Abstract
Objective: To assess mortality in family members of men seeking fertility assessment. Subfertility serves as a biomarker for overall somatic health, and poor semen quality is associated with increased risk of hospitalization and mortality from chronic conditions. However, it is unclear if these risks extend to family members of men with low sperm count. Design: Retrospective cohort study. Subjects: Family members, up to third-degree relatives, of men in the Subfertility, Health and Assisted Reproduction and the Environment cohort who underwent a semen analysis as part of a fertility assessment 1996–2017. Relatives of men with a recorded total sperm count who lived in Utah for ≥1 year 1904–2017 were included in the analysis (N = 22,280 families). Exposure: Individuals were classified by family membership. Families were classified as relatives of azoospermic (0M), oligozoospermic (<39M), or normozoospermic (≥39M) men. The average total sperm count of the proband (male relative) with fertility assessment was also included as a continuous exposure measure. Main Outcome Measures: The main outcomes were all-cause and cause-specific mortality risk by sex, age, and degree of relation: first-, second-, and third-degree. Cox proportional hazard models were used to test the association between fertility classification and mortality, controlling for sex, race/ethnicity, and birth year. Results: A total of 666,437 relatives of men with fertility assessment (Ndeaths = 183,974) were included in the analysis. Relative to normozoospermia families, all-cause mortality risk increased in oligozoospermia families (hazard ratio [HR]oligozoospermia, 1.03; 95% confidence interval [CI], 1.01–1.05). Close relatives, first- (HRoligozoospermia, 1.17; 95% CI, 1.07–1.28) and second-degree relatives (HRazoospermia, 1.11; 95% CI, 1.04–1.20; HRoligozoospermia, 1.05; 95% CI,1.01–1.09), of azoospermic and oligozoospermic men had the highest all-cause and cause-specific mortality risk, including death attributed to cardiovascular disease or congenital birth conditions. Conclusion: Our results suggest that familial all-cause and cause-specific mortality risk differ by fertility phenotype. Families of azoospermic and oligozoospermic men showed significantly increased risk, particularly for close relatives. This study provides further evidence that shared genetic and/or environmental factors could influence both fertility and somatic health.
| Original language | English |
|---|---|
| Pages (from-to) | 1235-1244 |
| Number of pages | 10 |
| Journal | Fertility and Sterility |
| Volume | 124 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 2025 |
Funding
The Utah Population Database (UPDB) is a University of Utah Core facility and a Huntsman Cancer Institute Comprehensive Cancer Center Shared Resource. It is funded in part by the University of Utah, the Huntsman Cancer Foundation, and the Cancer Center support grant (NCI: P30 CA2014). The authors thank the Pedigree and Population Resource of Huntsman Cancer Institute, University of Utah, for its role in the ongoing collection, maintenance, and support of UPDB. The authors also thank the University of CTSI (funded by NIH Clinical and Translational Science Awards), the Pedigree and Population Resource, University of Utah Information Technology Services, and Biomedical Informatics Core for establishing the Master Subject Index between the Utah Population Database, the University of Utah Health Sciences Center, and Intermountain Healthcare. The Utah Cancer Registry is funded by the National Cancer Institute's SEER Program, Contract No. HHSN261201800016I, the US Centers for Disease Control and Prevention's National Program of Cancer Registries, Cooperative Agreement No. NU58DP007131, with additional support from the University of Utah and Huntsman Cancer Foundation. This manuscript has been authored by UT-Battelle, LLC, under contract DE-AC05-00OR22725 with the US Department of Energy (DOE). The publisher, by accepting the article for publication, acknowledges that the US government retains a nonexclusive, paid-up, irrevocable, worldwide license to publish or reproduce the published form of this manuscript, or allow others to do so, for US government purposes. DOE will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan ( http://energy.gov/downloads/doe-public-access-plan ). This work was funded under GEMS: Genomic approach to connecting Elevated germline Mutation rates with male infertility and Somatic health (NICHD: R01 HD106112), The Utah Population Database (UPDB) is a University of Utah Core facility and a Huntsman Cancer Institute Comprehensive Cancer Center Shared Resource. It is funded in part by the University of Utah, the Huntsman Cancer Foundation, and the Cancer Center support grant (NCI: P30 CA2014). The authors thank the Pedigree and Population Resource of Huntsman Cancer Institute, University of Utah, for its role in the ongoing collection, maintenance, and support of UPDB. The authors also thank the University of CTSI (funded by NIH Clinical and Translational Science Awards), the Pedigree and Population Resource, University of Utah Information Technology Services, and Biomedical Informatics Core for establishing the Master Subject Index between the Utah Population Database, the University of Utah Health Sciences Center, and Intermountain Healthcare. The Utah Cancer Registry is funded by the National Cancer Institute's SEER Program, Contract No. HHSN261201800016I, the US Centers for Disease Control and Prevention's National Program of Cancer Registries, Cooperative Agreement No. NU58DP007131, with additional support from the University of Utah and Huntsman Cancer Foundation. Joemy M. Ramsay: Writing – review & editing, Writing – original draft, Methodology, Formal analysis, Data curation, Conceptualization. Cameron Shonnard: Writing – review & editing, Writing – original draft, Formal analysis. Heidi A. Hanson: Writing – review & editing, Writing – original draft, Methodology, Formal analysis, Conceptualization. Joshua J. Horns: Writing – review & editing, Writing – original draft, Methodology, Formal analysis, Data curation. Benjamin R. Emery: Writing – review & editing, Writing – original draft, Data curation. Kenneth I. Aston: Writing – review & editing, Writing – original draft, Methodology, Data curation. Joshua M. Stern: Writing – review & editing, Writing – original draft. James M. Hotaling: Writing – review & editing, Writing – original draft, Supervision, Conceptualization. Supported by GEMS: Genomic approach to connecting Elevated germline Mutation rates with male infertility and Somatic health (NICHD: R01 HD106112); partially supported by the Utah Population Database (UPDB) through grant P30 CA2014 from the National Cancer Institute, University of Utah and from the University of Utah’s program in Personalized Health and Utah Clinical and Translational Science Institute (CTSI). This work was funded under GEMS: Genomic approach to connecting Elevated germline Mutation rates with male infertility and Somatic health (NICHD: R01 HD106112)
Keywords
- Male fertility
- familial mortality risk
- mortality risk patterns