5α-reductase type 1 modulates insulin sensitivity in men.
BACKGROUND
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.


METHODS
This double-blind randomized controlled parallel group study at a clinical research facility included 46 men (20-85 years) studied before and after intervention.


METHODS
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.


METHODS
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.


CONCLUSIONS
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.
University/British Heart Foundation Centre for Cardiovascular Science (R.U., K.A.H., D.E.W.L., D.P.M., I.M., B.R.W., R.A.) and Clinical Research Imaging Centre (C.D.G.), University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom; and Radiology (F.C.M.) and Urology (L.H.S.) Departments, National Health Service Lothian University Hospitals Division, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.
Rita
R
Upreti
Katherine A
KA
Hughes
Dawn E W
DE
Livingstone
Calum D
CD
Gray
Fiona C
FC
Minns
David P
DP
Macfarlane
Ian
I
Marshall
Laurence H
LH
Stewart
Brian R
BR
Walker
Ruth
R
Andrew
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000502:physiology*; D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001378:Azasteroids / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001823:Body Composition / Q000187:drug effects; D004311:Double-Blind Method; D000068538:Dutasteride; D018120:Finasteride / Q000494:pharmacology*; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D011470:Prostatic Hyperplasia / Q000378:metabolism / Q000652:urine; D055815:Young Adult
D058891:5-alpha Reductase Inhibitors; D001378:Azasteroids; D001786:Blood Glucose; D018120:Finasteride; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D000068538:Dutasteride