Services de 1 Gynécologie, 2 Anatomie Pathologique and 3 Biochimie, Hôpital Hôtel-Dieu et Tenon, AP-HP, Paris, France
4 To whom correspondence should be addressed at: Service de Gynécologie, Hôpital Tenon, 4 rue de la Chine, 75020 Paris, France. e-mail: emile.darai{at}tnn.ap-hop-paris.fr
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Abstract |
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Key words: cytokines/endometriomas/interleukins/ovarian tumour/tumour necrosis factor
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Introduction |
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Cytokines and growth factors are protein or glycoprotein mediators of extra- and intracellular communications within the immune system. Among the cytokines, interleukin (IL)-6 is a regulator of inflammation and immunity, modulating the secretion of various cytokines, and promoting T-cell activation and B-cell differentiation (Lebovic et al., 2001). IL-6 inhibits the proliferation of human endometrial cells (Zarmakoupis et al., 1995
); however, in patients with endometriosis, high IL-6 levels were found in peritoneal fluid (Buyalos et al., 1992
; Koyama et al., 1993
; Keenan et al., 1994
; Rier et al., 1995
), and were correlated with both the grade (Cheong et al., 2002
) and stage of the disease (Khan et al., 2002
).
IL-8, a neutrophil-activating cytokine with angiogenic activity, has a direct proliferative effect on endometrial stromal cells (Arici et al., 1998a;b; Iwabe et al., 1998
). In vivo, ectopic endometrial cells express high concentrations of IL-8 regardless of the menstrual cycle phase (Akoum et al., 2001
). Increased concentrations of IL-8 have been found in the peritoneal fluid of women with endometriosis (Ryan et al., 1995
; Arici et al., 1996
).
Tumour necrosis factor-alpha (TNF-) is produced by neutrophils, activated lymphocytes, macrophages and natural killer cells, and promotes the adherence of cultured stromal cells to the mesothelium (Zhang et al., 1993
). It has been shown (Eisermann et al., 1988
; Calhaz-Jorge et al., 2000
) that, in women with endometriosis, peritoneal fluid TNF-
concentrations correlate with the stage of the disease.
Others (Fasciani et al., 2000; 2001) have suggested that a high cytokine level in endometriomas could be a specific event for both their progression and maintenance. However, few reports have evaluated serum and cyst fluid concentrations of cytokines and TNF-
in women with endometriomas compared with those found in women with benign or malignant ovarian cysts.
Therefore, in order to evaluate whether endometriomas have specific cytokine profiles, serum and cyst fluid concentrations of IL-6, IL-8 and TNF- were monitored in patients with endometriomas, and the levels compared to those in women with benign and malignant cystic ovarian tumours.
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Materials and methods |
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Sera were obtained immediately before the outset of surgery. Cyst fluid was sampled using protected cyst puncture in an endoscopic bag for both macroscopically benign lesions (no exophystic papillary growth, normal cortical ovarian vasculature, and absence of peritoneal implant) and for tumours with macroscopic signs of malignancy.
The mean age of women with endometrioma was 37 years (range 2254); 36 of the patients were premenopausal and one was post-menopausal. None had received GnRH analogues for at least 3 months before surgery. Twenty of the premenopausal women underwent surgery during the proliferative phase of the menstrual cycle, and 13 during the secretory phase. All the premenopausal women underwent cystectomy, and the post-menopausal woman underwent bilateral salpingo-oophorectomy.
The mean age of women with benign tumours was 52 years (range 1688); 16 of these women were post-menopausal (including three receiving hormonal replacement therapy, HRT), and 14 were premenopausal. All the premenopausal patients underwent cystectomy during the proliferative menstrual phase.
The mean age of women with malignant tumours was 68 years (range 5182). All of these patients were post-menopausal, and two were on HRT. No neoadjuvant chemotherapy was used before surgery, which included omentectomy and hysterectomy with bilateral salpingo-oophorectomy in every case, and pelvic and para-aortic lymphadenectomy in eight cases. Surgery was followed by chemotherapy.
The status of each tumour was confirmed histologically by reviewing haematoxylin and eosin-stained tissue sections. None of the endometriomas contained clear nuclear atypia.
Serum and cyst fluid cytokine measurements
Blood was collected in sterile EDTA tubes and the plasma rapidly separated by centrifugation. Serum and cyst fluid aliquots were immediately stored in pyrogen-free tubes at 80°C until use.
IL-6 was measured with an immunoradiometric assay (Medgenix two-step immunoradiometric IRMA; BioSource, Nivelles, Belgium), with a detection limit of 6 pg/ml and within- and between-run variability of 4.36.7% and 2.38.3% respectively. A tenuous cross-reaction with granulocyte-colony-stimulating factor (G-CSF) is known to occur.
IL-8 was measured with an immunoradiometric assay (Medgenix two-step immunoradiometric IRMA), with a detection limit of 104 pg/ml and within- and between-run variability of 4.718.33% and 6.710.0% respectively.
TNF- was measured with an immunoradiometric assay (Medgenix-TNF-
-IRMA), with a detection limit of 5 pg/ml and within- and between-run variability of 2.26.0% and 2.87.0% respectively. TNF-
does not cross-react with TNF-
, IL-1, IL-2 or interferon-
,
, or
in this assay.
All samples were tested in duplicate.
Statistical analysis
Statistical analysis was based on the 2-test for categorical variables, and the KruskalWallis and MannWhitney tests for continuous variables. A P-value < 0.05 was considered significant. IL-6, IL-8 and TNF-
values were not normally distributed, even after logarithmic transformation. Therefore, for independent samples, values in the three groups were compared using the non-parametric KruskalWallis test, and values in the two groups were compared using the non-parametric MannWhitney test and Bonferroni test (Epi-info software). Correlations between serum and cyst cytokine concentrations were identified using the Spearmann correlation coefficient. A P-value < 0.05 was considered to denote a significant difference.
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Results |
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Serum levels of TNF- differed between the three groups (P < 0.001), with values higher in women with endometriomas than in those with benign tumours (P < 0.01) (Table I). However, no difference was found between women with endometriomas and those with malignant tumours.
In women with endometriomas, no difference was found in serum IL-6, IL-8 or TNF- levels according to the phase of the menstrual cycle.
Mean (± SD) serum IL-6, IL-8 or TNF- levels in mucinous and serous benign tumours were 5.1 ± 2.8 and 5.0 ± 3.5, 56 ± 23 and 132 ± 112, and 34 ± 33 and 35 ± 19 pg/ml respectively. No difference was found in serum IL-6, IL-8 or TNF-
level between mucinous and serous benign tumours. Mean serum IL-6, IL-8 or TNF-
levels in mucinous and serous malignant tumours were 50 ± 75 and 112 ± 121, 83 ± 81 and 131 ± 75, and 47 ± 31 and 52 ± 24 pg/ml respectively. No difference was found in serum IL-6, IL-8 or TNF-
level between mucinous and serous malignant tumours.
IL-6, IL-8 and TNF- cyst fluid levels according to histological type
Although cyst fluid levels of IL-6 did not differ among the three groups, those of IL-8 differed significantly (P < 0.001), being higher in women with endometriomas than in those with benign ovarian tumours (P < 0.001), and lower in women with endometriomas than in those with malignant ovarian cysts (P = 0.03) (Table II).
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In women with endometriomas, no difference was found in cyst fluid IL-6, IL-8 or TNF- levels according to the phase of the menstrual cycle.
Mean (± SD) cyst fluid levels of IL-6, IL-8 or TNF- in mucinous and serous benign tumours were 2132 ± 3200 and 2544 ± 2089, 8x103 ± 19x103 and 11.7x103 ± 19x103, and 38 ± 30 and 52 ± 19 pg/ml respectively. No difference in cyst fluid levels of IL-6, IL-8 or TNF-
was found between mucinous and serous benign tumours. Mean cyst fluid levels of IL-6, IL-8 or TNF-
in mucinous and serous malignant tumours were 4022 ± 1910 and 5824 ± 1570, 34x103 ± 42x103 and 46x103 ± 53x103, and 171 ± 191 and 309 ± 134 pg/ml respectively. No difference was found in cyst fluid levels of IL-6, IL-8 or TNF-
between mucinous and serous malignant tumours.
Relationship between IL-6, IL-8, and TNF- serum and cyst fluid levels in endometrioma
A positive correlation was found between serum and cyst fluid IL-6 levels (P = 0.003, rho = 0.633) (Figure 1A), but no relationship was found between serum and cyst fluid levels of either IL-8 or TNF-.
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No relationship was found between cyst fluid levels of IL-6 and IL-8, IL-6 and TNF-, or between IL-8 and TNF-
.
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Discussion |
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Serum IL-6 levels were higher in women with endometriomas than in those with benign tumours, but lower than in women with malignant cystic ovarian tumours. These results are partly in keeping with those of others (DHooghe et al., 2001) who reported, in a preliminary study of 13 women with endometriosis, an increase in serum IL-6 levels. However, these authors did not find any variation in serum IL-6 levels according to deep or superficial endometriosis, probably due to the small sample size. More recently, another group (Bedaiwy et al., 2002
) suggested that a threshold of 2 pg/ml for serum IL-6 provided a sensitivity of 90% and a specificity of 67% to distinguish patients with endometriosis from those without. In contrast to the findings of this previous study, the present data showed that elevated serum levels of IL-6 (>2 pg/ml) were detected in women with benign tumours. This discrepancy could be explained by the variation in immunoradiometric assay, with a higher detection limit for IL-6 measured in the present study compared with that of others (Bedaiwy et al., 2002
). However, the present results underlined that an increase in serum IL-6 levels was not specific to women with endometriomas, but was also observed in women with cystic malignant ovarian tumours.
IL-8 is a cytokine which induces chemotaxis of neutrophils, local angiogenesis and stimulates cell proliferation (Arici, 2002). The adherence of endometrial cells induces further IL-8 expression by an integrin-dependent mechanism, suggesting that this cytokine might act as an autocrine growth factor in the pathogenesis of endometriosis (Arici, 2002
). In the present study, no difference in serum levels of IL-8 was found between the patient groups. The present data are in agreement with those reported previously and which showed that the peripheral blood concentration of IL-8 was not related to the presence of endometriosis (Gazvani et al., 1998
).
Serum levels of TNF- were higher in women with endometriomas than in those with benign tumours, but were similar in women with either endometrioma or malignant ovarian tumour. The present results are in keeping with those of others (De Jaco et al., 1991
), who reported higher TNF-
serum levels in women with ovarian carcinoma than in healthy subjects and women with benign ovarian cysts. As with serum IL-8 levels, the present results suggest that elevated serum TNF-
levels are of little diagnostic value in endometriosis; indeed, the results were in line with those of others (Hsieh et al., 2002
) who found that TNF-
gene polymorphisms were not predictive of susceptibility to endometriosis.
Although endometrioma cyst fluid contained higher levels of IL-8 than benign ovarian tumour cyst fluid, the levels of IL-6 and TNF- were similar. This increase in IL-8 cyst fluid seen in endometriomas might (in part) be related to the haemorrhagic feature of these cysts, although the present results are in line with those of others (Fasciani et al., 2000
; 2001) who demonstrated a higher IL-8 cyst fluid level in endometriomas and ovarian carcinoma compared with either follicular or serous ovarian cysts. The present results were, however, at variance with those of another group (Odukoya et al., 1997
) who found no increase in IL-8 and TNF-
mRNA levels between chocolate cysts and a control group composed of patients without ovarian cyst who underwent ovarian biopsy during laparoscopic sterilization. Furthermore, a significant difference was found in cyst fluid levels of IL-8 and TNF-
between endometriomas and malignant ovarian tumours. These results contrast with those of others (Punnonen et al., 1991
), who did not find any correlation between cytokine production and tumour malignancy. However, the present data are in agreement with those of earlier studies (Aderka et al., 1985
; Balkwill et al., 1987
) which showed that tumour cytokine production is a more non-specific marker of the inflammatory process than a specific response to malignant cells.
In contrast to IL-6 serum levels, in the present study no difference was found in cyst fluid IL-6 levels between women with endometriomas and those with benign or malignant ovarian tumours. This finding is in contrast to an earlier report (Odukoya et al., 1997) which identified higher IL-6 mRNA expression in endometriomas from 10 patients than in a control group. As with a previous study (Rier et al., 1994
), these authors suggested that the increase in IL-6 expression was most likely due to the neovascularization associated with endometriosis. However, in-vitro studies have shown that the ovarian surface epithelium produces various cytokines, such as IL-1, IL-6 and colony-stimulating factors (Buyalos et al., 1992
; Ziltener et al., 1993
). Moreover, resident leukocytes, T cells and macrophagesas well as granulosa and theca cellscontribute to ovarian cytokine production (Brännström and Norman, 1993
).
In the present study, no relationship was found between endometrioma cyst fluid levels of IL-6, IL-8 and TNF-, which contrasts with data of others (Iwabe et al., 1998
) that TNF-
produced by endometriotic stromal cells of chocolate cysts increased the expression of IL-6 mRNA and protein in concentration-dependent manner. However, a positive correlation was found between serum and cyst fluid levels of IL-6, and between serum levels of IL-6 and IL-8, suggesting that different autocrine and paracrine pathways might control the secretion of these cytokines and of TNF-
. No difference in serum and cyst fluid levels of IL-6, IL-8 or TNF-
was found between serous and mucinous ovarian cysts, most likely due to the small sample size. High cyst levels of IL-6 and IL-8 compared with serum levels were found, whereas TNF-
serum and cyst fluid levels were similar. The reason for this apparent discrepancy is not clear, but a possible cause might be the cystic nature of the tumours included in the present study. It has been hypothesized that the cyst wall acts as a barrier which prevents the diffusion of products released by ovarian epithelial cells into the blood (Fleuren et al., 1987
; Menczer et al., 1993
). However, these results are in accordance with previous studies on CD44 proteins, cadherins or CD31 expression in ovarian cystic tumours (Darai et al., 1998a
;b).
In conclusion, the results of these investigations suggest that the serum and cyst fluid cytokine profiles in women with endometriomas share certain features with those in women with cystic ovarian malignancies.
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Submitted on November 18, 2002; resubmitted on April 3, 2003; accepted on May 1, 2003.