Vasectomy, a widespread form of birth control, is associated with a small but significantly increased risk of prostate cancer over the long run, according to a comprehensive analysis of Danish nationwide registries.

"The precise etiology of prostate cancer is unknown, but cohort studies suggest that reproductive factors influence disease development," comment the authors, led by Anders Husby, MD, Statens Serum Institut, Copenhagen, Denmark.

"We showed that vasectomy is associated with a long-term increased risk of prostate cancer, which manifests itself from ten years after the procedure," investigators add.

"[However], the absolute increased risk of prostate cancer following vasectomy is...small and similar to the increased breast cancer risk in women following oral contraceptive use," they state.

The study was published online May 23 in the Journal of the National Cancer Institute (JNCI).

In an accompanying editorial, lead editorialist Lorelei Mucci, MPH, Harvard T.H. Chan School of Public Health in Boston, and colleagues remain unconvinced and conclude that "it remains unclear whether vasectomy is or is not a cause of prostate cancer."

In addition, they recommend that "a man's decision to undergo vasectomy should be decided based on the totality of evidence and consideration of benefits and possible risks."

Approximately 500,000 men in the United States undergo a vasectomy every year, they note.

Details of the Findings

The investigators used Danish national health registers to establish a nationwide cohort of 2,150,162 Danish males born between January 1937 and December 1996. The analysis involved some 53.4 million person-years of follow-up, or an average follow-up of 24.8 years per male.

At the end of the analysis, vasectomized men had a 15% increased relative risk of prostate cancer compared with nonvasectomized men, the investigators report.

The association between time since the procedure was done and the risk of both low and intermediate-to-advanced stage tumors was similar, except for the first year following vasectomy where investigators found a 3.5-fold higher risk of vasectomized men presenting with low-grade prostate cancer compared with men who had not undergone the procedure.

"When restricting the analysis to metastatic and extracapsular prostate cancer, we still found a statistically significant increased long-term prostate cancer risk associated with vasectomy," investigators point out.

In contrast, men who had undergone a vasectomy had, on average, a lower risk of other cancers compared with nonvasectomized men, suggesting that men who chose to undergo vasectomy are, on average, healthier than the general population.

Table. Relative Risk of Cancer Among Vasectomized Men Compared With Nonvasectomized Men

Prostate Cancer Advanced Prostate Cancer Nonadvanced Prostate Cancer Smoking/Alcohol Related Cancers Nonsmoking/Alcohol-Related Cancers Vasectomized 1.15 (95% CI, 1.10 - 1.20) 1.11 (95% CI, 1.02 - 1.21) 1.17 (95% CI, 1.11 - 1.23) 0.87 (95% CI, 0.84 - 0.91) 0.94 (95% CI, 0.91 - 0.96) Nonvasectomized Reference Reference Reference Reference Reference Abbreviation: Confidence Interval, CI

Number of Children

Investigators also noted that the only factor that appeared to modify prostate cancer risk in their cohort was the number of children men had fathered.

For example, the estimated relative risk of prostate cancer among vasectomized men was 16% higher compared with nonvasectomized men if participants had 3 children; 25% higher among men with 4 children, and 31% higher among men with 5 or more children.

As the authors note, prostate-specific antigen (PSA) screening in Denmark has been historically low compared with other countries, and routine PSA screening has never been recommended for Danish men.

The finding that the long-term association between vasectomy and both low and intermediate-to-advanced state prostate cancer thus argues against the possibility that their findings could be explained by a detection bias due to potentially higher PSA screening rates among vasectomized men, Husby and colleagues suggest.

What might explain the higher prostate cancer rates among vasectomized men is the potentially protective effect that frequent ejaculation may have on prostate cancer risk, the authors speculate.

In the Health Professionals Follow-up Study, for example, men reporting higher ejaculation rates in adulthood were less likely to be subsequently diagnosed with prostate cancer than those who reported lower ejaculatory rates.

Similarly, long-term follow-up of men evaluated for infertility indicated that sperm cell concentration was inversely proportional with prostate cancer risk and that the effect was dose-dependent.

"Together with our finding of a statistically significant adverse effect of vasectomy, this substantiates the evidence of a protective effect of high fecundity on prostate cancer risk, with evidence pointing to a protective effect of active testicular function," study authors conclude.

Different Results in PSA Era?

In the editorial, Mucci and colleagues made much of the fact that PSA screening rates can have a "profound confounding effect" on prostate cancer rates, strongly increasing the likelihood that a man will be diagnosed with prostate cancer compared with those who do not undergo PSA screening.

"The current study lacked PSA screening data, although the authors note that Danish men generally have low screening rates," they acknowledge.

In fact, since 31% of prostate cancer cases detected in the Danish study were advanced at the time of diagnosis, "the association of vasectomy and prostate cancer overall warrants a different interpretation compared to studies during the PSA era," the editorialists suggest.

In an era of PSA-driven studies — where cancers are primarily localized on diagnosis — the editorialists remain unconvinced that the risk between vasectomy and prostate cancer is causal.

On the other hand, given that almost one third of the prostate cancer cases diagnosed in the Danish study were advanced, "the interpretation of overall prostate cancer differs, although one cannot fully rule out that greater screening or diagnosis underlies that positive association," they note.

The study authors have disclosed no relevant financial relationships. Mucci serves as a consultant and has given paid expert testimony on behalf of Bayer. She also has a pending contract with AstraZeneca to undertake a whole exome sequencing project in prostate cancer and is coprincipal investigator of a registry that receives funding from Bayer, AstraZeneca, Janssen, and Astellas.

J Natl Cancer Inst. Published online May 23, 2019. Abstract, Editorial

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