Molecular Human Reproduction, Vol. 6, No. 1, 50-54,
January 2000
© 2000 European Society of Human Reproduction and Embryology
Uterus and pregnancy |
High concentrations of the vascular endothelial growth factor and interleukin-8 in ovarian endometriomata
1 Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Via Roma 56, 56126 Pisa, and 2 Department of Oncology, Division of Pharmacology and Chemotherapy; University of Pisa, 56126 Pisa, Italy
Abstract
Patients with endometriosis are characterized by the ability of the endometrium to implant and by the peritoneal response to the tissue; angiogenic factors may play a significant role in the aetiology of endometriosis supporting the implantation of ectopic endometrial cells. Vascular endothelial growth factor (VEGF) is a mitogen, morphogen and chemoactractant for endothelial cells and, in vivo, it is a powerful mediator for vessel permeability. Interleukin-8 (IL-8) is a chemoatractant for neutrophils and is a potent angiogenic factor. Women (n = 20) with ovarian endometriomata and 10 women with follicular cysts were enrolled in this study to investigate the role of VEGF and IL-8 in the development and maintenance of ovarian endometriomata. Cystic fluids were collected by laparoscopy, immediately centrifuged and stored until the enzyme-linked immunosorbent assays were performed. The VEGF and IL-8 concentrations were found to be significantly higher in the fluids of the ovarian endometriomata than in those of the follicular cysts of controls (P < 0.001 and P < 0.001 respectively); in addition, a significant inverse correlation between the VEGF cystic fluid concentrations and the diameter of the endometriotic adnexal masses was found (r = –0.56, P = 0.01). The evidence that the high concentrations of VEGF and IL-8 are present in the ovarian endometriomata indicates that angiogenesis could be a specific event both for the progression and maintenance of such cysts.
endometriosis/interleukin-8/ovarian cyst/vascular endothelial growth factor
Introduction
Endometriosis, defined as the presence of endometrial glandular and stromal cells outside the uterine cavity, is a benign gynaecological disorder which is associated with significant pain and morbidity occuring in ~10% of women of reproductive age and in up to 50% of women with infertility (Strathy et al., 1982
). Histological evidence of endometriosis can be found in up to 15% of biopsies of normal peritoneum mesothelium (Thomas, 1996) and the ovary is the most common location of endometrial implants being involved in 40–60% of cases (Jenkins et al., 1986).
The pathogenesis of endometriosis is poorly understood; probably the disease arises from the peritoneal seeding of viable endometrial cells during retrograde menstruation, but, as this event occurs in ~90% of cycling women (Halme et al., 1984) additional factors are necessary to explain why the disease occurs in some women and not in others.
Recent studies have pointed out the importance of the peritoneal response to the chronic stimulus of exfoliated endometrium: the macrophagic activation (Halme et al., 1983), the local production of cytokines and growth factors (Shifren et al., 1996; Tseng et al., 1996) and the neovascularization within the peritoneal cavity are all factors demonstrated to be detrimental for the establishment and maintenance of pelvic endometriosis.
These latter angiogenic dynamics would provide an adequate blood supply to the desquamated endometrium making it able to attach and implant on the mesothelial surface; new vascularization, therefore, has been considered to be a key factor in the progression of endometriosis (Smith, 1997) and such a pathological condition has been defined as one of the family of angiogenic diseases (Healy et al., 1998).
Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a 34–46 kDa homodimeric glycoprotein which is a highly specific mitogen for vascular endothelial cells, is capable of inducing angiogenesis (Leung et al., 1989), is a potent inducer of vascular permeability (Keck et al., 1989) and is a survival factor for newly formed blood vessels (Benjamin et al., 1997).
Peritoneal fluid concentrations of VEGF have been demonstrated to be significantly higher in women with endometriosis than in the control patients (McLaren et al., 1996) and a positive correlation between the severity of endometriosis and the concentrations of VEGF in peritoneal fluid has been observed (Shifren et al., 1996).
Interleukin-8 (IL-8) is a chemoattractant for neutrophils and angiogenic agents and it is a potent angiogenic factor (Koch et al., 1992; Desbaillets et al., 1997) produced by a wide variety of cell types including monocytes, neutrophils, endothelial cells and mesothelial cells (Arici et al., 1996). The concentrations of this cytokine in peritoneal fluids of patients with endometriosis have been demonstrated to be significantly greater than in patients without the disease and a significant correlation between such concentrations and the extent of active endometriosis has been noted (Iwabe et al., 1998).
This study was performed to investigate the presence of VEGF and IL-8 in the fluid of ovarian endometriomata and to determine if differences in the concentrations of such proteins existed between these endometriotic cysts and the ones of controls. In addition, the possibility of a correlation between the VEGF and IL-8 cystic concentrations and the diameters of the adnexal masses was investigated.
Materials and methods
Patients
A total of 30 pre-menopausal, not-pregnant, women were retrospectively enrolled for this study among 117 women undergoing laparoscopy between July 1997 and October 1998; 20 of these patients were admitted to our clinic, with an ultrasonographic (US) diagnosis of endometriotic cyst, for laparoscopic cystectomy of ovarian endometriomata. The remaining 10 women underwent operative laparoscopy for the occasional finding of an adnexal mass. The study was approved by the committee on human research at University of Pisa, Italy, and informed consent was obtained from each patient.
All 30 patients were women who had received neither hormones nor gonadotrophin-releasing hormone (GnRH) agonist therapy for at least 3 months before laparoscopy and who had not suffered from pathological conditions, e.g. other ovarian tumours or pelvic inflammatory disease. There were no significant differences both in terms of age and of cystic diameter between the patients with and without endometriosis (Table I).
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Patients were classified as endometriotic or not, following laparoscopic investigation and all the endometriotic patients presented with advanced endometriosis: i.e. all the ovarian endometriomas were >3 cm in diameter without any other endometriotic lesions or adhesions made the classification of stage III disease according to the criteria of the revised American Fertility Society classification (American Fertility Society, 1985
).
Interventions
In all these cases an operative laparoscopy was carried out on days 8–12 of the menstrual cycle subsequent to an analysis of the serum CA-125 concentrations and to an accurate transvaginal US evaluation of the adnexal mass; the phase of the menstrual cycle was confirmed by histological dating of eutopic endometrium samples taken simultaneously with the cystic samples. All the cystic tissues were biopsed and diagnosis confirmed histologically by an independent pathologist.
In the patients with previous diagnosis of endometriosis the US examination was performed following the criteria proposed by Guerriero (Guerriero et al., 1996). In addition, a careful measurement of each cyst was carried out by two different examiners and the mean of the three diameters measured was considered as the value representing the size of the adnexal mass. The cystic fluid was aspirated via a Verres needle immediately after the enucleation and just before the removal of the cyst.
Samples
Cystic fluids from 20 ovarian endometriomata and from 10 follicular cysts were collected for the study. After the collection, each sample was immediately centrifuged at 2000 g for 10 min at room temperature; the supernatant was separated and stored at –20°C until the assay.
VEGF enzyme-linked immunosorbent assay (ELISA)
VEGF concentrations were detected in cystic fluid samples by an enzyme immunoassay which measures the `free' forms of the growth factor (CYTElisaTM VEGF; Peninsula Laboratories Inc, Belmont, CA, USA), with a sensitivity of 12.5 pg/ml, an intra-assay variability of ±7.7% and an inter-assay variability of ±10.7%.
IL-8 enzyme-linked immunosorbent assay (ELISA)
IL-8 concentrations were detected in cystic fluid samples by an enzyme immunoassay which measures the chemokine (PREDICTA IL-8 Kit; Genzyme Diagnostic, Cambridge, MA, USA) having a sensitivity of 16 pg/ml, an intra-assay variability of ±5.5% and an inter-assay variability of ±8%.
CA-125 immunoradiometric assay
CA-125 was measured with a solid-phase immunoradiometric assay using a commercially available kit based on monoclonal antibodies (International CIS, Gif-star-Yvette, France). All determinations were done in duplicate.
Statistical analysis
Comparisons between the VEGF and IL-8 concentrations present in the cystic fluids were made using a non-parametric analysis of variance by Ranks (Mann–Whitney U test). The correlations between VEGF and IL-8 cystic concentrations and the diameter of the adnexal mass were analysed by linear regression analysis using the GraphPad PrismTM software package (GraphPad Software Inc., USA). Results are expressed as the mean ± SD. P < 0.05 was considered to be statistically significant.
Results
The clinical characteristics and the laboratory data of the patients with and without endometriosis are shown in Table I
. The CA-125 concentrations detected in the serum of the patients affected by ovarian endometriomata were found to be significantly greater than the concentrations for women with follicular cysts (P < 0.001) and for each case examined the tissue biopsy and the cystic fluid has provided the histological confirmation of the clinical diagnosis.
VEGF was detected in the cystic fluid of all the patients studied with significantly higher (P < 0.001) concentrations found in ovarian endometriomata (1140.0 ± 307.2 pg/ml) than in follicular cysts (189.9 ± 90.7 pg/ml) (Figure 1).
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The concentrations of IL-8 in cystic fluid were significantly higher (P < 0.001) in ovarian endometriomata (1521.0 ± 180.1 pg/ml) than in follicular cysts (27.2 ± 12.4 pg/ml) (Figure 1
).
The values of the VEGF cystic fluid concentrations were found to be inversely correlated to the diameter of the ovarian endometriomata (P < 0.05) (Figure 2) and directly correlated to the diameter of the follicular cysts (P < 0.05;). On the contrary, the correlation between the IL-8 cystic fluid concentrations and the diameter of the adnexal masses did not reach statistical significance for either the ovarian endometriomata (Figure 2) or the follicular cysts.
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Discussion
This study shows for the first time that immunoreactive VEGF and IL-8 are present in the cystic fluids of ovarian endometriomata and that the concentrations of these two proteins are significantly higher than those detected in the adnexal masses of controls (Figure 1).
The hypothesis that angiogenic phenomena may play an active role in the pathogenesis of the ovarian cyst formation is supported by the following evidence: (i) intra-tumoural arterial blood flow, detected by colour Doppler energy imaging, has been reported in 94% of the ovarian benign tumours (Guerriero et al., 1998); and (ii) VEGF immunostaining has been demonstrated in the epithelial lining of benign ovarian neoplasms (Gordon et al., 1996). Furthermore, recent data have pointed out that high concentrations of VEGF detected in thyroid nodules predict rapid accumulation of the cyst fluid (Sato et al., 1997) and that the expression of VEGF and its receptors is present in ovarian malign, borderline and benign neoplasms (Abu-Jawdeh et al., 1996).
Previous evidence that high concentrations both of VEGF (McLaren et al., 1996) and IL-8 (Iwabe et al., 1998) are present in the peritoneal fluid of women affected by endometriosis has led to the hypothesis that the peritoneum may play an important role in the maintenance of this disease by the promotion of neovascularization. Recently, Donnez et al. have clearly demonstrated significantly lower VEGF values in black lesions, as compared with eutopic endometrium of women affected by endometriosis and red lesions, the values of which were similar (Donnez et al., 1998). Furthermore, Gazvani et al., have reported that IL-8 concentrations in the peritoneal fluid are higher in women with early endometriosis than in women with later stages of the disease (Gazvani et al., 1998). These data support the idea that high VEGF and IL-8 concentrations provoke an increase in the subperitoneal vascular network, facilitating implantation and viability in the earlier attachment phases of the ectopic endometrium.
The key role of the peritoneum has been recently proposed in the genesis of the ovarian endometriomata: histological data, in fact, have demonstrated that the mesothelium covering the ovary can invaginate in the ovarian cortex and that some of the invaginations are continuous with endometrial tissue, strongly suggesting that metaplastic histogenesis of ovarian endometriotic lesions occurs (Donnez et al., 1996).
Once the process has become invasive, the lesion internalizes with compression of normal ovarian stroma beneath it and the normal tissue becomes compressed against the ovarian surface as the cyst enlarges. The ovarian endometriomata cause pain, usually dependent on the rapidity of enlargement and stretching of the ovarian capsule; conversely, ovarian endometriomata of considerable size may be symptomless.
The clinical trend observed in women affected by ovarian endometriotic masses seems to be biphasic: in the first active and painful phase, the cyst presents a rapid rate of enlargement and volume associated with a rise in CA-125 plasma concentrations. Subsequently, as the size increases, the ovarian endometriomata appear to achieve a relative `steady state'. In this study, the finding of high plasma CA-125 concentrations in women with ovarian endometriomata confirms the recent demonstration that elevated CA-125 concentrations are correlated with the clinical diagnosis of deep endometriosis (Koninckx et al., 1996); furthermore, the plasma CA-125 values have been used as additional data for a more accurate characterization of the patients in their respective group of the study.
To establish the importance of the angiogenic phenomena in the development of ovarian endometriomata we chose to investigate stage III of the disease to obtain a model in which VEGF was certainly produced by the cyst and not by phlogosis due to the peritoneal endometriotic lesions present in stage IV (McLaren et al., 1996).
The results of this study, demonstrating that VEGF concentrations are inversely correlated with the diameter of endometriotic cysts (Figure 2), may indicate that this growth factor is mainly determinant in the early phases of ovarian endometriomata progression.
On the contrary, although the constantly high concentrations of IL-8 detected in the chocolate cysts (Figure 2) seem to be more involved in the non specific pathways of phlogosis, this cytokine could play an important role in supporting the vascularization of the greater in size and less active ovarian endometriomata. In this later phase of the disease, all types of cells known to produce IL-8 are present in the endometriotic cyst: monocytes, lymphocytes, neutrophils, endothelial cells, fibroblasts, macrophages, peritoneal mesothelial cells (Arici et al., 1996) and endometriotic cells (Arici et al., 1993). This potential and abundant source of IL-8 could explain the high concentrations of this cytokine, whose production would be strongly stimulated by the reduced microenvironmental oxygen pressure present in the large endometriomata (Desbaillets et al., 1997). This present study appears to be the first time that high IL-8 concentrations have been detected in endometriotic cystic fluid, although Odukoya has reported no significant differences in terms of IL-8 mRNA expression between the endometriomata cystic wall and the biopsies of normal ovary (Odukoya et al., 1997).
In conclusion, the results of this study, demonstrating that the concentrations of the VEGF and IL-8 in the fluid of the ovarian endometriomata are significantly higher than the ones detected in the adnexal masses of control, would indicate that the angiogenic phenomena may be considered a peculiarity of the endometriotic cysts and not only a simple part of the phlogistic dynamics commonly observed in cyst formation. Furthermore, a different role of these two proteins is proposed in stimulating the neovascularization of the ovarian endometriomata with the major importance of the VEGF in the early progression and of the IL-8 in the maintenance of such cysts.
Notes
3 To whom correspondence should be addressed 
References
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