Endometriosis Diagnosis: Closing the 7-Year Gap with Biomarkers and Imaging Advances

Why Does Endometriosis Take So Long to Diagnose?

Endometriosis is a chronic inflammatory condition in which tissue similar to the endometrium grows outside the uterus, most commonly on the ovaries, fallopian tubes, peritoneum, and bowel. The World Health Organization estimates it affects approximately 190 million women and girls of reproductive age globally, roughly 10% of this population. Despite its high prevalence and significant impact on quality of life, fertility, and daily functioning, the average diagnostic delay remains 7 to 10 years across multiple healthcare systems worldwide.

Several factors contribute to this delay. Many patients and healthcare providers normalize dysmenorrhea (painful periods) and other pelvic pain symptoms, attributing them to "normal" menstrual experiences. Symptoms overlap extensively with irritable bowel syndrome, interstitial cystitis, pelvic inflammatory disease, and other conditions. There is no single blood test, imaging study, or clinical sign that definitively diagnoses endometriosis. Historically, the gold standard has been surgical visualization via laparoscopy with histological confirmation of endometrial glands and stroma outside the uterus.

The reliance on surgery for diagnosis creates an inherent barrier: many patients and clinicians are reluctant to proceed with an invasive procedure, particularly in adolescents. Studies have shown that the delay is even longer in younger patients, with adolescents waiting an average of 10.4 years compared to 6.4 years for those whose symptoms begin after age 30. Racial and socioeconomic disparities in healthcare access further compound these delays, with Black and Hispanic women experiencing longer diagnostic timelines.

What Non-Invasive Biomarkers Are Being Developed for Endometriosis?

The quest for a reliable non-invasive biomarker for endometriosis has been a major research focus for over two decades. CA-125, a glycoprotein tumor marker, is the most extensively studied blood biomarker. While CA-125 levels are often elevated in moderate to severe endometriosis, its sensitivity is only 28-50% for early-stage disease, with specificity of approximately 90%. This poor sensitivity makes it inadequate as a standalone screening test, though it may have value as part of a multi-marker approach.

MicroRNA (miRNA) panels have emerged as one of the most promising biomarker candidates. Several studies have identified specific miRNA signatures in blood, peritoneal fluid, and endometrial tissue that can distinguish endometriosis patients from controls. A 2023 systematic review in Human Reproduction Update identified miR-125b, miR-150, and miR-Let-7b as consistently dysregulated in endometriosis. Panel-based approaches combining multiple miRNAs have achieved sensitivities exceeding 90% in some studies, though validation in large, diverse populations is ongoing.

A French company, Ziwig, developed a saliva-based miRNA diagnostic test (Endotest) that achieved 96% sensitivity and 95% specificity in a validation study published in the New England Journal of Medicine in 2024. The test analyzes a panel of miRNA biomarkers from saliva samples. If validated in larger, prospective clinical trials, such non-invasive tests could dramatically reduce diagnostic delays. Other approaches under investigation include glycoproteomic profiling, volatile organic compound analysis in menstrual blood, and artificial intelligence algorithms combining clinical symptoms with biomarker data.

How Are Imaging Advances Improving Endometriosis Detection?

Advances in ultrasound technology and operator training have significantly improved the non-invasive detection of endometriosis. Expert transvaginal ultrasound (TVUS) can identify ovarian endometriomas ("chocolate cysts") with sensitivity of 93% and specificity of 96%. For deep infiltrating endometriosis (DIE), which affects structures such as the rectovaginal septum, uterosacral ligaments, and bowel, specialized TVUS performed by trained sonographers achieves sensitivity of 79-94% depending on the site, compared to near-zero detection rates with standard ultrasound.

The International Deep Endometriosis Analysis (IDEA) group has published consensus guidelines on a standardized approach to ultrasound assessment of endometriosis, including specific soft markers such as the "sliding sign" to assess posterior compartment obliteration. This standardization aims to make high-quality endometriosis imaging more widely available beyond specialized centers. Magnetic resonance imaging (MRI) is considered the best non-invasive modality for comprehensive mapping of endometriosis extent, achieving 94% sensitivity for DIE, and is particularly valuable for surgical planning.

Despite these advances, superficial peritoneal endometriosis, which is the most common form and often associated with pain in early-stage disease, remains invisible on both ultrasound and MRI. This represents a persistent diagnostic gap where biomarkers or clinical algorithms may fill the role. The emerging approach combines clinical history scoring, biomarker testing, and expert imaging in a sequential diagnostic pathway that may eventually eliminate the need for diagnostic laparoscopy in most patients.

What New Medical Treatments Are Available for Endometriosis Pain?

The treatment landscape for endometriosis-associated pain has expanded significantly with the development of oral GnRH (gonadotropin-releasing hormone) antagonists. Elagolix (Orilissa) was FDA-approved in 2018 as the first oral GnRH antagonist for moderate to severe endometriosis pain. Unlike older injectable GnRH agonists (such as leuprolide/Lupron) that initially cause a hormonal flare before suppression, elagolix produces rapid, dose-dependent suppression of estrogen without a flare. Two doses are available: 150 mg once daily (partial suppression, allowing some estrogen) and 200 mg twice daily (near-complete suppression).

In the Elaris EM-I and EM-II trials, elagolix 150 mg significantly reduced dysmenorrhea in 43-46% and non-menstrual pelvic pain in 50-56% of women at 3 months, compared to 23-26% and 37-38% with placebo, respectively. The higher dose showed greater pain reduction but with more hypoestrogenic side effects. Relugolix combination therapy (Myfembree), approved in 2024 for endometriosis pain, combines the GnRH antagonist relugolix with estradiol and norethindrone acetate as add-back therapy, providing pain relief while maintaining bone-protective estrogen levels.

Excision surgery remains an important treatment option, particularly for deep infiltrating endometriosis. Laparoscopic excision of endometriosis has been shown in a randomized trial to be superior to ablation for pain relief and reducing recurrence rates. For patients with endometriosis-related infertility, a multidisciplinary approach combining surgery when indicated, hormonal treatment, and assisted reproductive technology (particularly IVF with or without GnRH agonist pretreatment) is recommended by ESHRE guidelines.