression that may predispose to disease development, and
these have been nicely synopsized recently (44). A partial
list of promising candidates is provided in Table 1. Validation
ENDOMETRIAL CELL SURVIVAL of these genes/proteins requires temporally controlled exper-
The evidence for an innate or acquired condition of the endo- iments that can only be conducted using preclinical models
metrial cells as the predisposing factor toward implantation is such as the nonhuman primate, the only other species docu-
compelling. The eutopic endometrium from women with en- mented to spontaneously develop endometriosis (45).
dometriosis shares certain alterations with ectopic lesions that
are not observed in the endometrium from healthy women.
Up-regulation of the antiapoptotic gene BCL-2 has been ALTERED HORMONAL MILIEU: ESTROGEN
shown in both eutopic and ectopic endometrium from af- DEPENDENCE AND P RESISTANCE
fected women (31). In addition to decreased apoptosis, en- Hormonal alterations may inuence the ability of endome-
hanced proliferation may confer a selective survival trial cells to proliferate, attach to the mesothelium, and/or
advantage to the endometrium of women predisposed to en- evade immune-mediated clearance. Long appreciated clini-
dometriosis (32). cally, the concept of endometriosis as an estrogen-
A genetic alteration of the endometrial cells inuencing dependent disorder is well supported by molecular evidence
their tendency to implant may be hereditary, as a heritable (46). A striking nding in endometriotic tissue relative to eu-
component to the disease has been established. The risk for topic endometrium is the increased expression of the aroma-
rst-degree relatives of women with severe endometriosis is tase enzyme and decreased expression of 17b-hydroxysteroid

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endometriosis may further contribute to decreased clearance

TABLE 1
of lesions by this cell type.
Candidate factors implicated in the pathophysiology of
Further support for a fundamentally altered immune sys-
endometriosis. tem in the predisposition to endometriosis is derived from
studies demonstrating a high concordance of autoimmune
Gene Function Reference
(systemic lupus erythematosus, rheumatoid arthritis, Sjog-
17b-HSD-2 Hydroxysteroid dehydrogenase (47) ren's syndrome, autoimmune thyroid disease) and atopic dis-
BCL-2 Antiapoptosis (31)
CYP19 Aromatase enzyme (102)
ease (allergies, asthma, and eczema) in affected women (56). A
HOXA10 Transcription factor (103) number of non-organ-specic antibodies have been found in
IL-6 Cytokine (82) association with endometriosis (57). Several studies have
KRAS Oncogene (30) demonstrated clustering of autoimmune thyroid disease
MMP 3,7 Matrix metalloproteinases (65)
NF-KB Transcription factor (104) with endometriosis-associated infertility, as evidenced by
PGE2 Prostaglandin (105) a high prevalence of thyroid peroxidase antibodies in this co-
PTEN Tumor suppressor gene (30) hort of women (58, 59).
TGF-B Cytokine (61)
TNF-a Cytokine (81)
Burney. Pathogenesis and pathophysiology of endometriosis. Fertil Steril 2012.
ENDOMETRIAL CELL ATTACHMENT AND
INVASION
dehydrogenase (17b-HSD) type 2 (47). The sum consequence Although endometriosis is a benign disorder, the process by
of this differential expression prole is a marked increase in which endometrial cells attach and invade surfaces shares
the locally bioavailable E2 concentration. E2 stimulates the features of malignancy. The ESC fraction is primarily in-
production of prostaglandin E2, (PGE2) which further stimu- volved in the interaction of endometrial tissue with the meso-
lates aromatase activity (48). These ndings support the ca- thelial cell lining of the peritoneum. A study using ESCs and
pacity of endometriotic lesions for E2 biosynthesis and peritoneal mesothelial cells from a variety of sources in an in-
substantiate treatments aimed at promoting a hypoestrogenic vitro binding assay demonstrated that the source of the ESCs
peritoneal microenvironment. rather than the source of the peritoneal cells had the greatest
In addition to estrogen dependence, there is increasing impact on the rate of implantation (60).
evidence to support a prole of P resistance in the pathophys- A heritable or acquired condition of the peritoneum may
iology of endometriosis (49). Endometriotic lesions exhibit an predispose to the attachment and transmesothelial invasion
overall reduction in P receptor expression relative to eutopic by reuxed endometrial cells. An intact mesothelium is likely
endometrium and an absence of P receptor-B (50). Addition- to act as a protective barrier against the implantation of regur-
ally, endometrial expression proling has documented dysre- gitated endometrial tissue. Indeed, in vitro studies have shown
gulation of P-responsive genes in the luteal phase (51). An that endometrial fragments adhered to the peritoneum only at
incomplete transition of endometrium from the proliferative locations where the basement membrane or extracellular ma-
to secretory phase has signicant molecular implications to- trix was exposed owing to mesothelial layer damage (58).
ward enhancing the survival and implantation of reuxed Menstrual efuent has a harmful effect on the mesothelium
endometrium. and may autologously induce the local injury that promotes
the implantation of endometrial cells (59). However, the exact
factors involved in mediating mesothelial damage are un-
EVASION FROM IMMUNE CLEARANCE known. Gene expression proling of the peritoneum from
Normally, reuxed endometrial tissue is cleared from the subjects with and without endometriosis demonstrated up-
peritoneum by the immune system, and the dysregulation regulation of matrix metalloproteinase (MMP) -3 during the
of this clearance mechanism has been implicated in the pre- luteal phase and up-regulation of ICAM-1, transforming
disposition to implantation and growth of endometrial cells. growth factor-beta (TGF-b), and interleukin-6 (IL-6) during
Interestingly, larger tissue fragments as opposed to individual the menstrual phase (60). The differential expression of these
cells demonstrate an increased capacity to implant, presum- cytokines and growth factors may create a microenvironment
ably owing to the protection from immune clearance afforded that encourages implantation of endometrial cells or protects
the cells residing on the inner aspects of such fragments (52). them from immune-mediated clearance. Among the cytokines
Additionally, the eutopic endometrium from women with en- that are elevated in the peritoneal uid of women with endo-
dometriosis was found to be more resistant to lysis by natural metriosis (61), TGF-b was observed to induce endometrial cell
killer (NK) cells than the eutopic endometrium from women invasion in an in vitro model of the peritoneum (62).
without disease (53). Subsequent studies identied the consti- MMPs and their inhibitors (tissue inhibitors of metallo-
tutive shedding of intercellular adhesion molecule-1 (ICAM- proteinases [TIMPs]) are involved in extracellular matrix re-
1) by endometrial stromal cells (ESCs) from women with modeling and have been implicated in cyclic endometrial
endometriosis as the potential mechanism by which these turnover and menstruation (63, 64). Menstrual cycle phase
cells escape NK cellmediated clearance (54, 55). Impaired specic expression of MMPs suggests ovarian steroid
NK cell function may confer an immune-privileged status regulation. The balance between MMPs and TIMPs is critical
on the reuxed endometrial cells, thereby predisposing to dis- in maintaining the appropriate level of MMP activity, and
ease. Compromised macrophage function in women with failure to maintain this balance may contribute to matrix

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 Fertility and Sterility

breakdown and cellular invasion. Endometrial MMP-7 ex- endometriosis, and the level appears to correlate with stage
pression is normally suppressed by P during the secretory of disease (69). VEGF is abundantly expressed in the glandu-
phase, yet endometriotic lesions exhibit persistent expression lar compartment of peritoneal implants, in endometriomas,
of MMP-7 during this phase (64). In a compelling illustration and is secreted by activated peritoneal macrophages (70).
of intrinsic P resistance in the pathophysiology of endometri- The expression of VEGF exhibits a cycle phase dependence
osis, the in vitro treatment of eutopic endometrium acquired consistent with ovarian steroid regulation. Evidence for
from affected women with P failed to fully suppress pro- VEGF as the prominent angiogenic factor is compelling. Other
MMP-7 secretion and failed to prevent the ability of the trans- angiogenic factors implicated in disease pathophysiology in-
planted endometrium to establish experimental disease in clude angiogenin (71), platelet-derived endothelial growth
mice (65). factor (72), and macrophage migration inhibitory factor (73).
Growth factors may play a fundamental role in stimulat-
LESIONAL NEUROANGIOGENESIS/ ing ectopic endometrial growth and differentiation. Hepato-
cyte growth factor is a mitogen and morphogen for
VASCULOGENESIS AND GROWTH
endometrial epithelial cells when cocultured with stromal
A rich vascular supply is necessary for the development and cells and may play a role in the regeneration of endometrial
sustenance of endometriotic lesions, particularly in the peri- glands in ectopic locations (74). Epidermal growth factor
toneal microenvironment, which is relatively avascular com- (EGF) (75), insulin-like growth factors (IGF) (76), platelet-
pared with the eutopic endometrium. Neoangiogenesis and derived growth factor (77), and basic broblast growth factor
capillary recruitment are visibly associated with endometri- (75) are potent mitogens for endometrial stromal cells in vitro.
otic lesions at laparoscopy, most notably in the context of IGF-1 is an antiapoptotic growth factor and may enhance cell
the red vesicular phenotype (Fig. 2). In addition, nerves fre- survival. EGF and IGF mediate estrogen actions in many tis-
quently accompany angiogenesis (neuroangiogensis), likely sues and thus are potential participants in the pathophysiol-
contributing to the pain associated with this disorder (66). ogy of endometriosis.
Gene expression proling of menstrual phase endometrium
in women with endometriosis demonstrated up-regulation
of tumor necrosis factor-a (TNF-a), IL-8, and MMP-3 (68). INFLAMMATION
As IL-8 and TNF-a promote proliferation and adhesion of en- Increasing evidence supports the conceptualization of endo-
dometrial cells and angiogenesis, an overabundance of these metriosis as a pelvic inammatory condition. In women
cytokines may facilitate growth and local neovascularization. with endometriosis, the peritoneal uid is remarkable for an
In addition, neovasculogenesis of lesions involving endothe- increased number of activated macrophages and important
lial progenitor cells either from endometrium, bone marrow, differences in the cytokine/chemokine prole (78). A proteo-
or the circulation is believed to contribute to the hypervascu- mics approach identied a unique protein structurally similar
larized phenotype of endometriosis lesions (67). Vascular en- to haptoglobin in the peritoneal uid of patients with endo-
dothelial growth factor (VEGF) has been consistently detected metriosis (79). This protein was subsequently found to bind
in high concentrations in peritoneal uid from women with to macrophages, reduce their phagocytic capacity, and in-
crease their production of IL-6. Other cytokines or chemo-
kines found to be increased in the peritoneal uid of
FIGURE 2 patients with endometriosis include macrophage migration
inhibitory factor (80), TNF-a (81), IL-1b, IL-6 (82), IL-8, reg-
ulated on activation normal T expressed and secreted

FIGURE 3

Local E2 production in endometriotic lesions and eutopic

endometrium, inammation, and pain. 17b-HSD 17b-
Red vesicular lesions with focal hemorrhage observed on the posterior hydroxysteroid dehydrogenase; E1 estrone; E2 estradiol; PGE2
aspect of the broad ligament. Note prominent focal vascularity in prostaglandin E2; PGF2a prostaglandin F2a; NGF nerve
immediate vicinity of lesions. growth factor.
Burney. Pathogenesis and pathophysiology of endometriosis. Fertil Steril 2012. Burney. Pathogenesis and pathophysiology of endometriosis. Fertil Steril 2012.

VOL. 98 NO. 3 / SEPTEMBER 2012 515

VIEWS AND REVIEWS

FIGURE 4

Phenotypic subtypes of peritoneal endometriosis. (A) Red vesicular lesion. (B) Powder-burn lesion. (C) Fibrotic lesion. (D) Allen-Masters peritoneal
defect.
Burney. Pathogenesis and pathophysiology of endometriosis. Fertil Steril 2012.

(RANTES), and monocyte chemotactic protein-1 (83). The PGE2, which activates steroidogenic acute regulatory protein
latter three are chemoattractants, which facilitate the recruit- and aromatase (86). By up-regulating PGE2 synthesis, estro-
ment of macrophages. Whether observed cytokine proles are gen completes a positive feedback loop that promotes the in-
a cause or a consequence of endometriosis remains to be creased local bioavailability of E2 (87). This pathway
denitively determined. The nonhuman primate model of highlights the interplay of estrogen dependence and inam-
endometriosis may allow the dissection of the temporal mation in endometriosis.
relationship between lesional development and cytokine Inammation is not only present in the peritoneal micro-
proles. environment but also in the eutopic endometrium of women
The peritoneal microenvironment in the setting of endo- with endometriosis. As P has well described anti-
metriosis is notably rich in prostaglandins, and these media- inammatory properties, these changes may reect attenu-
tors likely play a central role in disease pathophysiology as ated P action at the level of the endometrium. An increase
well as clinical sequelae of pain and infertility. Peritoneal in macrophage numbers is present in women with endometri-
macrophages from women with endometriosis express higher osis throughout the menstrual cycle (88). Compared with
levels of cyclo-oxygenase-2 (COX-2) and release signicantly disease-free controls, eutopic endometrium from women
higher amounts of prostaglandins than macrophages from with endometriosis showed an increased basal production of
healthy women (84). At the lesional level, TNF-a promotes IL-6 (89). IL-6 plays a prominent role in many chronic inam-
endometrial cell production of prostaglandin F2a and PGE2 matory conditions and is secreted by macrophages as well as
(85). IL-1b activation of COX-2 increases production of epithelial endometrial cells. Interestingly, IL-6 was shown to

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signicantly stimulate aromatase expression in cultured en- ance are systems of interest in elucidating the establishment
dometriotic stromal cells (90). of endometriotic implants. Disease heterogeneity, particularly
The inammatory environment within the pelvis may in lesional phenotype, requires adherence to histopathologic
contribute to the pathophysiology of pain perception in conrmation of implants in clinical and molecular research.
symptomatic women with endometriosis. Figure 3 summa- The underpinnings for the observed hallmarks of inamma-
rizes the roles of E2 (local and systemic), growth factors, pros- tion, estrogen dependence, and P resistance in the pathophys-
taglandins, and other inammatory stimuli in the iology of endometriosis-associated pain and infertility are
pathogenesis of pain. It is believed that nerve bers in endo- areas of active research. With further advances in our under-
metriosis implants inuence dorsal root neurons within the standing of endometriosis, preventive strategies, novel non-
central nervous system, increasing pain perception in patients surgical diagnostic modalities, and targeted therapeutics
(66). The pathophysiology of pain has recently been exten- hold great promise of becoming realities.
sively reviewed (91).

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