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.
OBJECTIVE
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.


METHODS
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.
Yamaguchi
Ken
K
Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Mandai
Masaki
M
Toyokuni
Shinya
S
Hamanishi
Junzo
J
Higuchi
Toshihiro
T
Takakura
Kenji
K
Fujii
Shingo
S
D000080242:8-Hydroxy-2'-Deoxyguanosine; D002471:Cell Transformation, Neoplastic; D020420:Cyst Fluid / Q000737:chemistry* / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D016889:Endometrial Neoplasms / Q000473:pathology; D004715:Endometriosis / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007501:Iron / Q000009:adverse effects / Q000032:analysis*; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D010048:Ovarian Cysts / Q000737:chemistry / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology*; D011230:Precancerous Conditions / Q000473:pathology*; D017382:Reactive Oxygen Species
D017382:Reactive Oxygen Species; D000080242:8-Hydroxy-2'-Deoxyguanosine; D007501:Iron; D007770:L-Lactate Dehydrogenase; D003849:Deoxyguanosine