|dc.description.abstract||5α-reductases (5αRs) catalyse reduction of 4-pregnene steroids, most notably the
androgen testosterone to its more potent metabolite dihydrotestosterone (DHT).
Well-characterised isozymes of 5αR are designated 5αR1 and 5αR2. Inhibitors of
5αR, finasteride (a 5αR2 inhibitor) and dutasteride (a dual 5αR1 and 5αR2
inhibitor), are utilised in conditions where a reduction in androgen action is
desired, including benign prostatic hyperplasia. Although 5αR2 is
predominantly expressed in reproductive tissues, both isozymes, but
particularly 5αR1, are expressed in metabolic tissues including liver and adipose
and both metabolise glucocorticoids as well as androgens; therefore inhibition of
5αR may have consequences for metabolic health. This thesis addresses the
hypotheses that 5αR1 inhibition with dutasteride decreases insulin sensitivity
and causes dysregulation of the HPA axis in humans.
Metabolism and the HPA axis were studied in men prior to and following 3
months of dutasteride (0.5 mg daily; n=16), finasteride (5 mg daily; n=16) or
control (tamsulosin MR; 0.4 mg daily; n=14). Glucose disposal during
hyperinsulinaemia was the primary endpoint, measured during a
hyperinsulinaemic euglycaemic clamp, with d2-glucose and d5-glycerol tracers.
Peripheral insulin sensitivity for both glucose uptake and NEFA suppression
decreased with dutasteride versus both finasteride and control, while hepatic
insulin sensitivity was preserved. Body fat increased with dutasteride, though
was not accompanied by changes in metabolic or inflammatory gene transcript
abundance in subcutaneous adipose biopsies, nor any differences in abdominal
adipose depots on post-treatment MRI. Subtle dysregulation of the HPA axis
was evident with both 5αR inhibitors, though to a greater degree with
dutasteride and changes were largely compensated for.
In support of this study, this thesis also describes the development, validation
and application of two novel liquid chromatography tandem mass spectrometry
assays; establishing compliance by measuring serum drug levels, and
demonstrating effects of 5αR inhibitors on androgen metabolism and adrenal
steroidogenesis by measurement of testosterone, DHT and androstenedione.
In conclusion, 5αR1 inhibition with dutasteride, but not finasteride, induces
peripheral insulin resistance and increases body fat. Findings presented may
have important implications for patients prescribed dutasteride for benign