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Hum. Reprod. Advance Access published online on February 25, 2005

Human Reproduction, 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. For Permissions, please email: journals.permissions@oupjournals.org
Received May 19, 2004
Revised August 23, 2004
Accepted December 7, 2004

Article

Possible implication of midkine in the development of endometriosis

Yasushi Hirota 1, Yutaka Osuga 1*, Kaori Koga 1, Osamu Yoshino 1, Tetsuya Hirata 1, Miyuki Harada 1, Chieko Morimoto 1, Tetsu Yano 1, Osamu Tsutsumi 1, Sadatoshi Sakuma 2, Takashi Muramatsu 3, and Yuji Taketani 1

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

* To whom correspondence should be addressed.
Yutaka Osuga, E-mail: yutakaos-tky{at}umin.ac.jp


   Abstract

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.

Keywords: adhesions; endometriosis; midkine; peritoneal fluid; cell proliferation.
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