Bruner Tran - 2013 - Medical Management of Endometriosis - Emerging Evidence Linking Inflammation To Disease Pathophysiology

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Minerva Ginecol. Author manuscript; available in PMC 2014 April 01.
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Minerva Ginecol. 2013 April ; 65(2): 199–213.
Medical Management of Endometriosis: Emerging Evidence

Linking Inflammation to Disease Pathophysiology
Kaylon L. Bruner-Tran1, Jennifer L. Herington1,*, Antoni J. Duleba2, Hugh S. Taylor3, and
Kevin G. Osteen1
1Women's Reproductive Health Research Center, Department of Obstetrics and Gynecology,
Vanderbilt University School of Medicine, Nashville, TN USA 37232

2Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology,
University of California Davis, Sacramento, California USA 95817
3Department of Obstetrics and Gynecology and Reproductive Sciences, Yale University School of
Medicine, New Haven, CT USA 06510
Abstract
Progesterone action normally mediates the balance between anti-inflammatory and pro-
inflammatory processes throughout the female reproductive tract. However, in women with
endometriosis, endometrial progesterone resistance, characterized by alterations in progesterone
responsive gene and protein expression, is now considered a central element in disease
pathophysiology. Recent studies additionally suggest that the peritoneal microenvironment of
endometriosis patients exhibits altered physiological characteristics that may further promote
inflammation-driven disease development and progression. Within this review, we summarize our
current understanding of the pathogenesis of endometriosis with an emphasis on the role that
inflammation plays in generating not only the progesterone-resistant eutopic endometrium but also
a peritoneal microenvironment that may contribute significantly to disease establishment. Viewing
endometriosis from the emerging perspective that a progesterone resistant endometrium and an
immunologically compromised peritoneal microenvironment are biologically linked risk factors
for disease development provides a novel mechanistic framework to identify new therapeutic
targets for appropriate medical management.
Keywords
Endometriosis; inflammation; progesterone resistance
INTRODUCTION
Endometriosis, clinically defined as the growth of endometrial glands and stroma outside the
uterus, is a common gynecologic condition affecting millions of women worldwide. Despite
having been recognized within the medical literature for more than 100 years, the disease
remains a poorly understood condition affecting approximately 5–10% of all reproductive-
age women1. Endometriosis can be debilitating, with many patients experiencing severe
Send correspondence to: Kevin G. Osteen, PhD., Women's Reproductive Health Research Center, Department of Obstetrics and
Gynecology, Vanderbilt University School of Medicine, 1161 21st Ave S MCN B-1100, Nashville, TN 37232, Tel: 615-322-4196,
Fax: 615-343-7913, kevin.osteen@vanderbilt.edu.
*Current address: Department of Pediatrics/Neonatology, Vanderbilt University School of Medicine, Nashville, TN
The authors have nothing to disclose.
Bruner-Tran et al. Page 2
pelvic pain in addition to reduced fertility. Presently, clinical identification of endometriosis

requires laparoscopic surgery and microscopic analysis of excised tissues, likely
contributing to the near decade-long delay between onset of symptoms and accurate
diagnosis2.
Recognizing that the development of endometriosis is limited to menstruating species, Dr.

John Sampson proposed that peritoneal deposition of displaced menstrual tissue was the
primary cause of this disease3; however, retrograde tissue flow is only a mechanical process
occurring in most reproductive-age women, the majority of whom do not develop
endometriosis4. Thus, alternative hypotheses regarding the etiology of this disease have been
proposed, including the coelomic metaplasia theory and the development of disease
following activation of embryonic cell rests5. More recently, it has been suggested that adult
stem cells, which play a role in the recurrent process of endometrial self-renewal, may also
contribute to the pathogenesis of ectopic sites of endometrial growth6. Finally, given the
frequent occurrence of endometriosis in first-degree relatives, it is likely that a genetic
predisposition and/or environmental factors may also influence the development of this
disease7. Specifically, environmental toxicants capable of inducing epigenetic modifications
during development have been suggested to negatively impact the relationship of the
endocrine and immune systems within the adult reproductive tract8–10.
Although it is likely that numerous converging factors ultimately determine a woman's

individual risk for developing endometriosis, physicians and scientists generally accept
Sampson's theory of retrograde menstruation as a common contributing mechanism to the
development of ectopic endometrial growth. Nevertheless, since most cycling women
exhibit retrograde menstruation, alterations in key biological processes must additionally be
present that allow displaced endometrial tissue to successfully attach and survive ectopically
in only a subset of women. In this regard, recent research suggests that the reduced response
to progesterone noted in the eutopic endometrium of endometriosis patients5, 11–13,
combined with the altered nature of immune cells and their proinflammatory products within
the peritoneal fluid14–16, may collectively promote the successful establishment of ectopic
disease. Therefore, in this review we discuss the potential cooperative relationship of the
progesterone resistant endometrial phenotype and a pro-inflammatory peritoneal
microenvironment in the establishment and progression of this disease. Additionally, we
describe how viewing endometriosis as a complex inflammatory disease may provide insight
into the design of better strategies for targeted medical management.
The Unique Physiology of the Human Endometrium

The human endometrium is distinct among adult organs, undergoing steroid-driven cycles of
development-like tissue growth and differentiation in preparation for pregnancy, followed
by tissue breakdown and bleeding in the absence of nidation. Clearly, in order to

successfully initiate ectopic survival and growth, viable cells within fragments of retrograde
menstrual tissue must evade peritoneal immune surveillance, avoid post-differentiation
apoptotic processes, attach and invade the peritoneal mesothelium and subsequently
establish a vascular supply. To this end, the maturational state of various endometrial cell
types residing at the interface between the retained basalis region versus the post-mature,
shedding functionalis region can be quite different; thus shedding of tissues from the
regenerative basalis would likely contribute to a menstrual effluent with the capacity to
survive ectopically. Equally relevant, more than a decade ago, scientific reports began to
suggest that certain phenotypic properties of the functionalis region of the eutopic
endometrium differ between women with and without endometriosis (for example,5, 8, 17,
potentially providing the former tissue a survival advantage within the peritoneum.
Therefore, to design better medical and surgical therapies for the treatment of endometriosis
we must clarify the phenotypic characteristics of refluxed endometrial cells and how these

characteristics affect the interface of endometrial cells with both immune and somatic cells
within the peritoneal micro-environment.
At this juncture, it is not known whether the phenotype of individual cells within the menses
of certain patients contributes to the development of endometriosis via differential
expression of specific bioactive agents. Prior to menstruation, the behavior of each
individual cell type within the eutopic endometrium is influenced directly or indirectly by
their sequential exposure to the ovarian steroids estrogen and progesterone18–20.
Specifically, at the end of each nongravid menstrual cycle, the declining anti-inflammatory
effects of progesterone leads to activation of resident immune cells and affects the
recruitment of non-resident immune cells; together these cells create a heightened state of
inflammation involving the release of multiple cytokines and chemokines that set the
biological stage for endometrial breakdown20–21. Thus, the cyclic loss of endometrial tissue
occurs at menstruation as a consequence of inflammation-driven expression and activation
of proteolytic enzymes, including members of the matrix metalloproteinase (MMP)
family22. Multiple members of the MMP family are expressed in a cell-specific pattern and
these enzymes are critical for normal endometrial tissue remodeling across the cycle, with
the highest levels of MMP expression associated with tissue breakdown at menstruation22.
Importantly, menstruation represents a controlled inflammatory event and members of the
MMP family are intimately involved in mediating various aspects of tissue inflammation in
a manner that is independent of extracellular matrix (ECM) degradation within somatic
tissues. Indeed, our emerging understanding of the MMP system in regulating active tissue
inflammation has led some investigators to consider this family of enzymes to be key
components of the overall innate immune system23–24.
The ability of progesterone to largely suppress the MMP system within the endometrium is
critical to controlling proinflammatory cytokine activation of these enzymes as immune cells
migrate to the human uterus during the secretory phase of the menstrual cycle, in preparation
for pregnancy10, 22, 25. Reflecting the importance of progesterone action, in the absence of
nidation, the highest levels of expression and activation of MMPs occurs as the anti-
inflammatory action of this steroid is lost, resulting in menstruation22. Following each
episode of endometrial breakdown, inflammation-related MMP expression persists under the
influence of estrogen and focal expression of these enzymes mediates ECM remodeling
during the proliferative phase, as endometrial repair and re-growth of the functionalis
occurs. After a variable period of focal MMP expression related to estrogen-mediated
reconstruction of the glandular architecture of the functionalis region, progesterone rapidly
acts to stabilize the endometrium by limiting MMP expression during the invasive
establishment of pregnancy. Although menstruation and implantation are each inflammatory
processes, MMP expression during pregnancy establishment must be tightly regulated in
order to preserve endometrial integrity22. In contrast to healthy women, the elevated

endometrial MMP expression noted during the time of secretory maturation in tissues
acquired from women with endometriosis12, 26 strongly suggests a disease-related failure of
progesterone to appropriately regulate the cross-talk between the endometrial endocrine and
immune systems.
The Progesterone Resistant Endometriosis Phenotype

The ability of progesterone to balance the endocrine/immune physiology of the eutopic
endometrium is a critical component of the function of the entire female reproductive tract.
Among endometriosis patients, the specific failure of progesterone to act appropriately
during endometrial differentiation ultimately affects the phenotype of tissue shed at
menstruation, a key risk factor that affects not only the likelihood of successful ectopic
growth but progression of disease and development of its associated symptoms. For
example, initial studies comparing endometrial tissues from women with and without

endometriosis examined circulating progesterone levels relative to expected histological

responses across the secretory phase of the menstrual cycle27–29. These investigations
revealed that while women with endometriosis exhibit normal circulating ovarian
progesterone levels, the endometrium's ability to respond appropriately to this steroid

appeared to be reduced27–29. Subsequent studies confirmed that endometrial tissues from
women with endometriosis did not exhibit the changes in specific gene and protein
expression normally expected during the progesterone-dominated secretory phase12, 30–31.
Perhaps not surprisingly, altered expression of genes and proteins in endometriosis patients
was reported to be associated with changes in the expression pattern of progesterone
receptor (PR) isotypes (PR-A and PR-B), at both eutopic and ectopic sites of endometrial
growth11, 32–33.
At present, the biological origin of reduced endometrial progesterone responsiveness among

women with endometriosis remains to be fully elucidated; however, a number of research
groups have begun to examine whether chronic inflammatory processes may promote the
development of endometrial resistance to this steroid. Within the reproductive tract, an
important component of steroidal regulation of inflammation involves cellular signaling by
members of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB)
family. This signaling network has been suggested to play a critical role in triggering, or
enhancing, the inflammatory processes associated with the development and progression of
endometriosis34. The NF-kappaB family is best described as a protein complex that controls
DNA transcription, resulting in the regulation of a wide array of genes that collectively
mediate cellular processes such as cell proliferation, adhesion, apoptosis, angiogenesis and
immune responses35. Although NF-kappaB activity varies throughout the normal menstrual
cycle36, a mutual suppressive effect has been reported between NF-kappaB and
progesterone, suggesting that reduced PR protein expression in endometriosis patients would
lead to an increase in inflammation34. More specifically, at sites of ectopic endometrial
growth in women with endometriosis, continuous expression of pro-inflammatory cytokines
would promote NF-kappaB activation34; thereby mediating a loss of PR expression,
resulting in a failure to suppress NF kappaB action. Thus, constitutive activation of NF-
kappaB could contribute significantly to the development of the progesterone resistant
“endometriosis phenotype” and negatively influence multiple PR-dependent biological
processes involved in the pathogenesis of this disease.
Although the studies noted above support the concept that inflammatory processes may
represent a potential trigger for the loss of progesterone sensitivity related to endometriosis,
the precise cellular and molecular mechanisms leading to this disease phenotype remain
elusive. In this regard, a number of recent observations suggest that epigenetic modification,
mediated by chronic inflammation, could explain the progesterone resistant endometrial
phenotype observed in women with endometriosis. Specifically, several studies have

examined whether epigenetic modifications might affect the transcriptional regulation of the
PR isoforms PR-A and PR-B; nuclear isotypes that exhibit distinctly different effects on
uterine gene expression across the menstrual cycle. The truncated isoform, PR-A has been
associated with transcriptional inhibition of progesterone action while the ligand-bound PR-
B isoform promotes many of the unique anti-inflammatory effects of this steroid that
supports endometrial differentiation37. Therefore, epigenetic modifications leading to
alterations in PR isotype expression would likely negatively impact normal progesterone-
responsive gene expression and promote the development and progression of
endometriosis8, 18, 30. In vivo studies have clearly demonstrated a shift in the PR-A/PR-B
ratio at eutopic and ectopic sites of endometrial growth in tissues acquired from women with
endometriosis11, 32–33. Recent in vitro studies further suggest that reductions in PR-B
expression are linked to hypermethylation of the PR promoter and that partial methylation of
this gene could be induced by prolonged stimulation of cells with tumor necrosis factor

alpha (TNF-α)38–39. Alternatively, recent studies from the Mendelson laboratory suggest a
relationship between increased expression of the inhibitory PR-C isoform and the
heightened inflammatory response observed in women with endometriosis40. Clearly,
disease-related epigenetic modifications, specifically affecting expression levels of PR-A,

PR-B or PR-C would likely alter the anti-inflammatory actions of progesterone at both
eutopic and ectopic sites of endometrial growth.
The Basic Pathogenesis of Endometriosis

As discussed above, emerging evidence suggests that the pathogenesis of endometriosis is
related in part to a loss of progesterone's anti-inflammatory actions, a defect that not only
impacts the progression of ectopic disease but also affects the function of the eutopic
endometrium. Once inflammation-related patterns of cell-cell communication are
established the local proinflammatory microenvironment may further contribute to the
progesterone-resistant phenotype, creating a negative feedback loop that promotes disease
progression. In women with active endometriosis, reduced progesterone sensitivity within
the reproductive tract likely affects the progression of ectopic disease by impacting critical
elements of immune function within the peritoneal cavity, including: apoptosis, immune
surveillance, attachment/invasion and establishment of vasculature through angiogenesis
(Figure 1).
Disruption of Apoptosis—Apoptosis is an important mechanism by which autologous

cells are eliminated after death without eliciting an inflammatory response. Since apoptosis
plays a critical role in maintaining tissue homeostasis during periods of endometrial growth,
differentiation and at menstruation, the cycling human endometrium normally exhibits
variations in apoptotic activity. For example, endometrial expression of the B cell
lymphoma/leukemia-2 (BCL-2) gene, which suppresses apoptosis, is highest during the
maximum period of growth that occurs during the proliferative phase. In contrast, late
secretory phase endometrial tissue, under the influence of declining progesterone, exhibits
an increased expression of pro-apoptotic proteins41, a biological response that normally
promotes cell death and thus increases phagocytosis of sloughed menstrual tissue within the
peritoneal cavity. Therefore, apoptotic activity is normally lowest during periods of
endometrial proliferation and highest immediately prior to menstruation42, suggesting that
cell death acts to limit the likelihood of ectopic survival and growth. Importantly, the
activity of BCL-2 is opposed by BCL-2 associated X protein (BAX) and the resultant
apoptotic index within different regions of the endometrium can also vary during the
menstrual cycle related to the BCL-2/BAX ratio41. For example, in response to estradiol, the
human endometrium regenerates from the basalis region during each menstrual cycle;
therefore, as opposed to the cyclic regulation of BCL-2 and BAX within the endometrial
functionalis, the basalis exhibits continuous expression of BCL-2 and minimal apoptosis43.
Since cells arising from the basalis region, as opposed to the functionalis, avoid cell death
associated with terminal differentiation, it is logical to postulate that ectopic endometrial
growth could principally arise from tissue fragments shed from this compartment during
menstruation. Alternatively, the apoptotic indices have been found to be reduced within the
endometrial functionalis region of women with endometriosis compared to disease-free
women, primarily due to a decrease in apoptosis during the late secretory/menstrual and
early proliferative phases. For this reason, the endometrial functionalis of women with
endometriosis may exhibit basalis-like characteristics and thus be better able to survive
ectopically compared to tissues from disease-free women44–45. These reported differences in
the cyclic patterns of apoptosis-related proteins in the eutopic endometrium of women with
and without endometriosis suggest that alterations in progesterone-regulated apoptotic gene
expression may be part of the pathophysiology of this disease. Specifically, the progesterone

resistant endometrial phenotype of women with endometriosis would be expected to result

in a loss of progesterone mediated regulation of apoptotic proteins during endometrial
differentiation. Consistent with this theory, the number of non-apoptotic cells arising from
either the basalis or functionalis region and flowing into the peritoneal cavity during
retrograde menstruation appears to be greater in women with endometriosis46. Following
menstruation and the deposition of this tissue into the peritoneal cavity, these non-apoptotic
cells may further contribute to an altered innate immune response that allows displaced
menstrual tissues to avoid immunosurveillance.
Evading Immune Surveillance—Following menstruation, immune surveillance within

the peritoneal cavity by resident and migrating immune cells provides an important line of
defense against the development of endometriosis by removing displaced endometrial
tissues. Although alterations within the immune system of endometriosis patients has been
broadly noted by many investigators47, a lack of appropriate experimental models limits our
current understanding of the role of the innate immune system within the peritoneal
microenvironment related to a woman's risk for developing this disease. While prospective
human studies are not possible, we recently demonstrated in a humanized model of
experimental endometriosis that normal immune cell function within the peritoneal cavity
acts to limit the development of ectopic endometrial growth48. This finding suggests that
endometrial cells arising from the endometrium of women with endometriosis exhibit an
altered capacity to interact with peritoneal immune cells which promotes the establishment
of persistent sites of ectopic growth. In this regard, the inflammatory mediator,

prostaglandin E2 (PGE2), has been proposed as a master-regulator of endometriosis49, due
in part to the impact of this potent cytokine on macrophage behavior. PGE2 is abundant in
the peritoneal fluid of women with endometriosis and serves to inhibit MMP-9 activity as
well as the production of this enzyme by peritoneal macrophages50–51. Macrophages are the
major resident immune cell population within the peritoneal cavity which act to eliminate
apoptotic cells and debris, including endometrial tissues deposited via retrograde
menstruation. While the concentration of peritoneal macrophages has been shown to be
increased in patients with endometriosis compared to disease-free women4, their phagocytic
capacity and uptake of debris has been shown to be decreased due to a reduced expression
and activity of MMP-952 and a downregulation of the scavenger receptor, CD3650. Thus,
while defects in macrophage phagocytic behavior could be a critical factor in the initial
establishment of endometriosis, these cells continue to produce cytokines, growth factors
and potent angiogenic factors which may promote the ectopic growth of endometrial tissue
fragments that survive phagocytosis53. Supporting this possibility, investigators using an
experimental mouse model of endometriosis observed that the peritoneal environment can
dramatically influence the differentiation of macrophage precursors towards alternatively
activated mature macrophages, cells that can impact the vascularization and growth of
ectopic lesions54.
Defects in multiple cell types within the innate immune system, including natural killer
(NK) cells, may also affect the clearance of endometrial tissue within the peritoneal cavity
of endometriosis patients. Although there are conflicting reports on whether or not the
number of peritoneal NK cells is altered in women with endometriosis, most studies indicate
that NK cells from these patients display reduced cytotoxicity55–56 resulting from an
increased expression of killer inhibitory receptor (KIR) and altered antigenicity due to over-
expression of HLA class I57–58. Finally, the cytotoxicity of T cells is reduced in women with
endometriosis59 and the peritoneal fluid of women with this disease may contribute to the
survival of displaced endometrium by inducing apoptosis in cytotoxic lymphocytes via the
Fas-FasL pathway60. Collectively, macrophages, NK cells and cytotoxic T-lymphocytes in
women with endometriosis may provide a more immunotolerant peritoneal environment
than would normally exist, thus facilitating rather than inhibiting the disease process61.

Although endometriosis-related changes in peritoneal macrophage function leads to a

reduction in phagocytic activity, the continued ability of these cells to produce
proinflammatory cytokines, as noted above, may mediate the recruitment of additional
inflammatory immune cells to sites of peritoneal disease which may further exacerbate an
excessive inflammatory microenvironment62. For example, studies have indicated a higher
percentage of peritoneal neutrophils in women with endometriosis compared with disease-
free women63, although the activation status and function of these cells remains unclear. In
addition to neutrophils, type 17 T-helper (Th-17) cells and regulatory T-cells (Tregs) have a
suspected, though not well-studied, role in the pathogenesis of endometriosis. Recently,
Hirata et al.64 demonstrated recruitment of type 17 T-helper (Th-17) cells to endometriotic
tissues, cells that produce inflammatory signals affecting the recruitment, activation and
migration of neutrophils. At this juncture, it remains to be determined whether Th17 cell-
mediated signaling affects neutrophil migration and inflammatory behavior at sites of
ectopic endometrial growth among endometriosis patients.
As studies begin to focus on whether altered endometrial cell interactions with peritoneal
immune cells determines the risk for establishment of endometriosis, understanding the
potential role(s) of each specific immune cell populations will be necessary. In this regard,
emerging information suggests that Tregs may represent one of the most important immune
cells in the pathogenesis of endometriosis due to the potential role of these cells in the
regulation of disease-related inflammatory responses. In disease-free women, Tregs are most
prominent during the estrogen dominant proliferative phase, while their number is
significantly reduced during the progesterone-dominant secretory phase of the menstrual
cycle. However, Tregs remain abundant within the endometrium during the secretory-phase
in women with endometriosis, perhaps reflecting the reduced progesterone responsive
endometrial phenotype associated with this disease. It has been proposed that preservation of
Tregs in women with endometriosis decreases the ability of newly recruited immune cell
populations to effectively recognize and target endometrial antigens during menstruation,
potentially contributing to the survival and implantation of shed endometrial cells62.
Similarly, suppression of local immune responses by a Treg cell dependent mechanism
could underlie deficient clearing of ectopic tissues within the peritoneal microenvironment
as discussed above.
At this juncture, it remains to be determined how the trafficking and function of various
interactive immune cell populations is impacted by the progesterone resistant endometrial
and peritoneal microenvironments associated with endometriosis. However, progesterone
provides key immunosuppressive actions within the reproductive tract, therefore some of the
immunopathologies that have been noted among women with endometriosis likely reflect
the biological consequence of endometrial tissue microenvironments that are resistant to this
steroid. For instance, progesterone has been shown to antagonize estrogen-regulated

neutrophil recruitment and function within the uterus of mice65–66 while blocking
progesterone action promotes neutrophil recruitment and activation67. Peripheral NK cells
contain both PR isoforms, while peritoneal and endometrial macrophages also express
PR68–69. These and other related studies strongly suggest that the anti-inflammatory action
of progesterone not only regulates the behavior of somatic cell types but also affects their
interaction with multiple immune cells across the menstrual cycle. The studies noted above
demonstrate that alterations in the ability of progesterone to appropriately regulate the
trafficking and function of immune cells within the eutopic endometrium as well as within
the peritoneal cavity likely contributes to the pathophysiology of endometriosis. However, it
must also be considered that genetic or epigenetic defects within various somatic and/or
immune cell populations may equally impact an individual's risk of developing
endometriosis by disrupting endocrine-immune cell communication8, 18, 30.

The Invasive Establishment of Experimental Endometriosis—To accept

Sampson's theory of retrograde menstruation as a primary mechanism for establishment of
endometriosis, it is necessary to also accept that cells within fragments of endometrial tissue
are not only able to avoid apoptosis and immune defenses but also successfully accomplish a
significant invasive event in a short period of time. Specifically, for continued growth and
disease progression, endometrial cells which survive the peritoneal defenses must attach and
invade a mesothelial surface site and rapidly acquire a vascular supply. Since it is not
practical to examine each of these specific cell-cell interactions directly in women diagnosed
with endometriosis, investigators have turned to various in vitro and in vivo model systems.
More than a decade ago it was hypothesized that an injury of the mesothelial cell surface
would be necessary for successful invasion by menstrual endometrial cells70. Nevertheless,
endometrial cells obtained from either the proliferative or secretory phases of the menstrual
cycle were shown to have the in vitro ability to invade an intact mesothelium71–73. Using a
similar in vitro approach, Schenken and colleagues further demonstrated that viable
menstrual endometrial cells obtained from women with endometriosis exhibit a greater
capability for attachment to peritoneal mesothelial cells compared to cells obtained from the
tissue of disease-free women74. In addition to the potential that endometriosis patients
exhibit a unique endometrial cell phenotype, at least two studies have suggested that TNF-α,
a cytokine more abundant in the peritoneal fluid of these patients75, can increase the
adherence of endometrial stromal cells to mesothelial cells in vitro76. In contrast to these
studies, another research group demonstrated a dose-dependent inhibition of endometrial

stromal cell adhesion to a mesothelial cell monolayer by TNF-α and other pro-inflammatory
cytokines77. Currently, it is difficult to reconcile the conflicting findings of these various in
vitro studies; however, cell culture models of endometrial cell attachment to mesothelial
cells may not represent the same in vivo challenges that endometrial fragments face within
the peritoneal cavity at the time of retrograde menstruation.
The in vitro studies noted above represent important steps in our understanding of how
individual endometrial cell behavior in response to various biomolecules contributes to
peritoneal invasion during initiation of endometriosis. However, in vivo studies are equally
necessary to reveal the physiological role(s) of complex interactions that occur between
multiple cells types that characterize this invasive disease. As discussed below, some of the
most relevant experimental observations in regard to the capability of human endometrial
fragments to successfully establish ectopic sites of growth have been made using chimeric
models in which human endometrial tissue is injected into the peritoneal cavity of
immunocompromised mice. Chimeric models have allowed investigators to explore whether
an altered peritoneal cytokine/chemokine microenvironment may represent a key
contributory factor to the initial establishment of this disease by endometrial cells entering
the peritoneal cavity as well as modulate the action of steroids on disease progression. To
address the potential interactive role of various endocrine and immune factors in the
establishment of endometriosis our laboratory established an in vivo model using
immunocompromised nude mice, animals which accept human tissue xenographs. Using
this system, we initially demonstrated that under the influence of estrogen, cells within
normal human endometrial tissue fragments readily attach and invade an intact mesothelial
surface resulting in establishment of viable ectopic sites of growth78. Significantly,
compared to exposure of endometrial tissue fragments to estrogen alone, additional exposure
to IL-1α, an abundant proinflammatory cytokine within the peritoneal fluid of women with
endometriosis55, led to the development of larger and more numerous ectopic lesions in our
experimental model79. Taken together, numerous in vitro and in vivo studies from multiple
laboratories now suggest that invasion of an intact peritoneal mesothelial lining is unlikely
to represent a significant barrier to the establishment of endometriosis80. Additionally,
supporting in vitro observations, endometrial tissue obtained from endometriosis patients

has been shown to exhibit a greater capacity for the establishment of experimental
endometriosis in vivo when compared to endometrial tissue acquired from disease-free
tissue donors60, 66. Therefore, it is likely that the endometrial phenotype observed in
endometriosis patients together with a permissive inflammatory-like peritoneal

microenvironment ultimately determines the nature of the disease process leading to
medically significant disease.
A less understood, yet equally critical component in the successful establishment of

endometriosis, is the nature of the biological host site response of the mesothelial and other
cells at the site of ectopic invasion. In this regard, we recently reported that one of the
earliest events associated with ectopic endometrial lesion establishment in mice was an
apparent encapsulation of the human tissue fragment by the murine mesothelium within 16
hours of tissue injection81. Certainly, as discussed above, in vitro studies indicate that
eutopic endometrial tissue acquired from patients with endometriosis exhibits significantly
more invasion-related adhesive80 and proteolytic activity compared to similar tissue
acquired from control individuals82. Additionally, we have previously shown that
inflammation-related production of MMPs is a critical component of peritoneal invasion and
suppressing the expression of these enzymes by endometrial tissue fragments with
progesterone or blocking their activity with TIMP-1, a natural inhibitor of MMP action,
effectively inhibits the establishment of experimental endometriosis78. However, our
histological observations suggest that the “wound-like” mesothelial cell reaction at the initial
attachment site of endometrial tissue fragments within the peritoneal cavity may actively
participate in successful establishment and survival of the ectopic lesion. Given that patients
with endometriosis exhibit a generalized increase in peritoneal fluid proteolytic activity
compared to matched control samples83, proteolytic enzymes arising from peritoneal
sources likely increase the capacity of retrograde menstrual tissue from these patients to
successfully penetrate the peritoneal mesothelium. While fully understanding the role played
by the peritoneal mesothelial lining and other cells at the host site to successful
establishment of endometriosis will require further study, this information should contribute
significantly to the development of better therapeutics for the prevention or treatment of
endometriosis.
Inflammation and Experimental Endometriosis: Identifying Therapeutic Targets

As discussed above, although multiple biological triggers are involved in the initiation and
progression of endometriosis, the cellular and molecular mechanisms specifically
responsible for the progesterone resistant endometrial phenotype appear to involve
inflammation-like patterns of cell-to-cell and tissue-to-tissue signaling. Thus, an appealing
therapeutic approach for the medical management of this disease would be to utilize anti-
inflammatory agents capable of normalizing the progesterone resistant endometriosis
phenotype or which block key elements of the inflammatory processes associated with
successful ectopic growth. For example, among anti-inflammatory agents in current use for
other diseases, statins are known to decrease levels of various mediators and markers of
inflammation including c-reactive protein, TNF-α, several interleukins and monocyte
chemotactic protein-1 (MCP-1)84–86. Thus, we and others have explored the therapeutic
potential of different statins to reduce disease burden using in vivo models of experimental
endometriosis81, 87–89. In our study, we found that simvastatin treatment of mice bearing
experimental endometriosis led to a significant reduction in the number and volume of
ectopic lesions, partly through the ability of this statin to protect against inflammation81.
Although the precise mechanism(s) of simvastatin action in our experimental endometriosis
model has yet to be determined, statins are known to regulate multiple processes associated
with initiation of endometriosis, including cell proliferation, apoptosis, cell morphology and
motility/invasiveness. Following successful attachment, ectopic survival of endometrial

tissues within the peritoneal cavity requires acquisition of a vascular supply. Thus, another
critical area of endometriosis research related to inflammation is to unravel the biological
crosstalk between the host invasion sites and displaced endometrial tissue fragments which
promote new blood vessel growth.
Angiogenesis is a mandatory process in the pathogenesis of endometriosis in women90 as

well as in the development of experimental endometriosis in mice91. Therefore, it is not
surprising that vascular endothelial growth factor (VEGF) expression is increased in the
peritoneal fluid from patients with endometriosis compared with control women92–93, that
VEGF levels correlate with the stage of disease92–93 and that this growth factor appears to
play a prominent role in vascularization of endometriotic tissues94. Therapeutically, anti-
inflammatory agents would be expected to inhibit vascular development at ectopic sites of
endometrial growth since a number of pro-inflammatory cytokines modulate the expression
of VEGF by activated peritoneal macrophages, migrating neutrophils and by somatic cells
within the endometriotic lesions. In a collaborative study using an experimental
endometriosis model, we found that soluble flt-1, a VEGF receptor antagonist, was quite
effective in blocking the formation of ectopic human lesions95. This is consistent with
findings using a similar experimental endometriosis model in which murine vessels from the
peritoneum were found to invade endometrial implants 5–8 days after human tissue
introduction into mice, coinciding with an increase in VEGF production96. More recently,
we examined the influence of the anti-inflammatory drug pioglitazone on vascularization in
experimental endometriosis in nude mice97. Mice receiving pioglitazone treatment not only
exhibited markedly fewer lesions, but lesions that were present had a significant reduction in
microvessel density compared to lesions from control mice. Taken together, these studies
suggest that an additional benefit of anti-inflammatory agents for the treatment of
endometriosis may be to limit vascularization at ectopic sites of growth.
Future Directions: Targeting the Peritoneal Microenvironment of Endometriosis

As noted above, inflammatory processes play a key role in the early establishment of
experimental endometriosis and numerous studies now provide evidence that the
endometriosis-related endometrial phenotype and peritoneal inflammation may work in
concert to promote ectopic endometrial growth. Nevertheless, the key role that the peritoneal
microenvironment plays in the establishment of endometriosis is often underappreciated in
the clinical management of this disease. For example, in two recent studies, we examined
the peritoneal microenvironment associated with a recent surgical injury on the development
of experimental endometriosis using a nude mouse model97–98. In the initial study, mice
were injected with human endometrial tissues at various time points following ovariectomy
or sham surgery. Mice injected with human endometrial fragments within 16 hours of
ovariectomy exhibited more extensive ectopic disease compared to animals receiving tissues
after 36 hours from the time of surgery or following sham surgery. Importantly, surgical
injury had a profound effect on microvessel density (MVD), which was greatest in lesions
established closest to the time of peritoneal surgery. In a second study we demonstrated that
the anti-inflammatory action of dietary fish oil supplementation can reduce peritoneal
inflammation and thus limit the both the development of experimental endometriosis and
related adhesions98. Although surgical treatment of endometriosis is common, the
independent influence of the surgical procedure itself on the inflammatory state of the
peritoneal microenvironment is generally not considered as a potential trigger for the
reestablishment or progression of disease. Despite the apparent lack of appreciation of this
relationship, it is likely that the success of our fish oil therapy was also associated with a
reduction in peritoneal inflammation. As noted previously in this review, by utilizing a
severely immunocompromised murine model which allows the adoptive transfer of both
human immune cells and endometrial tissues, we demonstrated an important role of normal

immune cell function in controlling peritoneal inflammation and preventing development of

endometriosis48. Certainly, the occurrence of endometriosis in only certain women suggest
that the behavior of immune cells that participate in peritoneal inflammation may be altered
in women at risk for developing this disease and numerous groups have found that anti-
inflammatory agents are effective in reducing disease burden in experimental models of
endometriosis81, 99. In future studies, it will be important to examine the influence of
immune cells acquired from women with endometriosis relative to the establishment and
progression of experimental disease. Specifically, would immune cells acquired from
women with active endometriosis fail to impede the survival of ectopic disease? Answering
this question would no doubt contribute significantly to our understanding of the role that
immune system disruption plays in the initiation and progression of this disease and provide
a basis for the development of new therapeutic approaches.
CONCLUSION
Given the potential for many years of individual suffering as well as significant costs to the
healthcare system, there is an urgent need to better understand the basic cellular processes
leading to the development of endometriosis in order to improve medical management of
this disease. The experimental studies presented herein illustrate the evolving view that the
development of endometriosis is both an endocrine and immune disease. As such, the
proinflammatory nature of the endometriosis phenotype appears to contribute not only to
survival and propagation of ectopic endometrial tissues, but also to the infertility, adhesive
disease and pelvic pain which are frequently associated with this disease. Proinflammatory
cytokines are known to reduce endometrial progesterone responsiveness, further
exacerbating the disease and its symptoms. Importantly, it has been suggested that the
proinflammatory nature of the peritoneal fluid of women with endometriosis may promote
endometrial cell escape from immune surveillance, allowing survival and establishment of
disease100. Thus, inadequate removal of refluxed menstrual debris, coupled with an
enhanced ability of sloughed endometrial tissue to evade immune surveillance and invade a
peritoneal site, likely represent the most critical factors in determining an individual
woman's risk for developing endometriosis. Since predicting and treating inflammatory
processes related to the development of an endometriosis phenotype prior to recognition of
disease symptoms is not presently feasible; current medical strategies focus on treatment of
existing disease. However, treatment options for women with endometriosis remain limited
and frequently involve either hormonal manipulation and/or surgery. For many women, the
side effects of medical therapy are poorly tolerated, while surgical treatment is generally
non-curative with a high rate of recurrence. Developing a greater insight into the cellular and
molecular mechanisms by which a hyper-inflammatory state is initiated in both the
reproductive tract and peritoneal cavity of women with endometriosis is likely a prerequisite
to designing better and more effective medical management strategies in the future. As we
gain insight into the initial processes associated with the early establishment of ectopic
growth, it may be possible to design specific therapeutic targets which can prevent this
debilitating disease.
Acknowledgments
This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human
Development (NICHD) Grants: T32 HD007043, U54 HD052668 and RO1 HD055648, The National Institute of
Environmental Health Sciences (NIEHS) RO1 ES14942 and the International Endometriosis Association, Inc.
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FIGURE 1. Uterine and Peritoneal Microenvironments of Endometriosis

Tissue microenvironments of a disease-free patient (Left) and a patient with endometriosis
(Right). A normal pattern of stromal-epithelial cell communication within the eutopic
human endometrium is characterized by stromal dominant cell signaling which serves to
direct the behavior of adjacent epithelial cells (A). In contrast, stromal-epithelial

communication is disrupted in the eutopic endometrium of women with endometriosis,
leading to an epithelial dominant signaling pathway (B). This wound-like pattern of cell-cell
communication leads to an endometrial tissue phenotype with a reduced sensitivity to
progesterone. Within the peritoneal cavity, refluxed endometrial fragments are recognized
and cleared from the peritoneal cavity by the innate immune system (C). However,
endometrial fragments from women with endometriosis (D) are able to evade immune
system surveillance and clearance. Additionally, alterations within the peritoneal
microenvironment in women with endometriosis, such as aberrant immune cell function and
increased production of proinflammatory signals, may act to promote the survival of
refluxed endometrial tissue (E). Once attached to sites within the peritoneal cavity, ectopic
lesions exhibiting the endometriosis phenotype are better able to establish a vascular supply
(F) and recruit factors which promote disease progression. The hyperinflammatory
peritoneal microenvironment of ectopic endometrial growth may subsequently affect the
eutopic endometrium by promoting the proinflammatory endometrial phenotype (G).

Bruner Tran - 2013 - Medical Management of Endometriosis - Emerging Evidence Linking Inflammation To Disease Pathophysiology

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Minerva Ginecol. 2013 April ; 65(2): 199–213.

Medical Management of Endometriosis: Emerging Evidence

Vanderbilt University School of Medicine, Nashville, TN USA 37232

Endometriosis; inflammation; progesterone resistance

pelvic pain in addition to reduced fertility. Presently, clinical identification of endometriosis

Recognizing that the development of endometriosis is limited to menstruating species, Dr.

Although it is likely that numerous converging factors ultimately determine a woman's

The Unique Physiology of the Human Endometrium

by tissue breakdown and bleeding in the absence of nidation. Clearly, in order to

Minerva Ginecol. Author manuscript; available in PMC 2014 April 01.

order to preserve endometrial integrity22. In contrast to healthy women, the elevated

The Progesterone Resistant Endometriosis Phenotype

Minerva Ginecol. Author manuscript; available in PMC 2014 April 01.

endometriosis examined circulating progesterone levels relative to expected histological

progesterone levels, the endometrium's ability to respond appropriately to this steroid

At present, the biological origin of reduced endometrial progesterone responsiveness among

phenotype observed in women with endometriosis. Specifically, several studies have

Minerva Ginecol. Author manuscript; available in PMC 2014 April 01.

disease-related epigenetic modifications, specifically affecting expression levels of PR-A,

The Basic Pathogenesis of Endometriosis

Disruption of Apoptosis—Apoptosis is an important mechanism by which autologous

Minerva Ginecol. Author manuscript; available in PMC 2014 April 01.

resistant endometrial phenotype of women with endometriosis would be expected to result

Evading Immune Surveillance—Following menstruation, immune surveillance within

of persistent sites of ectopic growth. In this regard, the inflammatory mediator,

Minerva Ginecol. Author manuscript; available in PMC 2014 April 01.

Although endometriosis-related changes in peritoneal macrophage function leads to a

steroid. For instance, progesterone has been shown to antagonize estrogen-regulated

Minerva Ginecol. Author manuscript; available in PMC 2014 April 01.

The Invasive Establishment of Experimental Endometriosis—To accept

studies, another research group demonstrated a dose-dependent inhibition of endometrial

Minerva Ginecol. Author manuscript; available in PMC 2014 April 01.

endometriosis patients together with a permissive inflammatory-like peritoneal

A less understood, yet equally critical component in the successful establishment of

Inflammation and Experimental Endometriosis: Identifying Therapeutic Targets

Minerva Ginecol. Author manuscript; available in PMC 2014 April 01.

promote new blood vessel growth.

Angiogenesis is a mandatory process in the pathogenesis of endometriosis in women90 as

Future Directions: Targeting the Peritoneal Microenvironment of Endometriosis

Minerva Ginecol. Author manuscript; available in PMC 2014 April 01.

immune cell function in controlling peritoneal inflammation and preventing development of

Minerva Ginecol. Author manuscript; available in PMC 2014 April 01.

the peritoneal cavity. Am J Obstet Gynecol. 1927; 14:422–69.

Minerva Ginecol. Author manuscript; available in PMC 2014 April 01.

83:529–37. [PubMed: 15749474]

Minerva Ginecol. Author manuscript; available in PMC 2014 April 01.

43. Harada T, Kaponis A, Iwabe T, Taniguchi F, Makrydimas G, Sofikitis N, et al. Apoptosis in

62:1086–8. [PubMed: 7926125]

Minerva Ginecol. Author manuscript; available in PMC 2014 April 01.

Minerva Ginecol. Author manuscript; available in PMC 2014 April 01.

Minerva Ginecol. Author manuscript; available in PMC 2014 April 01.

99. Zulfikaroglu E, Kilic S, Islimye M, Aydin M, Zergeroglu S, Batioglu S. Efficacy of anti-tumor

Minerva Ginecol. Author manuscript; available in PMC 2014 April 01.

FIGURE 1. Uterine and Peritoneal Microenvironments of Endometriosis

direct the behavior of adjacent epithelial cells (A). In contrast, stromal-epithelial

Minerva Ginecol. Author manuscript; available in PMC 2014 April 01.

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