Having genetically higher testosterone levels increases the risk of metabolic diseases such as type 2 diabetes (T2D) in women, but reduces the risk in men, according to the results of research by scientists at the University of Cambridge and the University of Exeter. The findings, from the largest study to date on the genetic regulation of sex hormone levels, also found that higher testosterone levels increase the risks of breast and endometrial cancers in women, and prostate cancer in men. The collective data indicated that while there is a strong genetic component to circulating testosterone levels in men and women, the genetic factors involved were very different between the sexes.

“Our findings provide unique insights into the disease impacts of testosterone,” commented Katherine Ruth, PhD, at the University of Exeter. “In particular they emphasize the importance of considering men and women separately in studies, as we saw opposite effects for testosterone on diabetes.” Perry is co-lead author of the team’s published paper in Nature Medicine, which is titled, “Using human genetics to understand the disease impacts of testosterone in men and women.”

The role of testosterone in disease is largely unknown, despite strong epidemiological associations with many health conditions, and the widespread use of testosterone supplements, the authors wrote. “Previous studies have shown protective associations with testosterone on type 2 diabetes (T2D) and related metabolic traits in men, but harmful associations in women.” Despite such pointers, identifying true associations between testosterone and disease is difficult because of “confounding due to the substantial effects of aging and adiposity on circulating testosterone concentrations.” More than 3% of men in the U.S. aged 30 years were prescribed testosterone in 2013, before the FDA communicated that there may be potential cardiovascular risk issues linked to testosterone use.

Randomized controlled trials have demonstrated benefits of testosterone therapy on   sexual function, lean mass, muscle strength and bone mineral density, along with reductions in whole-body and intra-abdominal fat. These effects on body composition should predict concomitant benefits on T2D and cardiometabolic diseases. In contrast, the investigators noted, testosterone is known to promote the growth and metastasis of prostate cancers, while observational studies have suggested that testosterone replacement therapy may also increase susceptibility to future prostate cancer. “However, even the largest trials of testosterone have too few cases of incident T2D, cardiovascular disease or prostate cancer to provide informative data on these risks,” they noted. “… Similarly, in women, experimental evidence of testosterone administration is insufficient to confirm the apparently metabolically harmful associations in observational studies between testosterone and higher adiposity, risk of polycystic ovary syndrome (PCOS) and other cardiovascular disease risk.”

One approach to understanding the causal effects of putative risk factors such as testosterone levels on disease is to investigate the genetic variations that impact on their regulation, in the context of health outcomes. For the reported study the team used data from genome wide association studies (GWAS) in 425,097 UK Biobank participants to identify 2,571 genetic variations associated with differences in the levels of the sex hormone testosterone and its binding protein sex-hormone binding globulin (SHGB). “After extensive quality control, serum levels of SHBG, total testosterone and estradiol were available in up to 425,097 individuals with genetic data in UK Biobank … In total, we identified 2,571 genome-wide significant trait-signal pairs.”

The researchers 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. The team next applied an approach called Mendelian randomization (MR), which uses naturally occurring genetic variations to help understand whether known associations between testosterone levels and disease are causal rather than correlative. “Given the lack of overlap between men and women in sex hormone-associated variants, and the possible different metabolic effects of these hormones between sexes, we focused analyses on sex-specific disease outcomes,” the team noted.

The results of their analyses indicated that having higher testosterone levels reduces T2D risk in men by 14%. “In men, we found evidence of beneficial effects of higher testosterone on metabolic traits,” they wrote. In contrast, the team found that in women, genetically higher testosterone increases the risks of type 2 diabetes by 37%, and polycystic ovary syndrome (PCOS) risk is increased by 51%. “Despite evidence for a positive effect of total testosterone on lean body mass in women as well as men, testosterone was associated with several adverse metabolic outcomes in women,” the investigators stated. “We found consistent evidence supporting a causal effect of testosterone on high PCOS risk in women … MR analyses also showed a causal effect of bioavailable testosterone on higher T2D risk and higher fasting insulin in women ….”

Additionally, they found that genetically higher testosterone levels increased the risks of breast and endometrial cancers in women, and of prostate cancer in men. “MR analyses indicated that testosterone increases prostate cancer risk in men … We found evidence that testosterone increased the risk of estrogen receptor (ER)-positive but not ER-negative breast cancer … There was also evidence for a protective effect of SHBG on risk of endometrial cancer in women, which was consistent across all models, but a risk-increasing effect of SHBG on ER [estrogen receptor]-negative breast cancer.”

Joint senior study author John Perry, PhD, from the MRC Epidemiology Unit at the University of Cambridge, further 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 randomization are useful in understanding of the risks and benefits of hormone therapies.”

The researchers say their findings highlight the importance of sex-specific analyses, both for discovering genetic variants for sex hormone traits, and for analysing downstream effects. “In conclusion, our findings provide unique insights into the disease impacts of testosterone and highlight the importance of sex specific analyses of disease risk,” they wrote.

The investigators also noted that similar large-scale sex-specific data on cardiovascular disease aren’t yet available, but will be “critically important” to understanding the wider cardiometabolic impact of testosterone. “Hence, while the 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,” they stated. “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 acknowledged.

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