Objective:Endometriosis is a common gynecologic disease that frequently leading to chronic pelvic pain,severe dysmenorrhea,and subfertility.As first-line hormonal treatment can interfere with ovulation and may cause recurrent pelvic pain,exploration of new non-hormonal therapeutic approaches becomes increasingly necessary.This review aimed to evaluate the pre-clinical and clinical efficacy and safety of non-hormonal treatment for endometriosisData sources:Databases including PubMed,Embase,Cochrane Library,SINOMED,ClinicalTrials.gov,and Google Scholar were searched up to October 2019,using search terms endometriosis and non-hormonal therapy.Study selection:Twenty-four articles were reviewed for analysis,including nine animal studies and 15 human trials;all were published in English.Results:Twenty-four articles were identified,including 15 human trials with 861 patients and nine animal studies.Some agents have been evaluated clinically with significant efficacy in endometriosis-related pelvic pain and subfertility,such as rofecoxib,etanercept,pentoxifylline,N-palmitoylethanolamine,resveratrol,everolimus,cabergoline (Cb2),and simvastatin.Other drugs with similar pharmacological properties,like parecoxib,celecoxib,endostatin,rapamycin,quinagolide,and atorvastatin,have only been tested in animal studies.Conclusions:Clinical data about most of the non-hormonal agents are not sufficient to support them as options for replacement therapy for endometriosis.In spite of this,a few drugs like pentoxifylline showed strong potential for real clinical application.