Etiologies of endometriosis and model systems: is there a risk of a tunnel vision?

Mary Ann Manavalan, Mona Babtain, Myrthe Weessies, Annemiek Nap, Wouter P R Verdurmen, Sebastien Taurin, Sébastien Taurin, Mai S. Sater, Mai Sater, Roland Brock
Frontiers in medicine · 2025 · vol. 12 , pp. 1675051 · doi:10.3389/fmed.2025.1675051 · PMID:41158459 · PMC12554752 · W4415097817
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

This review argues that endometriosis may have multiple etiologies beyond retrograde menstruation, necessitating a revised diagnostic approach and model systems to reflect diverse cellular and molecular mechanisms.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-08 ⓘ

This paper is a review of experimental and mechanistic evidence for different proposed etiologies of endometriosis, focusing on how well the retrograde menstruation theory explains diverse lesion subtypes (superficial peritoneal lesions, deep infiltrating endometriosis, and ovarian endometriomas). It discusses high-level findings from human and baboon studies linking a higher propensity for retrograde menstruation with endometriosis, as well as molecular and histological support (e.g., shared mutations and endometrial mesenchymal stromal-like markers), while noting that other theories (metaplasia, embryonic rests, and stem-cell origins) are often supported more circumstantially and are not addressed by standard ex vivo model systems that assume retrograde menstruation. A key limitation it highlights is that current model systems typically reconstitute lesion structure rather than the etiologic events, potentially masking evidence for non-retrograde pathways. The review explicitly relates to adenomyosis as a frequent comorbidity (58–90%) and argues about etiologic heterogeneity across endometriosis forms. This paper is centrally about endometriosis — it critiques whether retrograde menstruation alone can explain all endometriosis subtypes and discusses alternative etiologies and model-system gaps.

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Abstract

Endometriosis is the growth of endometrial-like tissue at non-uterine locations, primarily within the peritoneal cavity. The disease can have diverse presentations with superficial lesions, deep invading lesions and ovarian cysts (endometrioma) as the main subtypes. Immune dysregulation, recurrent inflammatory processes and fibrosis are commonalities of all endometriosis forms. Most theories explaining the etiology of endometriosis take their origin in retrograde menstruation. However, other theories have been proposed, including metaplasia of mesothelial tissue, abnormal proliferation of Müllerian duct embryonic tissue remnants and a stem cell origin. We here argue that there is a lack of attention on whether retrograde menstruation can equally explain the various forms of endometriosis or whether the different endometriosis subtypes differ in etiology. As we show, there is a strong case in favor of several etiologies, as retrograde menstruation alone would require too many assumptions for some clinical appearances of endometriosis. Specific histological and molecular signatures have been associated with the different proposed etiologies. However, these are not part of the standard histopathological characterization of an endometriosis lesion. In addition, current ex vivo model systems aim to reconstitute the overall histological structure of a lesion but do not address the potential consequences that different etiologies may have on function and response to therapy. We thus propose to rethink the current diagnostic approach and direct research more specifically toward the cellular and molecular mechanisms underlying the various proposed etiologies, which should then be reflected in ex vivo model systems.

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endometriosisendometrioma

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