Abstract
SummaryObjectivePrevious studies suggest that androgens have a sexually dimorphic impact on metabolic dysfunction. However, the sex‐specific link between circulating androgens and risk of type 2 diabetes mellitus (T2DM) has not been examined in a large scale, longitudinal cohort, a task we undertook in this study.DesignA retrospective cohort study in a UK primary care database.PatientsWe included men and women with available serum testosterone and sex hormone‐binding globulin (SHBG) results.MeasurementsWe categorized serum concentrations according to clinically relevant cut‐off points and calculated crude and adjusted T2DM Incidence Rate Ratios (IRRs and aIRRs).ResultsSerum testosterone concentrations were available in 70 541 men and 81 889 women; serum SHBG was available in 15 907 men and 42 034 women. In comparison to a reference cohort with serum testosterone ≥20 nmol/L, men with lower serum testosterone had a significantly increased risk of T2DM, with the highest risk in those with serum testosterone <7 nmol/L (aIRR 2.71, 95% CI 2.34‐3.14, P < 0.001). In women, the risk of T2DM started to increase significantly when serum testosterone concentrations exceeded 1.5 nmol/L, with the highest risk in women with serum testosterone ≥3.5 nmol/L (aIRR 1.98, 95% CI 1.55‐2.52, P < 0.001). These observations were verified in a continuous rather than categorized analysis. The risk of T2DM increased in men and women with serum SHBG <40 and <50 nmol/L, respectively.Conclusions/InterpretationIn this longitudinal study, we found sexually dimorphic associations between serum testosterone and risk of incident T2DM. Androgen deficiency and excess should be considered important risk factors for diabetes in men and women, respectively.
Highlights
Sex differences are critical in the epidemiology and pathophysiology of metabolic disease, with an increased incidence of type 2 diabetes mellitus (T2DM) and cardiovascular disease in men 1
A total of 152,430 participants in the cohort with available serum testosterone measurement results and a total of 57,942 participants (15,907 men and 42,035 women) in the sex hormone-binding globulin (SHBG) cohort, both derived from the The Health Improvement Network (THIN) database, met the inclusion criteria and were included in the current study
A diagnosis of polycystic ovary syndrome (PCOS) was only documented in 6.3% (N=5,136) and 7.9% (N=3,303) of the female testosterone and SHBG cohorts, respectively
Summary
Sex differences are critical in the epidemiology and pathophysiology of metabolic disease, with an increased incidence of type 2 diabetes mellitus (T2DM) and cardiovascular disease in men 1. Sex hormones such as androgens may mediate these differences, but the association between androgens and metabolic dysfunction is complex and sex-specific 2. Female-to-male gender reassignment patients undergoing androgen therapy develop dyslipidemia and abnormal body composition striking similarity to that of female androgen excess; lower testosterone levels in men are associated with impaired glucose homeostasis, hepatic steatosis and coronary artery disease analyses support a sex-specific relationship between androgens and the risk of metabolic dysfunction, and suggest that low circulating sex hormone-binding globulin (SHBG) concentrations may be metabolically harmful in both sexes 9,10.
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