Our cohort study, based on more than 22 000 men undergoing evaluation for infertility, observed an association between infertility and the subsequent development of testicular cancer. Male partners of infertile couples were 1.3 times more likely to develop a testicular germ cell cancer than the California population, regardless of male fertility status. Among men with known male factor infertility, the risk of subsequent testicular cancer was more than twice that, such that these men were 2.8 times more likely to develop testicular cancer relative to the general population. When men without male factor infertility were examined, there was no excess risk of testicular cancer. In multivariable analyses, men with male factor infertility were 2.8 times more likely to develop cancer than those in the cohort without male factor infertility, after adjusting for age, duration of infertility, and treatment facility.
Given our understanding of the natural history and presentation of testicular cancer, it is unlikely that these findings represent a screening phenomenon in which men exposed to infertility care are more likely to be diagnosed as having an indolent testicular tumor as a result of diagnostic testing. In fact, testicular germ cell tumors in adults are almost exclusively diagnosed fairly rapidly by a simple physical examination that reveals a nodule or painless scrotal swelling.13
These data confirm the findings by Jacobsen and colleagues,7
who reported an increased cancer risk among Danish men undergoing semen analysis testing. Although similar in design, this study differs from the Danish cohort in that all men in this analysis were infertility partners rather than men presenting for semen analyses for a variety of reasons. Despite differences in the study populations, the US and Danish studies demonstrate a remarkably similar risk of developing testicular cancer. Although both studies observed an increased risk of cancer in men with male factor infertility, men in our cohort were dichotomized to the presence or absence of these factors but in the absence of semen analysis data; thus, we cannot comment on specific semen analysis variables that may place men at highest risk. On the contrary, our data do not confirm the nearly 20-fold increased risk of testicular cancer among infertile men reported by Raman and colleagues.6
Although provocative, this markedly increased risk likely reflects reverse causality, in which the analysis included all prevalent and incident tumors and not just those occurring after infertility. Despite the increased relative risk of testicular cancer among infertile men, the absolute risk of cancer remains low, even among men with male factor infertility.
Similar to both previous cohort studies, seminoma was the predominant cancer histologic feature observed in affected men. Furthermore, most cancers had favorable histologic features (seminoma) and were pathologically confined to the testicle at the time of diagnosis. Although it is possible that infertility is associated with this particular histologic feature, it is more likely that the age distribution of men in our cohort makes the development of seminoma (the most common testicular tumor in older men) more probable. Furthermore, it is possible that having more aggressive nonseminomatous germ cell tumors during or before the reproductive years effectively excluded such patients from our study cohort.14
These results suggest that male factor infertility may be a risk factor for the subsequent development of testicular germ cell cancer; however, potential sources of bias merit mention. The increased risk of testicular cancer among all cohort members may be the result of unmeasured confounding, whereby some additional factor, common to all members of the cohort, placed men at increased testicular cancer risk. Specifically, higher socioeconomic status has been shown to be a potential risk factor for the development of testicular cancer.15
Although this variable was not measured, men of higher socioeconomic status may be more likely to seek infertility evaluation and more likely to develop testicular cancer, thus increasing the SIR for all cohort members. Cryptorchidism is a commonly cited risk factor for infertility and testicular cancer.16
Because we do not know the prevalence of cryptorchidism among cohort members without cancer, we cannot assess the potential for confounding by this variable. By cancer registry data, only 1 man (3%) with cancer had a history of cryptorchidism, suggesting that infertility may be associated with testicular cancer, independent of cryptorchidism. However, this too must be interpreted with caution because a history of cryptorchidism may not be reliably identified by cancer registrars.
In interpreting these data, we considered the postulate that male factor infertility or its treatment could cause testicular cancer. However, this theory is highly improbable given that in many cases infertility treatment involves the use of assisted reproductive technologies rather than specific medical or surgical treatment of the male partner.17
A more plausible explanation is that a common exposure underlies infertility and testicular cancer. Prior work by us and others18-20
suggests that certain severe forms of male infertility are associated with faulty DNA repair. Faulty DNA repair has classically been associated with tumorigenesis, in human and animal models, and could underlie the association of infertility and testicular cancer.21,22
In addition to this biological basis, the testicular dysgenesis syndrome, as hypothesized by Skakkebæk and colleagues,23
is a theoretical construct that attempts to relate environmental modulators, genetics, and infertility in the development of testicular cancer. Thus, the association between infertility and testicular cancer has been shown to be biologically and clinically feasible. More importantly, the association between male infertility and testicular germ cell cancer should stimulate further research that focuses on the etiology of poor germ cell health in these populations.