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

Paolo Vercellini, Crosignani P, P.G. Crosignani, PierGiorgio Crosignani, Edgardo Somigliana, Paola Viganò, Laura Buggio, Giorgio Bolis, Luigi Fedele
Human Reproduction · 2011 · vol. 26(9) , pp. 2262–2273 · doi:10.1093/humrep/der211 · PMID:21724568 · W2134542679
Other OA: green CC0 ⤵ 52 in-corpus citations
🔓 Open OA copy View on OpenAlex View on PubMed View at publisher
⚙ AI-generated summary by gemini-2.5-flash-lite, 2026-06-09 ⓘ

This paper proposes that iron-induced oxidative stress from retrograde menstruation causes serous, endometrioid, and clear cell ovarian cancers, with bilateral salpingectomy and oral contraceptives potentially reducing risk.

One-sentence paraphrase of the abstract; not a substitute for reading it. No clinical advice. How this works

Abstract

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.

My notes (saved in your browser only)

Condition tags

endometriosis

MeSH descriptors

Contraceptives, Oral Menstruation Disturbances Ovarian Neoplasms Oxidative Stress Oxidative Stress Adult Adult Contraceptives, Oral Contraceptives, Oral Endometriosis Endometriosis Endometriosis Female Female Humans Humans Iron Iron Iron Menstruation Disturbances

Citation neighborhood (2-hop)

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. Outer rings show 2-hop neighbours — papers reached through the immediate citers/citees. [ collapse to 1-hop ]

References (100)

Cited by (50)

Source provenance

europepmc
last seen: 2026-10-21T06:16:17.486033+00:00
openalex
last seen: 2026-06-10T17:14:06.276822+00:00
pubmed
last seen: 2026-10-08T21:09:10.644269+00:00
License: CC0 · commercial use OK