Fertility Issues in Men Linked to Higher Cancer Risks in Their Families

For the first time, researchers discovered patterns of risk for multiple types of cancer in males with fertility issues and their families.

The study, published in Human Reproduction, discovered that families of men with very few or no sperm in their semen have a higher chance of having cancer, including cancer at a younger age, than families of fertile men.

The likelihood and type of cancer varied substantially depending on whether the men had a low sperm count (oligozoospermic) or none (azoospermic), with multiple malignancies found in distinct clusters of families.

The researchers, led by Dr. Joemy Ramsay, an assistant professor at the University of Utah in Salt Lake City, Utah, expect that their discoveries may help them better understand the basic pathways underlying cancer and infertility. This would allow clinicians to make more precise forecasts about the risk of cancer for men with fertility issues and their families, as well as improve the counseling they could provide.

Previous study has found that male infertility is associated with an increased risk of cancer in men and their families, although the findings have been inconsistent. The increased risks and kinds of cancer differed significantly between family groupings and whether the males were oligozoospermic or azoospermic.

“In this study, we wanted to describe the extent to which patterns of cancer risk vary between families of subfertile men, and whether this risk is seen in all families or is driven by a small subset of families, akin to the way mutations in the BRCA gene increase the risk of breast cancer in families that carry this mutation,” Dr. Ramsay said.

“By identifying families with similar patterns of cancer, we may be able to discover factors that are involved in both infertility and cancer.”

Dr. Ramsay and colleagues compared findings from semen analysis performed on 786 men attending Utah fertility clinics between 1996 and 2017 to information from 5,674 fertile men in the general population who had at least one child to confirm they were fertile. Among the men with fertility issues, 426 were azoospermic, whereas 360 were significantly oligozoospermic.

Using the Utah Population Database, the researchers gathered data on first, second, and third-degree relatives. Cancer diagnoses were obtained from the Utah Cancer Registry.

“We simultaneously assessed the risk for multiple types of cancer within each family and then we performed a cluster analysis to find groups of families with similar patterns of risk for multiple cancers,” said Dr. Ramsay. “This is the first study to describe these multicancer patterns in families of subfertile men.”

When the researchers examined all families of azoospermic men, they discovered a significantly higher risk of five cancers: bone and joint cancer (156% increased risk), soft tissue cancers such as sarcomas (56% increased risk), womb cancers (27% increased risk), Hodgkin lymphomas (60% increased risk), and thyroid cancers (54% increased risk).

Families of severely oligozoospermic men were much more likely to develop three types of cancer: colon cancer (16% higher risk), bone and joint cancer (143% increased risk), and testicular cancer (134% increased risk). The researchers also discovered a 61% decrease in the risk of esophageal cancer (gullet carcinoma).

The researchers discovered that the risk of cancer and the forms of cancer differed substantially among families of males with fertility issues, both by type of subfertility and within subfertility types. This could explain why earlier investigations found inconsistent links between subfertility and malignancy. For example, the study discovered an increased risk of testicular cancer in only one-third of oligozoospermic men’s families, but the risk increased four- to 24-fold depending on family cluster.

The researchers discovered 13 family groupings among azoospermic men. One cluster, which contained the majority of the families, had a cancer risk that was comparable to the overall population. However, the remaining 12 clusters all showed a higher risk of acquiring at least one type of cancer. There were 12 unique clusters among oligozoospermic men’s families, and all of them were at a higher risk of developing at least one malignancy.

“Our study identified several unique patterns of cancer risk in families of men with poor fertility. When family members share cancer risk patterns, it suggests that they have genetic, environmental, or health behaviors in common. Genetic and environmental exposures can also act together to increase cancer risk,” said Dr. Ramsay.

“By identifying which groups of families have similar cancer risk patterns we can improve our understanding of the biological mechanisms of both cancer and infertility. It will help us to assess the risk of cancer for families and provide improved patient counseling.”

The researchers conducted genetic sequencing tests to hunt for particular genetic alterations that could be causing the links between subfertility and cancer observed in this study.

The study’s strengths include the utilization of data from population registries to determine family structure, cancer diagnosis, and subfertility.

Limitations include a lack of semen measures for the fertile men, a lack of information on other health conditions, lifestyle risk factors such as smoking and body mass index, and exposure to environmental risk factors among the subfertile men; and, finally, that the men with fertility problems in this study were all seen at a fertility clinic and, thus, represent a subset of the overall population of subfertile men who had the socioeconomic means to be evaluated by a doctor.

For more information: Joemy Ramsay et al, Describing patterns of familial cancer risk in subfertile men using population pedigree data, Human Reproduction (2023). DOI: 10.1093/humrep/dead270