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Hum. Reprod. Advance Access originally published online on February 25, 2005
Human Reproduction 2005 20(4):1084-1089; doi:10.1093/humrep/deh720
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© The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

Possible implication of midkine in the development of endometriosis

Yasushi Hirota1, Yutaka Osuga1,4, Kaori Koga1, Osamu Yoshino1, Tetsuya Hirata1, Miyuki Harada1, Chieko Morimoto1, Tetsu Yano1, Osamu Tsutsumi1, Sadatoshi Sakuma2, Takashi Muramatsu3 and Yuji Taketani1

1 Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, 2 Cell Signals Inc., 505 Leading Venture Plaza, 75-1 Ono Tsurumi-ku, Yokohama 230-0046 and 3 Department of Health Science, Faculty of Psycological and Physical Sciences, Aichi Gakuin University, 12 Araike-cho, Nisshin, Aichi 470-0915, Japan

4 To whom correspondence should be addressed: Email: yutakaos-tky{at}umin.ac.jp

BACKGROUND: The present study was conducted to assess whether midkine (MK), a multifunctional molecule known to stimulate tumor growth, may be involved in the development of endometriosis. METHODS: The mitogenic activity of MK on cultured endometriotic stromal cells was examined by measuring 5-bromo-2'-deoxyuridine (BrdU) incorporation. Concentrations of MK in the peritoneal fluid (PF) of women without or with endometriosis and those under GnRH agonist treatment were measured using a specific enzyme immunoassay. The expression of MK mRNA in peritoneal bone marrow-derived cells, peritoneum and endometriotic tissues was evaluated by RT–PCR. RESULTS: MK significantly increased BrdU incorporation into the DNA of cultured endometriotic stromal cells. The MK concentrations in the PF of the women with advanced endometriosis (stages II, III and IV) Median: 1.21 ng/ml; interquartile range 0.80–2.27 were significantly higher than those of the women without endometriosis and with stage I endometriosis (0.06 ng/ml, 0.67–1.26, P<0.05). As for the menstrual phase, the MK concentration in PF in the inteal phase (1.32 ng/ml. 0.72–2.21) were significantly higher than those in the follicular phase (0.95 ng/ml, 0.68–1.24, P<0.05). In addition, women with adnexal adhesions had higher concentrations of MK in PF than those without adhesions (P<0.05). The MK concentrations of the women under GnRH agonist treatment were significantly lower than those of the other groups (P<0.001). The expression of MK mRNA was detected in peritoneal bone marrow-derived cells, peritoneum and endometriotic tissues. CONCLUSIONS: The present findings suggest that MK may play roles, such as stimulation of endometriotic cell proliferation, in the development of endometriosis.

Key words: adhesions/endometriosis/midkine/peritoneal fluid/cell proliferation


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