Endometriosis: Diagnostic and Treatment Challenges

Peter Kovacs, MD, PhD


December 31, 2019

Endometriosis is a chronic, benign gynecologic disease that is diagnosed when endometrial glands and stroma are found in extrauterine locations. Affecting as many as 1 in 7 women, endometriosis is associated with pelvic symptoms, dysmenorrhea, chronic pelvic pain, dyspareunia, intestinal or urinary tract problems, and infertility. Despite a host of well-described symptoms, the diagnosis is typically delayed by 6-10

Symptoms may suggest endometriosis, and the suspicion can be supported by findings during physical exam or imaging studies. The gold standard to confirm endometriosis requires histologic examination of endometrial glands and stroma obtained by surgical biopsy. However, surgery is often delayed when the symptoms are not specific, are not severe enough to interfere with quality of life, or when the patient elects not to undergo laparoscopy. In these cases, serum biomarkers with good positive and negative predictive value could shorten the time to proper diagnosis and treatment.

Can Endometriosis Be Diagnosed Noninvasively?

As a chronic inflammatory disease, hormones, cytokines, chemokines, and angiogenic factors play a role as etiologic factors in endometriosis. The next logical step, therefore, is to discover whether any of these biomarkers could be used for a noninvasive diagnosis.

A 2016 Cochrane review set the bar for the accuracy of biomarker screening at > 95% sensitivity and > 50% specificity. However, not one of 122 serum biomarkers (eg, interleukin-6, CA125, CA19.9, anti-endometrial antibody) tested in more than 15,000 women with endometriosis achieved these benchmarks. As screening tools, these biomarkers may have failed because they are nonspecific and can be elevated in other benign conditions. Moreover, small endometrial implants may not secrete enough to be detected, and as a heterogeneous disease, different forms of endometriosis may express different markers.

A second 2016 Cochrane review assessed the diagnostic accuracy of 22 endometrial biomarkers. Despite a few promising findings (endometrial proteome, 17ß-HSD2, Il-1R2, caldesmon, and neural markers), the overall evidence was insufficient to qualify these biomarkers as diagnostic tests. Oxidative stress is also believed to contribute to the development of endometriosis, but here again, the data are insufficient to support its having a diagnostic role.

Endometriosis thrives in an estrogen-dominant local environment, but hormonal markers (estradiol, progesterone, leptin, luteinizing hormone, activin) have not been shown to be useful serum markers of endometriosis. A recent meta-analysis evaluating seven different hormonal markers in 1279 women with endometriosis across 17 studies calculated a sensitivity of 79% and a specificity of 89% for aromatase. The researchers considered this to be a potentially good diagnostic test but acknowledged that their conclusions are based on moderate-quality studies.

Cytokines and chemokines associated with chronic inflammation are produced by macrophages, lymphocytes, and mesothelial cells, and are believed to promote endometriosis. Cytokines (eg, IL-6, TNF-alpha) and chemokines are not specific to endometriosis, and their use as diagnostic tests would be associated with high false-positive rates.

In recent years, genetic markers such as microRNA (non-coding RNAs that affect the translation of mRNA and gene expression) have been proposed as diagnostic tools for endometriosis. A meta-analysis from China reported that among 453 women with endometriosis, microRNA had a diagnostic sensitivity of 81% with a specificity of 77%. In contrast, the findings of another recent review could not support the use of single or a panel of microRNA as a biomarker.

Better understanding of the pathology of endometriosis opened up the possibility that we could diagnose endometriosis noninvasively, but further research with larger sample sizes will be needed to identify diagnostic tests with adequate sensitivity and specificity.

What's New in the Management of Endometriosis?

New treatment options for endometriosis are needed because not all affected women respond to the currently available methods, not all methods can be used over a longer period of time, and they are not without side effects. In general, endometriosis can be treated medically or surgically. Medical treatments are either nonspecific (eg, pain control) or they target the estrogen-dependent nature of endometriosis by interfering with estrogen supply. Currently accepted treatments include combined oral contraceptive pills (OCPs), progestins, anti-progestins, and gonadotropin-releasing hormone agonists. Elagolix is an FDA-approved oral gonadotropin-releasing hormone antagonist that has been shown to improve the pain and fatigue associated with endometriosis.

Blocking any of the biosynthetic pathways to estradiol production is another potential treatment strategy. Aromatase inhibitors (eg, letrozole) have already been shown to reduce pain related to endometriosis, but this agent has musculoskeletal side effects and induces follicle development so it must be combined with an OCP. A vaginal ring that releases aromatase and levonorgestrel is currently under evaluation now. Estrone-3-O-sulfamate, an inhibitor of steroid sulfatase that interferes with the release of free steroid from its conjugated from, is also in early-phase clinical studies. Estrone needs to be converted to estradiol by 17 ßHSD-1. Inhibitors of 17 ßHSD-1, the enzyme required for the conversion of estrone to estradiol, are under clinical evaluation. Although not yet on the market, these compounds could increase the medical treatment options for endometriosis in the near future.

Endometriosis in its severe form may significantly compromise quality of life. Early diagnosis and treatments that provide long-term relief with minimal to no side effects are needed to reduce its burden. Recent years have seen intensive research in this field, and hopefully in the near future a widening diagnostic and therapeutic armamentarium will help us manage these patients more effectively.


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