High testosterone levels may affect the risk of some metabolic diseases and cancers, according to the largest study to date on the genetic regulation of sex hormone levels.
The study, published last night (10 February 2020) in Nature Medicine, found that despite finding a strong genetic component to circulating testosterone levels in men and women, the genetic factors involved were different between the sexes.
Researchers from the UK Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge and the University of Exeter used genome wide association studies (GWAS) in 425,097 UK Biobank participants to identify 2,571 genetic variations 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.
When they went on to use Mendelian randomisation, they found that in women, genetically high testosterone increases the risks of type 2 diabetes by 37 % and polycystic ovary syndrome (PCOS) by 51%. There were also increased risks of breast and endometrial cancers.
In men, they found high testosterone levels reduced type 2 diabetes in men by 14% and increased the risk of prostate cancer.
Joint senior author Dr John Perry, from the MRC Epidemiology Unit at the University of Cambridge, says: "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.”
Dr Katherine Ruth, of the University of Exeter, a lead author of the paper, adds: "Our findings provide unique insights into the disease impacts of testosterone.”
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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