Sex-Specific Associations of Testosterone With Metabolic Traits

Abstract

Background: Testosterone levels are differentially linked with diabetes risk in men and women: lower testosterone levels in men and higher testosterone levels in women are associated with type 2 diabetes, though, the mechanisms are not fully clear. We addressed sex-specific links between testosterone and major pathogenetic mechanisms of diabetes.Methods: We analyzed data of 623 subjects (202 male, 345 female without, and 76 female with oral contraceptive therapy [OCT]) for whom insulin sensitivity and insulin secretion were assessed by oral glucose tolerance test. Body fat percentage was assessed by bioelectrical impedance. Testosterone was measured by enzyme-linked immunoassay; free testosterone and Framingham risk score were calculated.Results: There were significant interactions between testosterone and sex for all tested metabolic traits. Increasing testosterone was associated with less body fat, elevated insulin sensitivity, and reduced glycemia, independent of adiposity in men. In women without OCT, testosterone correlated with more body fat, insulin resistance, and higher glucose concentrations. Testosterone was not associated with insulin secretion in either sex, but with lower Framingham risk score in men and higher Framingham risk score in women.Conclusions: Similar to diabetes risk, insulin resistance has different association directions with testosterone levels in males and females. Insulin resistance could therefore constitute the best biological candidate linking testosterone levels and diabetes prevalence. The question of antiandrogen therapy being able to improve metabolism, glucose tolerance and cardiovascular risk in women was not clarified in our study but should be reviewed with higher numbers in a carefully matched study to reduce the influence of confounding variables.

Sex hormones, adiposity, and metabolic traits in men and women: a Mendelian randomisation study

“…These results are congruent with previous MR studies in the UKBB showing positive links between higher BioT and increased lean mass (24,48), reduced fat mass (48), and lower glucose (24). However, they are only partly consistent with observational data demonstrating inverse associations between circulating testosterone and risk of metabolic syndrome in men (31,32,(49)(50)(51), as well as clinical findings in men with physiologic or chemically induced hypogonadism, who were shown to be at increased risk of developing obesity and IR, as well as T2DM (8,52,53). On the other hand, our data are aligned with RCTs of testosterone therapy in men, which reported benefits on adiposity as reflected by lower HIPadjBMI herein, as well as diminished fasting glucose levels and T2D risk (54,55).…”

“…These results extend the MR findings of Ruth et al ( 24 ), which provided suggestive evidence of a causal link between higher BioT and elevated WHRadjBMI using anthropometric data from a smaller GWAS ( 29 ). They also complement results from observational studies, which have generally reported positive associations between higher androgen levels and central obesity, CVD risk burden, and T2D risk in women ( 11 , 12 , 13 , 30 , 31 , 32 , 33 , 34 ). The mechanisms accounting for these links are unclear.…”

Increase in testosterone levels is related to a lower risk of conversion of prediabetes to manifest diabetes in prediabetic males

“…Physiologically, sex hormones are involved in the regulation of glucose metabolism and are essential for maintenance of glucose homeostasis [ 2 ]. In men, testosterone is linked to insulin sensitivity and glycemic control [ 3 ]. Accordingly, in males there is a correlation between testosterone deficiency and the prevalence of prediabetes [ 4 ] and insulin resistance [ 5 ], meaning testosterone has favorable effects on glucose metabolism in males.…”

Differences in Hemodynamic, Hormonal and Heart Rate Variability Parameters in Complication-Free Pregnancies Compared to Individuals with Gestational Diabetes Mellitus and Preeclampsia: An Observational Retrospective Analysis

“…The long-term effects on women’s health of significantly increased levels of testosterone and cortisol compared to the control group and women that had preeclampsia several weeks postpartum is yet to be investigated. However, previous studies have shown that increased testosterone levels in women are associated with insulin resistance, higher glucose concentrations and increased body fat—a precursor of developing metabolic syndrome more rapidly than women without a history of GDM [ 12 ].…”