Higher levels of genetically derived testosterone are associated with an increased risk of type 2 diabetes and polycystic ovary syndrome (PCOS) in women but play a protective role against type 2 diabetes in men, according to a study in Nature Medicine.
Researchers from the United States, United Kingdom, and Europe examined testosterone levels and genetic data from 425,097 patients in the UK Biobank. The researchers investigated 2571 genome-wide significant trait/signal pairs, which ranged from 22 signals for estradiol in men to 658 signals for sex hormone-binding globulin in a sex-combined cohort. The findings from the analyses were verified in the EPIC-Norfolk and Twins UK studies, which demonstrated a high level of agreement with the UK Biobank analysis. Mendelian randomization was also used to identify potential causal associations between testosterone levels and disease risk.
The investigators found differences in genetic determinants of testosterone levels between men and women, with higher testosterone showing harmful and protective effects on women and men, respectively. In women, a genetically determined, per 1-standard deviation (SD) higher level of bioavailable testosterone was associated with an increased risk of type 2 diabetes (odds ratio [OR], 1.37; 95% CI, 1.22-1.53) and PCOS (OR, 1.51; 95% CI, 1.33-1.72). Conversely, a 1-SD higher testosterone level was associated with reduced risk of type 2 diabetes risk in men (OR, 0.86; 95% CI, 0.76-0.98). Testosterone was also associated with an increased risk of estrogen receptor (ER)-positive breast cancer and endometrial cancer.
A limitation of the study was the use of a single large study enriched for healthy, older people to determine genetic variants. According to the investigators, this may have underestimated the effect size of the associated variants.
The investigators concluded that while these “findings relating to adverse metabolic effects of testosterone in women may inform clinical practice, it is premature to infer wider beneficial metabolic effects in men.”
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Ruth KS, Day FR, Tyrrell J, et al. Using human genetics to understand the disease impacts of testosterone in men and women. Nat Med. 2020;26(2):252-258.