Endometriosis and CA-125

Blood levels of CA-125 are among the tests most often requested by gynaecologists in patients with an ovarian cyst. Often, however, the result causes more confusion than it helps. When CA-125 levels are raised, patients understandably worry about gynaecological cancer, while others are told that they cannot possibly have endometriosis because their CA-125 is normal! Both interpretations are often wrong. Let’s look at what information this test can (and cannot) really give us.

What is CA-125?

CA-125 is a protein normally produced by cells lining various tissues of the body, such as the peritoneum (the thin membrane that covers the pelvic organs) and the endometrium. It is known as a “tumour marker”, as it is used in the investigation and monitoring of ovarian cancer. A value equal to or greater than 35 U/mL is usually considered raised⁵.

Why is it often raised in endometriosis?

As we have discussed before, endometriosis lesions cause chronic inflammation and irritation of the peritoneum, which leads to more CA-125 being released into the blood. This is why women with endometriosis often have higher CA-125 levels than women without endometriosis. Levels are usually higher in the more “advanced” forms of the disease, such as endometriomas (chocolate cysts) and deep infiltrating endometriosis⁴.

Can CA-125 diagnose endometriosis?

The short answer is no. In a large meta-analysis of more than 3,600 women, CA-125 (with a cut-off of 30 U/mL) identified only about half of the women who had endometriosis (sensitivity 52%). When it was raised, however, it was rarely “falsely” raised in women without the disease (specificity 93%)¹. In other words, it had low sensitivity and high specificity for the diagnosis of endometriosis.

In practice, this means that:

• A normal CA-125 does not rule out endometriosis. About one in two women with endometriosis has a normal level¹. This is especially true of superficial endometriosis. In one study, only about 27% of women with mild disease had a level above 35 U/mL, compared with about 87% of women with advanced disease⁴.
• A raised CA-125 in a woman with symptoms suggestive of endometriosis strengthens the suspicion, but it does not make the diagnosis on its own.

For these reasons, a Cochrane review concluded that no blood marker, including CA-125, is accurate enough to be used to diagnose endometriosis². Similarly, the guidelines of the European Society of Human Reproduction and Embryology (ESHRE) do not recommend the use of blood biomarkers to diagnose the disease³. Diagnosis is based on the medical history, clinical examination and, above all, imaging with a specialist transvaginal ultrasound scan or MRI. (Non-invasive tests for the diagnosis of endometriosis are now available in several countries; however, this topic is beyond the scope of this article.)

What else can raise CA-125?

CA-125 is not specific either to endometriosis or to cancer. It can be raised, among other things⁵:

• during menstruation, ovulation and pregnancy,
• in benign gynaecological conditions, such as fibroids, benign ovarian cysts and pelvic inflammatory disease,
• in conditions of other organs, such as the liver, heart, pancreas, bowel and kidneys, as well as in autoimmune diseases,
• after recent surgery.

Does the timing of the test matter?

Yes. CA-125 naturally rises during menstruation and is lower on the other days of the cycle⁴. A level measured during a period may therefore be “falsely” raised. For this reason, unless your doctor advises otherwise, it is better to have the test outside your period. If it is repeated, it is best done in the same phase of the cycle, so that the results can be compared.

CA-125 and endometrioma: should I worry about cancer?

In women with an ovarian cyst, CA-125 is one of the tools that help assess the risk of malignancy. However, endometriomas often raise CA-125, and in rare cases, such as after rupture of the cyst, levels can be extremely high without any cancer being present⁶. Moreover, in women with endometriosis, CA-125 on its own does not appear to reliably distinguish benign from malignant lesions⁴.

In other words, a raised CA-125 in a woman with an endometrioma does not mean cancer. The assessment is always made as a whole, based mainly on the findings of a specialist ultrasound scan and/or MRI. You can read more about the link between endometriosis and ovarian cancer in a related article on our website.

Is it useful after surgery?

CA-125 usually falls after surgical removal of endometriosis or during hormonal treatment. In some studies, a new rise after surgery was associated with recurrence of the disease. The data, however, come mainly from small studies⁴. So, during follow-up, symptoms and ultrasound findings matter more than a single CA-125 value.

Key points to remember

• CA-125 is not a test for diagnosing endometriosis.
• A normal CA-125 does not rule out endometriosis.
• A raised CA-125 does not necessarily mean cancer, especially in women with an endometrioma.
• The result should always be interpreted by a specialist, together with the symptoms, the clinical examination and a specialist ultrasound scan/MRI.

If you have endometriosis or have questions about your test results, do not hesitate to contact us. Led by endometriosis gynaecologist-surgeon Dr Georgios Grigoriadis, we have a fully trained team of healthcare professionals, ready to treat endometriosis in any location, from the simplest to the most complex.

Endometriosis is common… get informed!

References

1. Hirsch M, Duffy J, Davis CJ, Nieves Plana M, Khan KS; International Collaboration to Harmonise Outcomes and Measures for Endometriosis. Diagnostic accuracy of cancer antigen 125 for endometriosis: a systematic review and meta-analysis. BJOG. 2016;123(11):1761-1768.
2. Nisenblat V, Bossuyt PMM, Shaikh R, et al. Blood biomarkers for the non-invasive diagnosis of endometriosis. Cochrane Database Syst Rev. 2016;(5):CD012179. doi:10.1002/14651858.CD012179
3. Becker CM, Bokor A, Heikinheimo O, et al. ESHRE guideline: endometriosis. Hum Reprod Open. 2022;2022(2):hoac009.
4. Chen Y, Pan M, Zuo Y, Yang B, Wang S. Research progress of CA125 in endometriosis: teaching an old dog new tricks. Gynecol Obstet Clin Med. 2022;2(4):191-198. doi:10.1016/j.gocm.2022.10.006
5. NHS Wales. Guideline for the management of raised serum CA 125 levels with normal pelvic ultrasound findings in primary and secondary care.
6. Bayramov V, Şükür YE, Pabuçcu E, Atabekoğlu CS. Extremely elevated CA 125 and CA 19-9 in endometrioma; a case series. Turk J Obstet Gynecol. 2010;7(1):45-48.