Using human genetics to understand the disease impacts of testosterone in men and women
Open accessAbstract
Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22–1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33–1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76–0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses. Genetic analysis of data from over 400,000 participants in the UK Biobank Study shows that circulating testosterone levels have sex-specific implications for cardiometabolic diseases and cancer outcomes.
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POR variant rs17853284 (P228L) has been linked to lower testosterone levels.
“Recent genome-wide association studies have indicated a link to lower testosterone levels with the presence of POR variant rs17853284 [22,23].”
From Loss of Protein Stability and Function Caused by P228L Variation in NADPH-Cytochrome P450 Reductase Linked to Lower Testosterone Levels (2022) · cites this paper as [22]
The Results section, “Distinct genetic architectures of testosterone regulation between sexes” (page unavailable), identifies POR-rs17853284 as a signal with an apparent female-specific effect on testosterone. Our copy does not state that the variant is P228L or that its presence is linked to lower testosterone levels. (LLM, conf=0.86)
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References 49 · Cited by 720
- Authors
- The Endometrial Cancer Association Consortium, Ruth, K. S., Day, F. R., Tyrrell, J., Thompson, D. J., Wood, A. R., Mahajan, A., Beaumont, R. N., Wittemans, L., Martin, S., Busch, A. S., Erzurumluoglu, A. M., Hollis, B., O’Mara, T. A., McCarthy, M. I., Langenberg, C., Easton, D. F., Wareham, N. J., Burgess, S., Murray, A., Ong, K. K., Frayling, T. M., & Perry, J. R. B.
- Affiliations
- University of Exeter (GB)
- University of Cambridge (GB)
- Centre for Human Genetics (GB)
- University of Copenhagen (DK)
- QIMR Berghofer Medical Research Institute (AU)
- Corresponding author
- Frayling, Timothy M
- Perry, John R. B.
- ORCID
- Ruth, Katherine S
- Day, Felix R
- Tyrrell, Jessica
- Thompson, Deborah J
- Wood, Andrew R
- Mahajan, Anubha
- Beaumont, Robin N
- Wittemans, Laura
- Martin, Susan
- Busch, Alexander S.
- Erzurumluoglu, A. Mesut
- O’Mara, Tracy A.
- McCarthy, Mark I
- Langenberg, Claudia
- Easton, Douglas F
- Wareham, Nicholas J
- Burgess, Stephen
- Murray, Anna
- Ong, Ken K
- Frayling, Timothy M
- Perry, John R. B.
- Venue
- Nature Medicine
- Published
- 2020-02
- Volume
- 26
- Issue
- 2
- Pages
- 252-258
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC7025895
- OpenAlex
- W3004892753
- Semantic Scholar
- 9a7e71fc7a80dec32fe4b23a1441054a3039bcf6
- Cited by
- 720
- References
- 49
- Citations by year
- 2026: 65 · 2025: 137 · 2024: 138 · 2023: 151 · 2022: 101 · 2021: 102 · 2020: 26
- FWCI
- 76.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Open Research Exeter (University of Exeter) (acceptedVersion)
- Figshare (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust (204623/Z/16/Z, 104150/Z/14/Z)
- National Institute for Health and Care Research (MS-2013-003-203, NF-SI-0617-10149, NF-SI-0617-10090)
- Academy of Medical Sciences (SBF004\1079)
- Medical Research Council (MR/T002239/1, MC_PC_13048, MC_UU_12015/2, MC_PC_17228, MC_UU_12015/1, MC_PC_12028)
- Engineering and Physical Sciences Research Council (1673172)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Keywords
- testosterone, sex differences, type 2 diabetes, polycystic ovary syndrome, breast cancer, endometrial cancer, prostate cancer, metabolic disease risk
- MeSH terms
- Body Composition, Breast Neoplasms, Diabetes Mellitus, Type 2, Estradiol, Female, Genotype, United Kingdom, Haplotypes, Humans, Male, Phenotype, Polycystic Ovary Syndrome, Prostatic Neoplasms, Sex Factors, Software, Testosterone, Biomarkers, Cluster Analysis, Odds Ratio, Endometrial Neoplasms, Biological Specimen Banks, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Mendelian Randomization Analysis
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