A Systematic Review and Meta-Analysis of Male Infertility and the Subsequent Risk of Cancer

Abstract

Objectives: The primary objective of this systemic review and meta-analysis was to investigate the risk of developing composite outcome of all cancers, regardless of the type of cancer among men with infertility diagnosis compared to fertile counterparts. The secondary objective was to compare the pooled risk of developing individual specific cancers between two groups.

Methods: A systematic literature search was performed on the databases of PubMed (including Medline), Scopus, and Web of Science to retrieve observational studies published in English language from 01.01.1990 to 28. 02. 2021. They assessed cancer events in males with an infertility diagnosis compared to controls without infertility. The outcomes of interest were a composite outcome of cancers including all known cancer types, and also specific individual cancers. The fixed/random effects model was used to analyze heterogeneous and non-heterogeneous results. Publication bias was assessed using the Harbord test, Egger test, Begg test, and funnel plot. The pooled odds ratio of cancers was calculated using the DerSimonian and Laird, and inverse variance methods. Studies' quality and risk of bias were assessed using structured standard tools.

Results: We included eight cohort studies involving 168,327 men with the diagnosis of infertility and 2,252,806 men without it. The total number of composite outcome of cancers as well as individual cancers including prostate, testicular and melanoma were 1551, 324, 183 and 121 in the infertile men and 12164, 3875, 849, and 450 in the fertile men, respectively. The pooled OR of the composite outcome of cancers, regardless of the type of cancer, in men with infertility was 1.4 folds higher than those without infertility (pooled OR = 1.43, 95% confidence interval [CI]: 1.25-1.64). Meta-analysis of individual cancers including prostate, testicular and melanoma between two groups was carried out. The pooled ORs of testicular and prostate cancers in men with the diagnosis of infertility were significantly higher than controls without infertility (pooled OR = 1.91, 95% CI: 1.52-2.42 and pooled OR = 1.48, 95% CI: 1.05-2.08, respectively). Additionally, the pooled OR of melanoma in men with infertility was 1.3 folds higher than those without infertility (pooled OR = 1.31, 95% CI: 1.06-1.62).

Conclusion: A greater risk of cancers in men with male infertility was found suggesting that the history of male infertility might be an important risk factor for developing cancers in later life. Further well-designed long-term population-based prospective studies, considering all known cancers and their accompanying risk factors should be conducted to support our findings.

Keywords: male infertility; melanoma; prostate cancer; risk; testicular cancer.

Figure 1

Flow diagram of the search strategy and study selection.

Figure 2

Forest plot of pooled odds ratio for (A) composite outcome of all cancers; (B) individual cancers of testicular, prostate and melanoma. (A) Forest plot of the pooled odds ratio for the composite outcome of all cancers. (B) Forest plot of pooled odds ratio for testicular cancer, prostate cancer and melanoma.

Figure 3

Plots of sensitivity analysis results (A) all cancers (B) testicular cancer (C) melanoma (D) prostate cancer. These graphs show the influence of each individual study on the overall meta-analysis summary estimate. Accordingly, the results of an influence analysis in which the meta-analysis is re-estimated omitting each study in turn has been shown. They provide the visual results, naming the omitted study on the left margin and omitted meta-analytic summary statistics as horizontal confidence intervals on the right side. The full, combined results have been shown as the solid vertical lines. For interpretation, an individual study is suspected of having an excessive influence if the point estimate of its omitted analysis lies outside the confidence interval of the combined analysis. (A) Sensitivity analysis plot for the composite outcome of cancers. (B) Sensitivity analysis plot for testicular cancer. (C) Sensitivity analysis plot for melanoma. (D) Sensitivity analysis plot for prostate cancer.

Figure 4

Funnel plot for the visual assessment of publication bias of the outcome of studies; (A) composite outcome of all cancers (B) testicular cancer, melanoma, and prostate cancer. (A) Composite outcome of cancers. (B) Testicular cancer, melanoma, and prostate cancer.