ORIGINAL RESEARCH

Serum CA-125 in Preoperative Patients at High Riskfor Endometriosis

Ya-Min Cheng, MD, Shan-Tair Wang, PhD, and Cheng-Yang Chou, MD

OBJECTIVE: To investigate the factors contributing to theelevated level of CA-125 in endometriosis and to studywhether CA-125 assay is useful to identify women whorequire preoperative bowel preparation.

METHODS: A total of 685 women undergoing surgery forendometriosis between July 1988 and June 1999 were stud-ied. Preoperative serum CA-125 levels were comparedbetween various pelvic conditions using F statistics. Multi-ple regression was employed to determine significant cor-relates of elevated serum CA-125, and the receiver operat-ing characteristic curve was applied to assess the utility ofserum CA-125 in preoperative preparation. Based on thetwo-sample Student t test, the sample size required to detecta difference in mean serum CA-125 levels of one-half of onestandard deviation with a power of 90% when the samplesize ratio of the two groups was 1:50 was 675 with asignificance level of 5%.

RESULTS: The mean serum CA-125 levels (IU/mL) forAmerican Society of Reproductive Medicine stages I, II, III,and IV endometriosis were 18.8 � 0.9, 40.3 � 2.8, 77.1 �3.5, and 182.4 � 14.0, respectively. CA-125 levels weresignificantly increased with advanced stages (P < .001, Ftest). Furthermore, serum CA-125 levels were significantlyhigher in patients with more extensive adhesions to theperitoneum, omentum, ovary, fallopian tube, colon, andcul-de-sac, or with ruptured endometrioma (P < .001, Ftest). We then classified patients with at least one of thethree factors including dense omentum adhesion, rupturedendometrioma, and complete cul-de-sac obliteration as thehigh-risk group that required preoperative bowel prepara-tion, and the others as the low-risk group. Receiver operat-ing characteristic curve analyses set a cutoff point of 65IU/mL, which gave a sensitivity of 76%, a specificity of 71%,a positive predictive value of 76%, and a negative predic-tive value of 93.2%.

CONCLUSION: Our results suggest that preoperative CA-125 assay is useful to decide which women should receivepreoperative bowel preparation. Endometriosis patientswith preoperative CA-125 levels higher than 65 IU/mL are

at high risk for severe pelvic adhesions that warrant thor-ough preoperative bowel preparation. (Obstet Gynecol2002;99:375–80. © 2002 by the American College of Ob-stetricians and Gynecologists.)

Endometriosis is a benign gynecologic lesion foundmostly in reproductive-age women with a prevalenceapproximating 10% or higher.1 It may cause dysmenor-rhea, dyspareunia, chronic pelvic pain, and subfertility.2

Confirmation of endometriosis is usually dependentupon laparoscopy or laparotomy. However, since Bar-bieri et al3 first demonstrated the association betweenelevated serum CA-125 concentration and the presenceof moderate-to-severe endometriosis, preoperative CA-125 measurement has been increasingly used for thediagnosis of endometriosis, especially in infertile pa-tients. Several studies4–7 and a meta-analysis8 have as-sessed the performance of serum CA-125 assay in thedetection of endometriosis, and the results show a spec-ificity of 85% and sensitivity between 20% and 50%.However, these studies focused on infertile women, andthe number of patients was small. Furthermore, only thediagnostic usefulness of CA-125 has been stressed inmost papers.

Surgical treatment of endometriosis either conservesfertility or relieves symptoms through hysterectomywith or without adnexectomy in women who have com-pleted childbearing and have severe pain. In these cases,severe adhesions between rectum, bowel wall, andpouch of Douglas are commonly found, makingsurgery at high risk for bowel trauma. Operative laparo-scopic surgery for the treatment of endometriosis offerspatients the advantage of reduced hospital stay and cost.9

However, bowel injury during laparoscopic surgery hasbeen reported, especially with severe adhesions.10 Fur-thermore, the risk of organ injury may be more pro-nounced when laparoscopic-assisted vaginal hysterec-tomy is performed.11 In this study, we attempt toinvestigate the factors that are associated with an ele-vated level of CA-125 in endometriosis, and to studywhether preoperative CA-125 assay is useful to identify

From the Departments of Obstetrics and Gynecology and Public Health, College ofMedicine, National Cheng Kung University, Tainan, Taiwan.

This work was supported by a National Cheng Kung University Hospital GrantNCKUH 89030.

375VOL. 99, NO. 3, MARCH 2002 0029-7844/02/$22.00© 2002 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc. PII S0029-7844(01)01731-8

women at high risk who would require bowel prepara-tion preoperatively.

MATERIALS AND METHODS

From July 1988 to June 1999, a total of 803 consecutivepatients who underwent surgery for endometriosis at theNational Cheng Kung University Hospital (Tainan, Tai-wan) were included. The diagnosis was made on thebasis of pathological examination. Informed consentfrom the patients was obtained, and the study was ap-proved by the institutional review board of NationalCheng Kung University Hospital. We reviewed themedical records including the obstetric and gynecologichistory and relevant medical history, clinical symptoms,preoperative serum CA-125 levels, types of operation,and operation findings in detail. We described the pelviccondition in each patient by the following parametersincluding adhesion in the peritoneum, omentum, ovary,fallopian tube, colon, and cul-de-sac, size and rupture ofendometrioma, and the corresponding American Societyof Reproductive Medicine stage. The assay for serumCA-125 was performed 1 day before surgery, and theconcentrations were measured with a two-site immuno-radiometric assay (CIS Bio International, Group ORIS,Cedex, France). Surgery method, including either lapa-rotomy or laparoscopic surgery, was according to sur-geon preference. All complications during or after sur-gery were recorded. Major operative complications weredefined as bowel, bladder, ureter, vascular injuries, ileusthat required prolonged hospital stay, or abdominal wallor intraperitoneal bleeding.

Based on the two-sample Student t test, the sample sizerequired for detecting a difference in mean serum CA-125 levels of one-half of one standard deviation with astatistical power of 90% when the sample size ratio of twogroups was 1:50 was 675 with a significance level of 5%.F test was used for the comparison of serum CA-125levels among different groups. �2 statistics based onlikelihood ratio principle were employed to analyze cat-egorical data. Multiple regression was performed to iden-tify significant correlates of elevated serum CA-125. A Pvalue of �.05 was considered significant. Receiver oper-ating characteristic (ROC) curve analysis was performedto assess the clinical utility of serum CA-125 in distin-guishing high-risk from low-risk patients. The cutoffvalues derived from ROC curves were evaluated interms of sensitivity, specificity, and positive and negativepredictive values.

RESULTS

From July 1988 to June 1999, 803 consecutive patientsunderwent surgical procedures for endometriosis that

was confirmed by pathologic examination. However,118 patients were excluded because of incomplete med-ical records or lack of data for CA-125. Thus, a total of685 patients were eligible for analysis. The age of pa-tients ranged from 14 to 68 years, with a mean age of33.7 � 7.0 years. The clinical symptoms, parity, andtypes of surgical procedures are summarized in Table 1.A total of 202 (29.5%) patients were operated on forinfertility, and the remainder experienced pelvic tumoror pain. Accordingly, in contrast to studies involvingmainly infertile patients, 219 patients underwent hyster-ectomy, and nearly 45% of the surgical procedures wereperformed by laparotomy.

The distribution of serum CA-125 levels in endome-triosis patients with regard to their pelvic conditions andAmerican Society of Reproductive Medicine stages aresummarized in Table 2. Forty-seven patients had theserum CA-125 examination during menstruation. Themean serum CA-125 levels were 18.8 � 0.9 IU/mL forstage I endometriosis, 40.3 � 2.8 IU/mL for stage IIdisease, 77.1 � 3.5 IU/mL for stage III, and 182.4 � 14.0IU/mL for stage IV endometriosis, respectively. Thevalue of CA-125 increased as the stage of endometriosisincreased, and the difference between stages was statisti-cally significant (P � .001, F test). Analyses as shown inTable 2 indicated that serum CA-125 levels were signif-icantly higher in patients with more extensive adhesionsto the peritoneum, omentum, ovary, fallopian tube, co-

Table 1. Parity, Clinical Symptoms, and Types of Surgeryin 685 Patients With Endometriosis

n � 685n (%)

Parity0 343 (50.1)1 96 (14.0)2 167 (24.4)�3 79 (11.5)

Clinical symptomsAbdominal pain 257 (37.5)Adnexal mass 83 (12.1)Infertility 202 (29.5)Dysmenorrhea 213 (31.1)Menorrhagia 25 (3.6)DUB 24 (3.5)

Types of surgeryLaparotomy 304 (44.4)

Lysis of adhesions 137 (45.1)Adnexal surgery 123 (18.0)Hysterectomy 181 (26.4)

Laparoscopy 381 (55.6)Lysis of adhesions 178 (46.7)Adnexal surgery 343 (50.1)Hysterectomy 38 (5.5)

DUB � dysfunctional uterine bleeding.

376 Cheng et al CA-125 and Endometriosis OBSTETRICS & GYNECOLOGY

lon, and cul-de-sac, or with the presence of rupturedendometrioma at surgery. The mean size for ovarianendometrioma was 4.19 � 2.91 cm, and no significantcorrelation was observed between the serum CA-125level and sizes of ovarian endometrioma (P � .05 byPearson correlation analysis). Multiple regressionshowed that stages III (P � .001) and IV (P � .001),omentum adhesion (P � .001), and ruptured endometri-oma (P � .001) were highly significantly associated withelevated serum CA-125. There was a substantial overlapof serum CA-125 levels between patients with and with-out complete cul-de-sac adhesion (Figure 1A), whichmight account for its lack of significant association withelevated serum CA-125 in multivariate analysis. How-ever, we thought that there was clinical importance for

complete cul-de-sac adhesion in bowel preparation, andtherefore included it for further analysis. As for omen-tum adhesion and rupture of endometrioma, the discrim-ination by CA-125 was better, but the case number waslimited to 18 (Figure 1B,C).

We then classified endometriosis patients to eitherhigh risk, in which at least one of these three factors, (ie,

Table 2. Distribution of Mean Serum CA-125 Levels inVarious Pelvic Conditions

PatientsCA-125 level

(IU/mL)

Pn (%) mean � SE

Revised ASRM stageI 87 (12.7) 18.8 � 0.9 �.001II 189 (27.6) 40.3 � 2.8III 270 (39.4) 77.1 � 3.5IV 139 (20.3) 182.4 � 14.0

Peritoneal adhesionsNone 312 (45.5) 92.0 � 5.8 �.001�1 cm 317 (46.3) 67.8 � 5.31–3 cm 56 (8.2) 93.4 � 16.2

Ovary adhesionsNone 49 (7.2) 30.6 � 10.6 �.001�1/3 321 (46.9) 56.5 � 4.31/3–2/3 286 (41.8) 111.6 � 6.8�2/3 29 (4.2) 134.1 � 21.5

Tube adhesionsNone 50 (7.3) 30.8 � 10.3 �.001�1/3 322 (47.0) 56.6 � 4.31/3–2/3 282 (41.2) 111.5 � 6.8�2/3 31 (4.5) 136.2 � 21.4

Cul-de-sac adhesionsNone 340 (49.6) 45.2 � 3.1 �.001Partial 233 (34.0) 96.3 � 6.9Complete 112 (16.4) 157.4 � 13.3

Colon adhesionsNone 476 (69.5) 51.89 � 2.70 �.001Present 209 (30.5) 147.07 � 9.65

Omentum adhesionsNone 673 (98.2) 74.58 � 3.24 �.001Present 12 (1.8) 437.05 � 74.46

Rupturedendometrioma

None 679 (99.1) 77.96 � 3.65 �.001Present 6 (0.9) 427.47 � 72.71

SE � standard error; ASRM � American Society of ReproductiveMedicine.

Analysis with F test, which reduces to squared Student t test sta-tistics in two-sample cases.

Figure 1. CA-125 levels in endometriosis patients with orwithout complete cul-de-sac adhesion (A), with or withoutomentum adhesion (B), and with or without rupturedendometrioma (C).Cheng. CA-125 and Endometriosis. Obstet Gynecol 2002.

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complete cul-de-sac adhesion, omentum adhesion, orrupture of endometrioma) was present, or low risk inwhich none of these three predictors was present. Ac-cordingly, a total of 121 patients were assigned to thehigh-risk group, and the mean serum CA-125 level was179.6 � 15.5 IU/mL. In the low-risk group, there were564 patients, and the mean serum CA-125 value was59.8 � 2.6 IU/mL, a significant difference from thehigh-risk group (P � .001, F test). The demographicdescriptions of high- and low-risk groups are shown inTable 3. Patients in high-risk groups were older, andwere more likely to receive laparotomy when comparedwith patients in low-risk groups (P � .01, �2 statistics).The ROC curve analyses showed that the area under theROC curve was 78.9%, which indicated that the modelcould accurately predict the subgroup allocations in78.9% of patients. From the ROC curve, we selected acutoff point of 65 IU/mL, which gave a sensitivity of 76%(95% confidence interval 68.4%, 83.6%), a specificity of71% (95% confidence interval 67.3%, 74.7%), a positivepredictive value of 76%, and a negative predictive valueof 93.2%. The fraction of CA-125 values among thehigh- and low-risk groups is depicted in Figure 2. For any

value of CA-125 along the abscissa, the fraction equal toor greater than a cutoff value was higher in the high-riskgroup than in the low-risk group. For example, approx-imately 80% of the CA-125 in the high-risk group wasequal to or greater than 65 IU/mL, whereas only 30%was equal to or greater than 65 IU/mL in the low-riskgroup.

DISCUSSION

This study demonstrates that preoperative CA-125 as-say is useful to distinguish high-from low-risk endome-triosis patients. Patients with preoperative CA-125 levelshigher than 65 IU/mL are at high risk for advancedstages or severe pelvic adhesion such as omentum adhe-sion or ruptured endometrioma, which may warrantpreoperative bowel preparation. Our results indicate anew use for preoperative serum CA-125 examination inaddition to the diagnosis of endometriosis. Our studywas not limited to infertility patients. Furthermore, weintended to emphasize that thorough preoperative plan-ning is necessary for complex surgical procedures suchas resection of endometriosis or hysterectomy.

Our results confirm previous reports that preoperativeCA-125 levels increase with the stages of endometrio-sis.3,4,6 It further extends the observations that omentumadhesion and rupture of endometrioma are also theleading causes of elevated CA-125 levels. Such pelvicpathology will increase the risk of bowel injury. How-ever, bowel preparation is unpleasant for the patient andincreases medical expenses. Thus, it is useful to identifythese high-risk patients who require preoperative bowelpreparation. Unfortunately, notable overlap of serumCA-125 levels among patients with and without com-plete cul-de-sac adhesion and the limited number ofpatients with omentum adhesion or ruptured endometri-oma render the differentiation unlikely. Although cul-de-sac adhesion was not significantly associated with ele-vated serum CA-125 in multivariate analysis, weincluded complete cul-de-sac adhesion because of itsclinical importance in bowel preparation. As shown inFigure 2, its inclusion gave reasonable sensitivity andspecificity. Therefore, we subgroup all eligible patientsinto either high- risk or low-risk groups. The ROC curveanalyses demonstrate that we are able to predict whichwomen should receive preoperative bowel preparationin nearly 80% of endometriosis patients. Analysis bydistribution curves of CA-125 levels as illustrated inFigure 2 further indicates that CA-125 is a valid markerin distinguishing between high- and low-risk patients. Acutoff point of CA-125 at 65 IU/mL gives a sensitivity of76% and a specificity of 71%. A shift of cutoff values ofCA-125 from 65 IU/mL to 35 IU/mL results in an

Table 3. Characteristics of Cases in High and Low-RiskGroups

High-riskgroup

(n � 121)

Low-riskgroup

(n � 564)

Pn (%) n (%)

Age (mean � SD) (y) 36.2 � 8.2 33.2 � 6.6 .007Parity .096

0 52 (43.0) 291 (51.6)1 14 (11.6) 82 (14.5)2 36 (29.8) 131 (23.2)�3 19 (15.6) 60 (10.7)

Medical diseases .72None 118 (97.5) 552 (97.9)Hyperthyroidism 2 (1.7) 5 (0.9)ITP 1 (0.8) 2 (0.4)Asthma 0 (0) 2 (0.4)Heart disease 0 (0) 2 (0.4)Hypertension 0 (0) 1 (0.2)

Clinical symptoms .07Abdominal pain 62 (51.2) 195 (34.6)Adnexal mass 15 (12.4) 68 (12.1)Infertility 47 (38.8) 155 (27.5)Dysmenorrhea 75 (62.0) 138 (24.5)Menorrhagia 9 (7.4) 16 (2.8)DUB 3 (2.4) 21 (3.7)

Type of surgery .008Laparotomy 67 (55.4) 237 (42.0)Laparoscopy 54 (44.6) 327 (58.0)

SD � standard deviation; ITP � idiopathic thrombocytopenia pur-pura. Other abbreviation as in Table 1.

P was calculated based on �2 statistics using likelihood ratio prin-ciple for categoric data and two-sample t test for continuous data.

378 Cheng et al CA-125 and Endometriosis OBSTETRICS & GYNECOLOGY

increase in sensitivity from 76% to 88.4% but a notabledecrease in specificity from 71% to 40.8%.

A limitation of the present analysis is that we areunable to predict the necessity of preoperative bowelpreparation in 20% of patients recruited. In addition,with the specificity of 71% for the cutoff value CA-125 at65 IU/mL, 29% of predicted high-risk patients will re-ceive an unnecessary bowel preparation. Koninckx et al2

report that nodularities at clinical examination duringmenstruation or follicular phase CA-125 concentrationsover 35 IU/mL are useful to decide that bowel prepara-tion should be given, achieving a sensitivity of 87% anda specificity of 83%. However, the finding of painfulnodularities at clinical examination is quite subjectiveand may require analgesia and experience of the sur-geons to obtain satisfactory results. Furthermore,women in certain geographic areas such as in Taiwan arereluctant to undergo pelvic examination during menstru-ation. The mechanism for high CA-125 level and severepelvic adhesion in endometriosis is not fully understood.The expression of intercellular adhesion molecule-1 andinterferon-� is reported to be associated with endometri-osis.12–14 Further studies involving the combined use ofCA-125 and cytokines are currently under investigation.

The use of operative laparoscopy in the treatment ofminimal and mild endometriosis has been widely ac-cepted.8 More complex gynecologic procedures includ-ing treatment for advanced endometriosis are being per-formed laparoscopically, which may account for anincreased rate of injuries to organs such as the bladder,ureter, intestine, and blood vessels.15 Indeed, in thisreport, nine women had complications, five of whichwere major, and all of them occurred in patients under-going laparoscopic surgery without preoperative bowelpreparation. Among them, three patients with coloninjuries had preoperative CA-125 values over 65 IU/mLand complete obliteration of the pouch of Douglas. Sur-gical repair was not attempted because none had re-ceived preoperative bowel preparation. They underwentcolostomy a few days after laparoscopy. In contrast, 66patients with CA-125 values over 65 IU/mL undergoingpreoperative bowel preparation did not have major com-plications after surgery, suggesting that preoperativebowel preparation may help to reduce the consequencesof intraoperative injury. It is noteworthy that preopera-tive use of gonadotropin-releasing hormone agonist hasthe benefit of decreasing the size of ovarian endometri-oma and the inflammatory reaction surrounding the

Figure 2. Curves for the fraction of CA-125 (IU/mL) levels equal to or greater than a cutoff value along the abscissa in high-and low-risk groups.Cheng. CA-125 and Endometriosis. Obstet Gynecol 2002.

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endometrioma, which would improve surgical perfor-mance.16,17

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12. Tabibzadeh S, Kong QF, Babaknia A. Expression ofadhesion molecules in human endometrial vasculaturethroughout the menstrual cycle. J Clin Endocrinol Metab1994;79:1024–32.

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Address reprint requests to: Cheng-Yang Chou, MD, NationalCheng Kung University Hospital, Department of Obstetricsand Gynecology, 138 Sheng-Li Road, Tainan, 704, Taiwan; E-mail: chougyn@mail.ncku.edu.tw.

Received July 2, 2001. Received in revised form October 25, 2001.Accepted November 1, 2001.

380 Cheng et al CA-125 and Endometriosis OBSTETRICS & GYNECOLOGY