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ORIGINAL RESEARCH article

Front. Endocrinol.
Sec. Reproduction
Volume 16 - 2025 | doi: 10.3389/fendo.2025.1456273

The Correlation between Primary Ovarian Insufficiency, Sex Hormones and Immune Cells: A Two-Step Mendelian Randomization Study

Provisionally accepted
Tongtong Hong Tongtong Hong Danhua Pu Danhua Pu Jie Wu Jie Wu *
  • First Affiliated Hospital, Nanjing Medical University, Nanjing, China

The final, formatted version of the article will be published soon.

    Background: Primary ovarian insufficiency (POI), one of the causes of female infertility, is characterized by elevated gonadotropin levels and fluctuating estrogen reductions, which is accompanied by irregular menstruation, osteoporosis, cardiovascular disease, and genitourinary syndrome of menopause. POI is a heterogeneous and multifactorial disorder, with immune factors implicated in 5% to 30% of cases. However, the exact causal relationships remain unclear. Sex hormones play a crucial role in immune regulation by influencing the function and distribution of immune cells, suggesting they may be key intermediaries between POI and immune cells.Methods: Utilizing genome-wide association studies (GWAS), we conducted a comprehensive bidirectional two-sample Mendelian randomization (MR) analysis to explore the causal relationship between 731 immune cell traits and POI. Furthermore, a two-step MR analysis was employed to examine the potential mediating effects of sex hormones between these two systems. To ensure the robustness of our findings, we performed extensive sensitivity analyses, evaluating heterogeneity and horizontal pleiotropy.Results: After FDR adjustment (PFDR < 0.05), ten immune cell phenotypes were significantly correlated with the risk of POI. Among these, one immune cell phenotype was identified as a risk factor for POI (OR > 1), while the other nine immune cell phenotypes were protective factors (OR < 1). In the reverse MR analysis, POI was positively correlated with seven immunophenotypes (OR > 1) and negatively correlated with eleven immunophenotypes (OR < 1). No potential mediating effects of ten sex hormones were found between POI and the immune cell traits.Our study comprehensively assessed the correlation between immune cell phenotypes and POI in the European population, excluding the mediating role of sex hormones, thus providing valuable insights into the biological mechanisms of POI and informing early prevention and treatment strategies.

    Keywords: Primary Ovarian Insufficiency, Immune cell traits, MR analysis, sex hormone, Genetics

    Received: 28 Jun 2024; Accepted: 15 Jan 2025.

    Copyright: © 2025 Hong, Pu and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Jie Wu, First Affiliated Hospital, Nanjing Medical University, Nanjing, China

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