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Contents of Endometriotic Cysts, Especially the High Concentration of Free Iron, Are a Possible Cause of Carcinogenesis in the Cysts through the Iron-Induced Persistent Oxidative Stress

Authors' Affiliations: Departments of ¹ Gynecology and Obstetrics and ² Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University; and ³ National Hospital Organization Kyoto Medical Center, Kyoto, Japan

Requests for reprints: Shingo Fujii, Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Phone: 81-75-751-3269; Fax: 81-75-761-3967; E-mail: sfu{at}kuhp.kyoto-u.ac.jp.

Purpose: Endometriotic cysts are known to transform into ovarian cancers, such as clear cell and endometrioid carcinomas. We hypothesized that an iron-rich environment produced by the repetition of hemorrhage in the endometriotic cysts during the reproductive period may play a crucial role in carcinogenesis in the cysts through the iron-induced persistent oxidative stress.

Experimental Design: Contents of human ovarian cysts, including 21 endometriotic cysts, 4 clear cell carcinomas, and 11 nonendometriotic cysts, were analyzed for the concentrations of free "catalytic" iron, lactose dehydrogenase, potential antioxidant, lipid peroxide, and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Iron deposition and 8-OHdG levels were also analyzed histologically. Reactive oxygen species and the mutagenicity of the contents in endometriotic cyst were determined in vitro.

Results: The concentration of free iron in endometriotic cysts (100.9 mmol/L) was significantly higher than that in nonendometriotic cysts (0.075 mmol/L; P < 0.01). The average concentrations of lactose dehydrogenase, potential antioxidant, lipid peroxide, and 8-OHdG were also significantly higher in endometriotic cysts (P < 0.01). There was a correlation between the concentration of free iron and that of 8-OHdG (P < 0.01). Histologically, we could observe iron deposits more abundantly in endometriotic cysts than in nonendometriotic cysts (P < 0.01). The level of 8-OHdG in carcinoma associated with endometriosis was higher than that of carcinoma without endometriosis (P < 0.05). In vitro analyses showed that the contents of endometriotic cyst could produce more reactive oxygen species and could induce gene mutations more frequently than the contents in the other cysts.

Conclusions: Abundant free iron in the contents of endometriotic cysts was strongly associated with greater oxidative stress and frequent DNA mutations. A long-standing history of the RBCs accumulated in the ovarian endometriotic cysts during the reproductive period produces oxidative stress that is a possible cause for the malignant change of the endometriotic cyst.

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