The mechanism isnt clear but abnormalities on the Y chromosome are in the frame

Poor sperm function (male infertility) causes nearly half of all infertility. The observation that poor sperm function is commonly associated with developmental genitourinary defects such as cryptorchidism suggests that male infertility could be a risk marker for later disease. Unfortunately, we know little about the natural history of male infertility beyond reproductive life, owing to historical social stigma experienced by affected men. Studies shedding light on the future health of infertile men should be welcomed, and in the linked paper (doi:10.1136/bmj.l5214) Al-Jebari and colleagues report analyses of registry data from the whole population of Sweden over 20 years. Their results provide the strongest evidence to date that risk of prostate cancer may be increased in infertile men. Importantly though, a causal relation cannot be assumed.1

Al-Jebari and colleagues included 1.2 million men in Sweden who fathered a first born child during the study period, either spontaneously (97% of men) or following one of the two leading assisted reproductive technologiesintra-cytoplasmic sperm injection (ICSI) and in vitro fertilisation (IVF). The study found that men becoming fathers through IVF and ICSI had a significantly higher risk of prostate cancer than men who fathered children naturally. The risk of early onset prostate cancer (diagnosed before age 55 years) was particularly high for men fathering children through ICSI, a technology used for men with the most severe forms of infertility.

The use of ICSI and IVF as proxies for poor sperm function is reasonable in a population study of this size, although it has obvious limitations; IVF is often given to couples with infertile female partners and male partners with entirely normal sperm function. Men who had assisted reproduction were older and educated for longer than fathers conceiving naturally. In view of that, the researchers adjusted for both paternal age and education level in their analysis. Furthermore, to prevent bias, men with previous cancer or testosterone replacement were excluded.

Previous studies have also observed an association between male infertility and subsequent prostate cancer.23 A population based study of 22562 infertile men reported that men with male infertility were 2.6 times more likely to develop a high grade prostate cancer than were their age matched controls.3 More recent observational research found a correlation between lower semen quality and worse scores on an index of general health. Cancer diagnoses were included in the index.4 The evidence is not entirely consistent, however. Some studies do not support an association between infertility and risk of prostate cancer.56 Others have concluded that men never fathering children actually have a reduced risk compared with men with at least one child,78910 although the absence of children is a poor surrogate for infertility.

These authors acknowledge the limitations of their study.1 Firstly, the study did not include infertile men who were unable to father children. These men might be expected to have a higher risk of prostate cancer than infertile men who managed to father children. Secondly, the mean age at follow-up was 45 years, so these findings are unlikely to quantify risk of prostate cancer over a lifetime. Lastly, the incidence of prostate specific antigen testing in population groups might have provided direct evidence that infertile men were not subjected to enhanced cancer screening.

How male infertility could be linked biologically to risk of prostate cancer is not yet clear. Possibilities include a genetic association between microdeletions in the Y chromosome, which are known to cause severe male infertility, and genes on the same chromosome known to be associated with prostate cancer.11 Mutations in DNA repair genes and epigenetic and environmental modulators have also been suggested to link male infertility and prostate cancer.1213

Middle aged men are often interested in their risk of prostate cancer; age, family history, and Afro-Caribbean ethnicity are major risk factors. However, screening is controversial owing to lack of survival benefit and the harms from overdiagnosis and overtreatment that can follow a positive screening test.14 In the absence of a plausible mechanism of action or proof of causation, justifying screening for prostate cancer in all infertile men is difficult. However, further research on the possible future complications of male infertility would be welcomed by patients and will help clinicians to counsel all infertile men about their future health.

We are grateful to our patient representative, James Tyerman, for providing valuable comments on the manuscript.

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Male infertility linked to risk of prostate cancer - The BMJ

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