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Université Paris Descartes, 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
Boston Center for Endometriosis, Boston Children’s Hospital and Brigham and Women’s Hospital; Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women’s Hospital and Harvard Medical School; Division of Gynecology, Boston Children’s Hospital and Harvard Medical School, Boston, MA
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, Boston, MADepartment of Obstetrics, Gynecology, and Reproductive Biology, Michigan State University, Grand Rapids, MI
Endometriosis can have a profound impact on women’s lives, including associated pain, infertility, decreased quality of life, and interference with daily life, relationships, and livelihood. The first step in alleviating these adverse sequelae is to diagnose the underlying condition. For many women, the journey to endometriosis diagnosis is long and fraught with barriers and misdiagnoses. Inherent challenges include a gold standard based on an invasive surgical procedure (laparoscopy) and diverse symptomatology, contributing to the well-established delay of 4–11 years from first symptom onset to surgical diagnosis. We believe 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 heterogeneous disease that presents with symptoms of pelvic pain and/or infertility, rather than focusing primarily on surgical findings and pelvic lesions. Using this approach, symptoms, signs, and clinical findings of endometriosis are anticipated to become the main drivers of clinical diagnosis and earlier intervention. Combining these factors into a practical algorithm is expected to simplify endometriosis diagnosis and make the process accessible to more clinicians and patients, culminating in earlier effective management. The time has come to bridge disparities and to minimize delays in endometriosis diagnosis and treatment for the benefit of women worldwide.
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 definitive diagnosis before beginning therapy, frequently result in prolonged delay between symptom onset, diagnosis, and subsequent treatment.
A SOLUTION: Enhanced use of clinical diagnostic techniques may reduce the delay in time to diagnosis and hence bring more rapid relief to affected patients, limit disease progression, and prevent sequelae.
Endometriosis has such wide-ranging and pervasive sequelae that it has been described as “nothing short of a public health emergency” requiring immediate action.
Thus more than 6 million American women may experience repercussions of endometriosis without the benefit of understanding the cause of their symptoms or appropriate management.
When discussing the patient’s experience with endometriosis, pain and infertility are usually of greatest concern, as they are 2 of the disease’s more common symptoms. However, the real toll is even greater: women with endometriosis experience diminished quality of life, increased incidence of depression, adverse effects on intimate relationships, limitations on participation in daily activities, reduced social activity, loss of productivity and associated income, increased risk of chronic disease, and significant direct and indirect healthcare costs.
There are no pathognomonic features or biomarkers necessary and sufficient to define endometriosis. Rather, key symptoms that currently prompt surgical evaluation, such as pain and infertility, can have multiple causes. Endometriosis is typically defined by its histology: extrauterine lesions consisting of endometrial glands, endometrial stroma, and/or hemosiderin-laden macrophages. Based on location and depth, lesions are further described as superficial peritoneal lesions, ovarian endometrioma, or deep endometriosis. However, the presence of lesions does not preclude other etiologies for the patient’s symptoms, and the lack of obvious lesions does not eliminate the possibility of endometriosis. Furthermore, there is poor correlation between symptoms and severity or extent of disease, as quantified by current staging systems.
From a clinical perspective, endometriosis may be better defined as a menstrual cycle−dependent, chronic, inflammatory, systemic disease that commonly presents as pelvic pain. Moving from a histological to a clinical definition opens the door to a different approach to diagnosis, one that emphasizes symptoms and their origins over lesion presence or absence, and that may, in the future, be validated by specific, noninvasive disease biomarkers.
Among those who ultimately receive a successful definitive diagnosis, contemporary literature describes delays from symptom onset to diagnosis ranging from 4 to 11 years.
Consequences of the delay in diagnosis are experienced by patients in multiple ways, including persistent symptoms and a commensurate detrimental impact on quality of life,
and development of central sensitization—a mechanism whereby persistent endometriosis-associated pain increases pain awareness, even at sites unconnected anatomically with the lesion(s).
Moreover, although the evidence is limited, failure of timely diagnosis and adequate endometriosis management may foster disease progression and adhesion formation that may compromise fertility and increase the risk of central sensitization and chronic pelvic pain.
The current diagnostic paradigm, endorsed by professional societies, requires laparoscopy with or without histologic verification as the gold standard, although many societies endorse the treatment of symptoms before obtaining a definitive surgical diagnosis.
Notably, the 2017 National Institute for Health and Care Excellence guidelines reflect a philosophical shift, presenting empiric therapy prior to laparoscopy in the diagnostic and treatment algorithm unless fertility is a priority.
Although the merits of laparoscopy and its role in disease management should not be minimized, its accuracy, risks, and cost-effectiveness warrant reevaluation. The poor correlation between reported symptoms and extent of disease found at laparoscopy further illustrates the limitations of surgical disease assessment.
Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients.
Detecting endometriosis via laparoscopy relies on the visual identification of lesions, a practice that is challenged by heterogeneous lesion appearance,
Laparoscopic excision of lesions suggestive of endometriosis or otherwise atypical in appearance: relationship between visual findings and final histologic diagnosis.
Treatment patterns, complications, and health care utilization among endometriosis patients undergoing a laparoscopy or a hysterectomy: a retrospective claims analysis.
From a pragmatic perspective, evaluation of laparoscopy for endometriosis diagnosis and management must include a discussion of costs, which are substantially higher compared with nonsurgical approaches.
Reliance on laparoscopy for endometriosis diagnosis supports the viewpoint that the presence of identifiable lesions in the pelvis is the central tenet of endometriosis, rather than approaching endometriosis as a menstrual cycle−dependent, chronic, inflammatory, systemic disease that often presents as pelvic pain. By shifting the paradigm to the patient rather than the lesion, the path to clinical diagnosis has the potential to be more inclusive with reduced diagnostic delay. Indeed, Soliman et al
reported diagnosing endometriosis by nonsurgical methods shortened the mean time from first consultation to diagnosis compared with surgical diagnosis. This shift, however, requires clinical diagnostic methodologies that accurately identify endometriosis. To that end, we have compiled data on the accuracy of clinical assessments for diagnosing endometriosis (Table 1). Notably, these studies were highly heterogeneous, which precluded performance of a meaningful meta-analysis.
Table 1Predictive value of signs, symptoms, and clinical findings for diagnosing endometriosis
Retrospective case-control study involving women who underwent laparoscopy for infertility evaluation (341 with endometriosis; 332 with a normal pelvis)
World Endometriosis Research Foundation Women's Health Symptom Survey Consortium Developing symptom-based predictive models of endometriosis as a clinical screening tool: results from a multicenter study.
World Endometriosis Research Foundation Women's Health Symptom Survey Consortium Developing symptom-based predictive models of endometriosis as a clinical screening tool: results from a multicenter study.
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.
Prospective, single-center study of women with a histological diagnosis of endometriosis (N = 211)
Histologically verified endometriosis
Infertility (primary or secondary)
Sensitivity, 51%; specificity, 73%; OR, 1.5; p = 0.003
Duration of pain >24 mo
Sensitivity, 62%; specificity, 81%; OR, 7.1; p < 0.001
VAS deep dyspareunia >5
Sensitivity, 69%; specificity, 59%; OR, 3.2; p = 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
Diagnostic accuracy of physical examination, transvaginal sonography, rectal endoscopic sonography, and magnetic resonance imaging to diagnose deep infiltrating endometriosis.
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.
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.
Pelvic pain, although common among women with endometriosis, is insufficient alone as an indicator of endometriosis, as it can be associated with several gynecologic (and nongynecologic) conditions.
However, pelvic pain that is described as chronic, cyclic, and persistent or progressive (ie, worsening over time) increases the likelihood of an association with endometriosis.
Pain is typically initially menstrual (dysmenorrhea), but may progress to include nonmenstrual pelvic pain, which is prevalent among women with diagnosed endometriosis.
universally described their pain as “severe and progressive during menstrual and nonmenstrual phases.” Women with endometriosis are more likely to report dyspareunia, dyschezia, and dysuria than unaffected women.
World Endometriosis Research Foundation Women's Health Symptom Survey Consortium Developing symptom-based predictive models of endometriosis as a clinical screening tool: results from a multicenter study.
Response of pain to treatment may be another indicator of endometriosis. Although nonsteroidal anti-inflammatory drugs (NSAIDs) effectively treat primary dysmenorrhea, pain reduction with these agents may be insufficient in women with endometriosis.
However, caution is indicated before dismissing NSAID-responsive pain as simply dysmenorrhea; early symptoms of endometriosis may be responsive to these agents, and we should not miss an opportunity to treat the disease before the development of serious sequelae.
Patient and family history
History of infertility is strongly associated with endometriosis, although this may be skewed due to more thorough evaluation of women with infertility increasing the chances of successful diagnosis.
World Endometriosis Research Foundation Women's Health Symptom Survey Consortium Developing symptom-based predictive models of endometriosis as a clinical screening tool: results from a multicenter study.
World Endometriosis Research Foundation Women's Health Symptom Survey Consortium Developing symptom-based predictive models of endometriosis as a clinical screening tool: results from a multicenter study.
World Endometriosis Research Foundation Women's Health Symptom Survey Consortium Developing symptom-based predictive models of endometriosis as a clinical screening tool: results from a multicenter study.
In a recent cross-sectional survey of approximately 50,000 women, several menstrual cycle characteristics were more prevalent among women with vs without diagnosed endometriosis, including heavy menstrual bleeding, excessive/irregular bleeding, passing clots, and irregular menstrual periods. Premenstrual spotting also correlates with endometriosis in infertile women.
Diagnostic accuracy of physical examination, transvaginal sonography, rectal endoscopic sonography, and magnetic resonance imaging to diagnose deep infiltrating endometriosis.
For example, using defined criteria for a positive bimanual pelvic examination (ie, palpable nodularity, stiffened and/or thickened pelvic anatomy, especially the uterosacral ligaments, vagina, rectovaginal space, pouch of Douglas, adnexa, rectosigmoid, or posterior wall of the urinary bladder), Hudelist et al
reported endometriosis diagnosis accuracy of 86–99%, depending on anatomic location. Diagnostic acumen of pelvic examination is lower for deep endometriosis,
Diagnostic accuracy of physical examination, transvaginal sonography, rectal endoscopic sonography, and magnetic resonance imaging to diagnose deep infiltrating endometriosis.
A caveat to bimanual examination is that it may not be feasible for non−sexually active adolescents/young adults and may not identify early-stage, superficial disease.
Combination assessments
The ability to identify endometriosis nonsurgically is enhanced when multiple factors are combined. Ballard et al
reported that the likelihood of endometriosis increased with the number of symptoms present, from an odds ratio of 5.0 with 1 symptom to 84.7 for 7 or more symptoms. Several investigators have used this approach to develop models for predicting endometriosis.
World Endometriosis Research Foundation Women's Health Symptom Survey Consortium Developing symptom-based predictive models of endometriosis as a clinical screening tool: results from a multicenter study.
World Endometriosis Research Foundation Women's Health Symptom Survey Consortium Developing symptom-based predictive models of endometriosis as a clinical screening tool: results from a multicenter study.
created a model combining symptoms and patient history with ultrasound findings that predicted revised American Society for Reproductive Medicine (rASRM) stage III and IV endometriosis with good accuracy. The authors suggest that such screening tools could reduce “diagnostic delay, high investigation costs, and personal suffering associated with endometriosis.”
World Endometriosis Research Foundation Women's Health Symptom Survey Consortium Developing symptom-based predictive models of endometriosis as a clinical screening tool: results from a multicenter study.
Imaging can be a useful adjunct to clinical diagnostic measures, and transvaginal ultrasound improves accuracy when used adjunctively with symptoms, patient history, and/or physical findings.
World Endometriosis Research Foundation Women's Health Symptom Survey Consortium Developing symptom-based predictive models of endometriosis as a clinical screening tool: results from a multicenter study.
Indeed, a Cochrane meta-analysis found that transvaginal ultrasound approaches the sensitivity and specificity needed to replace surgery for endometrioma detection.
The International Deep Endometriosis Analysis (IDEA) group consensus statement on systematic sonographic evaluation of the pelvis in women with suspected endometriosis provides standards for improved imaging.
Systematic approach to sonographic evaluation of the pelvis in women with suspected endometriosis, including terms, definitions and measurements: a consensus opinion from the International Deep Endometriosis Analysis (IDEA) group.
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 infrequently used for endometriosis diagnosis. Although many are currently being studied, as yet, no noninvasive or minimally invasive biomarker has been established to diagnose endometriosis.
Much of what is known about endometriosis comes from surgically diagnosed adults. Increased research into endometriosis among surgically diagnosed adolescents and prospective studies of those with suggestive signs and symptoms will help to better identify hallmarks of disease onset and risk factors for disease progression and treatment prognosis. Although a detailed review of endometriosis in adolescents is beyond the scope of this discussion, it is noteworthy that endometriosis occurs in adolescents and that patients who are younger at the time of symptom onset experience longer diagnostic delays than older patients.
This delay is attributed to prolonged time before seeking treatment and a longer interval between first clinical consultation and referral or diagnosis. It is important that clinicians evaluate symptoms that merit suspicion in adolescents as seriously as in adults.
In an effort to provide a unified, practical approach to clinically diagnosing endometriosis, we have developed an algorithm informed by evidence in the literature and clinical experience (Figure 1). The proposed algorithm uses techniques readily available to most practitioners and allows clinicians to initiate treatment without delay or invasive procedures. For each step, we identify findings that are consistent with endometriosis and those suggesting a possible alternative diagnosis. In general, persistent and/or worsening cyclic or constant pelvic pain, particularly in the presence of other endometriosis-associated symptoms, patient history, and findings on physical examination, suggest endometriosis. When these findings are unclear, imaging with transvaginal ultrasound is a widely available and low-cost option.
Figure 1Algorithm for a clinical diagnosis of endometriosis
This algorithm does not diminish the value of laparoscopy as a treatment option in those for whom medical therapy is insufficient, nor does it minimize laparoscopy as a diagnostic tool when clinical signs are uncertain or suggest nonendometriosis pathology (eg, other benign or malignant ovarian neoplasms). Rather, the algorithm is intended to make the diagnosis of endometriosis more accessible, reducing the negative impact of undiagnosed and untreated endometriosis on women’s lives. Practitioners should feel empowered to clinically diagnose this disease early and without an invasive procedure. Although the ramifications of early diagnosis and treatment have not been studied, the potential exists to relieve pain, to avoid central sensitization and pain persistence, to prevent infertility, and to change the trajectory of patients’ lives. It is increasingly recognized that chronic diseases such as endometriosis generate cumulative life-course impairment through limitations imposed on life choices, including education, career, and family.
Overall patient health may also be improved by addressing the psychosocial and physical manifestations often found in conjunction with endometriosis, such as persistent pelvic pain, depression, anxiety, fatigue, bloating/weight gain, gastrointestinal issues, and sexual dysfunction.
Now is the time to change the paradigm of the diagnosis of endometriosis by increasing speed and validity, leading to improved access to effective early treatment.
Acknowledgments
Medical writing support for development of this manuscript, funded by AbbVie, Inc., was provided by Crystal Murcia, PhD, and Lamara D. Shrode, PhD, CMPP, of JB Ashtin.
References
Hatch O.
This is nothing short of a public health emergency. CNN.
Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients.
Laparoscopic excision of lesions suggestive of endometriosis or otherwise atypical in appearance: relationship between visual findings and final histologic diagnosis.
Treatment patterns, complications, and health care utilization among endometriosis patients undergoing a laparoscopy or a hysterectomy: a retrospective claims analysis.
Diagnostic accuracy of physical examination, transvaginal sonography, rectal endoscopic sonography, and magnetic resonance imaging to diagnose deep infiltrating endometriosis.
Systematic approach to sonographic evaluation of the pelvis in women with suspected endometriosis, including terms, definitions and measurements: a consensus opinion from the International Deep Endometriosis Analysis (IDEA) group.
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.
Agarwal et al1 should be congratulated for emphasizing that patients with severe chronic pelvic pain should be managed actively. Indeed, years of inadequate treatment, with the assumption that this pain is normal, is deeply frustrating for these patients. Chronic pain may have significant negative impact on a patient’s quality of life, resulting in central sensitization, loss of self-confidence and trust in physicians, and making long-term management more difficult.
Thank you for your letter entitled “Years of unjustified hypoestrogenism, fear, and stress will not improve the management of chronic pelvic pain!” The goal of our manuscript entitled “Clinical diagnosis of endometriosis: a call to action” 1 was to highlight the current unacceptable delay in diagnosis and to encourage a focus on pain, functioning, and quality of life, with or without a previous surgical diagnosis endometriosis. We agree with your statement “Even minimally invasive surgery is too invasive to manage minimal endometriosis, which is not always progressive and may heal during medical treatment or even spontaneously.”
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