Glucocorticoid excess is associated with adverse metabolic effects which often limits their therapeutic use. As male rodents have been shown to respond more robustly to the anti-inflammatory effects of glucocorticoids, we aimed to determine whether there are also sex differences in the metabolic response to glucocorticoids.

Eight week-old CD1 mice were treated with vehicle or 50 μg/mL corticosterone (CS) in the drinking water for 4 weeks, at which point insulin tolerance (by ITT) and body composition (by DXA) were assessed in intact, castrated and DHT-replaced male and female mice with or without CS treatment.

Intact male mice rapidly developed severe insulin resistance and increased adiposity as a result of CS treatment. In contrast, both intact and overiectomised females maintained normal insulin sensitivity and body composition despite CS treatment, indicating that the gender difference in metabolic CS-sensitivity is not due to a protective effect of estrogens. When male mice were orchidectomized (ORC), treatment with CS no longer resulted in insulin resistance. To assess if the resilience of both females and ORC-males to the metabolic side-effects of CS was due to the absence of androgens, we implanted ORC and OVX mice with dihydrotestosterone (DHT).  While DHT alone had no effect on fat or insulin sensitivity in either gender, co-treatment with DHT and CS rendered both ORC-males and OVX-females severely insulin resistant and caused significant fat mass accumulation. In addition, CS treatment resulted in high serum insulin and leptin as well as brown fat dysfunction only in androgen replete animals. Ex vivo, DHT was found to prevent the insulin-induced reduction in leptin secretion in the context of GC excess.

Conclusion: Mice demonstrate a strong dichotomy in their metabolic response to excess glucocorticoids, with males being more sensitive than females. Our data indicate that androgens potentiate the adverse metabolic side effects of excess glucocorticoids.