5α-Reductase Type 1 Modulates Insulin Sensitivity in Men

Abstract

Context:5α-Reductase (5αR) types 1 and 2 catalyze the A-ring reduction of steroids, including androgens and glucocorticoids. 5α-R inhibitors lower dihydrotestosterone in benign prostatic hyperplasia; finasteride inhibits 5αR2, and dutasteride inhibits both 5αR2 and 5αR1. In rodents, loss of 5αR1 promotes fatty liver.Objective:Our objective was to test the hypothesis that inhibition of 5αR1 causes metabolic dysfunction in humans.Design, Setting, and Participants:This double-blind randomized controlled parallel group study at a clinical research facility included 46 men (20–85 years) studied before and after intervention.Intervention:Oral dutasteride (0.5 mg daily; n = 16), finasteride (5 mg daily; n = 16), or control (tamsulosin; 0.4 mg daily; n = 14) was administered for 3 months.Main Outcome Measure:Glucose disposal was measured during a stepwise hyperinsulinemic-euglycemic clamp. Data are mean (SEM).Results:Dutasteride and finasteride had similar effects on steroid profiles, with reduced urinary androgen and glucocorticoid metabolites and reduced circulating DHT but no change in plasma or salivary cortisol. Dutasteride, but not finasteride, reduced stimulation of glucose disposal by high-dose insulin (dutasteride by −5.7 [3.2] μmol/kg fat-free mass/min, versus finasteride +7.2 [3.0], and tamsulosin +7.0 [2.0]). Dutasteride also reduced suppression of nonesterified fatty acids by insulin and increased body fat (by 1.6% [0.6%]). Glucose production and glycerol turnover were unchanged. Consistent with metabolic effects of dutasteride being mediated in peripheral tissues, mRNA for 5αR1 but not 5αR2 was detected in human adipose tissue.Conclusion:Dual inhibition of 5αRs, but not inhibition of 5αR2 alone, modulates insulin sensitivity in human peripheral tissues rather than liver. This may have important implications for patients prescribed dutasteride for prostatic disease.

5α-Reductase Type 1 Deficiency or Inhibition Predisposes to Insulin Resistance, Hepatic Steatosis, and Liver Fibrosis in Rodents

“…This has been elegantly demonstrated by adverse metabolic phenotypes in mice overexpressing the glucocorticoid-regenerating enzyme 11b-hydroxysteroid dehydrogenase type 1 in liver (29) and adipose tissue (30). Our findings that 5aR1-KO mice eating a high-fat diet are predisposed to steatosis and insulin resistance were replicated in rats treated with a 5aR inhibitor, and align with recent findings of adverse changes in insulin sensitivity and adiposity in men receiving treatment with dual 5aR inhibitors for 3 months (20). Zucker rats were chosen for this study since pharmacological inhibitors of murine 5aR1 have not been characterized, and Zucker rats are a known model of glucocorticoid-sensitive obesity and insulin resistance (31).…”

“…Moreover, increased susceptibility to steatosis was accompanied by enhanced susceptibility to fibrotic liver injury, suggesting that 5aR deficiency or inhibition may be associated with accelerated progression of nonalcoholic fatty liver disease. Similar observations with pharmacological inhibition of 5aRs in rats emphasize the potential importance of these observations in men treated with 5aR inhibitors (20).…”

“…Testosterone and finasteride were quantified in rat plasma (1 mL) as described previously (20) but were adapted for larger volume (1 mL) by use of Oasis HLB cartridges (60 cm 3 ; Waters, Elstree, U.K.).…”

“…Finasteride was used to inhibit both 5aR1 and 5aR2 in male Zucker rats, since it is nonselective for isozymes in rats (21,25), achieving circulating concentrations of 14.2 6 0.67 ng/mL in treated animals, and is within the therapeutic window in humans (20). A pharmacodynamic effect was confirmed by a marked decrease in prostate weight compared with vehicle (vehicle 174.0 6 6.7 vs. finasteride 116.6 6 7.1 mg, P , 0.01).…”

“…However, they are important to elucidate as the finding that deficiency in 5aR1 adversely affects metabolism translates into human health. We have recently demonstrated that dual pharmacological inhibition of 5aR1 and 5aR2 (but not 5aR2 alone) adversely affects metabolism, causing increased adiposity and insulin resistance (20).…”