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Age at menarche, Tfh cells and subsequent reproductive performance: a follow-up and Mendelian Randomization study
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  • Xiao-Hong Li,
  • Mei-Yin Lu,
  • Xu Chen,
  • Dan-Ting Shen,
  • Li-Yan Zhang,
  • Xiao-Jun Shen,
  • Bin Liu
Xiao-Hong Li
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Mei-Yin Lu
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Dan-Ting Shen
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Li-Yan Zhang
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Xiao-Jun Shen
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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.