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Clinical diagnosis of endometriosis: a call to action

Article  in  American Journal of Obstetrics and Gynecology · April 2019

DOI: 10.1016/j.ajog.2018.12.039

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Clinical diagnosis of endometriosis: a call to action

Sanjay K. Agarwal, MD; Charles Chapron, MD; Linda C. Giudice, MD, PhD; Marc R. Laufer, MD; Nicholas Leyland, MD;
Stacey A. Missmer, ScD; Sukhbir S. Singh, MD; Hugh S. Taylor, MD

E ndometriosis has such wide-

ranging and pervasive sequelae
that it has been described as “nothing
THE PROBLEM: Endometriosis is undiagnosed in a large proportion of affected women,
resulting in ongoing and progressive symptoms with associated negative impacts on health
and well-being. Current practice standards, which rely primarily on laparoscopy for a
short of a public health emergency”
definitive diagnosis before beginning therapy, frequently result in prolonged delay between
requiring immediate action.1
symptom onset, diagnosis, and subsequent treatment.
Population-based data suggest that
more than 4 million reproductive-age
A SOLUTION: Enhanced use of clinical diagnostic techniques may reduce the delay in time
women have diagnosed endometriosis
to diagnosis and hence bring more rapid relief to affected patients, limit disease pro-
in the United States.2 As daunting as this
gression, and prevent sequelae.
number is, it only tells part of the story,
as an estimated 6 of 10 endometriosis
cases are undiagnosed.3 Thus more than
6 million American women may expe- limitations on participation in daily ac- define endometriosis. Rather, key
rience repercussions of endometriosis tivities, reduced social activity, loss of symptoms that currently prompt surgi-
without the benefit of understanding the productivity and associated income, cal evaluation, such as pain and infer-
cause of their symptoms or appropriate increased risk of chronic disease, and tility, can have multiple causes.
management. significant direct and indirect healthcare Endometriosis is typically defined by its
When discussing the patient’s experi- costs.4e8 Moreover, emerging data indi- histology: extrauterine lesions consisting
ence with endometriosis, pain and cate that endometriosis is associated of endometrial glands, endometrial
infertility are usually of greatest concern, with greater risk of obstetric and stroma, and/or hemosiderin-laden
as they are 2 of the disease’s more com- neonatal complications.9e12 macrophages. Based on location and
mon symptoms. However, the real toll is depth, lesions are further described as
even greater: women with endometriosis The challenge of diagnosing superficial peritoneal lesions, ovarian
experience diminished quality of life, endometriosis endometrioma, or deep endometriosis.
increased incidence of depression, There are no pathognomonic features or However, the presence of lesions does
adverse effects on intimate relationships, biomarkers necessary and sufficient to not preclude other etiologies for the

From the Center for Endometriosis Research and Treatment (Dr Agarwal), University of California San Diego, La Jolla, CA; Université Paris Descartes
(Dr Chapron), Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique
Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC),
Centre Hospitalier Universitaire (CHU) Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine, Paris, France; Department of
Obstetrics, Gynecology and Reproductive Sciences (Dr Giudice), University of California, San Francisco, CA; Boston Center for Endometriosis, Boston
Children’s Hospital and Brigham and Women’s Hospital; Department of Obstetrics, Gynecology, and Reproductive Biology (Dr Laufer), Brigham and
Women’s Hospital and Harvard Medical School; Division of Gynecology, Boston Children’s Hospital and Harvard Medical School, Boston, MA;
Department of Obstetrics and Gynaecology (Dr Leyland), McMaster University, Hamilton, Ontario, Canada; Boston Center for Endometriosis, Boston
Children’s Hospital and Brigham and Women’s Hospital; Department of Epidemiology, Harvard T.H. Chan School of Public Health (Dr Missmer), Boston,
MA; and Department of Obstetrics, Gynecology, and Reproductive Biology, Michigan State University, Grand Rapids, MI; Department of Obstetrics and
Gynaecology (Dr Singh), University of Ottawa, and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Obstetrics, Gynecology,
and Reproductive Sciences (Dr Taylor), Yale School of Medicine, New Haven, CT.
Received Aug. 24, 2018; revised Dec. 21, 2018; accepted Dec. 31, 2018.
S.K.A. is a consultant for and has received research support from AbbVie. C.C. is consultant for Ipsen, Bayer, AbbVie, and Gedeon Richter. He is an
advisor/consultant for AbbVie, Bayer, Ipsen, and Gedeon Richter Preglem. L.C.G. is a consultant for AbbVie, Myovant Sciences, ForEndo Pharma,
NextGen Jane, and Merck. M.R.L. is a consultant for AbbVie and NextGen Jane. N.L. is a consultant for and has received research support from AbbVie,
Allergan, and the Canadian Institutes for Health Research. S.A.M. is a consultant for AbbVie, Oratel Diagnostics, and Celmatix, and receives research
support from the National Institutes of Health and the Marriott Family Foundations. S.S.S. is a consultant for and has received research support from
AbbVie, Bayer, and Allergan. H.S.T. is a consultant for AbbVie, Bayer, Obseva, OvaScience, ForEndo, and DotLab.
Support for the development of this manuscript was provided by AbbVie, Inc. AbbVie had the opportunity to review the final manuscript draft, but the
manuscript content was solely at the discretion of the authors and reflects the opinions of the authors. The authors received no direct compensation for
their efforts.
Corresponding author: Hugh S. Taylor, MD. hugh.taylor@yale.edu
0002-9378
ª 2019 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
https://doi.org/10.1016/j.ajog.2018.12.039

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patient’s symptoms, and the lack of Health and Care Excellence guidelines compiled data on the accuracy of clin-
obvious lesions does not eliminate the reflect a philosophical shift, presenting ical assessments for diagnosing endo-
possibility of endometriosis. Further- empiric therapy prior to laparoscopy in metriosis (Table 1). Notably, these
more, there is poor correlation between the diagnostic and treatment algorithm studies were highly heterogeneous,
symptoms and severity or extent of dis- unless fertility is a priority.30 Although which precluded performance of a
ease, as quantified by current staging the merits of laparoscopy and its role in meaningful meta-analysis.
systems.13 From a clinical perspective, disease management should not be
endometriosis may be better defined as a minimized, its accuracy, risks, and cost- Symptoms. Pelvic pain, although com-
menstrual cycle
dependent, chronic, effectiveness warrant reevaluation. The mon among women with endometriosis,
inflammatory, systemic disease that poor correlation between reported is insufficient alone as an indicator of
commonly presents as pelvic pain. symptoms and extent of disease found at endometriosis, as it can be associated
Moving from a histological to a clinical laparoscopy further illustrates the limi- with several gynecologic (and non-
definition opens the door to a different tations of surgical disease assessment.31 gynecologic) conditions.39 However,
approach to diagnosis, one that empha- Detecting endometriosis via laparos- pelvic pain that is described as chronic,
sizes symptoms and their origins over copy relies on the visual identification of cyclic, and persistent or progressive (ie,
lesion presence or absence, and that may, lesions, a practice that is challenged by worsening over time) increases the
in the future, be validated by specific, heterogeneous lesion appearance,32 likelihood of an association with
noninvasive disease biomarkers. inaccessible lesion location (particularly endometriosis.2,40,41 Pain is typically
Among those who ultimately receive a for deep lesions),33 and interobserver initially menstrual (dysmenorrhea), but
successful definitive diagnosis, contem- variability.34 Surgical risks associated may progress to include nonmenstrual
porary literature describes delays from with laparoscopy are generally low,33,35 pelvic pain, which is prevalent
symptom onset to diagnosis ranging although they merit consideration, among women with diagnosed
from 4 to 11 years.5,14e18 Several factors given the potential for major (albeit rare) endometriosis.42 When asked about
exacerbate this delay,14,15,17,18 including complications36 and the need for re- their experiences living with
“normalization” of symptoms and treatment after initial laparoscopy endometriosis, participants in the
misdiagnosis.15 The presence of diag- because there is no surgical cure for qualitative study by Moradi et al5
nostic delays is a worldwide phenome- endometriosis.37 From a pragmatic universally described their pain as
non, occurring even in countries with perspective, evaluation of laparoscopy “severe and progressive during
universal healthcare.15,17 Consequences for endometriosis diagnosis and man- menstrual and nonmenstrual phases.”
of the delay in diagnosis are experienced agement must include a discussion Women with endometriosis are more
by patients in multiple ways, including of costs, which are substantially likely to report dyspareunia, dyschezia,
persistent symptoms and a commensu- higher compared with nonsurgical and dysuria than unaffected
rate detrimental impact on quality of approaches.38 women.2,40,43e46 Although the
life,14 erosion of the patient
physician sensitivity of dyspareunia is generally
relationship,4,5 and development of Argument for clinical diagnosis low,47e49 indicating that its presence is
central sensitization—a mechanism Reliance on laparoscopy for endome- not specific to endometriosis, deep
whereby persistent endometriosis- triosis diagnosis supports the viewpoint dyspareunia is associated with deep
associated pain increases pain aware- that the presence of identifiable lesions endometriosis.46
ness, even at sites unconnected in the pelvis is the central tenet of Response of pain to treatment may
anatomically with the lesion(s).14,19e21 endometriosis, rather than approaching be another indicator of endo-
Moreover, although the evidence is endometriosis as a menstrual metriosis. Although nonsteroidal anti-
limited, failure of timely diagnosis and cycle
dependent, chronic, inflamma- inflammatory drugs (NSAIDs) effec-
adequate endometriosis management tory, systemic disease that often pre- tively treat primary dysmenorrhea, pain
may foster disease progression and sents as pelvic pain. By shifting the reduction with these agents may be
adhesion formation that may compro- paradigm to the patient rather than the insufficient in women with endometri-
mise fertility and increase the risk of lesion, the path to clinical diagnosis has osis.26,28 However, caution is indicated
central sensitization and chronic pelvic the potential to be more inclusive with before dismissing NSAID-responsive
pain.22e24 reduced diagnostic delay. Indeed, Soli- pain as simply dysmenorrhea; early
The current diagnostic paradigm, man et al18 reported diagnosing endo- symptoms of endometriosis may be
endorsed by professional societies, re- metriosis by nonsurgical methods responsive to these agents, and we
quires laparoscopy with or without his- shortened the mean time from first should not miss an opportunity to treat
tologic verification as the gold standard, consultation to diagnosis compared the disease before the development of
although many societies endorse the with surgical diagnosis. This shift, serious sequelae.
treatment of symptoms before obtaining however, requires clinical diagnostic
a definitive surgical diagnosis.25e29 methodologies that accurately identify Patient and family history. History of
Notably, the 2017 National Institute for endometriosis. To that end, we have infertility is strongly associated with

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TABLE 1
Predictive value of signs, symptoms, and clinical findings for diagnosing endometriosis
Study design and population Method of diagnosis Assessment or parameter Results
Endometriosis (general)
Saha 201747a Endometriosis diagnosis listed in Severe dysmenorrhea Sensitivity, 58%; specificity, 70%
Cross-sectional survey of a electronic medical record
Chronic pelvic pain Sensitivity, 25%; specificity, 89%
Swedish twin cohort
(N ¼ 26,898) Dyspareunia Sensitivity, 16%; specificity, 96%
Infertility Sensitivity, 28%; specificity, 93%
Oral pill as contraceptive Sensitivity, 16%; specificity, 80%
2
Fuldeore 2017 Self-report (replying in the Menstrual pelvic pain/cramping OR, 1.6 (95% CI, 1.4e1.8)
Respondents to an online, affirmative that a doctor had
Nonmenstrual pelvic pain/ OR, 4.1 (95% CI, 3.6e4.6)
cross-sectional survey previously told the subject that
cramping
(N ¼ 48,020) she has or is suspected of
having endometriosis) Dyspareunia OR, 3.1 (95% CI, 2.8e3.5)
Heavy menstrual bleeding OR, 1.5 (95% CI, 1.3e1.7)
Excessive or irregular bleeding OR, 2.1 (95% CI, 1.8e2.4)
Passage of clots OR, 1.8 (95% CI, 1.6e2.0)
Irregular menstrual periods OR, 1.5 (95% CI, 1.3e1.7)
(timing/duration)
Constipation/bloating/diarrhea OR, 1.9 (95% CI, 1.7e2.2)
Fatigue/weariness/anemia OR, 2.2 (95% CI, 2.0e2.5)
Infertility OR, 3.6 (95% CI, 3.0e4.4)
Ashrafi 201650 Laparoscopically visualized Family history of endometriosis OR, 2.7 (95% CI, 1.06e7.1)
Retrospective case-control endometriosis
History of galactorrhea OR, 1.8 (95% CI, 1.1e3.05)
study involving women who
underwent laparoscopy for History of pelvic surgery OR, 14.5 (95% CI, 6.1e34.2)
infertility evaluation (341 with
endometriosis; 332 with a Dysmenorrhea OR, 1.8 (95% CI, 1.1e2.8)
normal pelvis) Pelvic pain OR, 4.1 (95% CI, 2.4e6.8)
Dyspareunia OR, 1.6 (95% CI, 1.09e2.4)
Premenstrual spotting OR, 2.2 (95% CI, 1.3e3.6)
Fatigue OR, 2.6 (95% CI, 1.3e5.1)
64
Apostolopoulos 2016 Laparoscopically visualized Noncyclical pain Endometriosis, 62.5%; no
Prospective, observational study endometriosis endometriosis, 70.8%; p ¼ 0.48
of women who underwent
Dysmenorrhea Endometriosis, 79.1%; no
laparoscopy for chronic pelvic
endometriosis, 87.5%; p ¼ 0.37
pain (N ¼ 144)
Dyspareunia Endometriosis, 25.0%; no
endometriosis, 33.3%; p ¼ 0.46
Dyschezia Endometriosis, 25.0%; no
endometriosis, 20.8%; p ¼ 0.69
Agarwal. Clinical diagnosis of endometriosis. Am J Obstet Gynecol 2019. (continued)

endometriosis, although this may be and a history of benign ovarian cysts without diagnosed endometriosis,
skewed due to more thorough evaluation and/or ovarian pain.43,45 including heavy menstrual bleeding,
of women with infertility increasing the excessive/irregular bleeding, passing
chances of successful diagnosis.2,41,43-47 Menstrual cycle characteristics. In a clots, and irregular menstrual periods.
Other factors associated with a greater recent cross-sectional survey of Premenstrual spotting also correlates
likelihood of successful endometriosis approximately 50,000 women, several with endometriosis in infertile
diagnosis are family history of the menstrual cycle characteristics were women.48,50 Although these disorders
disease,43,50 previous pelvic surgery,50 more prevalent among women with vs are common in women with

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TABLE 1
Predictive value of signs, symptoms, and clinical findings for diagnosing endometriosis (continued)
Study design and population Method of diagnosis Assessment or parameter Results
40
Schliep 2015 Surgically visualized Chronic pelvic pain Endometriosis, 44.2%; other,
Operative cohort from the endometriosis 39.0%; normal pelvis, 30.2%;
ENDO study—women without a p ¼ 0.04
history of surgically confirmed
Cyclic pelvic pain Endometriosis, 49.5%; other,
endometriosis who underwent
31.0%; normal pelvis, 33.1%;
laparoscopy or laparotomy
p < 0.001
(N ¼ 473)
Vaginal pain with intercourse Endometriosis, 54.7%; other,
41.5%; normal pelvis, 32.4%;
p < 0.001
Deep pain with intercourse Endometriosis, 53.2%; other,
38.1%; normal pelvis, 30.9%;
p < 0.001
Burning vaginal pain after Endometriosis, 33.2%; other,
intercourse 22.5%; normal pelvis, 22.1%;
p ¼ 0.03
Pain just before menstrual period Endometriosis, 75.3%; other,
61.9%; normal pelvis, 66.2%;
p ¼ 0.03
Level of cramps with period Endometriosis, 91.1%; other,
85.0%; normal pelvis, 79.4%;
p ¼ 0.01
Pain after period is over Endometriosis, 38.4%; other,
26.5%; normal pelvis, 38.2%;
p ¼ 0.04
Pain at ovulation (mid-cycle) Endometriosis, 67.4%; other,
49.0%; normal pelvis, 52.2%;
p ¼ 0.001
Dysuria Endometriosis, 22.6%; other,
19.1%; normal pelvis, 11.0%;
p ¼ 0.03
Dyschezia Endometriosis, 44.2%; other,
32.7%; normal pelvis, 25.7%;
p ¼ 0.002
Heitman 201448 Histologically verified Premenstrual spotting Sensitivity, 76%; specificity, 90%;
Retrospective cohort of endometriosis for 2 days PPV, 96%; NPV, 74%; accuracy,
consecutive women with or 81%
without pelvic pain who were
Dysmenorrhea Sensitivity, 87%; specificity, 63%;
evaluated for infertility (N ¼ 80)
PPV, 75%; NPV, 79%; accuracy,
76%
Dyspareunia Sensitivity, 38%; specificity, 83%;
PPV, 74%; NPV, 51%; accuracy,
58%
Agarwal. Clinical diagnosis of endometriosis. Am J Obstet Gynecol 2019. (continued)

endometriosis, most of these women endometriosis with high accuracy.51-53 adnexa, rectosigmoid, or posterior wall
have regular cycles without abnormal For example, using defined criteria for of the urinary bladder), Hudelist et al51
bleeding. a positive bimanual pelvic examination reported endometriosis diagnosis
(ie, palpable nodularity, stiffened and/ accuracy of 86e99%, depending on
Physical examination. Data from or thickened pelvic anatomy, especially anatomic location. Diagnostic
comparative studies suggest that findings the uterosacral ligaments, vagina, acumen of pelvic examination is lower
on physical examination can identify rectovaginal space, pouch of Douglas, for deep endometriosis,52,53 although

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TABLE 1
Predictive value of signs, symptoms, and clinical findings for diagnosing endometriosis (continued)
Study design and population Method of diagnosis Assessment or parameter Results
41b
Peterson 2013 Surgically visualized History of infertility OR, 2.43 (95% CI, 1.57e3.76)
ENDO Study—Prospective, endometriosis (operative cohort) [operative]; 7.91 (1.69e37.2)
matched-exposure cohort study Pelvic MRI-diagnosed [matched]
comprising women undergoing endometriosis (matched cohort)
Dysmenorrhea OR, 2.46 (95% CI, 1.28e4.72)
pelvic surgery (n ¼ 495) and a
[operative]; 1.41 (0.28e7.14)
matched cohort (n ¼ 131)
[matched]
Pelvic pain OR, 1.39 (95% CI, 0.95e2.04)
[operative]; 0.76 (0.09e6.54)
[matched]
Pelvic pain (surgical indication) OR, 3.67 (95% CI, 2.44e5.50)
[operative]
Nnoaham 201243 Laparoscopically visualized Model comprising multiple factors Sensitivity, 85%; specificity, 44%
Prospective, observational endometriosis (eg, dysmenorrhea, dyschezia,
study of symptomatic women nonmenstrual pelvic pain, ovarian
with scheduled laparoscopy cyst, family history, race, etc)
(N ¼ 1396)
Model and ultrasound Sensitivity, 58%; specificity, 89%
54
Paulson 2011 Laparoscopically or histologically Anterior vaginal wall tenderness Sensitivity, 93%
Prospective cohort of women confirmed endometriosis (endometriosis and other pathology)
with chronic pelvic pain
Anterior vaginal wall tenderness Sensitivity, 17%
(N ¼ 284)
(endometriosis only)
Droz 201165 Histologically verified Short-form MPQ pain descriptor:
Retrospective cohort of women endometriosis
Cramping Sensitivity, 92%; specificity, 33%;
evaluated for chronic pelvic pain
PPV, 40%, NPV, 89%
(N ¼ 331)
Sickening Sensitivity, 73%; specificity, 46%;
PPV, 40%; NPV, 78%
Tiring/exhausting Sensitivity, 77%; specificity, 38%;
PPV, 38%; NPV, 77%
Shooting Sensitivity, 70%; specificity, 43%;
PPV, 37%; NPV, 75%
Punishing/cruel Sensitivity, 49%; specificity, 65%;
PPV, 40%; NPV, 72%
Splitting Sensitivity, 36%; specificity, 77%;
PPV, 43%; NPV, 71%
Paulson 200955 Laparoscopically or histologically Anterior vaginal wall tenderness Sensitivity, 84%; specificity, 75%;
Prospective study of consecutive confirmed endometriosis PPV, 86%; NPV, 69%
women with unexplained infertility
(N ¼ 55)
Meuleman 200939 Histologically verified Pelvic pain Sensitivity, 59%; specificity, 56%;
Retrospective case series endometriosis PPV, 54%; NPV, 57%
comprising infertile women with
Pelvic pain and type of infertility, Sensitivity, 65%; specificity, 73%
regular cycles and no prior
age, and duration of infertility
endometriosis diagnosis (N ¼ 221)
Hudelist 200951c Histologically verified Vaginal examination Sensitivity, 23-88%; specificity,
Prospective study of consecutive endometriosis 89e100%; PPV, 65e100%; NPV,
women with symptoms of 85e99%; accuracy, 86e99%
endometriosis (N ¼ 200)
Vaginal examination and TVS Sensitivity, 67e100%; specificity,
86e100%; PPV, 50e100%;NPV,
93e100%; accuracy, 86e100%
Agarwal. Clinical diagnosis of endometriosis. Am J Obstet Gynecol 2019. (continued)

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TABLE 1
Predictive value of signs, symptoms, and clinical findings for diagnosing endometriosis (continued)
Study design and population Method of diagnosis Assessment or parameter Results
44
Flores 2008 Self-reported surgically confirmed Dysmenorrhea Cases, 82.5%; general population,
Respondents to a self- endometriosis 59.3%; p < 0.001
administered questionnaire
Severe dysmenorrhea Cases, 65.9%; general population,
(N ¼ 1285)
52.9%; p ¼ NS
Dyspareunia Cases, 52.0%; general population,
20.0%; p < 0.001
Problems conceiving Cases, 70.6%; general population,
25.2%; p < 0.001
Chronic pelvic pain Cases, 80.0%; general population,
22.9%; p < 0.001
Ballard 200845d Diagnostic or procedural codes Dysmenorrhea OR, 9.8 (95% CI, 8.8e10.9)
National case-control study consistent with endometriosis
Pelvic pain OR, 13.5 (95% CI, 11.7e15.7)
comprising women with recorded in a nationwide general
endometriosis (n ¼ 5540) and practice database Dyspareunia OR, 9.4 (95% CI, 8.0e11.1)
matched controls (n ¼ 21,239)
Abdominal pain OR, 5.9 (95% CI, 5.5e6.4)
Menorrhagia OR, 5.0 (95% CI, 4.6e5.5)
Intermenstrual pain OR, 6.9 (95% CI, 4.7e10.2)
Infertility/subfertility OR, 6.2 (95% CI, 5.4e7.1)
Pelvic inflammatory disease OR, 6.4 (95% CI, 5.6e7.4)
Ovarian cysts OR, 12.2 (95% CI, 9.9e15.0)
Ovary pain OR, 9.1 (95% CI, 3.2e26.0)
Endometriosis (stages III and IV)
Peterson 201341b Surgically visualized endometriosis History of infertility OR, 4.74 (95% CI, 2.57e8.75)
ENDO Study—prospective, (operative cohort)
Dysmenorrhea OR, 3.43 (95% CI, 1.02e11.5)
matched exposure cohort study
comprising women undergoing Pelvic pain OR, 1.60 (95% CI, 0.89e2.87)
pelvic surgery (n ¼ 495)
Pelvic pain (surgical indication) OR, 4.47 (95% CI, 2.39e8.38)
43
Nnoaham 2012 Laparoscopically visualized Model comprising multiple factors Sensitivity, 71%; specificity, 85%
Prospective, observational study of endometriosis (eg, dyschezia, ovarian cyst,
symptomatic women with infertility, cycle length, GI/bladder
scheduled laparoscopy (N ¼ 1396) symptoms, race, etc)
Model with ultrasound Sensitivity, 82%; specificity, 76%
Endometriosis and other peri-ovarian dhesions
Agarwal. Clinical diagnosis of endometriosis. Am J Obstet Gynecol 2019. (continued)

examination during menses improves Combination assessments. The ability prospective, multinational study,
detection.26 Anterior vaginal wall to identify endometriosis nonsurgically Nnoaham et al43 created a model
tenderness has low sensitivity for is enhanced when multiple factors are combining symptoms and patient
detecting endometriosis in women with combined. Ballard et al45 reported that history with ultrasound findings that
chronic pelvic pain,54 but demonstrates the likelihood of endometriosis predicted revised American Society for
prognostic value for endometriosis increased with the number of Reproductive Medicine (rASRM) stage
among women with unexplained symptoms present, from an odds ratio III and IV endometriosis with good
infertility.55 A caveat to bimanual of 5.0 with 1 symptom to 84.7 for 7 or accuracy. The authors suggest that such
examination is that it may not be more symptoms. Several investigators screening tools could reduce
feasible for non
sexually active have used this approach to “diagnostic delay, high investigation
adolescents/young adults and may not develop models for predicting costs, and personal suffering associated
identify early-stage, superficial disease. endometriosis.43,46,56 Using data from a with endometriosis.”43

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TABLE 1
Predictive value of signs, symptoms, and clinical findings for diagnosing endometriosis (continued)
Study design and population Method of diagnosis Assessment or parameter Results
49
Marasinghe 2014 Laparoscopically visualized Dyspareunia Sensitivity, 46%; specificity, 77%;
Prospective, observational study endometriosis PPV, 52%; NPV, 73%; accuracy,
comprising women evaluated for 47%
infertility and/or chronic pelvic pain
Dysmenorrhea Sensitivity, 76%; specificity, 70%;
(N ¼ 110)
PPV, 57%; NPV, 84%; accuracy,
71%
Dyspareunia and dysmenorrhea Sensitivity, 78%; specificity, 64%;
PPV, 54%; NPV, 85%; accuracy,
68%
Vaginal examination Sensitivity, 73%; specificity, 88%;
PPV, 77%; NPV, 86%; accuracy,
83%
Dyspareunia, dysmenorrhea, and Sensitivity, 84%; specificity, 62%;
vaginal examination PPV, 54%; NPV, 88%; accuracy,
69%
Fixed ovaries on TVS Sensitivity, 78%; specificity, 94%;
PPV, 88%; NPV, 89%; accuracy,
88%
Dyspareunia, dysmenorrhea, Sensitivity, 92%; specificity, 61%;
vaginal examination and fixed PPV, 56%; NPV, 93%; accuracy,
ovaries 71%
Deep endometriosis
Perello 201756 Histologically verified Model including previous Sensitivity, 80%; specificity, 84%
Retrospective analysis of endometriosis pregnancy, history of surgery for
consecutive women with ovarian endometriosis, endometriosis-
endometrioma who underwent associated pelvic pain score
surgery (N ¼ 178)
Lafay Pillet 201446e Histologically verified Infertility (primary or secondary) Sensitivity, 51%; specificity, 73%;
Prospective, single-center study of endometriosis OR, 1.5; p ¼ 0.003
women with a histological diagnosis
Duration of pain >24 mo Sensitivity, 62%; specificity, 81%;
of endometriosis (N ¼ 211)
OR, 7.1; p < 0.001
VAS deep dyspareunia >5 Sensitivity, 69%; specificity, 59%;
OR, 3.2; p ¼ 0.007
VAS GI symptoms 5 Sensitivity, 75%; specificity, 76%;
OR, 9.3; p < 0.001
Severe dysmenorrhea Sensitivity, 55%; specificity, 75%;
OR, 3.5; p < 0.001
Hudelist 201152c Histologically verified Vaginal examination Sensitivity, 25e78%; specificity,
Prospective study of endometriosis 80e100%; PPV, 43e100%; NPV,
premenopausal women with 84e98%; accuracy, 73e98%
suspected endometriosis (N ¼ 129)
TVS Sensitivity, 50e96%; specificity,
96e100%; PPV, 50e100%; NPV,
90e99%; accuracy, 90e99%
Agarwal. Clinical diagnosis of endometriosis. Am J Obstet Gynecol 2019. (continued)

Additional considerations. Imaging history, and/or physical findings.43,49,51 transvaginal ultrasound approaches the
can be a useful adjunct to clinical diag- Ultrasound is particularly sensitive for sensitivity and specificity needed to
nostic measures, and transvaginal ultra- detecting ovarian endometriomas and replace surgery for endometrioma
sound improves accuracy when used deep endometriosis.25,57,58 Indeed, a detection.57 The International Deep
adjunctively with symptoms, patient Cochrane meta-analysis found that Endometriosis Analysis (IDEA) group

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TABLE 1
Predictive value of signs, symptoms, and clinical findings for diagnosing endometriosis (continued)
Study design and population Method of diagnosis Assessment or parameter Results
53c
Bazot 2009 Laparoscopically visualized Vaginal examination Sensitivity, 18e74%; specificity,
Retrospective, longitudinal endometriosis 72e96%; PPV, 40e97%; NPV,
study of consecutive women 24e90%; accuracy, 54e87%
with clinical evidence of
TVS Sensitivity, 9e94%; specificity,
endometriosis (N ¼ 92)
67e100%; PPV, 50e100%; NPV,
25e89%; accuracy, 77e96%
Rectal endoscopic sonography Sensitivity, 7e89%; specificity,
44e100%; PPV, 33e100%; NPV,
9e90%; accuracy, 48e90%
MRI Sensitivity, 55e87%; specificity,
86e99%; PPV, 73e99%; NPV,
38e94%; accuracy, 84e94%
To identify relevant studies, a search of the MEDLINE database was performed using the following search terms: endometriosis AND (pain OR cycle OR infertility OR “physical exam” OR “physical
examination” OR “pelvic exam” OR “pelvic examination”) AND (specificity OR sensitivity OR accuracy). Articles were limited to clinical studies published in English from 2008 through March 2018.
Additional studies identified via citations in associated manuscripts were added if applicable.
ENDO, Endometriosis: Natural History, Diagnosis, and Outcomes Study; GI, gastrointestinal; HR, hazard ratio; MPQ, McGill Pain Questionnaire; MRI, magnetic resonance imaging; NPV, negative
predictive value; PPV, positive predictive value; TVS, transvaginal sonography; VAS, visual analogue scale.
a
Reported are the agreement between self-reported symptoms of endometriosis and diagnosis of endometriosis recorded in medical records; b Data are adjusted odds ratios; c Ranges reflect
different values based on anatomic locations of the endometriotic lesions; d Shown here are symptoms and signs with an odds ratio for predicting endometriosis of 5.0 or greater; e Lafay Pillet et al18
evaluated combining multiple signs, symptoms, and findings to predict the presence of deep endometriosis. Presented here are the individual measures included in the final model.
Agarwal. Clinical diagnosis of endometriosis. Am J Obstet Gynecol 2019.

consensus statement on systematic

FIGURE 1 sonographic evaluation of the pelvis in
Algorithm for a clinical diagnosis of endometriosis women with suspected endometriosis
provides standards for improved
imaging.59 Traditional routine
transvaginal ultrasound may be limited
to endometrioma diagnosis; however,
“expert-guided” imaging, as outlined
by the IDEA group, will help improve
clinical assessment across
endometriosis manifestations.
Nonetheless, not all endometriosis will
be visualized by imaging, and imaging
cannot be used to rule out
endometriosis.
Magnetic resonance imaging is a
noninvasive option; however, it is
expensive, not universally available, and
lacks sensitivity, and is therefore infre-
quently used for endometriosis diag-
nosis. Although many are currently
being studied, as yet, no noninvasive or
minimally invasive biomarker has been
established to diagnose endometri-
osis.60-62
Much of what is known about endo-
metriosis comes from surgically diag-
nosed adults. Increased research into
Agarwal. Clinical diagnosis of endometriosis. Am J Obstet Gynecol 2019. endometriosis among surgically diag-
nosed adolescents and prospective

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Call to Action ajog.org

studies of those with suggestive signs and the negative impact of undiagnosed and lives: a qualitative study. BMC Womens Health
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6. Kvaskoff M, Mu F, Terry KL, et al. Endome-
hallmarks of disease onset and risk fac- lives. Practitioners should feel empow- triosis: a high-risk population for major chronic
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beyond the scope of this discussion, it is diagnosis and treatment have not been Haley J, Snabes MC, Surrey ES. The effect of
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noteworthy that endometriosis occurs in studied, the potential exists to relieve presenteeism in the workplace and at home.
adolescents and that patients who are pain, to avoid central sensitization and J Manag Care Spec Pharm 2017;23:745–54.
younger at the time of symptom onset pain persistence, to prevent infertility, 8. Soliman AM, Surrey E, Bonafede M,
experience longer diagnostic delays than and to change the trajectory of patients’ Nelson JK, Castelli-Haley J. Real-world evalua-
older patients.17,18 This delay is attrib- lives. It is increasingly recognized that tion of direct and indirect economic burden
among endometriosis patients in the United
uted to prolonged time before seeking chronic diseases such as endometriosis States. Adv Ther 2018;35:408–23.
treatment and a longer interval between generate cumulative life-course impair- 9. Harada T, Taniguchi F, Onishi K, et al.
first clinical consultation and referral or ment through limitations imposed on Obstetrical complications in women with endo-
diagnosis. It is important that clinicians life choices, including education, career, metriosis: a cohort study in Japan. PLoS One
evaluate symptoms that merit suspicion and family.5,63 Overall patient health 2016;11:e0168476.
10. Berlac JF, Hartwell D, Skovlund CW,
in adolescents as seriously as in adults.42 may also be improved by addressing the Langhoff-Roos J, Lidegaard O. Endometriosis
psychosocial and physical manifestations increases the risk of obstetrical and neonatal
Implementing clinical diagnosis often found in conjunction with endo- complications. Acta Obstet Gynecol Scand
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clinical practice, albeit inconsistently depression, anxiety, fatigue, bloating/ 11. Zullo F, Spagnolo E, Saccone G, et al.
Endometriosis and obstetrics complications: a
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initiate treatment without delay or 14. Nnoaham KE, Hummelshoj L, Webster P,
Medical writing support for development of
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ABSTRACT
Clinical diagnosis of endometriosis: a call to action
Endometriosis can have a profound impact on women’s lives, and/or infertility, rather than focusing primarily on surgical find-
including associated pain, infertility, decreased quality of life, and ings and pelvic lesions. Using this approach, symptoms, signs,
interference with daily life, relationships, and livelihood. The first and clinical findings of endometriosis are anticipated to become
step in alleviating these adverse sequelae is to diagnose the the main drivers of clinical diagnosis and earlier intervention.
underlying condition. For many women, the journey to endome- Combining these factors into a practical algorithm is expected to
triosis diagnosis is long and fraught with barriers and mis- simplify endometriosis diagnosis and make the process accessible
diagnoses. Inherent challenges include a gold standard based on to more clinicians and patients, culminating in earlier effective
an invasive surgical procedure (laparoscopy) and diverse symp- management. The time has come to bridge disparities and to
tomatology, contributing to the well-established delay of 4e11 minimize delays in endometriosis diagnosis and treatment for the
years from first symptom onset to surgical diagnosis. We believe benefit of women worldwide.
that remedying the diagnostic delay requires increased patient
education and timely referral to a women’s healthcare provider
and a shift in physician approach to the disorder. Endometriosis
should be approached as a chronic, systemic, inflammatory, and Key words: chronic pelvic pain, cyclic progressive pain syndrome,
heterogeneous disease that presents with symptoms of pelvic pain diagnosis, endometriosis, infertility, pelvic pain

APRIL 2019 American Journal of Obstetrics & Gynecology 354.e1

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