The current cohort study, based on more than 22,000 men undergoing evaluation for infertility, observed a strong association between infertility and the subsequent diagnosis of a high-grade prostate cancer. Although men with male factor infertility did not appear to have a statistically significant increased risk of low-grade prostate cancer compared with all at-risk men in California (SIR, 1.2; 95% CI, 0.8-1.6), they were found to be twice as likely to be diagnosed with high-grade prostate cancer (SIR, 2.0; 95% CI, 1.2-3.0). On multivariate analyses, men with male factor infertility were found to be >2.5 times (HR, 2.6; 95% CI, 1.4-4.8) more likely to develop a high-grade prostate cancer than those in the cohort without male factor infertility, after adjusting for age, duration of infertility treatment, and infertility treatment facility.
These results suggest that male factor infertility may be a risk factor for the subsequent development of clinically significant prostate cancer; however, several factors may contribute to our findings. Of concern when evaluating risk factors for prostate cancer is the possibility of bias being introduced through cancer screening. Men who are seeking evaluation for infertility may have a higher likelihood of prostate cancer diagnosis given their generally higher socioeconomic status, possibly improved access to healthcare, and their greater propensity to seek medical attention, all of which are known risk factors for prostate cancer screening.8
The analysis using SIRs would be particularly subject to biases because of these issues. Based on comparison with age-matched men in the general California population, overall, men in our cohort had a similar rate of prostate cancer diagnoses. In particular, we observed no positive association among men who were evaluated and found not to be infertile. Men with male factor infertility may have a higher likelihood of urological evaluation and thus prostate cancer screening. The lack of a significant excess of low-grade prostate cancer cases suggests that prostate cancer screening biases alone may not account for the increased risk of high-grade prostate cancer among those with male factor infertility.
Data from large observational cohorts of men diagnosed with prostate cancer have described a subset of men at very low risk of prostate cancer-specific mortality during their lifetime.9,10
Autopsy studies have described the unique prevalence of clinically indolent prostate cancer in men dying of other causes.11-13
In the current study, cohort members as a whole were not found to be more likely to be diagnosed with prostate cancer, regardless of grade. However, when using grade stratification, although men with male factor infertility demonstrated no clear evidence of an increased risk of low-grade prostate cancer (SIR, 1.2; 95% CI, 0.8-1.6), their risk was 2-fold higher for the development of high-grade prostate cancer (SIR, 2.0; 95% CI, 1.2-3.0). On multivariate analyses of men from the cohort only, men with male factor infertility were found to be 2.6 times more likely to be diagnosed with high-grade cancer (HR, 2.6; P
=.003) compared with men without male factor infertility.
The results of the current study are consistent with the findings of Jorgensen et al demonstrating a decreased prostate cancer risk with increased paternity.2
The interpretation of the study by Jorgensen et al2
is limited by its inability to account for a man’s intention to cause a pregnancy and serves as the striking difference between their study and the current one. In the current analysis, all men were attempting to conceive a child, and underwent specific evaluation for infertility. The current study results are not consistent with the findings of studies indicating that childless men have a lower risk of prostate cancer compared with men who have fathered at least 1 child.3-5
Similarly, these studies are difficult to interpret because the underlying reason that a human is childless can be because of a lack of opportunity, choice, or low reproductive potential (ie, infertility).
The Jerusalem Perinatal Study cohort provides additional insight into the association between male infertility and prostate cancer. Men who had sired stillborn offspring and had decreased paternity were found to have an increased risk of developing prostate cancer compared with those without this history.14
Citing the recent implication of the Y chromosome as an etiologic factor in male infertility and prostate cancer, the authors hypothesized that gene defects on the Y chromosome may be a common link between prostate cancer and the decreased ability of the carrier to conceive males.15
The authors found that men with few male offspring had an increased odds of developing prostate cancer, and that this risk appeared to follow a dose-response correlation. In addition, among all cohort members who developed prostate cancer, those with the fewest sons appeared to have the highest risk of disease-specific mortality, suggesting that these men may have more aggressive cancers.
Infertility may be related to the subsequent development of prostate cancer as a result of the treatment for infertility increasing the risk or ≥1 factors that infertility and prostate cancer share. The former postulate is improbable given that many cases of infertility are treated with assisted reproductive technologies rather than specific medical or surgical treatment of the male partner.16
A more plausible explanation is that a common exposure underlies both infertility and prostate cancer. In addition to the aforementioned hypotheses surrounding the Y chromosome, prior work has suggested that certain severe forms of male infertility are associated with faulty DNA repair.17-19
Faulty DNA repair has classically been associated with tumorigenesis, both in humans and animal models, and could underlie the association between infertility and cancer.20,21
Importantly, defects in DNA mismatch repair also have been implicated in the etiology of prostate cancer.22
These and other genetic abnormalities may play a role the development of both infertility and prostate cancer. Although the downstream effects of these abnormalities may lead directly to disease, they also may increase susceptibility to the negative influence of environmental factors. A study by Skinner et al suggested that in utero exposure of rats to the ubiquitous fungicide vinclozine leads initially to poor fertility, and subsequently to increased cancer diagnoses and poor prostate health.23
The results of the current study provide novel evidence of a potential link between male factor infertility and aggressive prostate cancer risk. They warrant further confirmation and should stimulate additional research focusing on possible common biological pathways underlying infertility and prostate cancer. These results, if confirmed, also suggest that men identified with male factor infertility earlier in life may be considered for prostate cancer screening, given the elevated risk specifically for high-grade disease.