Re: Evaluation of high sensitivity C- reactive protein in comparison with C- reactive protein as biochemical serum markers in women with endometriosis

To the Editor:

We read the article by Lermann et al. (1) with great interest. The aim of the study was to compare high-sensitivity C-reactive protein (hs-CRP) with CRP as a soluble serum marker for the diagnosis of women with endometriosis. There were no significant differences between hs-CRP and CRP levels in endometriosis, unknown endometriosis and non endometriosis. However, the authors reported that hs-CRP had positive correlations between CRP in endometriosis (also in all stages), unknown endometriosis and non endometriosis.

It has been widely accepted that endometriosis is an inflammatory disease. Studies have demonstrated that serum levels of inflammatory markers are increased in endometriosis (2-4).

In this study hs-CRP and CRP levels did not differ in endometriotic, unknown endometriotic and nonendometriotic groups. There were 48 women in the endometriotic, 82 women in the unknown endometriotic and 34 women in the nonendometriotic group. The largest group was unknown endometriotic group that may consist of both endometriotic women and nonendometriotic women. Moreover, 12 women were infertile and 48 women had pain symptom in this group.

This study would be better if the number of the women in each group was equal or similar and there was no heterogeneous group that was defined as unknown group, only this heterogeneous group can change all the results statistically because of its largest number. We can see the same controversy in the number of the participants in stage I, II, III and IV endometriosis. The study would be better if the number of these subgroups were larger and equal, the results might be different statistically.

The authors concluded that low hs-CRP might serve as a marker for an absence of endometriosis. We think it is an assertive conclusion to the readers. It would be better to make this conclusion if hs-CRP had been significantly lower in nonendometriotic group and if they had showed a significant correlation between low hs-CRP and the group of women without endometriosis. Morerover, if they had had positive correlation with low hs-CRP and the absence of endometriosis, they had to perform ROC analysis and showed the sensitivity, specifity values and cut off levels of low hs-CRP as a promising marker in nonendometriotic group.

Dr. Fatma Ferda Verit
Dr. Nese Gul Hilali
Department of Obstetrics and Gynecology
Harran University, Faculty of Medicine
Sanliurfa, Turkey

References
1. Lermann J, Mueller A, Körber F, Oppelt P, Beckmann MW, Dittrich R, et al. Evaluation of high-sensitivity C-reactive protein in comparison with C-reactive protein as biochemical serum markers in women with endometriosis. Fertil Steril 2010;93:2125-9.

2. Bedaiwy MA, Falcone T, Sharma RK, Goldberg JM, Attaran M, Nelson DR, et al. Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial. Hum Reprod 2002;17: 426–31.
3. Pizzo A, Salmeri FM, Ardita FV, Sofo V, Tripepi M, Marsico S. Behaviour of cytokine levels in serum and peritoneal fluid of women with endometriosis. Gynecol Obstet Invest 2002;54:82–7.

4. Koumantakis E, Matalliotakis I, Neonaki M, Froudarakis G, Georgoulias V. Soluble serum interleukin-2 receptor, interleukin-6 and interleukin-1a in patients with endometriosis and in controls. Arch Gynecol Obstet 1994;255:107–12.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.05.038

The Authors Respond:

We appreciate the letter by Verit and Hilali and their comments regarding the evaluation of high-sensitivity C-reactive (hs-CRP) protein in comparison with C-reactive protein (CRP) as biochemical serum markers in women with endometriosis (1).

The aim of our study was to evaluate whether hs-CRP is a more useful biochemical marker in women with endometriosis in comparison with the conventional method using CRP. Recently, several automated high-sensitivity CRP (hs-CRP) assays have been developed that are suitable for routine use, with improved sensitivity and greater precision at low concentrations of CRP with a limit of quantification of 0.19 mg/L (2). Moreover we aimed to find a correlation between hs-CRP levels and the stage of the disease.

In our study, a trend toward higher CRP levels and higher hs-CRP levels was observed in women with histological confirmed endometriosis, while the lowest levels of both markers were found in the absence of endometriosis. No differences between the different stages of the disease were found with either marker.

Verit and Hilali suggested that if the number of women included and if the groups were more homogeneous there might result a significant advantage using hs-CRP as a diagnostic marker of endometriosis. To our knowledge, our report includes the largest number of women yet investigated to evaluate the role of CRP levels in women with endometriosis using two different CRP assays. In clinical practice the clinician is confronted without knowing definitively if there is endometriosis or not. Therefore this group reflects the majority of patients in our analysis. It seems to be important to us to show that the CRP values of women with unknown status of endometriosis are in a close range in comparison to women with endometriosis and without endometriosis independently which assay was used.

We completely agree that endometriosis is an inflammatory disease and there is promise that peripheral biomarkers may serve as a non-invasive diagnostic tool to detect endometriosis. However the published data are inconsistent. These results may reflect the different activity of the disease. Furthermore all other forms of inflammatory disease have to be excluded using other diagnostic methods. This seems to be questionable in clinical practice and may explain the heterogeneity of the published data. The use of unspecific inflammation markers for the diagnosis of endometriosis may be questionable at all. Moreover the clinical relevance may be questionable considering the differences in both markers between the groups studied.

Therefore using multiple markers may increase sensitivity and specificity of the diagnostic test (3). However neither a single serum marker nor a combination of different serum markers has been found to diagnose endometriosis with adequate sensitivity and specificity (4, 5).

Verit and Hilali suggested that performing ROC analysis might benefit the hypothesis that low levels of hs-CRP may serve as a promising marker to detect women without endometriosis. However this was definitively not the aim of our study.

In our opinion, currently there are not sufficient data to affirm that CRP levels may allow discrimination between patients with endometriosis and without endometriosis independently of the used assay.

Johannes Lermann, M.D.
Andreas Mueller, M.D., Ph.D.
Frauke Körber, M.D.
Peter Oppelt, M.D., Ph.D.
Matthias W Beckmann, M.D., Ph.D.
Ralf Dittrich, Ph.D.
Stefan P Renner, M.D.
Department of Obstetrics and Gynecology
Erlangen University Hospital
Erlangen, Germany

References
1. Lermann J, Mueller A, Körber F, Oppelt P, Beckmann MW, Dittrich R, Renner SP. Evaluation of high-sensitivity C-reactive protein in comparison with C-reactive protein as biochemical serum markers in women with endometriosis. Fertil Steril. 2010;93:2125-9.

2. Roberts WL, Moulton L, Law TC, Farrow G, Cooper-Anderson M, Savory J et al. Evaluation of nine automated high-sensitivity C-reactive protein methods: implications for clinical and epidemiological applications. Part 2. Clinical Chemistry 2001; 47:418–25.

3. May KE, Conduit-Hulbert SA, Villar J, Kirtley S, Kennedy SH, Becker CM. Peripheral biomarkers of endometriosis: a systematic review. Hum Reprod Update. 2010 May 12. [Epub ahead of print]

4. Hsu AL, Khachikyan I, Stratton P. Invasive and noninvasive methods for the diagnosis of endometriosis. Clin Obstet Gynecol. 2010;53:413-9.

5. Xavier P, Belo L, Beires J, Rebelo I, Martinez-de-Oliveira J, Lunet N et al. Serum levels of VEGF and TNF-alpha and their association with C-reactive protein in patients with endometriosis. Archives of Gynecology and Obstetrics 2006;273:227–231.

Published online in Fertility and Sterility