5α-Reductase (5αR) inhibitors decrease prostatic dihydrotestosterone in benign prostatic hyperplasia (BPH) treatment; finasteride inhibits 5αR type 2, while dutasteride inhibits 5αR1 and 2. 5αRs, especially 5αR1, are also expressed in metabolic tissues regulating actions of androgens and other substrates, including glucocorticoids.
Hypothesis: 5αR1 inhibition with dutasteride induces metabolic dyshomeostasis.
Study: With ethical approval, in a double-blind RCT, we studied metabolism in 47 men (2085 years) before and after 3 months of either dutasteride (0.5 mg daily; n= 17; D), finasteride (5 mg daily; n= 16; F) or control (tamsulosin; 0.4 mg daily; n= 14). The primary outcome was insulin sensitivity, measured during a two-step (10; 40 mU/m2 per min) hyperinsulinaemic euglycaemic clamp, with d2-glucose and d5-glycerol tracers. Data are mean (95% CI; P value) difference in change from baseline, compared by one-way ANOVA with LSD post-hoc tests where appropriate.
Results: D, but not F, impaired insulin sensitivity. During high-dose insulin, the M value (mean steady state glucose infusion rate) decreased with D vs both control and F, by 10.1 mg/kg fat-free mass/min (−16.3; −3.9; P=0.002); signifying impaired skeletal muscle insulin sensitivity. Glucose and glycerol rates of appearance during low-dose insulin were unchanged. Tracer infusion alone induced hyperinsulinaemia only with D by 11 pmol/l (3; 20; P=0.009). D increased HOMA-IR and fasting C-peptide by 15% (3; 27; P=0.015), and 114.5 pmol/l (31.5; 197.6; P=0.007) respectively. Fasting glucose, cholesterol, body mass index, waist:hip ratio and blood pressure were unaltered. Body fat (bioimpedance) increased 2.6% (0.9; 4.2; P=0.003) with D. Post-treatment visceral and subcutaneous adipose volumes (magnetic resonance imaging; L4/5), and hepatic fat (1H spectroscopy), were unchanged. Serum adiponectin, resistin, IL8, and MCP1 were unchanged, however leptin increased 44% (16; 73; P=0.03) with D. In all indices F was not different to control.
Conclusion: 5αR inhibition with dutasteride, but not finasteride, impairs peripheral (principally muscle) insulin sensitivity, and increases body fat and leptin. 5αR1 inhibition is potentially detrimental to metabolic health; this may have important implications for BPH treatment.
Declaration of funding
This work was supported by the Chief Scientist Office (grant number CZB/4/462, 2009).