**6. Challenges to Clinical Application and Future Directions**

Linear lncRNAs and circRNAs promise great results as biomarkers for the early detection and disease recurrence of endometriosis. ncRNAs are resistant to RNase degradation and remain stable in biologic fluids, allowing for transport stability to specialized clinical laboratories that may not be local for all women. Studies show promising results but with little consistency among them, especially if considering single lncRNAs as biomarkers. Signature panels of miRNAs, such as the miR-20 or miR-200 families, have been widely investigated but partially have the same problem [126]. A possible solution could be to combine different molecules to obtain a more powerful signature of lncRNAs and miRNAs or other circulating markers (such as CA125) to create a more accurate diagnostic tool.

The main contemporary challenge is the heterogeneity of endometriosis cases and controls. The World Endometriosis Research Foundation (WERF) Endometriosis Phenome and Biobanking Harmonisation Project (EPHect) has provided guidelines [127]. The detailed characterization of women with endometriosis in terms of pain symptoms, lesion location, and molecular profiles is critical to homing in on useful diagnostic tools. While most of the studies interrogate the use of medications, most do not consider nutritional factors, over-the-counter supplements, or drugs. For example, the dietary intake of omega-6 fatty acids, omega-3 fatty acids, vitamin D, and N-acetylcysteine may affect endometriosis development. Further, supplements containing quercetin and L-carnitine may be involved in the progression of endometriosis [128]. Nutraceuticals, nutritional products that are also used as medicines [129], are emerging within the realm of endometriosis therapy [130]. As studies within other gynecologic diseases have shown an effect of nutraceuticals on noncoding RNA expression [125], the role of these natural products, nutrients, and supplements on lncRNAs requires additional study in endometriosis.

Each woman with endometriosis is a unique individual, and small studies are insufficient to evaluate a large number of clinical features. The collaborative, detailed characterization of the phenotype of women with endometriosis is critical. Unfortunately, an optimal non-endometriosis control population is challenging without putting healthy women through laparoscopic surgery for research purposes. While detailed guidelines are helpful for translational studies, additional guidelines are needed to report endometriosis mouse models and in vitro model systems, including multicellular aggregates, spheroids, and organoids. Preclinical studies on lncRNAs and circRNAs show promise for the translation to well-characterized human studies.

**Author Contributions:** Conceptualization, X.W., L.P. and S.M.H. literature review, X.W., L.P. and S.M.H.; data curation, X.W., L.P. and S.M.H.; writing—original draft preparation, X.W., L.P. and S.M.H.; writing—review and editing, X.W., L.P. and S.M.H.; visualization, X.W., L.P. and S.M.H.; supervision, S.M.H.; project administration, S.M.H.; funding acquisition, S.M.H. All authors have read and agreed to the published version of the manuscript. All authors contributed substantially to the work reported.

**Funding:** This research was funded by R21HD102653-01A1 (to S.M.H.).

**Institutional Review Board Statement:** This review study did not involve human subjects directly. This review study did not involve animals directly.

**Conflicts of Interest:** The authors declare no conflict of interest.
