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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: Jan 2019. | This topic last updated: Jan 20, 2019.

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. 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

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 [28]. In four studies of mainly asymptomatic women
undergoing tubal ligation, the prevalence of endometriosis ranged from 1 to 7 percent [29-32]. 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 [33]. 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 [34]. 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 [35], up
to 50 percent of women with infertility [36], and up to 70 percent of women and adolescents with pelvic
pain [37-40].

Factors associated with an increased risk of endometriosis include nulliparity [33,41,42], prolonged
exposure to endogenous estrogen (eg, early menarche [before age 11 to 13 years] [43-45] or late
menopause [44]), shorter menstrual cycles (defined as ≤27 days) [33], heavy menstrual bleeding [33],
obstruction of menstrual outflow (eg, Müllerian anomalies [44,46]), exposure to diethylstilbestrol in utero
[47], height greater than 68 inches [41], lower body mass index [33,41], exposure to severe physical
and/or sexual abuse in childhood or adolescence [48], and a high consumption of trans unsaturated fat
[49].

Factors associated with a decreased risk of endometriosis include multiple births [50,51], extended
intervals of lactation [50,52], and late menarche (after age 14 years) [43]. Increased consumption of
long-chain omega-3 fatty acids has been associated with a reduced risk of endometriosis in one
prospective study [49]. Race may also be a risk factor, as the prevalence of endometriosis has been
reported as being higher in Caucasian and Asian women compared with black and Hispanic women
[50]. 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) [53].

PATHOGENESIS

Endometriosis results when ectopic endometrial cells implant, grow, and elicit an inflammatory response
[44]. 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 [54]. 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 [55]. 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 [56]. Other potential sources of ectopic endometrial cells include mesothelium,
stem cells, Müllerian rests [57], bone marrow stem cells [57,58], and embryonic vestiges [59] as well as
lymphatic or vascular dissemination [60] and coelomic metaplasia [61]. 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 [35,62]. However, while up to 90 percent of women have retrograde menstruation [63], 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 [64], that these lesions are preexisting antecedents to the classic form of
endometriosis [65], and that the lesions are the result of neonatal uterine bleeding, including retrograde
bleeding, caused by maternal hormone exposure [66,67].

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 [68-72]. An increase of nerve
fibers [68,73] and imbalance of sympathetic and sensory nerve fibers [74,75] 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 [76], inflammation stimulating peripheral nerve sensitization [77], and chronic pain inducing
changes in the central nervous system [78].

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 women 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 [1,28,42].
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
[50,79], the disease has been reported in premenarcheal girls [80] and in 2 to 5 percent of
postmenopausal women [81].

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) [42]. 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 [82,83]. Pelvic pain or pressure are also the most
common symptoms associated with an adnexal mass [84].

Additional endometriosis symptoms include bowel and bladder dysfunction, abnormal uterine bleeding,
low back pain, or chronic fatigue, although these symptoms are less common [1,42,85,86]. Symptoms
can occur alone or in combination. An increased number of symptoms has been associated with
increased likelihood of endometriosis [33,87].

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 [88]. Introital, or superficial, dyspareunia
can result from lesions of the cervix [89,90], hymen [26], perineum [91], and episiotomy scars [92-
94]. (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 [95]. 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 [96,97]. Women with deeply infiltrating endometriosis implants of the posterior cul-de-sac
and rectovaginal septum typically present with dyspareunia and painful defecation [98,99]. 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.

● Women with thoracic endometriosis can present with chest pain, pneumothorax or hemothorax,
hemoptysis, or scapular or cervical (neck) pain [100,101]. 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 [33]. 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 [87].
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 [102]. 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) [28]. 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 [103-105]. Serum cancer antigen (CA) 125 concentration can be elevated in women with
endometriosis (ie, greater than 35 units/mL) [106,107], 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) [108,109]. Endometriomas are generally easily classifiable on sonography [110].

Abdominal wall endometriosis appears as a hypoechoic, vascular, and/or solid mass (although cystic
changes can be present) on ultrasound [111]. Margins are irregular, often spiculated, and may appear to
infiltrate adjacent tissues [112]. Thoracic endometriosis can be identified on computed tomography
(image 3) and MRI studies [100,113]. MRI will accurately diagnose thoracic endometriosis in up to 95
percent of cases [100,114-116].

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 "Evaluation of chronic pelvic pain in women")
● Women with dyspareunia (see "Approach to the woman with sexual pain", 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

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) [117,118]. While visual
confirmation of endometriosis without biopsy is considered diagnostic by some experts [85], visual
confirmation alone is of limited value because the accuracy is impacted by the surgeon's expertise
[85,119,120]. (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 gynecological 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 [121-125].

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 [126,127]. A clinical diagnosis can be sufficient to
initiate therapy that is low risk and easily tolerated (eg, estrogen-progestin contraceptives). However, the
presence or absence of a response to empiric treatment cannot be construed as definitive confirmation
or exclusion of the diagnosis [128]. (See 'Patient presentation' above and "Endometriosis: Treatment of
pelvic pain".)

Nonsurgical diagnosis — Some endometriosis experts use a series of examination and imaging
findings to make a nonsurgical diagnosis of endometriosis. Although this approach does not require
laparoscopy, tissue biopsy can still provide a definitive diagnosis while imaging findings make the
diagnosis highly likely [129-134]. Of note, this approach is useful only for clinicians with significant skill in
the examination, sonography, and cystoscopy of women with endometriosis.

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 [135].

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 "Evaluation of chronic pelvic pain in women", 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 [136,137]. 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 [138]. 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 [120], 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 [139,140], 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 [85].

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) [117]:

● 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 [88,102,141]. However, studies have reported an inverse correlation between advanced
stages of endometriosis and the prognosis for fertility treatments [142,143]. (See "Treatment of infertility
in women 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 [144].

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
[33]. 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 [145]. 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 [146-148]. 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 [149]. 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
[64] and is believed to affect up to 2 to 4 percent of postmenopausal women [150,151]. 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 [152]. At least one case of
postmenopausal endometriosis that required pelvic exenteration for treatment has been reported [153].

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 [154]. However, decidualization of lesions does not make them biologically inactive. Case
reports have described complications caused by endometriosis in pregnant women, including intestinal
perforation [155], hemoperitoneum [156-159], uroperitoneum [160,161], acute appendicitis [162,163],
and ruptured or infected ovarian endometrioma [164]. 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)
[164]. As these events are rare overall, no additional monitoring or interventions are recommended for
pregnant women with a history of endometriosis.

Endometriosis appears to negatively impact pregnancy outcome, particularly increasing the risk of
preterm birth [165-171]. 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 [165]. 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 [166]. 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 [172]. These large studies support the findings of prior smaller
studies that noted an increased risk of preterm birth [167-170] and miscarriage [169,173] 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 [174,175]. The mechanism behind these
associations is not known, and additional surveillance for pregnant women with known endometriosis is
not advised [164].

ASSOCIATED OUTCOMES

Link to cancer — Endometriosis appears to be associated with some epithelial ovarian cancers (EOC)
[176]; whether women with endometriosis are at risk for other types of cancers is unclear, but the overall
risk appears to be low [177-179]. 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 [180]. 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 [181]. 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 [176]. The risk of malignant transformation of endometriosis has
been estimated at 1 percent for premenopausal women [182] and 1 to 2.5 percent for postmenopausal
women [183,184]. 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 [152].

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 [185,186]. 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 [187]. (See
"Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum", section on 'Prognosis'.)

Atherosclerosis and cardiovascular disease — As systemic chronic inflammation and increased

oxidative stress are present in the pathogenesis of both atherosclerosis and endometriosis, an elevated
risk of atherosclerosis and subsequent coronary heart disease (CHD) has been hypothesized in women
with endometriosis [188]. This association has been strengthened by studies reporting a proatherogenic
profile [189,190] and increased subclinical atherosclerosis [191] in women with endometriosis. A study
of over 116,000 women without heart disease or stroke reported that women with laparoscopically
confirmed endometriosis had an increased risk of myocardial infarction, coronary artery bypass graft
surgery or coronary angioplasty procedure/stent, or combined CHD endpoints compared with women
without endometriosis [192]. The risk of combined CHD was also higher in women who underwent
hysterectomy/oophorectomy compared with those who did not, which may explain some of the
association between endometriosis and CHD. 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 stoma (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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Topic 7384 Version 51.0

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.

Graphic 59765 Version 5.0

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.

Graphic 80415 Version 1.0

Conditions associated with an elevated serum CA 125 concentration

Gynecologic malignancies Nongynecologic conditions

Epithelial ovarian, fallopian tube, and primary peritoneal Cirrhosis and other liver disease
cancers
Ascites
Endometrial cancer
Colitis
Benign gynecologic conditions Diverticulitis
Benign ovarian neoplasms Appendicular abscess
Functional ovarian cysts Tuberculosis peritonitis
Endometriosis Pancreatitis
Meig syndrome Pleural effusion
Adenomyosis Pulmonary embolism
Uterine leiomyomas Pneumonia
Pelvic inflammatory disease Cystic fibrosis
Ovarian hyperstimulation Heart failure
Pregnancy Myocardiopathy
Menstruation Myocardial infarction

Pericardial disease

Renal insufficiency

Urinary tract infection

Recent surgery

Systemic lupus erythematosus

Sarcoidosis

Nongynecologic cancers
Breast

Colon

Liver

Gallbladder

Pancreas

Lung

Hematologic malignancies

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.

Graphic 81621 Version 7.0

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.

Graphic 77161 Version 3.0

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.

Graphic 82183 Version 3.0

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.

Graphic 105235 Version 2.0

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.

Graphic 100735 Version 4.0

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.

Graphic 61500 Version 1.0

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.

Graphic 65789 Version 1.0

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.

Graphic 89648 Version 2.0

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.

Graphic 66366 Version 2.0

Contributor Disclosures
Robert S Schenken, MD Consultant/Advisory Boards: Mitsubishi Tanabe [Evestra]. Robert L Barbieri,
MD Nothing to disclose Kristen Eckler, MD, FACOG Nothing to disclose

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