Endometriosis risk is associated with shorter anogenital distance by meta-analysis

Background: Anogenital distance is a well-validated marker of prenatal testosterone, with shorter distances indicating lower levels during early gestation. A suite of studies has linked anogenital distance with risk of endometriosis, but the findings are variable, leading to uncertainty in interpretation. The relationship of anogenital distance with endometriosis is especially important because lower testosterone has been associated with endometriosis in recent Mendelian Randomization studies, which implies causality in the association, with direct implications for future research and treatment. Methods: A systematic review and meta-analysis was conducted on the association of endometriosis with anogenital distance. Three databases were queried in the identification phase, and a random-effects meta-analysis was applied to the data in studies that met the inclusion criteria. Results: Shorter anogenital distance AF, measured from the anus to the posterior fourchette, was significantly associated with higher risk of endometriosis in the meta-analysis. By contrast, there was no such association for anogenital distance AC, measured from the anus to the clitoral surface. Both analyses demonstrated significant heterogeneity across studies. Too few studies were available for robust investigation of publication bias. Conclusions: The association of short anogenital distance with endometriosis risk provides support for the hypothesis that endometriosis represents, in part, a disorder mediated by relatively low testosterone levels in early prenatal development. This conclusions has notable implications for understanding the causes and treatment of endometriosis. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by Discovery Grant 2018-04208 from the Canadian Natural Sciences and Engineering Research Council. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data used in the meta-analyses are available in Figure 2