New concepts on the etiology of endometriosis

Abstract

Endometriosis is a serious, chronic disorder where endometrial tissue grows outside the uterus, causing severe pelvic pain and infertility. It affects 11% of women. Endometriosis is a multifactorial disorder of unclear etiology, although retrograde menstruation plays a major role. It has a genetic component with over 40 genetic risk factors mapped, although their mechanism of action is still emerging. New evidence suggests a role for retrograde menstruation of endometrial stem/progenitor cells, now that identifying markers of these cells are available. Recent lineage tracing and tissue clearing microscopy and 3D reconstruction has provided new understanding of endometrial glandular structure, particularly the horizontal orientation and interconnection of basalis glands. New sequencing technologies, particularly whole genome DNA sequencing are revealing somatic mutations, including in cancer driver genes, in normal and eutopic endometrium of patients with endometriosis, as well as ectopic endometriotic lesions. Methylome sequencing is offering insight into the regulation of genes and the role of the environmental factors. Single cell RNA sequencing reveals the transcriptome of individual endometrial cells, shedding new light on the diversity and range of cellular subpopulations of the major cell types present in the endometrium and in endometriotic lesions. New endometrial epithelial organoid cultures replicating glandular epithelium are providing tractable models for studying endometriosis. Organoids derived from menstrual fluid offer a non-invasive source of endometrial tissue and a new avenue for testing drugs and developing personalized medicine for treating endometriosis. These new approaches are rapidly advancing our understanding of endometriosis etiology.

Keywords: endometrial stem/progenitor cells; endometriosis; genetic variants; retrograde menstruation; somatic mutations.

FIGURE 1

Schematic showing that advanced technologies and methodologies are enabling the generation of new concepts on the etiology of endometriosis.

FIGURE 2

Schematic showing the location of endometrial stem/progenitor cells in the basalis, functionalis and luminal epithelium of human endometrium based on specific surface markers of these cells demonstrating adult stem cell activity. Note the horizontal gland structure in the basalis gland from which emanates the vertical gland in the functionalis. It is likely that the NCAD⁻SSEA‐1⁺nSOX9⁺basalis epithelial cells re‐epithelialize the raw endometrial surface during menstruation to become the luminal epithelial cells. In endometriosis, most functionalis glandular epithelial cells are SSEA‐1⁺nSOX9⁺ (purple, right hand side), in contrast to normal endometrium, where they are only occasionally found in the functionalis (purple, left hand side). CD140b, PDGFRβ; eMSC, endometrial mesenchymal stem cells; NCAD, N‐cadherin; NTPDase2, nucleoside triphosphate diphosphohydrolase‐2 Source: Adapted from Salamonsen et al. and Cousins et al.