The adverse metabolic side-effects of glucocorticoids often limit 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 exogenous glucocorticoids.
Eight-week-old CD1 mice were treated with vehicle or 50 μg/ml corticosterone (CS) in the drinking water for 4 weeks. Insulin tolerance and body composition (by DXA) were assessed in intact, castrated and DHT-replaced male and female mice treated with either vehicle or CS.
Intact male mice developed severe insulin resistance and increased adiposity as a result of CS treatment (fat mass males: vehicle +3% vs. CS +42%, p<0.001). In contrast, both intact and overiectomised females maintained normal insulin sensitivity and body composition in the presence of CS, 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 or abnormal fat accrual. To assess if the resilience of females and ORC-males to the metabolic side-effects of CS was due to a lack of androgens, ORC-males and OVX-female mice were implanted with the minimally aromatizable dihydrotestosterone (DHT). DHT alone had no effect on fat or insulin sensitivity in either gender, however co-treatment with DHT and CS rendered both ORC-males and OVX-females severely insulin resistant and caused significant fat accrual (fat mass OVX-females+DHT: vehicle +37% vs. CS +94% p<0.05 and ORC-males+DHT: vehicle +21% vs. CS +98% p<0.001).
Mice demonstrate a strong dichotomy in their metabolic response to excess glucocorticoids, with males being more sensitive than females. Our data indicate that androgens strongly potentiate the adverse metabolic side effects of glucocorticoids.