The

n e w e ng l a n d j o u r na l

of

m e dic i n e

review article
Mechanisms of Disease

Endometriosis
Serdar E. Bulun, M.D.
From the Division of Reproductive Biology Research, Department of Obstetrics
and Gynecology, Feinberg School of
Medicine, Northwestern University, Chicago. Address reprint requests to Dr. Bulun at the Division of Reproductive Biology Research, Dept. of Obstetrics and
Gynecology, Feinberg School of Medicine, Northwestern University, 303 E. Superior St., Rm. 4-123, Chicago, IL 60611,
or at s-bulun@northwestern.edu.
N Engl J Med 2009;360:268-79.
Copyright 2009 Massachusetts Medical Society.

268

ndometriosis is an estrogen-dependent inflammatory disease

that affects 5 to 10% of women of reproductive age in the United States.1 Its
defining feature is the presence of endometrium-like tissue in sites outside
the uterine cavity, primarily on the pelvic peritoneum and ovaries. The main clinical
features are chronic pelvic pain, pain during intercourse, and infertility.1 Endometriosis can be the result of diverse anatomical or biochemical aberrations of uterine
function. For example, endometriosis commonly develops in young women with vaginal obstruction of outflow, possibly because of large quantities of backwashed menstrual tissue that has become implanted on pelvic organs.2 In contrast, endometriosis can also involve mechanisms that are independent of anatomical abnormalities;
for example, the incidence of endometriosis is increased in women who were exposed in utero to environmental toxins or potent estrogens such as diethylstilbestrol.3 As cellular and molecular mechanisms involved in endometriosis are being
uncovered, the diseases classification is evolving from a local disorder to a complex,
chronic systemic disease. Endometriosis can be inherited in a polygenic manner; its
incidence in relatives of affected women is up to seven times the incidence in women
without such a family history.4 There is evidence of linkage to chromosomes 7 and
10, but no relevant genes in these regions appear to have yet been identified.5,6
The three clinically distinct forms of endometriosis are endometriotic implants
on the surface of the pelvic peritoneum and ovaries (peritoneal endometriosis), ovarian cysts lined by endometrioid mucosa (endometriomas), and a complex solid mass
comprised of endometriotic tissue blended with adipose and fibromuscular tissue,
residing between the rectum and the vagina (rectovaginal endometriotic nodule). All
three types may be variants of the same pathologic process or they can be caused
by different mechanisms.7,8 Their common histologic features are the presence of
endometrial stromal or epithelial cells, chronic bleeding, and signs of inflammation. These lesions can occur singly or in combination and are associated with an
increased risk of infertility or chronic pelvic pain.9,10 The inflammation involved in
endometriosis can stimulate nerve endings in the pelvis and thereby cause pain,
impair the function of uterine tubes, decrease receptivity of the endometrium, and
hinder development of the oocyte and embryo.11,12 Endometriosis can also cause
infertility by physically blocking the fallopian tubes.9,10
The treatment of infertility caused by endometriosis is surgical removal of endometriotic tissue or assisted reproductive technology, whereas the usual treatment of
pain is a combination of medical suppression of ovulation and surgery. Peritoneal
implants are resected or vaporized by means of an electric current or laser. Ovarian
endometriomas and rectovaginal endometriotic nodules, however, can be removed
effectively only with the use of full dissection. Epidemiologic and laboratory data suggest a link between ovarian endometriosis and distinct types of ovarian cancer.13,14
Clinical evidence clearly points to a deleterious effect of uninterrupted ovulatory
cycles on the development and persistence of endometriosis.15,16 First, symptoms
of endometriosis usually appear after menarche and vanish after menopause.17 Occan engl j med 360;3 nejm.org january 15, 2009

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Mechanisms of Disease

sionally, a rectovaginal nodule remains symptomatic in a postmenopausal woman, suggesting that

its persistence is independent of ovarian estrogen
secretion.18 Second, multiparity is associated with
a decreased risk of endometriosis.17 Third, the
disruption of ovulation by analogues of gonadotropin-releasing hormone (GnRH), oral contraceptives, or progestins reduces pelvic disease and
the associated pain.16
In line with these clinical observations are the
findings that indicate major roles of the ovarian
steroids estrogen and progesterone in the development of endometriosis. In humans and other
primates, estrogen stimulates the growth of endometriotic tissue, whereas aromatase inhibitors
that block estrogen formation are beneficial, as
are antiprogestins, in patients with endometriosis.19-21 Levels of nuclear receptors for estrogen
and progesterone are strikingly perturbed in endometriotic tissue as compared with normal endometrium.22-24 Finally, biologically significant quantities of progesterone and estrogen are produced
locally in endometriotic tissue, through an abnormally active steroidogenic cascade that includes
aromatase.25 This review deals mainly with steroid-related mechanisms of endometriosis.

Cel lul a r Or igins

There is no consensus concerning the histologic
origin of endometriosis. Sampson proposed that
fragments of menstrual endometrium pass backward through the fallopian tubes and then become implanted on peritoneal surfaces and persist there.26 This mechanism was shown in primate
models, was observed in humans, and is supported by the observation that endometriosis occurs
exclusively in species that menstruate (i.e., humans
and other primates).27 In contrast, the coelomicmetaplasia hypothesis proposes that the genesis
of endometriotic lesions within the peritoneal cavity is the differentiation of mesothelial cells into
endometrium-like tissue.28 A third hypothesis argues that menstrual tissue from the endometrial
cavity travels to other sites through veins or lymphatic vessels.29 Another proposal is that circulating blood cells originating from bone marrow
can differentiate into endometriotic tissue at various sites.30 Proving or disproving these hypotheses is challenging because of the difficulty in constructing clinically relevant models.
Sampsons implantation hypothesis is a plausible mechanism for most endometriotic lesions

but does not explain why endometriosis develops

in some, but not most, women. Most women have
reflux menstruation into the peritoneal cavity, but
endometriosis occurs in only 5 to 10%. One of two
mechanisms could explain the successful implantation of refluxed endometrium onto the peritoneal surface: molecular defects or immunologic
abnormalities (or both).31 In endometriosis, the
eutopic endometrium exhibits multiple subtle but
biologically important molecular abnormalities,
including the activation of oncogenic pathways
(e.g., the Wingless-type MMTV integration site
family member Wnt or the rat sarcoma viral oncogene homologue Ras) or biosynthetic cascades
favoring increased production of estrogen, cyto
kines, prostaglandins, and metalloproteinases.1,32-36
When the eutopic endometrium, biologically distinct tissue, attaches to mesothelial cells, the magnitude of the molecular abnormalities is amplified drastically, enhancing the survival of the
implant.37 A possible second mechanism of implant survival entails a failure of the immune system to clear implants from the peritoneal surface.1,38,39 Both mechanisms may contribute to the
development of endometriosis.

Mol ecul a r Mech a nisms

There are clear molecular distinctions between endometriotic tissue and endometrium, such as the
overproduction of estrogen, prostaglandins, and
cytokines in endometriotic tissue (Fig. 1).32,40,41
Subtle forms of these abnormalities also occur in
endometrium from a woman with endometriosis
as compared with endometrium from a woman
without the disease (Fig. 1).32,40,41 Moreover, geneexpression profiling of endometrium from women
with endometriosis as compared with endometrium from disease-free women has revealed candidate genes related to implantation failure, infertility, and progesterone resistance.35,42
Inflammation, a feature of endometriotic tissue, is associated with the overproduction of prostaglandins, metalloproteinases, cytokines, and
chemokines.1,32-36,43 Increased levels of acute inflammatory cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor probably
enhance the adhesion of shed endometrial-tissue
fragments onto peritoneal surfaces, and proteolytic membrane metalloproteinases may further
promote implantation of the fragments.1,32-36,43
Monocyte chemoattractant protein 1, interleukin-8,
and RANTES (regulated upon activation normal

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269

The

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A Endometrium in disease-free women

Precursor
Precursor
Estradiol

COX-2

Aromatase
ma
HSD17B2

Low PGE2

Estrogen
trog

Low PGE2 locally

Estrone

B Endometrium in women with endometriosis

Precursor
Precursor
Estradiol

COX-2
Aromatase
HSD17B2

Moderate PGE2
Moderate
PGE2, and low
estradiol, locally

Estrogen
Estrone

C Ectopic endometriotic tissue

Precursor
Precursor
Estradiol

COX-2
Aromatase

HSD17B2
D1

High PGE2
High PGE2
and estradiol
locally

High estrogen

Estrone
tro

Figure 1. Normal Endometrium and Endometriosis.

In normal endometrial tissue (Panel A), activity of the enzyme cyclooxygenase-2 (COX-2), and thus production
of prosCOLOR FIGURE
taglandin E2 (PGE2), is low. Estrogen is not produced locally, owing to the absence of aromatase.
the12/29/08
luteal
DraftDuring
5
phase, the progesterone-dependent 17-hydroxysteroid dehydrogenase 2 (HSD17B2) enzymeAuthor
catalyzes
the conversion
Bulun
1 endometriosis
Fig #
of the biologically active estradiol to estrone that is less estrogenic. In the endometrium of women
with
Endometriosis
Title
(Panel B), there is a subtle increase in COX-2 activity and detectable aromatase activity. In ectopic
endometriotic
tissue
ME
(Panel C), full-blown molecular abnormalities include high COX-2 and aromatase levels. Increased PGE2 formation in
DE
Schwartz
endometrial and endometriotic tissues can cause severe menstrual cramps and chronic pelvic
Tissue estradiol
Artist pain.Knoper
AUTHOR to
PLEASE
NOTE:
levels should be high, because estradiol is overproduced by aromatase and is not metabolized owing
deficient
Figure has been redrawn and type has been reset
PleaseBulun
check carefully
HSD17B2 activity. Increasing enzyme activity is denoted by increasing thickness of arrows. Modified from
et al.25
Issue date

T-cell expressed and secreted) attract the granulocytes, natural killer cells, and macrophages that
are typical of endometriosis.1,32-36,44,45 Autoregulatory positive-feedback loops ensure further accumulation of these immune cells, cytokines, and
chemokines in established lesions.46
In patients with endometriosis, inflammatory
and immune responses, angiogenesis, and apoptosis are altered in favor of the survival and replenishment of endometriotic tissue.38,39,47-49 These
basic pathologic processes depend in part on estrogen or progesterone. Excessive formation of
estrogen and prostaglandin and the development
of progesterone resistance have emerged as clinically useful points of study because the therapeutic targeting of aromatase in the estrogen biosynthetic pathway, cyclooxygenase-2 (COX-2) in the
270

1/15/09

prostaglandin pathway, or the progesterone receptor reduces pelvic pain or laparoscopically visible
endometriosis or both (Fig. 1).9,20,50,51 These three
critical targets have been linked through specific
epigenetic markers (hypomethylation) that cause
overexpression of the nuclear receptors steroidogenic factor 1 (SF1) and estrogen receptor .24,52
Estrogen Formation in Endometriosis

Estrogen production plays a key role in endometriosis. Its inhibition by GnRH analogues, oral contraceptives, progestins, and aromatase inhibitors
reduces pelvic disease and pain (Fig. 2A).16 Steroidogenic acute regulatory protein (STAR) facilitates the initial step of estrogen formation (i.e., the
entry of cytosolic cholesterol into the mitochondrion). Then, five proteins catalyzing six enzymatic

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Mechanisms of Disease

A Sources of estradiol in endometriotic tissue

Pituitary
FSH
LH

GnRH analogues
Oral contraceptives
Progestins

Endometriosis

Induction of
gene expression

Cholesterol

Cholesterol

Adrenal gland

Androstenedione

Androstenedione

Androstenedione

Aromatase

Aromatase
inhibitor

Aromatase

Aromatase

Estrone

Estrone

Estrone

1-Estradiol

3-Estradiol

2-Estradiol

Ovary

Fat and skin

B Survival and inflammation of endometriotic tissue

Interleukin-1

VEGF
+

+
Cholesterol
STAR

Inflammation

PGE2

COX-2

Arachidonic acid

+
SCC
+

SF1

ER-

Estradiol

HSD3B2
17-hydrolyase
17-20-lyase
Androstenedione

Survival

HSD17B1
Aromatase

Estrone

Figure 2. Molecular Distinctions between Endometriotic Tissue and Endometrium.

Panel A shows the three sources of estradiol, biologically active estrogen, in endometriotic tissue. The
COLORfirst
FIGURE sources
Draft 8 of ovarian
12/29/08
are follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which induce the expression
steAuthor
Bulun
roidogenic genes, including aromatase, for biosynthesis of estradiol. Ovarian secretion of estradiol
can be reduced
2
Fig #
through suppression of FSH and LH by gonadotropin-releasing hormone (GnRH) analogues,
combination
oral conEndometriosis
Title
traceptives, or progestins. The second source of estrogen is the estradiol that arises from aromatase
activity in fat
ME
or skin. The third source of estradiol is local production in endometriotic tissue. Aromatase
in peripheral
DEinhibition
Schwartz
Artistin endometriosis.
Knoper
tissue (fat and skin) and endometriotic tissue stops estradiol biosynthesis and is therapeutic
As
AUTHOR PLEASE NOTE:
shown in Panel B, high levels of local estradiol and prostaglandin E2 (PGE2) are maintainedFigure
in endometriotic
tissue
has been redrawn and type has been reset
Please check carefully
by autoregulatory positive-feedback mechanisms (indicated by plus signs) that involve nuclear receptors
(steroidoIssue date 1/15/09
genic factor 1 [SF1] and estrogen receptor [ER-]), enzymatic pathways, cytokines, and growth factors. COX-2 denotes cyclooxygenase-2, HSD17B1 17-hydroxysteroid dehydrogenase 1, HSD3B2 3-hydroxysteroid dehydrogenase
2, SCC side-chain cleavage enzyme, STAR steroidogenic acute regulatory protein, and VEGF vascular endothelial
growth factor. Modified from Bulun et al.25

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271

The

n e w e ng l a n d j o u r na l

steps (side-chain cleavage enzyme, 3-hydroxy

steroid dehydrogenase 2, 17-hydroxylase17-20lyase, aromatase, and 17-hydroxysteroid dehydrogenase 1) convert cholesterol to biologically
active estradiol (Fig. 2B).25 The key step, the conversion of C19 steroids to estrogens, is catalyzed
by aromatase, inhibition of which effectively eliminates all estrogen production (Fig. 2B).25
Origins of Estrogen in Endometriosis

Three major sites in the body produce estrogen in

women with endometriosis. First, estradiol secreted by the ovary reaches endometriotic tissue
through the circulation. Moreover, follicular rupture during each ovulation causes spillage of large
amounts of estradiol directly onto pelvic implants.
Second, aromatase in adipose tissue and skin catalyzes the conversion of circulating androstenedione to estrone that is subsequently converted to
estradiol, and this estrone and estradiol can enter
the circulation and reach sites of endometriosis.
Another source of estradiol is cholesterol, which
is converted to estradiol locally in endometriosis
because endometriotic tissue expresses a complete
set of steroidogenic genes, including aromatase.25
Peripheral or local aromatase activity, or both, may
be particularly important in the persistence of endometriosis the use of a combination of a GnRH
agonist plus an aromatase inhibitor is superior to
the use of a GnRH agonist alone for long-lasting
relief of pain (Fig. 2A).53
Estrogen Production and Inflammation

Cell survival and inflammation are responsible

for chronic pelvic pain and infertility, the primary
symptoms of endometriosis. Estrogen enhances
the survival or persistence of endometriotic tissue,
whereas prostaglandins and cytokines mediate
pain, inflammation, and infertility.54,55 A link between inflammation and estrogen production in
endometriosis was uncovered in a feedback cycle
that favors the overexpression of key steroidogenic
genes (most notably aromatase), overexpression
of COX-2, and continuous local production of estradiol and prostaglandin E2 in endometriotic
tissue.41,56-58
Prostaglandin E2 and Biosynthesis of Estradiol

Prostaglandin E2 coordinately stimulates the expression of all steroidogenic genes necessary to enable the endometriotic stromal cell to synthesize
estradiol from cholesterol.25 Among the six ste272

of

m e dic i n e

roidogenic genes, the regulation of two STAR

and CYP19A1, the aromatase gene has been characterized extensively (Fig. 2B).25
Endometriotic and endometrial stromal cells
express each of the prostaglandin E2 receptor subtypes, EP1, EP2, EP3, and EP4.59 Activation of the
EP2 receptor raises the intracellular levels of cyclic
AMP (cAMP), which is responsible for inducing the
expression of STAR and CYP19A1 by way of prostaglandin E2 in endometriotic stromal cells.25,57,59
Prostaglandin E2 or a cAMP analogue increases
STAR and aromatase levels and activity in endometriotic cells but not in endometrial stromal
cells.25,41,57 Thus, steroidogenesis dependent on
prostaglandin E2 and cAMP in endometriotic stro
mal cells requires downstream effectors, whereas
inhibitory mechanisms or a lack of stimulatory
effectors downstream of cAMP account for the
absence of steroidogenesis in normal endometrial
stromal cells.
The nuclear receptor SF1, which is present in
endometriotic tissue and absent in endometrium,
is the key transcription factor that mediates the
expression dependent on prostaglandin E2 and
cAMP of STAR, CYP19A1, and possibly other
steroidogenic genes in endometriotic stromal cells.
In prostaglandin E2 treated endometriotic cells,
SF1 binds coordinately and assembles an enhancer
transcriptional complex recruited to the promoters
of the STAR and CYP19A1 genes to induce their
expression (Fig. 2B).25
The absence of SF1 in endometrial cells is a
major cause of the lack of responsiveness of steroidogenic genes to prostaglandin E2. In addition,
the redundancy of transcriptional inhibitors of
STAR and CYP19A1 gene promoters in endometrial
cells constitute a fail-safe system for silencing
these steroidogenic genes. These repressors are
chicken ovalbumin upstream promotertranscription factor (COUP-TF), the Wilms tumor 1 transcription factor (WT1), and CCAAT/enhancer binding protein (C/EBP). Levels of WT1 and C/EBP
are much higher in normal endometrium than in
endometriotic tissue. In the absence of SF1, a transcriptional complex composed of repressors binds
the steroidogenic promoters and suppresses them
in endometrial cells.25
In summary, on induction of prostaglandin E2,
coordinated recruitment of SF1 to the promoters
of the essential steroidogenic genes is the key event
for estradiol synthesis in endometriotic stromal
cells. A suitable therapeutic target among the ste-

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Mechanisms of Disease

roidogenic enzymes is aromatase, because its inhibition blocks all estradiol biosynthesis. Aromatase
inhibitors diminish or eradicate endometriotic
implants and associated pain that is refractory to
currently available treatments.19
Prostaglandin Production in Endometriosis

Prostaglandins, locally produced hormones involved in inflammation and pain, are important
in the pathogenesis of endometriosis. In particular, prostaglandin E2 and prostaglandin F2 are
produced in excess in uterine and endometriotic
tissues of women with endometriosis.60 The vasoconstrictive properties of prostaglandin F2, together with its ability to cause uterine contractions,
contributes to dysmenorrhea, whereas prostaglandin E2 can induce pain directly.60 These prostaglandins are clinically relevant because the reduction of prostaglandin formation by nonselective
COX inhibitors (e.g., naproxen sodium and ibuprofen) decreases pelvic pain associated with endometriosis.16,50 Care must be taken in long-term
administration of nonselective COX inhibitors because they have gastrointestinal side effects. Selective COX-2 inhibitors with milder side effects
(e.g., rofecoxib and valdecoxib) were approved by
the Food and Drug Administration for the treatment of primary dysmenorrhea, and their longterm administration could potentially reduce the
chronic pelvic pain associated with endometriosis.
The use of COX-2 inhibitors has, however, been
limited by their link to an increased risk of cardiovascular disease.50
Cyclooxygenase catalyzes the conversion of
arachidonic acid (released by phospholipase A2)
to prostaglandin H2 in most cells, including those
in myometrium, endometrium, and endometriotic
tissue.61 Of the two isoforms, COX-1 is generally
responsible for basal prostaglandin synthesis,
whereas COX-2 is important in inflammation.
The coupling of COX-dependent synthesis of prostaglandin H2 to its metabolism by enzymes downstream is orchestrated in a cell-specific fashion.
Uterine cells are rich in prostaglandin F synthase and microsomal prostaglandin E synthase,
which catalyze the conversion of prostaglandin
H2 to prostaglandin F2 and prostaglandin E2,
respectively.60
Excessive prostaglandin E2 production during
inflammation through coordinated induction of
multiple enzymes, in particular COX-2 and microsomal prostaglandin E synthase, is a concept

in development.61,62 Endometriotic stromal cells

produce large quantities of prostaglandin E2,
which induce local estrogen biosynthesis and pelvic pain.41,56,57,63 COX-2 is up-regulated to a greater
degree in endometriotic stromal cells as compared
with endometrial stromal cells; moreover, its expression is also increased in the endometrium of
women with endometriosis as compared with that
of disease-free women.64,65 Expression of micro
somal prostaglandin E synthase has been shown
in both benign and malignant endometrium.66-68
Thus, increased synthesis of prostaglandin E2 in
endometriotic tissue may be due to coordinated
hyperactivity of COX-2 and microsomal prostaglandin E synthase.
At least four hormones, present in high quantities in endometriotic tissue, induce COX-2 expression and prostaglandin E2 production in endometriotic and uterine cells (Fig. 2B). The cytokine
interleukin-1 or prostaglandin E2 itself (in an
autocrine manner) induces COX-2 expression in
endometriotic and endometrial stromal cells.69,70
The angiogenic factor vascular endothelial growth
factor or estradiol rapidly induces, through estrogen receptor , COX-2 expression in uterine endothelial and endometriotic stromal cells.69-71
These redundant mechanisms maintain large
quantities of prostaglandin E2 in endometriotic
tissue (Fig. 2B).
Thus, cytokines, angiogenic factors, prostaglandin E2 itself, and estradiol all induce COX-2
expression in patients with endometriosis and
thereby ensure production of large quantities of
prostaglandin E2. Estrogen receptor mediates
the induction of COX-2 by estradiol in endometriotic tissue.
Progesterone Resistance in Endometriosis

In contrast to the clearly unfavorable effect of estrogen on endometriosis, the role of progesterone
has remained ambiguous for the following three
reasons. First, the protective role of progesterone
with regard to endometrial cancer, in which there
is epithelial-cell proliferation, has been inappropriately attributed to endometriosis, which consists
primarily of stromal cells with a low rate of apoptosis and little differentiation.49 Paradoxically, progesterone induces the transient proliferation of
stromal cells in normal endometrium during the
secretory phase. Second, progestin-based treatments for pain are at best variably effective, especially in patients who have previously received other

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273

The

Estradiol

HSD17B2

RA
XR
R
RAR RXR
Sp1
DNA

Sp3

n e w e ng l a n d j o u r na l

Estrone
tro

HSD17B2
mRNA

X
HSD17B2
promoter

Epithelium

Stroma

Other
paracrine factors

CH3
C

RA

X
Lack of binding

X
PR

Progesterone
Figure 3. Disrupted Paracrine Action of Progesterone in Endometriotic
Tissue.
COLOR FIGURE
In endometriotic tissue, the paracrine action of progesterone
is disrupted
Draft 5
12/29/08
by the decreased progesterone receptor (PR) levels
in the Bulun
stromal cell. In
Author
3
contrast, in the endometrium, progesterone induces
of epiFig #the expression
Title
thelial 17-hydroxysteroid dehydrogenase 2 (HSD17B2)
byEndometriosis
activating stromal PRs. These receptors mediate the formation of ME
retinoic acid (RA) and
DE
Schwartz
other unknown paracrine factors, which induce the
binding
to, and thus acArtist
Knoper
tivation of, the HSD17B2 promoter by a transcriptional AUTHOR
activator
complex
of
PLEASE
NOTE:
Figure has been redrawn and type has been reset
the transcription factors Sp1 and Sp3, retinoic acid receptor
(RAR),
and
Please
check
carefully
retinoid X receptor (RXR). The outcome is a decrease
local biologicalIssue date in
1/15/09
ly active estrogen, estradiol. The term mRNA denotes messenger RNA.

forms of treatment.72,73 Progestins probably reduce

pain by suppressing or attenuating ovulation. A direct effect of progestins on endometriotic tissue
cannot be ruled out, however. Third, a spectrum
of antiprogestins with a mix of agonist and an274

of

m e dic i n e

tagonist properties (selective progesterone-receptor

modulators) may reduce endometriosis-associated
pelvic pain more effectively than progestins.74,75
To add a further twist, endometriotic tissue produces large quantities of progesterone and contains much lower levels of progesterone receptors
than endometrium.23,57 These seemingly disparate
observations make it difficult to form a unified
hypothesis regarding the role of progesterone in
endometriosis.
Estrogen and progesterone are essential and
sufficient to control all endometrial function by
regulating expression of hundreds to thousands
of genes during the menstrual cycle.76 Indeed, the
administration of estradiol and progesterone is
sufficient to prepare the endometrium for implantation in postmenopausal women undergoing donor embryo transfer.77 Progesterone induces the
differentiation of endometrial stromal cells (called
decidualization) and epithelial cells (resulting in
the secretory phenotype). Molecular markers of
progesterone action include increased production
of epithelial glycodelin (a glycoprotein produced
by the secretory endometrium during the luteal
phase) and stromal prolactin in endometrium.76,78,79
Progesterone, however, induces much lower levels
of prolactin expression in endometriotic cells than
in endometrial stromal cells, suggesting that progesterone resistance may be at play in endome
triosis.80
In the endometrium, progesterone exerts an
antiestrogenic effect, in part by inducing 17-
hydroxysteroid dehydrogenase 2 (HSD17B2), which
catalyzes the conversion of biologically potent estradiol to the much less estrogenic estrone.81-84
Progesterone acts by way of progesterone receptors
in endometrial stromal cells to increase formation
of retinoic acid, which in turn induces HSD17B2
expression in endometrial epithelial cells, in a
paracrine fashion.85-87 Endometriotic stromal cells,
however, fail to respond to progesterone and thus
do not produce retinoic acid (Fig. 3).88 In endometriotic tissue, this lack of retinoic acid leads
to the lack of epithelial HSD17B2 and the failure
to inactivate estradiol.88,89 In combination with
high estradiol production due to aberrant aromatase activity, this additional defect contributes
to the abnormally high levels of estradiol in endometriotic tissue.80
Gene-expression profiles of the endometrium
of women with and those without endometriosis
have shown that a number of genes targeted by

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Mechanisms of Disease

progesterone are deregulated during implantation,

at which time the endometrium is exposed to the
highest levels of progesterone.35,42 For example,
the prototypic gene responsive to progesterone,
glycodelin, is down-regulated in the endometrium
of women with endometriosis as compared with
women without endometriosis.35 These findings
suggest that eutopic endometrium of women with
endometriosis also exhibits progesterone resistance.35,90
Progesterone resistance is explicable by the extremely low progesterone-receptor levels in endometriotic tissue.23 In endometrium, levels of the
progesterone receptor isoforms, PR-B and PR-A,
progressively increase during the proliferative
phase, peak immediately before ovulation, and
diminish after ovulation, suggesting that estradiol
23 In constimulates progesterone-receptor levels.
Endometriosis
trast, PR-B is undetectable, and PR-A is markedly
reduced, in endometriotic tissues. Moreover, deficiency of the cochaperone FK506-binding protein of 52 kD, a peptidyl prolyl isomerase necessary for progesterone-receptor function in the
endometrium of baboons with endometriosis, may
contribute to progesterone resistance.91
Epigenetic Changes in Endometriosis

Levels of the nuclear receptors SF1, estrogen receptors and , and progesterone receptors are
much different in endometriotic tissue than in
endometrium. The virtual absence of the orphan
nuclear receptor SF1 in endometrium and its presence at levels more than 12,000 times higher, in
endometriotic tissue, is in part determined by a
classic CpG (cytosinephosphateguanine) island
at its promoter that is heavily methylated in endometrial stromal cells and unmethylated in endometriotic stromal cells.52 In endometrial cells,
the silencer-type transcription factor methyl-CpGbinding domain protein 2 is recruited to the methylated SF1 promoter and prevents its interaction
with transcriptional activators (Fig. 4). In endometriotic cells, the transcription factor, upstream
stimulatory factor 2, binds to the unmethylated
SF1 promoter and activates it.92 Upstream stimulatory factor 2 levels are much higher in endometriotic tissue than in the endometrium. Thus, differential SF1 expression in endometriotic tissue as
compared with endometrium is primarily controlled by an epigenetic mechanism that permits
the binding of activator complexes, rather than inhibitor complexes, to its promoter.52,92

Endometriotic tissue

Endometrium

Coactivator

Corepressor

MeCP2
SF1 or ER-
promoters
Methylated
CpG

Coding
region

SF1 or ER-
promoters

Coding
region

Unmethylated
CpG

SF1 or ER-

Arachidonic acid
COX-2

ER-

ER-

PGE2

PR

SF1

RA

Cholesterol

Aromatase

Estradiol

HSD17B2

Estrone

Figure 4. Epigenetic Changes in Endometriotic Tissue.

COLOR FIGURE
Draft
7
12/29/08
The promoters of two nuclear receptors, steroidogenic
factor
1 (SF1)
and
Bulun
estrogen receptor (ER-), are heavily methylatedAuthor
and thus
silenced in en4
Fig #
dometrial stromal cells. A lack of promoter methylation
is associated with
Endometriosis
Title
promoter activation and pathologic overexpression
of these nuclear recepME
tors in endometriotic stromal cells. SF1 mediates DE
prostaglandin
Schwartz E 2 (PGE 2)
Knoper estrogen redependent induction of estradiol production. ER-Artist
suppresses
AUTHOR PLEASE NOTE:
ceptor (ER-) and progesterone receptors (PRs),Figure
leading
to progesterone
has been redrawn
and type has been reset
Please check carefully
resistance and deficient inactivation of estradiol. Consequently,
in endodate 1/15/09
metriotic tissue, estradiol and PGE2 are producedIssue
in large
quantities and
enhance cell survival and inflammation. The corepressor and coactivator
are hypothetical. COX-2 denotes cyclooxygenase-2, CpG a cytosinephosphateguanine sequence, HSD17B2 17-hydroxysteroid dehydrogenase 2,
MeCP2 methyl-CpG-binding domain protein 2, and RA retinoic acid.

Among estrogen receptors, estrogen receptor

levels in endometriotic tissue are 142 times the
levels in endometrium, whereas estrogen receptor levels are 9 times the levels in endometrium.24 Hypomethylation of a CpG island at the
promoter region of the estrogen receptor gene
causes high levels of expression of the gene in
endometriotic stromal cells, and hypermethylation
silences it in endometrial stromal cells (Fig. 4).
Estrogen receptor in endometriotic stromal cells
occupies the estrogen receptor promoter and
down-regulates its activity, thus favoring the suppression of estrogen receptor levels.24 The high
ratio of estrogen receptor levels and estrogen
receptor levels in endometriotic stromal cells in
turn leads to increased estrogen receptor bind-

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275

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Cross section of a 5-week, 46,XX embryo

Location of
cross section
Yolk sac

Wolffian
duct

Origin of
mllerian duct
Aorta

Migrating
germ cells

Genital
ridge

Genetic or
environmental effects
Epigenetic aberrations in progenitor cells
Hypomethylation of SF1 and ER- promoters
Subtle differentiation defects of uterus,
ovaries, or pelvic peritoneum

Endometriotic phenotype

Gonadal
ridge

Coelomic
cavity

Hindgut

Figure 5. Speculated Changes in DNA Methylation from Genetic or Environmental Factors.

COLOR FIGURE
Draft factors
6
12/29/08
During the embryonic differentiation of the female genital tract, various environmental or genetic
may
cause
Author
Bulun
changes in DNA methylation, shown here for a 5-week embryo. If these epigenetic alterations
pathologically
affect
5
Fig #
the expression of critical genes such as steroidogenic factor 1 (SF1) or estrogen receptor Title
(ER-) in
progenitor
Endometriosis
cells destined to form various pelvic tissues, the ensuing molecular abnormalities may predispose
the
adult woman
ME
to endometriosis.
DE
Schwartz
Artist

Knoper
AUTHOR PLEASE NOTE:

Figure has been redrawn and type has been reset

Please check carefully

ing to the progesterone-receptor promoter and endometrium, whereas theIssue

lack
of methylation redate 1/15/09
mediates the down-regulation of expression of sults in extraordinarily high levels of SF1 and esprogesterone receptors (Fig. 4).
trogen receptor in endometriotic tissue (Fig. 4).
In response to the exposure of endometriotic cells
to prostaglandin E2, SF1 coordinately binds to the
C onclusions
promoters of multiple steroidogenic genes, includIncreased cell survival, inflammation, and defi- ing that of aromatase, and causes the formation of
cient differentiation in endometriosis have been large quantities of estradiol. Estradiol acts by way
linked to a stromal-cell defect involving the exces- of estrogen receptor to stimulate COX-2, leading
sive formation of estrogen and prostaglandin, as to the overproduction of prostaglandin E2. Thus,
well as progesterone resistance, all of which origi- inflammation and estrogen are linked in a feednate from two distinct epigenetic changes that af- back cycle involving the overexpression of genes
fect the transcription factors SF1 and estrogen re- that encode the aromatase and COX-2 enzymes
ceptor . The CpG islands occupying the promoters and continuous formation of the products of aroof the genes encoding SF1 and estrogen receptor matase and COX-2 estradiol and prostaglandin
are heavily methylated and silence these genes in E2 in endometriotic tissue. Moreover, estrogen
276

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Mechanisms of Disease

receptor suppresses progesterone-receptor levels, resulting in progesterone resistance and disruption of a paracrine pathway that inactivates estradiol. Large amounts of estradiol accumulate,
owing to its increased formation and deficient
inactivation in endometriotic tissue (Fig. 4).
This working model (Fig. 4) is clinically relevant because the targeting of aromatase, COX-2,
estrogen receptor , or progesterone receptors reduces pelvic pain and ablates visible endometriotic
tissue.93 Finally, I speculate that genetic predisposition or the exposure to environmental toxins
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Supported in part by grants from the National Institutes of
Health (HD38691 and HD40093) and from the Friends of Prentice.
Dr. Bulun reports receiving consultation fees from Meditrina
Pharmaceuticals, GlaxoSmithKline, and Novartis. No other potential conflict of interest relevant to this article was reported.
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