Lateral distribution of endometriotic lesions: the anatomical recesses hypothesis. A systematic review and meta-analysis

STUDY QUESTION: Are endometriotic lesions affecting bilateral organs or anatomical structures distributed symmetrically on both sides of the body? SUMMARY ANSWER: The left-sided preponderance of pelvic endometriotic lesions, and the right-sided dominance of thoracic and inguinal lesions, suggest that endometriotic lesions exhibit a non-random, asymmetric lateral distribution. WHAT IS KNOWN ALREADY: Evaluating the anatomical distribution of endometriotic lesions may elucidate the underlying pathogenic mechanism(s) of the disease. If the coelomic metaplasia or embryonic cell remnant theory is correct, a symmetrical right-left pattern would be expected. Conversely, retrograde menstruation would likely result in asymmetrical distribution, influenced by gravity, peritoneal fluid circulation, and anatomical niches. STUDY DESIGN, SIZE, DURATION: This systematic review with meta-analysis included full-length, English-language articles published up to 10 June 2024. Literature searches were performed in PubMed/Medline and Embase databases with the keyword ‘endometriosis’, ‘lateral’, ‘distribution’, ‘right’, ‘left’, and ‘asymmetry’. PARTICIPANTS/MATERIALS, SETTING, METHODS: The review focused on anatomical structures commonly affected by endometriosis with surgically defined right or left laterality: ovaries, uterosacral ligaments, colon, ureters, inguinal regions, and hemithorax (diaphragm, pleura, lungs). Case reports were excluded. Risk of bias was assessed using ROBINS-I for non-randomized studies and a dedicated tool for case series. Meta-analyses of proportions were conducted in R. Heterogeneity was quantified using the I2 statistic. Funnel plots for publication bias and Egger tests were performed using Stata. MAIN RESULTS AND THE ROLE OF CHANCE: Of 6356 articles screened, 154 met the inclusion criteria. A statistically significant leftsided preponderance was observed for ovarian (58%; 95% CI: 57–60%; P < 0.001), uterosacral ligament (56%; 95% CI: 54–59%; P < 0.001), ureteral (71%; 95% CI: 67–76%; P < 0.001), and bowel (72%; 95% CI: 64–79%; P < 0.001) lesions, whereas thoracic (98%; 95% CI: 96–100%;P < 0.001) and inguinal (92%; 95% CI: 83–98%; P < 0.001) lesions were predominantly right-sided. These findings were confirmed in the sensitivity analyses. Egger’s test indicated a possible small study effect only for ovarian lesions (P¼ 0.012). LIMITATIONS, REASONS FOR CAUTION: The preponderance of retrospective studies, the variability in surgical procedures, and the potential difficulties in accurately distinguishing unilateral from bilateral lesions may have influenced the magnitude of the estimated difference. However, the large patient cohorts, geographical diversity, and consistent asymmetry across lesion types strengthen the results’ validity and generalizability. WIDER IMPLICATIONS OF THE FINDINGS: The pattern of endometriotic lesion distribution, including the opposite asymmetry observed in the pelvis and upper abdomen/thorax, can be explained by factors influencing dissemination and implantation of refluxed endometrial cells. However, it cannot be explained as well by the coelomic metaplasia or embryonic cell remnant theories. This may have important clinical implications, providing a pathogenic basis for secondary prevention strategies. STUDY FUNDING/COMPETING INTEREST(S): The open access facility of this paper was funded by the Italian Ministry of Health, Current research IRCCS Ca’ Granda Ospedale Maggiore Policlinico. P.V. is a member of the Editorial Board of Human Reproduction Open, Journal of Obstetrics and Gynaecology Canada, and International Editorial Board of Acta Obstetricia et Gynecologica Scandinavica; has received royalties from Wolters Kluwer for chapters in UpToDate. All other authors declare no conflicts of interest. REGISTRATION NUMBER: CRD42024511356 (PROSPERO).