Department of Obstetrics and Gynecology, University of Tokyo, Tokyo 113-8655, Japan
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Abstract |
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Key words: endometriosis/hepatocyte growth factor/peritoneal fluid
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Introduction |
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Recently the presence of c-MET, the receptor of HGF, on human endometrial epithelial cells has been reported (Wagatsuma et al., 1998). Furthermore, HGF has been shown to stimulate the proliferation, migration and morphogenesis of endometrial epithelial cells (Sugawara et al., 1997a
). With these observations in mind, we postulated that HGF may be relevant to the pathophysiology of endometriosis, and we therefore set out to examine the presence of HGF in peritoneal fluid (PF) in women affected by endometriosis.
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Materials and methods |
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HGF concentrations in PF were measured in duplicate, using a specific enzyme-linked immunosorbent assay (ELISA) in a blind fashion (Institute of Immunology, Tokyo, Japan). The limit of sensitivity of this ELISA was 0.1 ng/ml per sample. The coefficients of variation were <10%.
Statistical significance was determined with the MannWhitney test. Results are expressed as median and interquartile range. Statistical significance was defined as P < 0.05.
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Results |
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Discussion |
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Another finding of the present study is that the elevated concentrations of HGF in non-treated women were comparable with those in women treated with GnRH analogue in the endometriosis group. Given the fact that HGF concentrations in PF from non-endometriotic women also did not differ with or without GnRH analogue treatment, it may be that HGF concentrations in PF are not affected by ovarian functions. Whatever the mechanism, it is conceivable that HGF may make a sharp contrast with IL-1 and tumour necrosis factor, their higher concentrations in PF with endometriosis decreasing after GnRH analogue treatment (Taketani et al., 1992).
Serum HGF concentration has been reported to show cyclic variation during the menstrual cycle (Negami et al., 1995). In our study, no particular variation during the menstrual cycle was detected in HGF concentrations in PF. At this time, it is difficult to explain the disparity between HGF concentrations in serum and those in PF in relation to the menstrual cycle. Although the sources of HGF present in serum are not clarified, HGF coming from endometrial tissue seems to constitute a substantial percentage, given the cyclic change in its serum concentrations during the menstrual cycle. Endometriotic implants can respond to gonadal hormones. However, the majority of the implants do not demonstrate synchronous histological changes with the comparable uterine endometrium. More specifically, about one-half of the implants demonstrate no morphological changes induced by cyclic secretion of ovarian steroids (Ochs and Schweppe, 1995
). On the assumption that HGF in PF derives largely from endometriotic implants, differential hormonal responses of the implants may, in part, explain the lack of apparent changes in HGF concentrations in PF during the menstrual cycle.
HGF has been shown to be mitogenic in endometrial epithelial cells in vitro (Sugawara et al., 1997a). In addition, recent studies provided evidence suggesting that HGF stimulates angiogenesis (Moriyama et al., 1998
; Van Belle et al., 1998
). Assuming that these properties of HGF are at play in endometriotic tissues, an elevation of HGF concentration in PF may work to accelerate the growth of endometriosis. A recent study has suggested that HGF produced by peritoneal fibroblasts may modulate mesothelial cell morphology and thereby promote peritoneal dissemination of cancer cells (Yashiro et al., 1996
). Given this possibility, it is intriguing to speculate that HGF might play a role in facilitating the implantation of endometrial cells onto the peritoneal surface in addition to its potential growth-promoting effect.
Like HGF, epidermal growth factor (EGF) and fibroblast growth factor (FGF) are thought to be mitogenic to endometrial cells (Smith, 1994). Furthermore, EGF has been shown to have a mitogenic effect on endometriotic cells of endometrial cyst (Taketani and Mizuno, 1992
). However, EGF and FGF concentrations in PF do not differ between women with endometriosis and without endometriosis (Huang et al., 1996
). In this sense, HGF is unique among growth factors mitogenic to endometrial cells, and therefore, may be a possible central player in the proliferation of endometriotic cells.
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Acknowledgments |
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Notes |
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References |
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Submitted on December 7, 1998; accepted on March 1, 1999.