Testosterone levels causally affect disease risk

Author: Louise Prime

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Genetically higher testosterone levels increase women’s risk of metabolic diseases including type 2 diabetes but reduce the risk in men, and also increase women’s risk of breast and endometrial cancers and men’s risk of prostate cancer, UK-led research has shown. The authors of the study*, published in Nature Medicine, said their results not only show the disease impacts of testosterone, they also emphasise the importance of studies considering men and women separately; but they added that they do not support the use of testosterone supplements.

The researchers noted that although testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, its effects on disease outcomes are unknown; and, for example, the association between a woman’s higher testosterone level and her risk of polycystic ovarian syndrome (PCOS) could have been cause or consequence.

They identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants and identified 2,571 genetic variations that were associated with differences in the levels of testosterone and its binding protein sex-hormone binding globulin (SHGB). They verified their genetic analyses in additional studies, including the EPIC-Norfolk study and Twins UK, and found a high level of agreement with their results in UK Biobank.

They then used Mendelian randomisation, using naturally occurring genetic differences to see whether associations between testosterone levels and disease were simply correlative – or causal. This revealed that in women, genetically higher testosterone increased the risks of type 2 diabetes by 37% and of PCOS by 51%, whereas it reduced men’s risk by 14%. They also found that genetically higher testosterone levels raised the risks of breast and endometrial cancers in women and prostate cancer in men.

The authors commented: “Our findings that genetically higher testosterone levels increase the risk of PCOS in women is important in understanding the role of testosterone in the origin of this common disorder, rather than simply being a consequence of this condition.

“Likewise, in men testosterone-reducing therapies are widely used to treat prostate cancer, but until now it was uncertain whether lower testosterone levels are also protective against developing prostate cancer. Our findings show how genetic techniques such as Mendelian randomisation are useful in understanding of the risks and benefits of hormone therapies.”

They added: “Our findings provide unique insights into the disease impacts of testosterone. In particular they emphasise the importance of considering men and women separately in studies, as we saw opposite effects for testosterone on diabetes. Caution is needed in using our results to justify use of testosterone supplements, until we can do similar studies of testosterone with other diseases, especially cardiovascular disease.”


*Ruth KS, Day FR, Tyrrell J, et al. Using human genetics to understand the disease impacts of testosterone in men and women. Nature Medicine; 10 February 2020; DOI: 10.1038/s41591-020-0751-5

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