Department of Obstetrics & Gynecology, Tohoku University School of Medicine, Sendai, Japan
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Abstract |
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Key words: angiogenesis/endometriosis/erythropoietin/peritoneal fluid
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Introduction |
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Studies have demonstrated that angiogenic factors may be localized to endometriotic tissues and were also found to be increased in the peritoneal fluid (PF) of women with endometriosis (Oosterlynck et al., 1993; Ferriani et al., 1993
; Oosterlynck et al., 1994
; Ryan et al., 1995
; McLaren et al., 1996a
, b
; Shifren et al., 1996
; Donnez et al., 1998
; Gazvani et al., 1998
; Iwabe et al., 1998
; Osuga et al., 1999
). The release of angiogenic factors into the peritoneal cavity may well stimulate increased neovascularization of endometriotic tissues (Ramey and Archer, 1993
; Koninckx et al., 1998
). Therefore, the detection and evaluation of potent angiogenic factors in endometriosis is important and could potentially lead to the design of novel therapeutic strategies aimed at both preventing and treating endometriosis.
Recent studies have indicated that several cytokines and interleukins (IL) including granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), IL-6 and IL-8, which were formerly thought to be predominantly specific for the haematopoietic cells, are also capable of affecting certain endothelial cell functions including angiogenesis (Bikfalvi and Han, 1994). Erythropoietin (Epo) is a key factor in the regulation of erythropoiesis and stimulates the proliferation of early erythroid precursors and the differentiation of late erythroid precursors of the erythroid lineage (Krantz, 1991
; Jelkmann, 1992
). However, important recent studies have demonstrated the angiogenic potential of Epo (Carlini et al., 1995
; Yasuda et al., 1998
; Masuda et al., 1999
; Ribatti et al., 1999
). In addition, the Epo receptor has been demonstrated in endothelial cells both in vitro and in vivo (Anagnostou et al., 1994
). Furthermore, Epo stimulation of endothelial cells may elicit an angiogenic response in vitro and in vivo (Carlini et al., 1995
; Ribatti et al., 1999
). Lastly, physiological angiogenesis occurs within the female reproductive organs of the adult and a recent study demonstrated that Epo is involved in the oestrogen-dependent cyclical angiogenesis occurring within the mouse uterus (Yasuda et al., 1998
; Masuda et al., 1999
).
It was therefore postulated that Epo is one of the angiogenic factors involved in endometriosis. This hypothesis was addressed by initially determining if Epo was present in PF and then comparing the concentrations of Epo in PF from patients with and without endometriosis.
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Materials and methods |
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Results |
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Discussion |
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The angiogenic response of the chick embryo chorioallantoic membrane blood vessels to Epo is comparable with that elicited by the prototypic angiogenic cytokine basic fibroblast growth factor (Ribatti et al., 1999). Fibroblast growth factor is one of the potent angiogenic factors in endometriosis (Ferriani et al. 1993
). Several other angiogenic factors are also considered to be involved in the pathogenesis of endometriosis (Oosterlynck et al., 1993
, 1994
; Ryan et al., 1995
; McLaren et al., 1996a
, b
; Shifren et al., 1996
; Donnez et al., 1998
; Gazvani et al., 1998
; Iwabe et al., 1998
; Osuga et al., 1999
). Therefore, the relative strength of the action of Epo should be investigated in endometriotic tissues.
The cellular source of origin of PF Epo remains to be investigated. The major site of erythropoietin production in the adult is the kidney although extrarenal sites of Epo production may include bone marrow macrophages (Vogt et al., 1989), early colony-forming cells (Hermine et al., 1991
), brain astrocytes (Masuda et al., 1994
) and trophoblast cells (Conrad et al., 1996
). Diffusion rates between PF and the blood stream decreases with increasing molecular weight to become extremely slow for molecules with a molecular weight >100 kDa (Dunselman et al., 1988
). Prolactin (molecular weight: 20 kDa) and albumin (molecular weight: 60 kDa) concentrations are 67% of those in serum (Koninckx et al., 1980
; Pattinson et al., 1981
). The molecular weight of Epo is approximately 30 kDa (Tilbrook and Klinken, 1999
). If the origin of the PF Epo is from the serum, theoretically, Epo concentrations in the paired serum should be higher than those in PF. However, Epo concentrations of PF were significantly higher than those of the paired serum. In addition, no correlations were detected between the paired serum and PF Epo concentrations. Therefore, extrarenal sites of Epo production should be considered as a potential source. A recent in-vitro study demonstrated that the mouse uterus expressed Epo mRNA and produced Epo protein in an oestrogen dependent manner (Yasuda et al., 1998
; Masuda et al., 1999
). This suggests that refluxed endometrial tissues may be direct candidates for a source of Epo production and secretion into PF. However, in the present study differences in PF Epo concentrations according to disease severity were detected. In addition, refluxed endometrial tissues are not specific to patients with endometriosis. Therefore, it is likely that endometrial tissues are not the sole source of Epo in PF. Endometriosis is associated with increased concentrations of activated macrophages, which may produce many cytokines, growth factors and angiogenic factors (Koninckx et al., 1998
). Indeed, it has been demonstrated that activated macrophages are a major source of VEGF in endometriosis (McLaren et al., 1996b
) and it may be that they are also a potential source of Epo in PF. Furthermore, red peritoneal lesions have significantly higher VEGF content as compared with black lesions (Donnez et al., 1998
). Thus, a potential source of Epo may also include endometriotic tissues.
In conclusion, this study suggests that Epo may play a role in the pathogenesis of endometriosis, particularly during the early stages of the disease. Further studies to clarify a role of Epo in PF may provide a better understanding of the pathogenesis of endometriosis.
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Acknowledgements |
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Notes |
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References |
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Submitted on November 6, 2000; accepted on January 26, 2001.