From Retrograde Menstruation to Endometrial Determinism and a Brave New World of "Root Treatment" of Endometriosis: Destiny or a Fanciful Utopia?

Abstract

Practically unknown outside of China, the "endometrial determinism" theory was proposed to account for the apparent gap between the relatively low prevalence of endometriosis and nearly universal retrograde menstruation. Attracting uncritical advocacy, the theory culminates in a recent consensus by elite Chinese gynecologists in favor of "root treatment", intended to nip endometriosis in the bud. Correcting endometrial "defects" can gain further momentum by the presence of cancer-driver mutations such as KRAS mutations in the endometrium of women with endometriosis and the recent introduction of therapeutics aiming to rectify the effect of these mutations for cancer treatment. We provide a critical appraisal of evidence for endometrial aberrations in endometriosis and relevant experimental evidence. All available evidence of endometrial "defect" is invariably post hoc and may well be secondary to induced endometriosis. We propose that the theory of "endometrial determinism" needs to demonstrate a clear causal and a phylogenetic relationship between endometrial aberrations and endometriosis. We argue that while it is highly likely that endometriosis is a consequence of retrograde menstruation, the case that molecular aberrations as a sole or a necessary determinant remains to be proven. "Root treatment" is a worthy ambition but as of now it is close to a fanciful Utopia.

Keywords: aberration; causal; endometrial determinism; endometriosis; phylogenetic; retrograde menstruation; root treatment.

Figure 1

Possible scenarios in which endometrial aberrations do not cause endometriosis exclusively. (A) In this scenario, endometrial aberration A may be associated with a particular symptom, which is not specific to endometriosis. (B) Endometrial aberration B could lead to multiple conditions, including endometriosis. (C) Endometrial aberrations C₁ and C₂ are the consequences of endometriosis, where C₁ and C₂ are induced by different lesions of possibly different subtypes and/or their proximity to uterus. (D) Endometrial aberration D, along with endometriosis, is the result of a third, unknown factor. Lines without arrows indicate an association. The directional arrows indicate the causal relationship.

Figure 2

Two scenarios showing the complex phylogenetic relationship between the polyclonal endometrium and monoclonal endometriotic lesion. (A) Both eutopic and ectopic endometria are each evolving at their own pace and tempo and in their separate microenvironments, which makes any inference related to the phylogenetic relationship between the two entities challenging. (B) Because of cancer-associated mutations that confer selective growth advantages, the endometrium may become oligoclonal. Some clones may dominate and occupy larger areas of the endometrium. Since the chance of test sample coming from the dominant clone is thus increased substantially, this would help establish the phylogenetic relationship between eutopic and ectopic endometrium should the retrograde menstruation theory be true. However, it poses a challenge in establishing that a clone harbouring a particular mutation confers higher risk of developing endometriosis than those without.