Male infertility associated with raised risk of prostate cancer in large cohort study

Published 04 October 2019

A comprehensive registry study from Sweden involving more than 1.2 million fathers links a significantly higher risk of prostate cancer to male subfertility - but not to ICSI and IVF treatment.

A cohort study on the association of ART and risk of prostate cancer first presented at ESHRE's 2018 Annual Meeting in Barcelona has been updated and reported in full in the British Medical Journal.(1) The study, which sourced data from three comprehensive Swedish registries to identify all fathers and their first child born in Sweden between 1994 and 2014, found that those who had had ART (and especially ICSI) to help conceive their children were at an overall statistically significant higher risk of prostate cancer than controls (who had conceived their children naturally). This overall risk in the ICSI fathers was mainly explained by and especially pronounced with prostate cancer diagnosed before the age of 55 ('early onset', HR 1.86), where the risk was almost triple that of controls. Overall, among men achieving fatherhood naturally 3244 (0.28%) were diagnosed with prostate cancer compared with 77 (0.37%) in the IVF group and 63 (0.42%) in the ICSI group.

Despite the study's observational design and its inability to detect causation, the authors nevertheless conclude that 'men who achieved fatherhood through assisted reproduction techniques, particularly through ICSI, are at high risk for early onset prostate cancer and thus constitute a risk group in which testing and careful long term follow-up for prostate cancer may be beneficial'.

While the authors themselves (as well as several commentators) are unable to offer any biological explanation for the findings, they do stress that, because ICSI is a reasonable marker for male infertility - especially in Sweden where its indication remains exclusively for male cases - 'our results, specifically the trend showing an increasing risk of prostate cancer and of early onset prostate cancer, may indicate that it is the underlying level of infertility that is associated with the man’s risk of this malignancy'. This was the conclusion also reported by the investigators at ESHRE in 2018: 'The increased risk of prostate cancer is definitely not because of the ICSI treatment per se,' said first author Yahia Al-Jebari from the University of Lund, 'which we know has no biological impact on the male.' Which is why it was 'important', he added, that the study took place in Sweden, where ICSI as a treatment is only indicated in cases of male factor infertility. As ESHRE and ICMART data have shown for a decade or more, ICSI is unnecessarily used for fertilisation in cases of non-male infertility in many countries - and in a few countries in every procedure of assisted reproduction.

In suggesting a possible explanation for the findings a BMJ editorial accompanying the study and stressing the link with male infertility and not ICSI itself noted a genetic association between microdeletions on the Y chromosome (well established as a cause of severe male infertility) and genes on the same chromosome known to be associated with prostate cancer.(2) The editorial added that mutations in DNA repair genes and epigenetic and environmental modulators had also suggested a link between male infertility and prostate cancer.

Some previous studies, though not all, have found a link between male infertility and risk of prostate cancer. A 2010 NIH study, for example, found that infertility may double a man's risk of aggressive prostate cancer; although the number of prostate cancer cases between infertile and fertile men didn’t differ, the nature of their cancers did.(3)

The authors of this Swedish study conclude that after adjustments men who achieved fatherhood through ART had a 'remarkably' high risk of prostate cancer. Fathers who used ICSI had a 60% higher risk and those who used IVF had a 30% higher risk than men who conceived naturally. And given the incidence of 'early onset' disease in this study and its poor prognosis generally, they propose that men having ART 'may benefit from early screening'. Screening by prostate specific antigen testing, they write, seems to be the most appropriate, most cost effective, and least invasive first line method for early detection. The accompanying editorial, however, notes that 'screening is controversial owing to lack of survival benefit and the harms from overdiagnosis and overtreatment that can follow a positive screening test'.

1. Al-Jebari Y, Elenkov A, Wirestrand E, et al. Risk of prostate cancer for men fathering through assisted reproduction: nationwide population based register study. BMJ 2019; 366: doi.org/10.1136/bmj.l5214.

2. Sharma A, Jayasena CN. Male infertility linked to risk of prostate cancer. BMJ 2019; 366: doi: 10.1136/bmj.l5525.

3. Walsh TJ, Schembri M, Turek PJ, et al. Increased risk of high-grade prostate cancer among infertile men. Cancer 2010; 116: 2140-2147.