The 'incessant menstruation' hypothesis: a mechanistic ovarian cancer model with implications for prevention

Serous, endometrioid, clear cell and mucinous histotypes are the most common epithelial ovarian cancer. Most serous cancers appear to originate from precursor lesions at the fimbriated tubal end, whereas most endometrioid and clear cell cancers seem to derive from atypical endometriosis. Data regarding hormonal factors and associated gynaecologic conditions were critically analysed with the objective of defining a carcinogenic model for sporadic epithelial ovarian cancer complying with epidemiologic and pathologic findings. Oral contraceptives and tubal ligation substantially reduce the risk of serous, endometrioid and clear cell subgroups, but have no significant effect on mucinous tumours, which probably follow a different oncogenic pathway. We hypothesize that serous, endometrioid and clear cell cancers share a common pathogenic mechanism, i.e. iron-induced oxidative stress derived from retrograde menstruation. Fimbriae floating in bloody peritoneal fluid are exposed to the action of catalytic iron and to the genotoxic effect of reactive oxygen species, generated from haemolysis of erythrocytes by pelvic macrophages. This would explain the distal site of tubal intraepithelial neoplasia. Collection of blood inside endometriomas would lead to the same type of genotoxic insult on gonadal endometrial implants. This would explain why endometriosis-associated cancers develop much more frequently in the ovary than at extragonadal sites. In women not seeking conception, bilateral salpingectomy could be advised whenever planning surgery for independent indications, thus possibly reducing cancer risk, while preserving ovarian function. The use of oral contraceptives should be favoured for prolonged periods of time, especially in women with endometriosis, a population at doubled risk of gonadal malignancy.