The Association Risk of Male Subfertility and Testicular Cancer: A Systematic Review

Citation: Peng X, Zeng X, Peng S, Deng D, Zhang J ( The Association Risk of Male Subfertility and Testicular Cancer: A Systematic Review Xiaoning Peng 0 Xiaomin Zeng 0 Sihua Peng 0 Defeng Deng 0 Jian Zhang 0 Roberta W. Scherer, Johns Hopkins Bloomberg School of Public Health, United States of America 0 1 Department of Internal Medicine, College of Medicine, Hunan Normal University , Changsha , People's Republic of China, 2 Department of Health Statistics and Epidemiology, School of Public Heath, Central South University , Changsha , People's Republic of China, 3 Department of Pathology, School of Medicine, Zhejiang University , Hangzhou , People's Republic of China, 4 Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center , Houston , Texas, United States of America, 5 Department of Biochemistry and Molecular Biology, College of Life Science, Hunan Normal University , Changsha , People's Republic of China Background: An association between male subfertility and an increased risk of testicular cancer has been proposed, but conflicting results of research on this topic have rendered this theory equivocal. To more precisely assess the association between subfertility and the risk of testicular cancer, we performed a systematic review of international epidemiologic evidence. Principal Findings: We searched the Medline database for records from January 1966 to March 2008 complemented with manual searches of the literature and then identified studies that met our inclusion criteria. Study design, sample size, exposure to subfertility and risk estimates of testicular cancer incidence were abstracted. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated using the DerSimonian and Laird model. All statistical tests were two-sided. We identified seven case-control studies and two cohort studies published between 1987 and 2005. Analysis of the seven case-control studies that included 4,954 participants revealed an overall statistically significant association between subfertility and increased risk of testicular cancer (summary RR = 1.68, 95% CI: 1.22 to 2.31), without heterogeneity between studies (Q = 8.46, P heterogeneity = 0.21, I2 statistics = 0.29). The association between subfertility and testicular cancer was somewhat stronger in the United States (summary RR = 1.75, 95% CI: 1.01 to 3.02) than it was in Europe (summary RR = 1.53, 95% CI: 1.22 to 1.92). The source of the control subjects had a statistically significant effect on the magnitude of the association (population-based summary-RR = 2.15, 95% CI: 1.11 to 4.17; hospital-based summary-RR = 1.56, 95% CI: 0.93 to 2.61). After excluding possible cryptorchidism, an important confounding factor, we also found a positive association between subfertility and increased risk of testicular cancer (summary RR = 1.59, 95% CI: 1.28 to 1.98). These results were consistent between studies conducted in the United States and in Europe (Q = 0.20, P heterogeneity = 0.66). Of the two cohort studies that reported standardized incidence ratios, both reported a statistically significant positive association between subfertility and increased risk of testicular cancer. Conclusions: Our findings support a relationship between subfertility and increased risk of testicular cancer and apply to the management of men with subfertility, and prevention and diagnosis of testicular cancer. - Funding: This project was supported by NSFH (Natural Science foundation of Hunan) grants (No. 07JJ6059) to Xiaoning Peng and with Talent Young Scientists Fund of Hunan Normal University to Xiaoning Peng (No. 070626). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Testicular cancer is uncommon in most countries with an incidence that ranges from ,1/100,000 to 10/100,000 and accounts for ,1% of all cancers in men but ,60% of all cancers in young males 1535 years of age. Moreover, the incidence of testicular cancer has doubled in the last 2040 years [1,2]. The most common type of testicular cancer is testicular germ cell tumor (TGCT) and accounts for 95% of testicular cancers. TGCTs are presumed to arise from a common precursor lesion, carcinoma in situ (CIS), which is found within the seminiferous tubules. TGCTs comprise two histologically distinct subtypes: seminomas and non-seminomas. The seminoma subtype consists of cells that resemble CIS but that are not constrained within the seminiferous tubules. The non-seminoma subtype represents tumors of mixed histology, including embryonal carcinoma, teratoma, and polyembryoma, choriocarcinoma, or yolk sac tumor [3]. At present, the etiology of testicular cancer is not well understood, but many risk factorsincluding cryptorchidism (a condition in which one or both testes fail to descend normally); inguinal hernia; contralateral testicular cancer; familial testicular cancer; testicular trauma; mumps orchitis; elevated testicular temperature; vasectomy; electromagnetic fields (EMF); and hormonal, prenatal, and occupational factorshave been implicated in this cancers development in young adults [4]. The nature of these factors suggests that both genetic and environmental influences contribute to the development of testicular tumors. Until now, the most established factor associated with testicular cancer is cryptorchidism, which is associated with a 2- to 4-fold increase in the risk of testicular cancer but accounts for fewer than 10% of all cases [5]. Over the last 2040 years, reports in the literature indicate a decrease in the quality of sperm and an increase in the frequency of testicular malignancies (especially seminoma) [68]. As many as 10 to 15% of all couples in western countries experience subfertility (the condition of being less than normally fertile though still capable of effecting fertilization), and in one third of these cases, the problem can be attributed to the male partner [6 8]. An association between the world-wide decrease in male fertility and testicular cancer has been suggested [917], although evidence for this type of association has been inconsistent [1821], and the exact etiology of such an association remains debatable. The potential association between subfertility and the testicular cancer has evoked a huge interest from clinicians, scientists, and the public [22]. Thus, to elucidate and to provide a quantitative assessment of the association between male subfertility and testicular cancer, we performed a systematic review of studies that evaluated such an association and our results indicated that male subfertility is significantly related to an increased risk for testicular cancer. Search strategy We conducted a literature search of the Medline database (records from January 1, 1966, through March 31, 2008) using three search terms, which were combined by the Boo (...truncated)