Xin Xin,1,2 Lu Guan,3 Jiaxi Li,4 Jinfu Zhang,1,5 Haicui Wu6 

1Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200052, People’s Republic of China; 2Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 3Shandong University of Traditional Chinese Medicine, Jinan, 250011, People’s Republic of China; 4Shandong Wendeng Osteopathic Hospital, Wendeng, Shandong, 264400, People’s Republic of China; 5Shanghai University of Traditional Chinese Medicine, Shenzhen Hospital, Shenzhen, Guangdong, 518001, People’s Republic of China; 6Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, People’s Republic of China

Correspondence: Jinfu Zhang, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200052, People’s Republic of China, Email zhangjinfu@tongji.edu.cn Haicui Wu, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, People’s Republic of China, Email haicui_w@163.com

Background: Female reproductive disorders (FRDs) are common diseases among women of childbearing age, affecting their reproductive health. Age at first sexual intercourse (AFS) is potentially linked to FRDs, and this study aims to investigate these associations and underlying mechanisms, to offer new insights and guidance for sex education in adolescent women and reproductive health management.
Methods: Mendelian randomization (MR) analysis was performed using summary data from genome-wide association studies (GWASs). The AFS summary data were sourced from 397,338 European participants, and the outcome data were obtained from the FinnGen consortium. Additionally, multivariate MR (MVMR) and mediation analyses were also adopted to explore more detailed association. The MR results were rigorously validated, with the inverse variance weighted (IVW) method employed as the primary approach to assess causal relationships.
Results: There is a significant causal relationship between AFS and ovarian dysfunction (OD), polycystic ovarian syndrome (PCOS), and spontaneous abortion (0.45 [0.25– 0.81], p=0.008; 0.35 [0.17– 0.74], p=0.006; 0.76 [0.63– 0.92], p=0.006). Among them, the genetic association between AFS and spontaneous abortion remained significant even after adjusting for more confounding variables (0.73 [0.55– 0.95], p=0.020; 0.76 [0.61– 0.95], p=0.015), and Body mass index (BMI) may be an important mediating factor in the association between AFS and PCOS (38.41%, p=7.17e-6) or OD (35.64%, p= 1.51e-6).
Conclusion: Our research suggested that early AFS is closely associated with a higher risk of reproductive disorders, and timely interventions targeting BMI may partially alleviate the adverse effects of early sexual activity on reproductive health. The analysis based on genetic data emphasizes the importance of early sex education for adolescents, while weight management can to some extent avoid the occurrence of reproductive disorders during childbearing age, which also provide scientific basis for understanding the pathogenesis of FRDs and formulating appropriate reproductive health education strategies.

Keywords: female reproductive disorders, spontaneous abortion, age at first sexual intercourse, body mass index, Mendelian randomization, mediation effect