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 prostatic hyperplasia.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:676215 |
| Date | January 2013 |
| Creators | Upreti, Rita |
| Contributors | Andrew, Ruth ; Walker, Brian |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/11745 |
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