Families of Men With Subfertility May Have Increased Risk of Several Types of Cancers

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Investigators have found that the families of subfertile men may have a higher risk of developing certain types of cancers at younger ages compared with the families of fertile men, according to a recent study published by Ramsay et al in Human Reproduction.


Previous research has shown that male infertility may be linked to an increased risk of cancer in men and their families; however, the results have been inconsistent. The risks and types of cancers varied considerably between family groups and depending on whether the men had oligozoospermia or azoospermia.

“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,” explained lead study author Joemy Ramsay, PhD, Assistant Professor at the University of Utah. “By identifying families with similar patterns of cancer, we may be able to discover factors that are involved in both infertility and cancer,” he added.

Study Methods and Results

In the recent study, the investigators examined the results from semen analyses involving 786 subfertile men who visited fertility clinics between 1996 and 2017 and 5,674 matched fertile men in the general population who had at least one child. Among the subfertile men, 426 of them had azoospermia and 360 of them had severe oligozoospermia with less than 1.5 million sperm per mL of semen. The investigators then used the Utah Population Database and Utah Cancer Registry to collect information on the men’s first-, second-, and third-degree relatives and their cancer diagnoses.

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

The investigators discovered that the families of men with azoospermia had a 156% increased risk of bone and joint cancer, 60% increased risk of Hodgkin lymphomas, 56% increased risk of soft-tissue cancers such as sarcomas, 54% increased risk of thyroid cancers, and 27% increased risk of endometrial cancer. The families of men with severe oligozoospermia had a 143% increased risk of bone and joint cancer, 134% increased risk of testicular cancer, and 16% increased risk colon cancer. However, these families also had a 61% decreased risk of esophageal cancer.

Further, the investigators found that the risk of cancer and the types of cancers varied significantly among the families of subfertile men, both by type of subfertility and within subfertility type. They suggested that the variations could explain the inconsistent associations between subfertility and cancer demonstrated in previous studies. For instance, only a third of the clusters of families of men with oligozoospermia had an increased risk of testicular cancer, but the increased risk ranged from four- to 24-fold depending on the family cluster.

Among the families of men with azoospermia, the investigators identified 13 clusters of families—one of which included the majority of the families and had a risk of cancer similar to that of the general population. However, among the remaining 12 clusters, there were 12 distinct clusters that all had increased risks of developing at least one type of cancer.


The investigators hope their findings may advance the understanding of the biological mechanisms involved in both cancer and infertility, enable physicians to make more accurate predictions of the risk of cancer among men with fertility issues and their families, and improve the counseling that could be offered to these patients. They have also carried out genetic sequencing studies to search for specific genetic mutations that may be driving the associations between subfertility and cancer observed in the recent study.

The investigators noted that the strengths of the study included the use of data from population registries for family structure, cancer diagnosis, and subfertility; whereas the limitations included a lack of semen measures for the fertile men and 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. Additionally, the subfertile men involved in the study were all seen at a fertility clinic and, therefore, represent a subset of the overall population of subfertile men who had the socioeconomic means to be evaluated by a physician.

“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. 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,” Dr. Ramsay concluded.

Disclosure: For full disclosures of the study authors, visit

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