In the Journals

‘Distinct genetic architectures’ between sexes lead to opposite testosterone effects on diabetes risk

John R. B. Perry

Women are more likely and men less likely to develop type 2 diabetes if they have elevated levels of testosterone, which may be partially explained by distinct genetic makeups for regulating sex hormones, according to findings published in Nature Medicine.

John R. B. Perry, PhD, of the Medical Research Council Epidemiology Unit at the University of Cambridge, and colleagues used data on testosterone, estradiol and sex hormone-binding globulin levels from 425,097 adults from the UK Biobank. The researchers also examined genetic data from which they “identified 2,571 genome-wide significant trait–signal pairs” related to testosterone, estradiol and SHBG levels.

The researchers wrote that different genes played a role in regulating testosterone levels in women than in men, indicating that there were “distinct genetic architectures of testosterone regulation between sexes.”

“Testosterone levels are regulated completely differently in men and women ,” Perry told Healio. “Higher testosterone appears protective of metabolic diseases such as type 2 diabetes in men, but increases the risk of diabetes and polycystic ovary syndrome in women.”

 
Women are more likely and men less likely to develop type 2 diabetes if they have elevated levels of testosterone, which may be partially explained by distinct genetic makeups for regulating sex hormones.
Source: Adobe Stock

The researchers found that women were more likely to develop type 2 diabetes (OR = 1.37; 95% CI, 1.22-1.53) and polycystic ovary syndrome (OR = 1.51; 95% CI, 1.33-1.72) when testosterone levels were increased by 1 standard deviation.

“We were surprised to see that testosterone appeared to increase the risk of women developing polycystic ovary syndrome,” Perry said. “The prevailing thought has been that increased testosterone was solely the consequence of the disease, but our research suggests that testosterone may also play a direct role in disease susceptibility.”

The researchers also found that men were less likely to develop type 2 diabetes when testosterone was increased by 1 standard deviation (OR = 0.85; 95% CI, 0.77-0.95). Conversely, men were more likely to develop prostate cancer when testosterone was increased by 1 standard deviation (OR = 1.23; 95% CI, 1.13-1.33).

“We don’t recommend anyone to take medication to alter testosterone levels on the basis of our findings,” Perry said. “There is clearly a trade-off when considering treatment in men — a reduction in metabolic health risk but increased susceptibility to prostate cancer. In general, much more information is needed on the impacts of other diseases, particularly heart disease, to inform more widespread use of supplementation in otherwise healthy people.”

Beyond the specific results of this study, the researchers also stated that the methods of this study could affect future research methodology.

“Our findings provide unique insights into the disease impacts of testosterone and highlight the importance of sex-specific analyses of disease risk,” the researchers wrote. – by Phil Neuffer

For more information:

John R. B. Perry, PhD, can be reached at john.perry@mrc-epid.cam.ac.uk; Twitter: @jrbperry.

Disclosure: Perry reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

John R. B. Perry

Women are more likely and men less likely to develop type 2 diabetes if they have elevated levels of testosterone, which may be partially explained by distinct genetic makeups for regulating sex hormones, according to findings published in Nature Medicine.

John R. B. Perry, PhD, of the Medical Research Council Epidemiology Unit at the University of Cambridge, and colleagues used data on testosterone, estradiol and sex hormone-binding globulin levels from 425,097 adults from the UK Biobank. The researchers also examined genetic data from which they “identified 2,571 genome-wide significant trait–signal pairs” related to testosterone, estradiol and SHBG levels.

The researchers wrote that different genes played a role in regulating testosterone levels in women than in men, indicating that there were “distinct genetic architectures of testosterone regulation between sexes.”

“Testosterone levels are regulated completely differently in men and women ,” Perry told Healio. “Higher testosterone appears protective of metabolic diseases such as type 2 diabetes in men, but increases the risk of diabetes and polycystic ovary syndrome in women.”

 
Women are more likely and men less likely to develop type 2 diabetes if they have elevated levels of testosterone, which may be partially explained by distinct genetic makeups for regulating sex hormones.
Source: Adobe Stock

The researchers found that women were more likely to develop type 2 diabetes (OR = 1.37; 95% CI, 1.22-1.53) and polycystic ovary syndrome (OR = 1.51; 95% CI, 1.33-1.72) when testosterone levels were increased by 1 standard deviation.

“We were surprised to see that testosterone appeared to increase the risk of women developing polycystic ovary syndrome,” Perry said. “The prevailing thought has been that increased testosterone was solely the consequence of the disease, but our research suggests that testosterone may also play a direct role in disease susceptibility.”

The researchers also found that men were less likely to develop type 2 diabetes when testosterone was increased by 1 standard deviation (OR = 0.85; 95% CI, 0.77-0.95). Conversely, men were more likely to develop prostate cancer when testosterone was increased by 1 standard deviation (OR = 1.23; 95% CI, 1.13-1.33).

“We don’t recommend anyone to take medication to alter testosterone levels on the basis of our findings,” Perry said. “There is clearly a trade-off when considering treatment in men — a reduction in metabolic health risk but increased susceptibility to prostate cancer. In general, much more information is needed on the impacts of other diseases, particularly heart disease, to inform more widespread use of supplementation in otherwise healthy people.”

Beyond the specific results of this study, the researchers also stated that the methods of this study could affect future research methodology.

“Our findings provide unique insights into the disease impacts of testosterone and highlight the importance of sex-specific analyses of disease risk,” the researchers wrote. – by Phil Neuffer

For more information:

John R. B. Perry, PhD, can be reached at john.perry@mrc-epid.cam.ac.uk; Twitter: @jrbperry.

Disclosure: Perry reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.