Diagnosis of Endometriosis

Robert Z. Spaczynski, MD, PhD, Antoni J. Duleba, MD

Disclosures

Semin Reprod Med. 2003;21(2) 

In This Article

Laboratory Tests

Multiple attempts have been made to identify serum markers that would serve as reliable screening tests for endometriosis. However, to date, none of the evaluated serum proteins, including CA-125, has adequate sensitivity and specificity to function as a screening tool. At present, there is limited evidence supporting selective use of laboratory tests for therapy follow-up and monitoring of endometriosis recurrence in selected populations at risk.

CA-125

CA-125 is the cell surface antigen expressed by derivatives of coelomic and müllerian epithelia, including endocervix, endometrium, fallopian tube, peritoneum, pleura, and pericardium. This antigenic determinant of high-molecular-weight glycoprotein is detected by monoclonal antibody OC-125. In the mid-1990s a second-generation CA-125 assay of greater precision at low concentrations and reduced variability was introduced. In the CA-125 II assay, the M11 murine monoclonal antibody is used as the capture antibody, followed by labeled OC-125 tracer antibody. Originally, the increased serum levels of CA-125 were detected in patients with invasive epithelial ovarian cancer. However, elevated CA-125 levels have also been observed in serum, menstrual effluent, and the peritoneal fluid of women with endometriosis.[91,92,93,94,95,96,97]

Although CA-125 is often elevated in advanced endometriosis, the low sensitivity of this assay limits its usefulness in the detection of minimal and mild disease. Several studies performed in populations at high risk for endometriosis have demonstrated that serum CA-125 has good specificity (86-100%) but poor sensitivity (as low as 13%; Table 2 ).[177] Sensitivity was improved with the introduction of the new CA-125 II assay as well as other assay modifications.[97,98] The combination of elevated serum CA-125 with positive clinical findings (detection of pelvic nodularities) further improved the diagnostic power of this test, achieving a sensitivity of 87%.[84]

In a meta-analysis of 23 studies (1986-1997) comparing serum CA-125 levels and laparoscopically confirmed endometriosis, the estimated summary receiver operating curve (ROC) revealed a poor diagnostic performance of this test.[99] For example, for a specificity of 90% the sensitivity was only 28%, and the improvement of sensitivity to 50% resulted in a drop in specificity to 72%. CA-125 measurement was a better screening test for diagnosis of moderate to severe endometriosis (stages III and IV). For a specificity of 89% the estimated summary ROC curve showed a sensitivity of 47%, and the increase in sensitivity to 60% was associated with a drop of specificity to 81%.[99] However, the meta-analysis did not account for the effects of the phase of the menstrual cycle. Studies assessing correlation of the assay with clinical parameters (such as pelvic nodularities) are lacking.

Timing of blood collection for CA-125 in relation to the menstrual cycle significantly affects this test. Both in healthy women and in patients with endometriosis, the highest concentrations of CA-125 were detected during menstruation whereas the lowest levels were encountered during the midfollicular and periovulatory phases.[100,101] Koninckx et al[94] suggested that testing in the late luteal phase or during menstruation may be more reliable than testing in the follicular phase. The same group observed that women with superficial disease have pronounced variations in CA-125 levels, whereas women with deep endometriosis and endometriomas have continuously elevated CA-125 throughout the cycle.[94] Interestingly, a subsequent study indicated that the midfollicular CA-125 may be more reliable than the menstrual or the luteal CA-125 in detecting deep endometriosis and endometriomas.[84] Hornstein et al[95] observed that the sensitivity and specificity of the CA-125 assay were comparable during menstruation and in the midfollicular phase, with CA-125 levels consistently higher during menstruation. The reproducibility of CA-125 serum sampling during consecutive menstrual cycles was assessed in a prospective multicenter study.[102] The reproducibility of the test was good during the midfollicular phase in both controls and endometriosis patients, and the CA-125 concentrations during menstrual phase were not reproducible in patients with endometriosis and did not correlate with the disease severity. This study suggests that the best diagnostic accuracy may be achieved by CA-125 determination during the midfollicular phase. O'Shaughnessy et al[96] proposed using the ratio of menstrual to midfollicular CA-125 concentrations (cutoff at a ratio ≥ 1.5) as a better test predicting endometriosis. However, this observation was not confirmed by Hompes et al,[102] who found that the CA-125 menstrual/midfollicular ratio was not reproducible.

Despite the poor sensitivity, several reports have demonstrated that serum CA-125 level correlates with the severity of endometriosis and may predict the response to medical and surgical treatment.[92,103,104] In infertile women who underwent surgical treatment of endometriosis, persistent postoperative elevation of CA-125 independently predicted a poor prognosis, even after accounting for the stage of endometriosis.[105,106] Yet, Chen et al[107] found that CA-125 was not a reliable marker of the effectiveness of medical therapy and observed persistent endometriosis at laparoscopy performed during danazol treatment, despite a reduction of serum CA-125 to normal levels.

Serum CA-125 may also be helpful in differentiating endometriomas from nonendometriotic benign cysts.[108] In a prospective study, most endometriomas contained very high levels of CA-125 (>10,000 U/mL in 78% of cases) while the contents of blood-filled corpus luteum cysts invariably had lower CA-125 concentrations.[109]

Other Laboratory Markers

The search for a reliable marker for endometriosis has been extended to various proteins either naturally secreted by the endometrium or produced in the course of an immune reaction to endometrial and endometrium-related tissues. Markers evaluated for their diagnostic potential in detection of endometriosis comprised CA-72, CA-15-3, TAG-72, and CA-19-9, all of which demonstrated unacceptably low sensitivity.[110,111,112] One initially promising marker, a product of late secretory endometrium -- placental protein 14 (PP14) -- was shown to be elevated in endometriosis and to correlate with the severity of the disease.[113] However the relatively good sensitivity (59%) of PP14 assays in the diagnosis of endometriosis obtained in the original report was not substantiated by further studies. In a prospective study, serum levels of tumor-associated trypsin inhibitor (TATI) were found to be elevated in patients with endometriosis and positive correlation with the stage of endometriosis was described. TATI is not a useful screening test, but it may constitute an adjunct diagnostic tool because its combination with the CA-125 assay showed a sensitivity of 59% in detection of all stages of endometriosis and 89% for stage III/IV.[114] Elevated levels of acute inflammatory phase proteins (C-reactive protein and serum amyloid A) have also been demonstrated in severe endometriosis, but the usefulness of these assays remains to be elucidated.[115]

Despite the early promising observations of elevated serum antiendometrial antibodies in patients with endometriosis,[116,117] subsequent studies have failed to show the difference in the antibodies' concentration using immunofluorescence, hemagglutination, enzyme-linked immunosorbent assays, and protein blotting.[118,119] In addition, the correlation between the levels of antiendometrial antibodies and the severity of the disease is very poor.[118]

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