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

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.

Keywords: endometriosis etiology; fibrosis; organoids; retrograde menstruation; tissue-on-a-chip.

Figure 1

Etiologies and lesion types in endometriosis. Retrograde menstruation, the most widely studied etiology, posits that refluxed endometrial cells during menstruation implant in the peritoneal cavity, forming superficial lesions, deep infiltrating lesions, and endometriomas (ovarian cysts). Coelomic metaplasia suggests that peritoneal mesothelial cells undergo differentiation into endometrial-like tissue, contributing to lesion development. The Müllerian duct hypothesis proposes that embryonic remnants of the Müllerian ducts persist and evolve into endometriotic lesions, particularly deep infiltrating subtypes. Created in BioRender. Brock, R. (2025) https://BioRender.com/4zwz9th.

Figure 2

Models of endometriosis. (A) 2D tissue cultures of immortalized or primary cells are the most fundamental and easy to handle model from which (B) 3D spheroid models can be generated. (C) By comparison organoids are obtained through differentiation of stem cells isolated from patient biopsies (either endometrial or endometriosis-derived) in the presence of growth factors in a 3D matrix. (D) Alternatively, patient-derived material can be cut into thin tissue slices for direct use in ex vivo tissue culture. (E) Stem cell-derived organoid cultures recapitulate lesion heterogeneity and cell differentiation. (F) All types of models can be implemented into microfluidic devices for tight control of the physiological environment and co-culture of cells such as of spheroids/organoids embedded into a stromal matrix. Created in BioRender. Brock, R. (2025) https://BioRender.com/i3p6hjg.