Infertility and Prostate Cancer May Have Common Cause

From Medscape Medical News
Janis C. Kelly

March 25, 2010 — Infertile men could be at increased risk of developing high-grade prostate cancer, but more work is needed before recommending early screening, according to a new study published online March 22 in Cancer.

"I think the key point is that this study clearly has generated more questions than it has answered," lead author Thomas J. Walsh, MD, from the University of Washington in Seattle, told Medscape Oncology. "We need to keep in mind that one of the greatest concerns with prostate cancer is overdiagnosis and overtreatment of low-grade indolent cancer. Our goal should be to identify the most aggressive cancer in the youngest men — and to that end, our findings may prove insightful."

First Study of Men With Proven Infertility

Previous studies using the number of offspring sired as a surrogate marker for male fertility have produced conflicting results related to this association. Dr. Walsh and colleagues examined prostate cancer rates in men with proven male-factor infertility.

The study examined data from 22,562 men evaluated for infertility from 1967 to 1998 in 15 California infertility centers. The incidence of prostate cancer in these men was compared with that in a sample of men in the general population who were of similar ages and from similar geographic locations.

The researchers identified 168 cases of prostate cancer in the men who had been evaluated for infertility, a rate not significantly different from that expected in the general population (185 cases).

Two-Fold Higher Risk

However, men who had been evaluated and found to be infertile were 2.6 times more likely to be diagnosed with high-grade prostate cancer than men who had been evaluated but were found not to be infertile.

According to Dr. Walsh, "this suggests that we may want to search for common etiologies that underlie both male-factor infertility and prostate cancer."

Dr. Walsh suggested that the most clarity will come from studies that identify risk factors for male infertility. "Subjects assembled for such a study could then be followed longitudinally, with standardized prostate cancer screening, to determine whether or not they develop prostate cancer," he said.

"We were surprised to find significant risk only for high-grade cancers," Dr. Walsh added. "This fact alone raises many questions. . . . What are the etiologies that may lead some men to have poor sperm production early in life and high-grade cancer later in life? Could this association be translated into a tool to identify men who are at greatest risk for dangerous cancer?"

Questions About Ethnic Composition of Study Population

Aleksander Giwercman, MD, professor of andrology at Malmö University Hospital's Scanian Andrology Center in Sweden, was asked by Medscape Oncology to comment on this study. "I think that the study has some limitations," he said "First of all, the use of a white population as the control group is questionable for me. The risk of prostate cancer is highly race-dependent, and it is also likely that testicular function — and therefore semen quality — may differ between races. Therefore, not strictly controlling for race in matching the cases and the controls may introduce a serious bias that, theoretically, could affect the risk-ratio estimates in both directions."

Dr. Giwercman also pointed out that the researchers had complete data on less than 50% of all subjects. "This could also be a source of serious bias, as cancer data were, apparently, not available for half of the men," he said. Dr. Giwercman reported in an earlier study a reduced risk for prostate cancer in men who are childless (Int J Cancer. 2005;115:994-997).

"From a biological point of view, it is not easy to understand why men with infertility problems should have a higher risk of prostate cancer/high-grade disease. The authors propose a mechanism related to the ability to repair DNA, but this needs to be explored further," Dr. Giwercman said. "I think that we need further studies elucidating the risk of prostate cancer in men with testicular dysfunction. It seems plausible that testicular failure leads to a lower risk of prostate cancer — a disease considered to be androgen-dependent. However, it needs to be confirmed — or [refuted] — if the results presented by Walsh et al hold in additional studies."

Is Undiagnosed Prostate Cancer Causing Infertility?

Kristian Tore Jørgensen, MSc, from the Department of Epidemiology Research at Statens Serum Institut in Copenhagen, Denmark, was also asked to comment on the study. Mr. Jørgensen has studied fatherhood status and prostate cancer risk (Cancer. 2008;112:919-923).

"The authors suggest that gene defects on the Y chromosome or faulty DNA repair might be at play in the association between male-factor infertility and high-grade prostate cancer risk," he said. "However, there are a number of important factors that have to be considered as perhaps more likely explanations for the findings in this study. Prostate cancer development normally takes decades to cause clinical symptoms, so some cases of male-factor infertility might actually have been caused by an undiagnosed prostate cancer interfering with normal prostate gland function, a situation of reverse causality."

"Even though the authors excluded men diagnosed with prostate cancer in the year after infertility evaluation, a possible biological explanation for the study findings could be that the association between male-factor infertility and high-grade prostate cancer is related to impaired prostate function in men with yet undiagnosed prostate cancer," he added.

Mr. Jørgensen is also concerned about the racial composition of the cohort. "It was assumed that men in the cohort were predominantly white, even though ethnic data were not available. The rate of prostate cancer in the cohort was therefore compared with the rate in whites in California. The incidence of prostate cancer among black men is approximately 60% higher than it is in white men. So this simplification might have led to an overestimation of the risk of prostate cancer in the group of male-factor infertile men."

Mr. Jørgensen echoed Dr. Walsh's caution about rushing to early screening, pointing out that the observed 2-fold risk for prostate cancer was based on only 19 cases of high-grade prostate cancer in male-factor infertile men.

The study was supported by the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the California Urology Foundation. Dr. Walsh has disclosed no relevant financial relationships.

Cancer. Published online March 22, 2010. Abstract