October 25, 2019
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Study offers insight into correlation between infertility, prostate cancer risk

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Yahia Al-Jebari 
Yahia Al-Jebari
Michael Eisenberg, MD 
Michael Eisenberg

Men who fathered children through assisted reproduction methods demonstrated higher risk for prostate cancer and early-onset prostate cancer than men who conceived children naturally, according to study results published in British Medical Journal.

“The association between infertility and the risk [for] prostate cancer has been studied for a few decades,” Yahia Al-Jebari, doctoral student of reproductive medicine in the department of translational medicine at Lund University in Malmö, Sweden, said in an interview with HemOnc Today. “Looking at semen parameters as a marker for infertility can have a host of issues and individual variations, and looking at fatherhood status can present its own problems. We thought assisted reproduction might be a good marker for male infertility.”

Previous studies have shown higher risk among men with impaired semen quality, whereas others have found lower risk among childless men or no association between prostate cancer risk and fatherhood.

“It’s an important study,” Michael Eisenberg, MD, associate professor of urology at Stanford University, who was not involved with the study, said in an interview with HemOnc Today. “Kudos are due to a big journal like the British Medical Journal for shedding light on such an important topic, as well as to the investigators for conducting the study.”

Fertility methods, cancer risks

Al-Jebari and colleagues evaluated data from national registers on more than 1 million children born in Sweden between 1994 and 2014.

The researchers stratified fathers of the children by fertility status based on method of conception, with 20,618 (1.7%) achieving fatherhood by in vitro fertilization (IVF), 14,882 (1.3%) by intracytoplasmic sperm injection (ICSI) and 1,145,990 (97%) through natural conception.

Men who became fathers through IVF and ICSI had an average age of 37 years at childbirth vs. 32 years for fathers who conceived naturally.

The researchers utilized cancer registries to identify new prostate cancer diagnoses up to 20 years after childbirth. Prostate cancer diagnosis, age of onset and androgen deprivation therapy, which served as a proxy for the severity of malignancy, served as the primary endpoints.

Of the men who conceived children naturally, 3,244 (0.28%) were diagnosed with prostate cancer during the study period, compared with 77 men (0.37%) who fathered through IVF and 63 men (0.42%) who fathered through ICSI.

After adjusting for potential confounders, including age and level of education, men who conceived through both methods of assisted reproduction had significantly higher risk for prostate cancer than those who fathered children without assistance (ICSI, HR = 1.64; 95% CI, 1.25-2.15; IVF, HR = 1.33; 95% CI, 1.06-1.66).

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“These results had nothing to do with the method used,” Al-Jebari told HemOnc Today. “The men gave semen samples, and what happened to the samples after that didn’t affect the biology of the men.”

Instead, the method of assisted reproduction required to achieve conception was likely an indicator of the degree of infertility. The researchers found men treated with ICSI had an especially high risk for prostate cancer diagnosis before age 55 years (HR = 1.86; 95% CI, 1.25-2.77) compared with men who conceived naturally. ICSI is often reserved for men with the most severe forms of infertility. These men also had the highest rate of receipt of ADT (19.2%) — a treatment usually given to patients with more severe cases of prostate cancer — than the natural conception group (13%) and IVF group (11.8%).

The risk for early-onset diagnosis also appeared higher for men who became fathers through IVF (HR = 1.51; 95% CI, 1.09-2.08). These increased risks persisted after excluding men with a prior cancer diagnosis.

‘Strongest evidence to date

Al-Jebari acknowledged the study was limited in that it did not include men with infertility who failed to father children with assistance. These men may be at even higher risk for prostate cancer than those who are able to conceive through assisted reproduction. Additionally, the 45-year mean follow-up was not sufficient to determine prostate cancer risk over a lifetime.

This study offers the “strongest evidence to date” that men with infertility may be at increased risk for prostate cancer, but it does not establish cause, Aditi Sharma, PhD, clinical research fellow and specialist trainee in endocrinology, and Channa N. Jayasena, MD, PhD, clinical senior lecturer and consultant in reproductive endocrinology and andrology, both at Imperial College London, wrote in a related editorial.

“How male infertility could be linked biologically to risk [for] 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,” the editorial authors wrote. “Mutations in DNA repair genes and epigenetic and environmental modulators have also been suggested to link male infertility and prostate cancer.”

Screening considerations

Because the causal link between prostate cancer and infertility is not yet understood, and considering the potential harms of overdiagnosis, there is no consensus on the need for earlier prostate cancer screening.

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“Screening is a controversial topic that has been debated for many decades, especially testing for PSA,” Al-Jebari said. “So, it’s not easy to just say ‘screen them all.’ Having said that, current clinical recommendations indicate that there are high-risk groups for whom screening might be appropriate.”

Recommendation from the European Association of Urology do not recommend wide-ranging screening, but emphasize a focus on high-risk men, including those aged 50 years or older, African American men aged 45 years or older, and those with a family history of prostate cancer.
[for] prostate cancer for men being treated for infertility and studies on the efficacy and benefits of screening for this risk group, similarly to what is currently offered for other high-risk groups,” Al-Jebari and colleagues wrote.

For these high-risk groups, the risks associated with being overdiagnosed are outweighed by the benefits of being screened, according to Al-Jebari.

“Infertile men might constitute another high-risk group that might benefit from screening,” he said.

Understanding the correlation

Eisenberg said the study may be useful in educating patients on the still not completely understood association between prostate cancer risk and infertility.

“We’re still in the infancy of understanding what some of these studies mean, but I think it’s reasonable to talk to men broadly about the link between fertility and health, and to give them more awareness,” Eisenberg told HemOnc Today. “Often, reproductive-aged men in their 20s, 30s and 40s are not used to going to the doctor, so there aren’t a lot of touchpoints with the health care system. This is an opportunity to help them understand their health a bit more.”

Eisenberg said the current study also provided valuable insight into contradictions in the literature regarding infertility and prostate cancer risk. The researchers noted that previous studies showing a lower risk for prostate cancer among men with infertility were generally limited to men with a mean age of 60 years or older, which could indicate that men with early-onset or aggressive prostate cancer may have already died of the disease. Additionally, studies among older men may fail to identify increased risk for early-onset prostate cancer and may even reach the opposite conclusion.

“There have been previous studies that show that infertile men are at higher risk for cancer, for cardiovascular disease, even for premature mortality,” Eisenberg said. “There have also been some studies that showed a lower risk for prostate cancer among infertile men. I think this study is an important addition to the literature both for its scientific findings, as well as the thoughtful discussion of the discrepancy with prior studies.” – by Jennifer Byrne

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References:

Al-Jebari Y, et al. BMJ. 2019;doi:10.1136/bmj.l5214.

Mottet N. et al. Eur Urol. 2017;doi:10.1016/J.eururo.2016.08.003.

Sharma A and Jayasena, CN. BMJ.2019;doi:10.1136/bmj.l5525.

For more information:

Yahia Al-Jebari, can be reached at Lund University, Box 117, SE-221 00, Lund, Sweden; email: yahia.al-jebari@med.lu.se.

Michael Eisenberg, MD can be reached at 1000 Welch Road, Ste. 100, MC 5756, Palo Alto, CA 94304; email: eisenberg@stanford.edu.

Disclosures: Al-Jebari reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Eisenberg, Sharma and Jayasena report no relevant disclosures.