Male infertility and the risk of developing prostate cancer: a bidirectional two-sample Mendelian randomization study

Sep 23, 2026

Uploaded by hdkawk

Observational findings suggest an association between male infertility and prostate cancer (PCa), but causality remains unresolved. This bidirectional two-sample Mendelian randomization study used genome-wide association study summary data to test causal effects between male infertility and PCa, applying inverse variance weighted as the primary method with additional MR approaches, heterogeneity and pleiotropy checks, and linkage disequilibrium score regression for genetic correlation. Multivariable MR adjusted for obesity and prostatitis and assessed PSA-related effects, alongside summary data-based MR and candidate gene expression exploration. Results showed no causal link in either direction, while prostatitis showed an independent causal effect on PCa risk.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

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Abstract

Background

Methods

Results

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Introduction

Shao et al. European Journal European Journal of Medical Research (2026) 31:21 [https://doi.org/10.1186/s40001-025-03461-y](https://doi.org/10.1186/s40001-025-03461-y of Medical Research)[ of Medical Research](https://doi.org/10.1186/s40001-025-03461-y of Medical Research) RESEARCH Open Access Male infertility and the risk of developing prostate cancer: a bidirectional two-sample Mendelian randomization study Junjie Shao1†, Aireti Apizi1†, Xiaojie Zheng2†, Ning Tao3* and Hengqing An1,4* Abstract Background Although observational studies have suggested an association between male infertility and prostate cancer (PCa) risk, the causal relationship has not been established. Methods We conducted a bidirectional two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary data to investigate the causal relationship between male infertility and PCa. The primary analysis was performed using the inverse variance weighted (IVW) method, supplemented by three additional MR approaches. We systematically evaluated the heterogeneity and pleiotropy of the instrumental variables and employed linkage disequilibrium score regression (LDSC) to assess the genetic correlation between the two conditions. Furthermore, we incorporated factors such as obesity and prostatitis into a multivariable Mendelian randomization framework. Additionally, within the bidirectional MR framework, we explored the causal association between the expression of the PCa biomarker prostate-specific antigen (PSA) and male infertility. Finally, we employed a summary data-based Mendelian randomization (SMR) analysis to identify genes potentially involved in the pathogenesis of PCa. We then performed a preliminary analysis of the differential expression of these significant candidate genes between normal and cancerous tissues using publicly available databases. Results Based on the fundamental principles of MR, six instrumental variables for male infertility were selected for analysis with PCa. All four analytical methods (primarily the IVW method, OR = 1 . 0044, 95% CI = 0 .9824–1. 0269, P = 0 . 697) consistently indicated the absence of a causal association. Reverse MR analysis suggested no significant causal relationship (IVW, OR = 0 . 9769, 95% CI = 0 .85–1. 1123, P = 0 . 724) . Sensitivity analyses, including heterogeneity tests (Cochran’s Q), pleiotropy assessment (MR-Egger intercept), and leave-one-out validation, confirmed the robustness of these findings. Furthermore, LDSC indicated no significant genetic correlation between male infertility and PCa (Rg = − 0 . 1102, P = 0 .494) . After excluding the influence of other exposure factors, multivariable Mendelian randomization results suggested an independent causal effect of prostatitis on PCa risk (IVW, OR = 1 . 093, 95% CI = 1 .0206–1. 1707, P = 0 . 011) . No significant causal association was demonstrated between PSA and male infertility (IVW, OR = 0 . 981, 95% CI = 0 .8055–1. 1942, P = 0 . 847) . †Junjie Shao, Aireti Apizi and Xiaojie Zheng have contributed equally to this work. *Correspondence: Ning Tao [38518412@qq.com](38518412@qq.com)[ ](38518412@qq.com)Hengqing An [9269735@qq.com](9269735@qq.com) Full list of author information is available at the end of the article © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or

FAQs

Does the study find a causal relationship between male infertility and prostate cancer?

No. Forward MR and reverse MR analyses did not show a significant causal association between male infertility and prostate cancer risk.

What methods were used to assess causality?

The study used bidirectional two-sample Mendelian randomization with inverse variance weighted as the primary analysis, supplemented by additional MR approaches, sensitivity tests for heterogeneity and pleiotropy, and linkage disequilibrium score regression for genetic correlation.

What role did multivariable Mendelian randomization play?

Multivariable MR accounted for other exposure factors, and it suggested an independent causal effect of prostatitis on prostate cancer risk after excluding influences of other exposures.

Sep 23, 2026

Uploaded by hdkawk