Background Early menarche is reported with the risk of endometriosis (EMS) with varying conclusions. Objective To assess the association between menarche age and EMS risk. Search strategy PubMed, Medline and Embase were searched using “endometriosis”, “early menarche” , “EMS”, “menarche age”, and “early menstrual characteristics”. Selection criteria Articles that reported the EMS risk in early menarche from Jan 2000 to May 2020 were included. Studies without control group, and lack of data of menarche age were excluded. Data collection and analysis EMS risks in these articles were collected and analysed through in random effects meta-analysis. In addition, subgroup analyses and meta-regressionwere were also performed. Main results A total of 16 studies (8913 EMS cases and 876477 controls) were included in the meta-analysis. The pooled risk of EMS in early menarche (<12 years) was 1.34 (95% CI: 1.16–1.54), with statistically significant heterogeneity across the studies (I2 = 72.0%). Stratified analysis showed that the risks of EMS by earlier menarche was increased in studies started after 2000, and in developing area, which was further confirmed by meta-regression analysis. In addition, higher quality in assessment of the exposure (menarche age) and control of potential confounders can elimenate heterogeneity. Conclusions The earlier age of menarche is a major risk factor of EMS, and its risk has an increasing trend in recent years and in developing countries. Large-scale studies in different ethnic groups are warranted.

Objective: The subsequent reproductive events induced by early age at menarche (AAM) are tightly linked to immune dysfunction. This study aimed to analyze whether immune functions mediate the association between AAM and subsequent reproductive performance. Design: a follow-up and Mendelian Randomization (MR) study. Setting: A women’s and Children’s hospital in Shenzhen, China. Population: Sixty-eight healthy reproductive Chinese women were admitted to pre-pregnancy physical examinations. Methods: Pre-pregnancy immune functions were analyzed by flow cytometry. Subsequent reproductive performance was studied by a 15-month follow up. The associations of immune functions with AAM or pregnancy status were analyzed. Lastly, the important association was further validated by a two-sample MR test using public data. Main Outcome Measures: Miscarriages, thyroid function at early pregnancy, and metabolic indexes at mid pregnancy. Results: We found that AAM was negatively associated with Tfh1/Tfh2 ratio (Spearman r=-0.283, P=0.019). Moreover, this pre-pregnancy index was positively associated with TSH at early pregnancy (Spearman r=0.363, P=0.032), a risk for spontaneous miscarriage (adjusted Relative risk (RR)=12.25, 95% confidence interval (CI)=1.72-87.46, P=0.013), and a shorter time to miscarriage (42 days vs. 115 days, log-rank P=0.038). Moreover, the MR test showed that 84 AAM-related SNPs can explain 19% of variance in PD1- naïve Tfh cells (Directionality P=4.28×10-10); LIN28B and chromosome 9p12 (LINC01505, TAL2 and TMEM38B) were their share genetic factors. Conclusion: The present study implied that Tfh cells might mediate the process of early AAM-induced reproductive events. Larger population studies and functional studies are warranted. Funding: None.