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"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

Early diagnosis of endometriosis is essential for managing this debilitating condition, yet accurate diagnosis is often delayed by many years owing to the nonspecific nature of symptoms. For many patients the path to diagnosis has been long and strewn with barriers and misdiagnoses.

Although invasive surgery followed by histopathological assessment of extrauterine endometrial cells remains the diagnostic gold standard, gynecologists have recently challenged the earlier diagnostic algorithm culminating in laparoscopy.

"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," said the authors of a 2019 in the American Journal of Obstetrics & Gynecology, which championed earlier intervention.

"Using this approach, symptoms, signs, and clinical findings of endometriosis are anticipated to become the main drivers of clinical diagnosis and earlier intervention," wrote Sanjay K. Agarwal, MD, of the University of California San Diego, and colleagues. "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."

According to Hugh S. Taylor, MD, of Yale University School of Medicine in New Haven, Connecticut, endometriosis should now be considered a whole-body disease that has consequences well beyond the pelvic region and these can facilitate and complement clinical diagnosis. "We have to look at all its manifestations and the totality of its effects on the patient," said Taylor, co-author of a on clinical challenges in the diagnosis of endometriosis.

How Useful Is Symptomatology?

The initial workup begins with a history of patient symptoms and comorbidities suggestive of the condition and having varying odds ratios of association with endometriosis -- which can mimic or co-exist with irritable bowel syndrome (IBS) and painful bladder syndrome, for example.

A British of 5,540 women of whom 1.5% had endometriosis looked at the correlation between symptoms and risk, and found the following odds ratios for association (with 95% confidence intervals):

• Infertility/subfertility: 8.2 (6.9-9.9)

• Dysmenorrhea: 8.1 (7.2-9.3)

• Ovarian cysts: 7.3 (5.7-9.4)

• Dyspareunia and/or postcoital bleeding: 6.8 (5.7-8.2)

• Abdominal or pelvic pain: 5.2 (4.7-5.7)

• IBS: 1.6 (1.3-1.8)

Other common endometriosis-associated symptoms are:

• Menorrhagia

• Dysuria

• Rectal pain during menstruation

• Menses of more than 7 days

• Intervals of less than 21 days between periods

• Nausea

• Fatigue

• Pain during intercourse

Agarwal said the most suggestive classic symptoms are severe dysmenorrhea, non-cyclical pelvic pain at other times of the month, pain during sexual activity, and prolonged infertility. "I would like to see all women asked about menstrual pain as part of a routine medical examination," he said. "Nurses could ask them while taking blood pressure measurements and ask if they've considered discussing the pain with their doctor."

Other classic indicators, added Taylor, are chronic progressive pelvic pain that worsens over time and bladder and bowel irritation. "A young girl can start her periods at age 12 and they won't be too bad but if she has endometriosis, they worsen progressively over time."

Non-pelvic symptoms can be diffuse and include depression, anxiety, and hypersensitivity to pain at distant sites, "These often cloud the diagnosis of endometriosis and cause it to be missed. Some patients will have had colonoscopies long before they're correctly diagnosed endometriosis," Taylor said.

Pelvic Exam

Palpation during the initial physical exam may detect tender nodular masses owing to fibrotic implants in the cul-de-sac as well as reduced mobility of the cervix and uterus. Pelvic findings, however, can be nonspecific and further investigation with imaging may be advisable.

Ultrasound

Nowadays physicians are more likely to proceed quickly to a trial of empiric treatment based on symptoms and pelvic findings rather than on extensive imaging or surgery, but ultrasound is a useful tool. "Transvaginal ultrasound is the standard method for ruling out other causes such as fibroids and ovarian cysts, but it can't rule out endometriosis," said Taylor.

This modality can reliably detect cystic endometriomas with 89% sensitivity and 91% specificity, although it does not reliably detect smaller endometrial implants.

Magnetic Resonance Imaging

MRI can offer more detailed information, particularly for deeper rectosigmoid and ureteral infiltrating lesions, but it is not a routine diagnostic tool because of the high costs and low sensitivity.

Hysterosalpingogram

This technique is generally reserved for related fertility investigations to check for tubal blockage.

Laparoscopy

Laparoscopy is typically performed in patients who have not responded to first- and second-line hormonal treatments, Taylor noted. "We've moved away from the approach where surgery is considered essential to diagnosis. That may have been the case when endometriosis patients were getting harsh drugs such as danazol that induced a profound menopausal state and we had to be sure the diagnosis was right before we subjected them to this therapy. Now with kinder drugs such as the gonadotropin-releasing hormone [GnRH] antagonists it's much easier to skip the surgery."

Location

The most of endometriosis identified by imaging and surgery are (by percentage of patients):

• Ovaries -- 55% of patients

• Anterior cul-de-sac -- 35%

• Posterior broad ligaments -- 35%

• Posterior cul-de-sac -- 34%

• Uterosacral ligaments -- 28%

Staging Methods

Disease staging "has traditionally been more about the lesions than the patient," Agarwal said. "But the approach has changed since the 1980s and '90s when the FDA would ask investigators trying to get a drug approved to stage the disease and see how the drug works to improve the stage. Now the FDA wants to know how quickly a drug works to improve not the stage of disease but the patient's pain and quality of life."

Furthermore, the lack of a gold-standard staging and classification system is concerning to many researchers. Scoring systems developed by several professional organizations around the world have been based on lesion appearance, extent of pelvic adhesions, ovarian endometriomas, and anatomic location as determined by surgery.

All these systems, however, have limitations: None accurately predicts fertility outcome, pelvic pain, response to medications, disease recurrence, risks for associated disorders, quality-of-life measures, and other endpoints important for guiding appropriate therapeutic options and prognosis.

Most widely accepted is the . But according to a the system correlates poorly with pain, fertility outcomes, and prognosis. The from Austria also has limited correlation with symptoms and infertility. The predicts fertility outcomes, but includes unrelated fertility factors such as age, and it is unclear how much of the scoring system relates specifically to endometriosis.

There is general agreement that more definitive classifications with better prognostic value are needed.

"But precise staging is not done clinically anyway," said Agarwal. "Who cares? it's not the lesions that matter, it's the pain. So staging is used mainly for research purposes, and sometimes physicians or patients want to know the stage out of curiosity."

Furthermore, disease severity does not equate to pain, he continued. "A woman with a speck of endometriosis can have great pain and be in bed all the time while another with lesions everywhere can have no symptoms. So we can't go by extent of disease."

The degree of pain may be a function of different signaling pathways in the brain and the brain's sensitization to pain in certain women, he said.

In Agarwal's algorithm, a woman with severe menstrual pain, the first step is to exclude other conditions such as ovarian cysts and PID and then treat directly with an oral contraceptive. "If that doesn't work, there's no use trying a different pill," he said. "Go to second-line treatment with a GnRH antagonist. If that fails, then it's time for surgery."

Biomarkers

Several studies have advanced the idea of using noninvasive biomarkers for diagnosing endometriosis. The CA125 assay has been extensively researched, but a large systematic showed it had limited diagnostic value. While the antigen is often elevated in women with endometriosis, the specificity is low.

A 2020 y by Taylor and colleagues found that microRNA biomarkers can reliably differentiate between endometriosis and other gynecological pathologies with an area under the curve >0.9 across 2 independent studies. "We validated the performance of an algorithm based on previously identified microRNA biomarkers, demonstrating their potential to detect endometriosis in a clinical setting, allowing earlier identification and treatment. The ability to diagnose endometriosis noninvasively could reduce the time to diagnosis, surgical risk, years of discomfort, disease progression, associated comorbidities, and health care costs," the researchers wrote.

The presence of nerve fibers in eutopic endometrial tissue may also be predictive.

Agarwal noted that current research is looking at possible biomarkers in urine, blood, and saliva. "As always, the overarching goal is to prevent decades of pain and make women's lives better without major surgery."

Resources

The American College of Obstetrics and Gynecology provides a on the diagnosis and management of endometriosis, ASRM has an , and the European Society of Human Reproduction and Embryology recently issued a on best practices for diagnosis and treatment.

Read Part 1 of this series: Endometriosis: Understanding the Pathogenesis and Pathophysiology