Endometriosis: Pathogenesis, Clinical Features, and Diagnosis - UpToDate

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Endometriosis: Pathogenesis, clinical features, and

diagnosis
Author: Robert S Schenken, MD
Section Editor: Robert L Barbieri, MD
Deputy Editor: Kristen Eckler, MD, FACOG
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2021. | This topic last updated: Apr 27, 2021.
INTRODUCTION
Endometriosis is defined as endometrial glands and stroma that occur outside the uterine cavity.
The lesions are typically located in the pelvis but can occur at multiple sites including the bowel,
diaphragm, and pleural cavity. While endometriosis is a common and nonmalignant process,
ectopic endometrial tissue and resultant inflammation can cause dysmenorrhea, dyspareunia,
chronic pain, and infertility. Symptoms can range from minimal to severely debilitating.
Endometriosis is an estrogen-dependent, benign, inflammatory disease that affects women
during their premenarcheal, reproductive, and postmenopausal hormonal stages.
This topic will review the clinical presentation and diagnosis of endometriosis. Information on the
treatment of endometriosis is presented separately.
● (See "Endometriosis: Treatment of pelvic pain".)

● (See "Endometriosis: Surgical management of pelvic pain".)
● (See "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists".)
PATHOLOGY AND SITES OF INVOLVEMENT
Gross and microscopic pathology — Endometriosis lesions in the pelvis can be categorized as
superficial peritoneal, ovarian, and deeply infiltrating [1]. Similar to eutopic endometrial tissue,
endometriosis lesions contain endometrial glands and stroma ( picture 1). Unlike eutopic
endometrium, however, endometriosis implants often contain fibrous tissue, blood, and cysts.
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Breakdown of red blood cells by inflammatory cells results in formation of pigmented histiocytes
and hemosiderin-laden macrophages; the older the lesion, the more likely it is to be pigmented
[2]. The gross appearance and size of the implants are quite variable at the time of surgery [3].
(See 'Surgical exploration' below.)
Superficial peritoneal lesions — While superficial peritoneal lesions classically contain

endometrial glands and stroma, diagnostic challenges arise when there are alterations or absence
of glandular or stromal components [3]. The glandular component can be absent, sparse, or
transformed by hormonal and metaplastic changes or cellular atypia. The stromal component can
be obscured by infiltrates of foamy and pigmented histiocytes, fibrosis, or other processes.
Inflammatory and reactive changes within or adjacent to foci of endometriosis can also confuse
the histologic findings. Histologic diagnosis can also be hindered by a small biopsy sample.
Ovarian lesion (endometrioma) — An ovarian cyst, or endometrioma, is formed when ectopic

endometrial tissue within the ovary bleeds and results in a hematoma surrounded by duplicated
ovarian parenchyma [4]. Both ovaries are involved in one-third of cases. In contrast with most
hemorrhagic physiologic ovarian cysts, endometriomas typically have fibrotic walls and surface
adhesions; are filled with syrup-like chocolate-colored material; are surrounded by duplicated
ovarian parenchyma [1]; and are lined by endometrial epithelium, stroma, and glands [5].
Epithelial abnormalities, such as complex hyperplasia or atypia, can develop in the cyst lining; the
clinical significance of these changes has not been determined [6-10]. The endometrial epithelium
and stroma lining the endometrioma can be lost over time and replaced by granulation tissue and
dense fibrous tissue, which makes histological diagnosis difficult. In these cases, the contents of
the cyst (semi-fluid chocolate-colored material versus watery fluid), presence of adhesions and
hemosiderin-filled macrophages (indicative of chronic bleeding), and histologically proven
endometriosis at other sites in the pelvis aid the diagnosis.
Management of ovarian endometriomas is presented separately. (See "Endometriosis:

Management of ovarian endometriomas".)
Deeply infiltrating endometriosis — Deeply infiltrating endometriosis (DIE) is defined as a

solid endometriosis mass situated more than 5 mm deep to the peritoneum [11]. DIE generally is
found in the retrovaginal septum (also referred to as the rectocervical septum), rectum,
retrosigmoid colon, bladder, ureter, and other pelvic fibromuscular structures such as the uterine
ligaments and vagina [12]. (See "Endometriosis: Clinical manifestations and diagnosis of
rectovaginal or bowel disease" and "Endometriosis of the bladder and ureter".)
Anatomic sites — In general, the most common sites of endometriosis, in decreasing order of
frequency, are the ovaries, anterior and posterior cul-de-sac, posterior broad ligaments,
uterosacral ligaments, uterus, fallopian tubes, sigmoid colon and appendix, and round ligaments
[13,14]. A prospective observational study of 1101 consecutive patients with laparoscopically-
confirmed endometriosis reported the most frequent sites of endometriosis were the ovary (67
percent), uterosacral ligaments (46 percent), ovarian fossa (32 percent), the pouch of Douglas (30
percent), and the bladder (21 percent) [15]. Fourteen percent of patients were diagnosed with
deeply infiltrating endometriosis. Other sites less commonly involved include the vagina, cervix,
rectovaginal septum, cecum, ileum, inguinal canals, perineal scars, urinary bladder, ureters, and
umbilicus [16-18].
Occasionally, an endometrioma arises in the anterior abdominal wall, usually in the vicinity of a
surgical incision [19-25], although these lesions can occur in women with no history of surgery or
history of endometriosis. Rarely, endometriosis has been reported in the breast, pancreas, liver,
gallbladder, kidney, urethra, extremities, vertebrae, bone, peripheral nerves, spleen, diaphragm,
central nervous system, hymen [26], and lung [27]. Most women have multiple areas of
involvement. (See "Thoracic endometriosis: Pathogenesis, epidemiology, and pathology".)
EPIDEMIOLOGY AND RISK FACTORS
While the prevalence varies with the population being studied, approximately 10 percent of
reproductive-age women globally have endometriosis [28-30]. Determining the prevalence of
endometriosis in the general population is challenging because some women are asymptomatic,
those with symptoms can have varied and nonspecific presentations, and definitive diagnosis
typically requires surgery [31]. In four studies of mainly asymptomatic women undergoing tubal
ligation, the prevalence of endometriosis ranged from 1 to 7 percent [32-35]. In a case-control
study of over 5500 women from a national database, the prevalence of endometriosis varied from
1.2 to 1.5 percent, depending upon the inclusion criteria [36]. In a retrospective cohort study of
over 9500 women undergoing laparoscopic or abdominal hysterectomy for benign indications, 15
percent of women were diagnosed with endometriosis [37]. When the prevalence of
endometriosis was assessed by surgical indication, endometriosis was present in 57 percent of
women with endometriosis as a preoperative indication, in 21 percent of women with
preoperative pelvic pain, and in 8 percent of women without anticipated endometriosis or pelvic
pain.
The prevalence of endometriosis in symptomatic referral populations appears to be much higher.

Endometriosis has been reported in up to 40 percent of adolescents with genital tract anomalies
[38], up to 50 percent of women with infertility [39], and up to 70 percent of women and
adolescents with pelvic pain [40-43].
Factors associated with an increased risk of endometriosis include nulliparity [36,44,45],
prolonged exposure to endogenous estrogen (eg, early menarche [before age 11 to 13 years] [46-
48] or late menopause [47]), shorter menstrual cycles (defined as ≤27 days) [36], heavy menstrual
bleeding [36], obstruction of menstrual outflow (eg, müllerian anomalies [47,49]), exposure to
diethylstilbestrol in utero [50], height greater than 68 inches [44], lower body mass index [36,44],
exposure to severe physical and/or sexual abuse in childhood or adolescence [51], and a high
consumption of trans unsaturated fat [52].
Factors associated with a decreased risk of endometriosis include multiple births [53,54],
extended intervals of lactation [53,55], and late menarche (after age 14 years) [46]. Increased
consumption of long-chain omega-3 fatty acids has been associated with a reduced risk of
endometriosis in one prospective study [52]. Race may also be a risk factor, as the prevalence of
endometriosis has been reported as being higher in White and Asian women compared with Black
and Hispanic women [53]. Regarding risk of endometrioma, one retrospective study reported that
among women with peritoneal endometriosis, ovarian endometrioma was less common in those
women who had used oral contraceptive pills compared with women who had not (18 versus 49
percent) [56].
PATHOGENESIS
Endometriosis results when ectopic endometrial cells implant, grow, and elicit an inflammatory
response [47]. The pathogenesis of endometriosis appears to be multifactorial, including ectopic
endometrial tissue, altered immunity, imbalanced cell proliferation and apoptosis, aberrant
endocrine signaling, and genetic factors. Meta-analysis of eight genome-wide association studies
has identified at least six genomic regions that are statistically associated with endometriosis [57].
In addition, a study that analyzed exome sequencing of nonmalignant deep endometriosis lesions
reported somatic mutations in 79 percent of lesions and mutations in the known cancer driver
genes ARID1A, PIK3CA, KRAS, and PPP2R1A in 26 percent of lesions [58]. The presence of cancer
driver mutations in nonmalignant cells may partly explain the aggressive nature of deeply invasive
lesions compared with superficial peritoneal lesions. In addition, these mutations were only found
in the epithelial, but not stromal, cells, which suggests a unique selective pressure. More studies
are needed to elucidate the role of these genes and gene alterations in deep endometriosis
lesions.
According to the most common theory of ectopic endometrial cells (Sampson's theory of
retrograde menstruation), endometrial cells flow backwards through the fallopian tubes and into
the peritoneal cavity during menses [59]. Other potential sources of ectopic endometrial cells
include mesothelium, stem cells, müllerian rests [60], bone marrow stem cells [60,61], and
embryonic vestiges [62] as well as lymphatic or vascular dissemination [63] and coelomic
metaplasia [64]. Evidence supporting retrograde menstruation comes from the observation that
the incidence of endometriosis is increased in girls with genital tract obstructions that prevent
drainage of menses through the vagina and therefore increase tubal reflux [38,65]. However,
while up to 90 percent of women have retrograde menstruation [66], most women do not develop
endometriosis, which suggests that additional factors are involved [1].
The existence of endometriosis in girls prior to menstruation, and thus not yet exposed to
retrograde menstruation, challenges the retrograde menstruation hypothesis regarding the
etiology of endometriosis. Possible explanations for premenarcheal endometriosis include the
existence of müllerian embryonic rests [67], that these lesions are preexisting antecedents to the
classic form of endometriosis [68], and that the lesions are the result of neonatal uterine bleeding,
including retrograde bleeding, caused by maternal hormone exposure [69,70].
Once endometriosis is established, the process appears to cause symptoms through inflammatory
changes. Endometriosis-related pelvic pain is associated with increased production of
inflammatory and pain mediators as well as neurologic dysfunction related to the implants [71-
75]. An increase of nerve fibers [71,76] and imbalance of sympathetic and sensory nerve fibers
[77,78] have been demonstrated in women with endometriosis-related pain. Proposed
mechanisms for pain symptoms include estrogen acting as a neuromodulator that selectively
repulses the sympathetic axons while preserving sensory innervation [79], inflammation
stimulating peripheral nerve sensitization [80], and chronic pain inducing changes in the central
nervous system [81].
The mechanism for subfertility appears to involve anatomic distortion from pelvic adhesions and
endometriomas and/or production of substances (eg, prostanoids, cytokines, growth factors) that
are "hostile" to normal ovarian function/ovulation, fertilization, and implantation. (See "Treatment
of infertility in females with endometriosis", section on 'Pathogenesis of infertility from
endometriosis'.)
CLINICAL MANIFESTATIONS
Patient presentation — Women with endometriosis classically present during their reproductive
years with pelvic pain (including dysmenorrhea and dyspareunia), infertility, or an ovarian mass
[1,31,45]. Women can also present with endometriosis that was incidentally diagnosed during
surgery or imaging for other indications. While the peak prevalence of endometriosis occurs in
women 25 to 35 years of age [53,82], the disease has been reported in premenarcheal girls [83]
and in 2 to 5 percent of postmenopausal women [84].
In a study of 1000 women with endometriosis, approximately 80 percent presented with pain, 25
percent with infertility, and 20 percent with an endometrioma (ovarian mass) [45]. Dysmenorrhea
associated with endometriosis is dull or crampy pelvic pain that typically begins one to two days
before menses, persists throughout menses, and can continue for several days afterward. Pelvic
pain is typically chronic and described as dull, throbbing, sharp, and/or burning [85,86]. Pelvic
pain or pressure are also the most common symptoms associated with an adnexal mass [87].
Additional endometriosis symptoms include bowel and bladder dysfunction, abnormal uterine
bleeding, low back pain, or chronic fatigue, although these symptoms are less common
[1,45,88,89]. Symptoms can occur alone or in combination. An increased number of symptoms has
been associated with increased likelihood of endometriosis [36,90].
The type of endometriosis is suggested by the constellation of symptoms. Examples include:
● Women with peritoneal or deeply infiltrating endometriosis often present with dyspareunia.
Deeply infiltrating endometriosis lesions can occur on the uterosacral and cardinal ligaments,
pouch of Douglas, posterior vaginal fornix, and anterior rectal wall [91]. Introital, or
superficial, dyspareunia can result from lesions of the cervix [92,93], hymen [26], perineum
[94], and episiotomy scars [95-97]. (See 'Anatomic sites' above and "Endometriosis: Clinical
manifestations and diagnosis of rectovaginal or bowel disease", section on 'Clinical
manifestations'.)
● Women with bladder endometriosis typically present with nonspecific urinary symptoms of
frequency, urgency, and pain at micturition [98]. Symptoms can be worsened with menses.
Ureteral endometriosis can be asymptomatic or associated with colicky flank pain or gross
hematuria. (See "Endometriosis of the bladder and ureter", section on 'Bladder endometriosis'
and "Endometriosis of the bladder and ureter", section on 'Ureteral endometriosis'.)
● Women with bowel endometriosis can present with diarrhea, constipation, dyschezia, and
bowel cramping [99,100]. Women with deeply infiltrating endometriosis implants of the
posterior cul-de-sac and rectovaginal septum typically present with dyspareunia and painful
defecation [101,102]. Rectal bleeding may occur but is rare. (See "Endometriosis: Clinical
manifestations and diagnosis of rectovaginal or bowel disease", section on 'Clinical
manifestations'.)
● Women with endometriosis of the abdominal wall typically present with a painful abdominal
wall mass; the pain may be cyclic with menses or continuous [24]. Bleeding may also occur.
Cyclic bleeding has also been reported with vulvar endometriosis [103].
● Women with thoracic endometriosis can present with chest pain, pneumothorax or
hemothorax, hemoptysis, or scapular or cervical (neck) pain [104,105]. The symptoms are
often catamenial. (See "Clinical features, diagnostic approach, and treatment of adults with
thoracic endometriosis".)
Symptoms — In a national case-control study of over 5500 women with endometriosis, 73 percent
of women with endometriosis reported abdominopelvic pain, dysmenorrhea, or heavy menstrual
bleeding compared with 20 percent of control women [36]. A cohort study including over 600
women with endometriosis identified a visceral syndrome of seven symptoms associated with
endometriosis that included abdominal pain with no relation to menstruation, pain during
urination, pain during defecation, constipation or diarrhea, irregular bleeding, nausea or
vomiting, and feeling tired or lacking energy [90]. Women with endometriosis were more likely to
report five to seven symptoms compared with unaffected women (20 versus 2 percent).
Physical examination — Physical examination findings in women with endometriosis are variable
and depend upon the location and size of the implants [106]. Findings suggestive of
endometriosis include tenderness on vaginal examination, nodules in the posterior fornix,
adnexal masses, and immobility or lateral placement of the cervix or uterus ( figure 1) [31].
Rarely, an endometriosis lesion will be visualized on the cervix or vaginal mucosa ( picture 2).
While physical examination findings are helpful, the examination can also be normal; lack of
findings does not exclude the disease. The approach to the pelvic examination is reviewed in detail
separately. (See "The gynecologic history and pelvic examination", section on 'Components of the
examination'.)
Laboratory — There are no pathognomonic laboratory findings for endometriosis. While several
urinary and endometrial biomarkers have been studied for the noninvasive diagnosis of disease,
none are clinically useful [107-109]. Serum cancer antigen (CA) 125 concentration can be elevated
in women with endometriosis (ie, greater than 35 units/mL) [110,111], although the role of serum
CA 125 in primary diagnosis is undefined [1]. However, serum CA 125 concentrations are not
routinely ordered in women being evaluated or treated for endometriosis because other diseases,
notably ovarian carcinoma, also elevate the serum CA 125 concentration ( table 1). (See "Serum
biomarkers for evaluation of an adnexal mass for epithelial carcinoma of the ovary, fallopian tube,
or peritoneum", section on 'Cancer antigen 125'.)
Imaging — Imaging findings suggestive of pelvic endometriosis include ovarian cysts

(endometriomas) ( image 1A-B), nodules of the rectovaginal septum, and bladder nodules (
image 2). These findings are typically seen with transvaginal ultrasound but can also be viewed
with magnetic resonance imaging (MRI) [112,113]. Endometriomas are generally easily classifiable
on sonography [114].
Abdominal wall endometriosis appears as a hypoechoic, vascular, and/or solid mass (although
cystic changes can be present) on ultrasound [115]. Margins are irregular, often spiculated, and
may appear to infiltrate adjacent tissues [116]. Thoracic endometriosis can be identified on
computed tomography ( image 3) and MRI studies [104,117]. MRI will accurately diagnose
thoracic endometriosis in up to 95 percent of cases [104,118-120].
DIAGNOSTIC EVALUATION
The diagnostic evaluation is guided by the patient presentation, symptoms, and physical
examination findings. For a detailed discussion by patient presentation, refer to the following
topics:
● Women with pelvic pain (see "Chronic pelvic pain in adult females: Evaluation")
● Women with dyspareunia (see "Female sexual pain: Evaluation", section on 'Diagnostic
evaluation')
● Women with infertility (see "Evaluation of female infertility", section on 'Initial approach')
● Women with an adnexal mass (see "Approach to the patient with an adnexal mass", section on
'Clinical approach')
● Women suspected of having thoracic endometriosis (see "Clinical features, diagnostic

approach, and treatment of adults with thoracic endometriosis")
DIAGNOSIS
Definitive diagnosis — Endometriosis is definitively diagnosed by histologic evaluation of a lesion

biopsied during surgery (typically laparoscopy) ( picture 1 and picture 3 and picture 4 and
movie 1) [121,122]. While visual confirmation of endometriosis without biopsy is considered
diagnostic by some experts [88], visual confirmation alone is of limited value because the accuracy
is impacted by the surgeon's expertise [88,123,124]. (See 'Surgical exploration' below.)
Definitive diagnosis of endometriosis is often delayed because the symptoms of endometriosis

are vague, the symptoms overlap with a number of gynecologic and gastrointestinal processes,
and a surgical diagnosis entails risk. Studies have reported an average diagnostic delay of 7 to 12
years in women with endometriosis [125-129].
Role of presumptive diagnosis — While definitive diagnosis requires tissue biopsy and histologic
confirmation, the combination of symptoms, signs, and imaging findings can be used to make a
presumptive, nonsurgical diagnosis of endometriosis [130,131]. A clinical diagnosis can be
sufficient to initiate therapy that is low risk and easily tolerated (eg, estrogen-progestin
contraceptives in women who are not trying to conceive). However, the presence or absence of a
response to empiric treatment cannot be construed as definitive confirmation or exclusion of the

diagnosis [132]. (See 'Patient presentation' above and "Endometriosis: Treatment of pelvic pain".)
Nonsurgical diagnosis — Possible options for non-surgical diagnosis include clinical diagnosis
based upon examination and imaging findings or serum diagnosis using microRNA markers
[133,134].
A nonsurgical diagnosis of endometriosis includes: (1) ultrasonographic finding of ovarian

endometrioma, (2) visual inspection of the posterior vaginal fornix and biopsy of rectovaginal
lesions, (3) cystoscopic evaluation and biopsy of detrusor lesions, and (4) physical examination
findings of rectovaginal endometriosis that are confirmed with imaging [133]. Although this
approach does not require laparoscopy, tissue biopsy can still provide a definitive diagnosis while
imaging findings make the diagnosis highly likely [135-140]. Of note, this approach is useful only
for clinicians with significant skill in the examination, sonography, and cystoscopy of women with
endometriosis.
SURGICAL EXPLORATION
Indications — Indications for surgical exploration include diagnosis of persistent pelvic pain that
does not respond to medical therapy, evaluation of severe symptoms that limit function, and
treatment of anatomic abnormalities, such as bladder lesions. Surgery, almost always
laparoscopy, allows both definitive diagnosis and treatment. (See 'Diagnosis' above and
"Endometriosis: Treatment of pelvic pain", section on 'Our approach' and "Chronic pelvic pain in
adult females: Evaluation", section on 'Role of laparoscopy'.)
Findings — During laparoscopy, areas of peritoneal endometriosis appear as raised flame-like

patches, whitish opacifications, yellow-brown discolorations, translucent blebs, or reddish or
reddish-blue irregularly-shaped islands ( picture 3 and picture 4 and movie 1). The
appearance of some blue/brown lesions has been described as "powder burns." The peritoneal
surface can be scarred or puckered, have defects (Allen-Masters syndrome), or give rise to nodules
or cysts. Rarely, endometriosis appears as a polyploid mass, which may mimic the appearance of
malignant tumor. Dense fibrous adhesions signify severe disease. (See 'Surgical staging of disease'
below.)
The accuracy of laparoscopic diagnosis depends upon the location and type of the lesion, the
experience of the operator, and the extent of disease [141,142]. In a study of 976 women who
underwent laparoscopy and biopsy for pelvic pain and/or infertility, the laparoscopic findings had
a sensitivity of 98 percent, specificity of 79 percent, positive predictive value of 72 percent, and
negative predictive value of 98 percent in diagnosing endometriosis compared with histology
alone [143]. Women with classic endometriosis lesions at laparoscopy but negative histology are
treated for endometriosis because negative biopsies can result from inadequate sampling.
Laparoscopy that does not demonstrate visual or histologic disease is highly reliable for excluding
endometriosis [124], although occult microscopic submesothelial implants can be present in
normal-appearing peritoneum. It is not known if these implants cause symptoms. While
endometriosis can be present in the absence of an apparent lesion [144,145], it is not standard
practice to perform random biopsies during laparoscopy. Given that endometriosis lesions can
regress in response to hormonal treatment, laparoscopy is not typically performed during or
within three months of hormonal treatment to minimize the risk of under-diagnosis of disease
[88].
The technique for laparoscopic exploration for women with suspected endometriosis is discussed
in detail separately. (See "Endometriosis: Surgical management of pelvic pain", section on
'Exploration and diagnosis'.)
Surgical staging of disease — Endometriosis is surgically staged according to the revised

American Society for Reproductive Medicine scoring system ( form 1 and figure 2) [121]:
● Stage I – Minimal disease is characterized by isolated implants and no significant adhesions.
● Stage II – Mild endometriosis consists of superficial implants that are less than 5 cm in
aggregate and are scattered on the peritoneum and ovaries. No significant adhesions are
present.
● Stage III – Moderate disease exhibits multiple implants, both superficial and deeply invasive.
Peritubal and periovarian adhesions may be evident.
● Stage IV – Severe disease is characterized by multiple superficial and deep implants, including
large ovarian endometriomas. Filmy and dense adhesions are usually present.
The utility of the classification system is that it provides a standard approach for reporting
operative findings. The stage of endometriosis does not correlate with the occurrence or severity
of pain symptoms [91,106,146]. However, studies have reported an inverse correlation between
advanced stages of endometriosis and the prognosis for fertility treatments [147,148]. (See
"Treatment of infertility in females with endometriosis".)
Of note, a separate classification exists for patients with pain to document pelvic adhesions and
characteristics of lesions, but it is not widely used [149].
DIFFERENTIAL DIAGNOSIS
Many of the symptoms of endometriosis overlap with other conditions. A case-control study of
over 5500 women with endometriosis reported symptoms of abdominopelvic pain,
dysmenorrhea, or heavy menstrual bleeding in 20 percent of control women as well as 73 percent
of women with endometriosis [36]. The overlap of symptoms emphases the need for tissue biopsy
and histology to confirm the diagnosis and exclude other possible causes. (See 'Diagnosis' above
and 'Diagnostic evaluation' above.)
NATURAL HISTORY
The number of peritoneal areas affected by endometriosis appears to increase during

adolescence until the early 20s [150]. However, not all disease progresses. In studies where
second-look laparoscopy was performed 6 to 12 months after a diagnostic laparoscopy confirmed
endometriosis, disease progressed in 29 to 45 percent of untreated women, regressed in 22 to 29
percent, and remained stable in 33 to 42 percent [151-153]. In a prospective study that followed 88
asymptomatic women with rectovaginal disease for one to nine years, fewer than 10 percent of
the women had disease progression, defined as development of symptoms or increase in lesion
size [154]. Factors that cause endometriosis to progress, regress, or remain stable are not yet
known.
While endometriosis generally effects reproductive age women, endometriosis has been
confirmed in premenarcheal girls (without associated obstructive uterine anomalies) as young as
8.5 years of age [67] and is believed to affect up to 2 to 4 percent of postmenopausal women
[155,156]. It is not known if postmenopausal endometriosis results from lesions established
during the reproductive years or if postmenopausal endometriosis arises de novo. Symptomatic
postmenopausal endometriosis occurs in women both on and off hormone therapy. In a study of
72 women with symptomatic postmenopausal endometriosis, only two were using hormone
therapy at the time of surgery [157]. At least one case of postmenopausal endometriosis that
required pelvic exenteration for treatment has been reported [158].
PREGNANCY
Course during pregnancy — During pregnancy, endometriosis lesions and their resultant
symptoms often disappear or improve, which has been attributed to decidualization of the lesions
in response to the altered hormonal environment [159]. However, decidualization of lesions does
not make them biologically inactive. Case reports have described complications caused by
endometriosis in pregnant women, including intestinal perforation [160], hemoperitoneum [161-
164], uroperitoneum [165,166], acute appendicitis [167,168], and ruptured or infected ovarian
endometrioma [169]. Possible mechanisms of endometriosis-induced complications during
pregnancy include traction by the growing uterus on adhesions, increased friability of inflamed
tissues, and alteration of vessel walls by decidualized lesions (either intrusion or retraction) [169].
As these events are rare overall, no additional monitoring or interventions are recommended for
pregnant women with a history of endometriosis.
Obstetric outcomes — Endometriosis appears to negatively impact pregnancy outcome,

particularly increasing the risk of preterm birth [170-176]. In a retrospective population-based
study of over 82,000 singleton pregnancies, endometriosis was associated with an increased risk
of preterm birth, preeclampsia, and cesarean delivery when compared with no endometriosis
[170]. In a different national population-based cohort study of over 14,500 women followed over a
30-year time period, women with endometriosis had an increased risk of miscarriage, ectopic
pregnancy, placenta previa, unexplained antepartum hemorrhage, postpartum hemorrhage, and
preterm birth when compared with unaffected women [171]. Lastly, a meta-analysis of 33 studies
that included over 3 million pregnant women reported that, among women who conceived
spontaneously, endometriosis was associated with placenta previa, cesarean delivery, preterm
birth, and low birth weight [177]. These large studies support the findings of prior smaller studies
that noted an increased risk of preterm birth [172-175] and miscarriage [174,178,179] in women
with endometriosis. In contrast, other studies have reported decreased or no change in risk of
hypertensive disorders of pregnancy in women with endometriosis [180,181]. The mechanism
behind these associations is not known, and additional surveillance for pregnant women with
known endometriosis is not advised [169].
ASSOCIATED OUTCOMES
Link to cancer — Endometriosis appears to be associated with some epithelial ovarian cancers
(EOC) [182]; whether women with endometriosis are at risk for other types of cancers is unclear,
but the overall risk appears to be low [183-185]. In a meta-analysis of 13 case-control studies
including nearly 8000 women with EOC, women with a self-reported history of endometriosis had
three times the risk of clear cell EOC and double the risk of endometrioid and low-grade serous
EOC but no change in risk of high-grade serous or mucinous EOC [186]. A subsequent population-
based study of nearly 50,000 Finnish women with endometriosis again reported an overall
increased risk of ovarian cancer (endometrioid, clear cell, and serous types) in women with ovarian
endometriomas (ie, ovarian endometriosis; overall standardized incidence ratio 2.56, 95% CI 1.98-
3.27), but not for women with peritoneal or deep infiltrating endometriosis [187]. The excess risk
of ovarian cancer for women with ovarian endometriosis resulted in two additional cases per 1000
women followed for 10 years. In this study, there was no statistically significant association with
isolated peritoneal endometriosis and ovarian cancer.
Activation of oncogenic KRAS and PI3K pathways and inactivation of tumor suppressor genes PTEN
and ARID1A have been suggested as mechanisms for the transformation of endometriosis,
particularly ovarian endometriomas, to malignancy [182]. The risk of malignant transformation of
endometriosis has been estimated at 1 percent for premenopausal women [188] and 1 to 2.5
percent for postmenopausal women [189,190]. In a study of women with postmenopausal
endometriosis, 35 percent (20 of 57) had different grades of metaplasia, hyperplasia, atypia, and
endometrioid carcinoma arising in ovarian endometriosis [157].
While there appears to be an association between endometriosis and EOC, endometriosis is not
considered a premalignant lesion, and screening is not recommended. There are no data
indicating that prophylactic removal of endometriosis lesions reduces the risk of EOC. However,
use of oral contraceptive pills decreases the risk of ovarian cancer in all users. (See "Epithelial
carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis" and
"Screening for ovarian cancer".)
Endometriosis-associated EOC appears to develop in younger women and has a better prognosis
than most cases of EOC [191,192]. In one retrospective series of 84 women with clear cell EOC,
women with carcinoma arising in endometriosis lesions were younger (49 versus 59 years old) and
had a better medial overall survival (196 versus 34 months) than women without endometriosis
[193]. (See "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum", section
on 'Prognosis'.)
Atherosclerosis and cardiovascular disease — A possible association between atherosclerosis

and endometriosis is supported by studies reporting a proatherogenic profile [194,195] and
increased subclinical atherosclerosis [196] in women with endometriosis. Two studies of women
with endometriosis reported increased risk of cardiovascular disease, including risk of myocardial
infarction, composite cardiovascular disease, and all-cause mortality [197,198].
In the prospective Nurses Health Study II, among 116,430 women enrolled in 1989, 5296 reported
laparoscopically confirmed endometriosis. In follow-up through 2009, there were 1438 incident
cases of coronary heart disease (CHD). The risk of combined CHD endpoints was increased in
women with endometriosis (risk ratio 1.62, 95% CI 1.39-1.89). Among the women with
endometriosis, compared with not having a hysterectomy, having had a
hysterectomy/oophorectomy was associated with an increased risk of CHD (1.51, 95% CI 1.34-
1.71). More data are needed on the risk of CHD in women with endometriosis and potential
benefits of CHD screening for these women.
RESOURCES FOR PATIENTS AND CLINICIANS
● www.endometriosis.org – A nonprofit website dedicated to information about endometriosis

and treatment.
● American College of Obstetricians and Gynecologists – Frequently asked questions about

endometriosis.
● Center for Young Women's Health – An informational site sponsored by Boston Children's
Hospital.
● American Society for Reproductive Medicine – Provides free materials on reproductive health
issues for patients.
● The Endometriosis Association – An independent, nonprofit, self-help organization of women

with endometriosis, clinicians, and others interested in the disease.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Endometriosis".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics."
The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have about a given condition.
These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and
more detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Endometriosis (The Basics)")
● Beyond the Basics topic (see "Patient education: Endometriosis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
● Pelvic endometriosis lesions can be categorized as superficial peritoneal, ovarian, and deeply
infiltrating. These lesions contain fibrous tissue, blood, and cysts in addition to endometrial
glands and stroma ( picture 1). The gross appearance and size of the implants vary. (See
'Pathology and sites of involvement' above.)
● The pathogenesis of endometriosis has not been definitively established and appears to be
multifactorial, including ectopic endometrial tissue, altered immunity, imbalanced cell
proliferation and apoptosis, aberrant endocrine signaling, and genetic factors. (See
'Pathogenesis' above.)
● Women with endometriosis classically present during their reproductive years with pelvic pain
(including dysmenorrhea and dyspareunia), infertility, and/or an ovarian mass. Less common
symptoms include bowel and bladder dysfunction (eg, dyschezia and dysuria), abnormal
uterine bleeding, low back pain, or chronic fatigue. For some women, the disease is
asymptomatic and is an incidental finding at the time of surgery or imaging done for other
indications. (See 'Clinical manifestations' above.)
● Physical examination findings consistent with endometriosis include: posterior vaginal fornix
tenderness; palpable tender nodules in the posterior cul-de-sac, uterosacral ligaments, or
rectovaginal septum; lateral displacement of the cervix; fixation of the cervix, adnexa, or
uterus; and/or a tender adnexal mass. (See 'Physical examination' above.)
● Endometriosis does not cause laboratory abnormalities. While endometriosis can cause an
elevation in serum cancer antigen (CA) 125 levels, CA 125 levels are not useful in the primary
diagnosis of endometriosis as multiple other processes can elevate the level ( table 1). (See
'Laboratory' above.)
● Imaging findings suggestive of endometriosis include ovarian endometriomas ( image 1A-B

), deep nodules of the rectovaginal septum (deeply infiltrating endometriosis), and bladder
detrusor lesions ( image 2). (See 'Imaging' above.)
● Endometriosis is definitively diagnosed by histologic evaluation of lesions biopsied during

surgery, typically laparoscopy. During surgery, endometriosis is staged according to the
revised American Society for Reproductive Medicine scoring system ( form 1 and figure 2
). The wide range of symptoms and etiologies emphasizes the need for tissue biopsy and
histology to establish the diagnosis and exclude other causes. (See 'Diagnosis' above and
'Surgical exploration' above and 'Differential diagnosis' above.)
● Although a presumptive diagnosis of endometriosis can be made based upon history, physical
examination, and imaging findings, surgical diagnosis is advised before initiating treatments
with a high risk of adverse effects (eg, danazol). (See 'Role of presumptive diagnosis' above.)
● Endometriosis has been associated with an increased risk of poor pregnancy outcomes,
epithelial ovarian cancer, and atherosclerosis. More data are needed before changes in
screening or patient care are made. (See 'Associated outcomes' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
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institution experience. Arch Gynecol Obstet 2012; 286:1571.
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endometriosis in the United Kingdom: a retrospective matched cohort study. BJOG 2021.
Topic 7384 Version 62.0
GRAPHICS
Peritoneal endometriosis
Light micrograph of peritoneal endometriotic implant shows endometrial glandular

epithelium (arrow) and surrounding stroma.
Courtesy of Robert Schenken, MD.
Graphic 71136 Version 2.0
Endometriosis can be associated with lateral displacement of the

cervix
Lateral displacement of the cervix, which can be documented by visual examination

of the cervix on speculum examination or by digital examination, is probably
caused by the asymmetric involvement of one uterosacral ligament by
endometriosis, causing one ligament to shorten and pull the cervix to that side of
the body.
Reproduced with permission from: Propst AM, Storti K, Barbieri RL. Lateral cervical displacement
is associated with endometriosis. Fertil Steril 1998; 70:568. Copyright © 1998 Elsevier Science.
Endometriotic lesion of the posterior vaginal fornix
These endometriotic lesions (dark lesions) infiltrate the vaginal mucosa and are
visible on speculum examination of the posterior vaginal fornix.
Conditions associated with an elevated serum CA 125 concentration
Gynecologic malignancies Nongynecologic conditions

Endometrial cancer Ascites
Epithelial ovarian, fallopian tube, and primary peritoneal Appendicular abscess

cancers
Cirrhosis and other liver disease
Benign gynecologic conditions Colitis
Adenomyosis Cystic fibrosis
Benign ovarian neoplasms Diverticulitis
Endometriosis Heart failure
Functional ovarian cysts Myocardial infarction
Meig syndrome Myocardiopathy
Menstruation Pancreatitis
Ovarian hyperstimulation Pericardial disease
Pelvic inflammatory disease Pleural effusion
Pregnancy Pneumonia
Uterine leiomyomas Pulmonary embolism
Recent surgery
Renal insufficiency
Sarcoidosis
Systemic lupus erythematosus
Tuberculosis peritonitis
Urinary tract infection
Nongynecologic cancers
Breast
Colon
Gallbladder
Hematologic malignancies
Liver
Lung
Pancreas
CA: cancer antigen.
Data from:
1. Buamah P. Benign conditions associated with raised serum CA-125 concentration. J Surg Oncol 2000; 75:264.
2. Miralles C, Orea M, Espana P, et. al. Cancer antigen 125 associated with multiple benign and malignant pathologies. Ann Surg Oncol
2003; 10:150.
3. Moss EL, Hollingworth J, Reynolds TM. The role of CA125 in clinical practice. J Clin Pathol 2005; 58:308.
Endometrioma
Transvaginal ultrasound image of the right adnexa showing an endometrioma of

the right ovary. The homogeneous echo pattern of the cyst contents (ie, "ground-
glass" appearance) is characteristic of an endometrioma (short arrow).
Reproduced with permission from: Thomas D Shipp, MD. Copyright © Thomas D Shipp, MD.
Endometriosis of the ovary
Axial CT scan of the pelvis in a 29-year-old woman demonstrates a well-

circumscribed, low attenuation mass (arrow) in the left pelvis immediately posterior
to the uterus. This mass was found to be an endometrioma of the left ovary at
surgery.
CT: computed tomography.
Courtesy of Jonathan Kruskal, MD.
Transabdominal ultrasound image of bladder endometriosis
Transabdominal sagittal pelvic ultrasonography showing a heterogeneous endometriotic nodule protruding from the posterior
wall of the bladder into the vesical lumen.
Reproduced with permission from: Berlanda N, Vercellini P, Carmignani L, et al. Ureteral and vesical endometriosis: Two different clinical entities
sharing the same pathogenesis. Obstet Gynecol Surv 2009; 64:830. DOI: 10.1097/OGX.0b013e3181c4bc3a. Copyright © 2009 Wolters Kluwer Health.
Unauthorized reproduction of this material is prohibited.
Chest computed tomography of a patient with thoracic endometriosis
Computed tomogram (CT) of the chest showing opacities in the right lower lobe (arrow) in a young
woman with chest pain during menstruation (panel A). The opacities have completely resolved two
weeks later after menstruation (panel B), illustrating the importance of obtaining imaging when
patients with suspected thoracic endometriosis are symptomatic peri-menstruation.
From: Chung SY, Kim SJ, Kim TH, et al. Computed tomography findings of pathologically confirmed pulmonary
parenchymal endometriosis. J Comput Assist Tomogr 2005; 29:815. Copyright © 2005. Reproduced with permission from
Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited.
Peritoneal endometriosis
The peritoneum in this woman with endometriosis is studded with reddish,

irregularly shaped implants.
Reprinted with permission. Copyright 1990 Syntex Laboratories, Inc. All rights reserved.
The top, middle, and bottom series are representative of red, white, and black
implants, respectively
Reproduced with permission from: Revised American Society for Reproductive Medicine classification of
endometriosis: 1996. Fertil Steril 1997; 67:817. Copyright ©1997 American Society for Reproductive Medicine.
American Society for Reproductive Medicine revised classification of

endometriosis
* If the fimbriated end of the fallopian tube is completely enclosed, change the point assignment to 16.
Denote appearance of superficial implant types as red ([R], red-pink, flamelike, vesicular blobs, clear
vesicles), white ([W], opacifications, peritoneal defects, yellow-brown), or black ([B], black, hemosiderin
deposits, blue). Denote percent of total described as R__ percent, W__ percent, and B __ percent. Total should
equal 100 percent.
Original figure modified for this publication. American Society for Reproductive Medicine classification of
endometriosis: 1996. Fertil Steril 1997; 67:817. Illustration used with the permission of Elsevier Inc. All rights
reserved.
Examples of the classification of endometriosis
Original figure modified for this publication. Revised American Society for Reproductive Medicine classification of
endometriosis: 1996. Fertil Steril 1997; 67:817. Illustration used with the permission of Elsevier Inc. All rights
reserved.
Contributor Disclosures
Robert S Schenken, MD Equity Ownership/Stock Options: Evestra. Grant/Research/Clinical Trial Support:
Evestra [Endometriosis, fibroids]. Consultant/Advisory Boards: Mitsubishi Tanabe [Endometriosis,
fibroids]. Robert L Barbieri, MD Nothing to disclose Kristen Eckler, MD, FACOG Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.
Conflict of interest policy

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Endometriosis: Pathogenesis, clinical features, and

● (See "Endometriosis: Treatment of pelvic pain".)

PATHOLOGY AND SITES OF INVOLVEMENT

Superficial peritoneal lesions — While superficial peritoneal lesions classically contain

Ovarian lesion (endometrioma) — An ovarian cyst, or endometrioma, is formed when ectopic

Management of ovarian endometriomas is presented separately. (See "Endometriosis:

Deeply infiltrating endometriosis — Deeply infiltrating endometriosis (DIE) is defined as a

EPIDEMIOLOGY AND RISK FACTORS

The prevalence of endometriosis in symptomatic referral populations appears to be much higher.

Factors associated with an increased risk of endometriosis include nulliparity [36,44,45],

The type of endometriosis is suggested by the constellation of symptoms. Examples include:

Imaging — Imaging findings suggestive of pelvic endometriosis include ovarian cysts

● Women suspected of having thoracic endometriosis (see "Clinical features, diagnostic

Definitive diagnosis — Endometriosis is definitively diagnosed by histologic evaluation of a lesion

Definitive diagnosis of endometriosis is often delayed because the symptoms of endometriosis

response to empiric treatment cannot be construed as definitive confirmation or exclusion of the

A nonsurgical diagnosis of endometriosis includes: (1) ultrasonographic finding of ovarian

Findings — During laparoscopy, areas of peritoneal endometriosis appear as raised flame-like

Surgical staging of disease — Endometriosis is surgically staged according to the revised

● Stage I – Minimal disease is characterized by isolated implants and no significant adhesions.

The number of peritoneal areas affected by endometriosis appears to increase during

Obstetric outcomes — Endometriosis appears to negatively impact pregnancy outcome,

Atherosclerosis and cardiovascular disease — A possible association between atherosclerosis

RESOURCES FOR PATIENTS AND CLINICIANS

● www.endometriosis.org – A nonprofit website dedicated to information about endometriosis

● American College of Obstetricians and Gynecologists – Frequently asked questions about

● The Endometriosis Association – An independent, nonprofit, self-help organization of women

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Basics topic (see "Patient education: Endometriosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Imaging findings suggestive of endometriosis include ovarian endometriomas ( image 1A-B

● Endometriosis is definitively diagnosed by histologic evaluation of lesions biopsied during

Use of UpToDate is subject to the Subscription and License Agreement.

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172. Stephansson O, Kieler H, Granath F, Falconer H. Endometriosis, assisted reproduction

endometriosis-affected women. Hum Reprod 2016; 31:1014.

188. Oxholm D, Knudsen UB, Kryger-Baggesen N, Ravn P. Postmenopausal endometriosis. Acta

Light micrograph of peritoneal endometriotic implant shows endometrial glandular

Courtesy of Robert Schenken, MD.

Graphic 71136 Version 2.0

Endometriosis can be associated with lateral displacement of the

Lateral displacement of the cervix, which can be documented by visual examination

Graphic 59765 Version 5.0

Endometriotic lesion of the posterior vaginal fornix