Isotopic metabolic fractionation of endogenous steroids by 5α-reductase inhibitors

5α-Reductase inhibitors are drugs commonly used in the treatment of benign prostatic hyperplasia, androgenic alopecia and hirsutism. The only two pharmaceutical product commercially available and FDA-approved for clinical purpose are Finasteride and Dutasteride. They are both synthetic 4-azasteroids that irreversibly inhibit the 5α-reductase, competing against the substrate, testosterone (T), in the linkage with enzymeNADH complex and in its conversion into dihydrotestosterone (DHT). Dutasteride inhibits both 5α-reductase isozymes (type 1 and 2) with an high effectiveness, while Finasteride preferentially inhibits the isozyme type 2, located not only in prostate but also in hair follicles. In anti-doping analyses, the use of 5α-reductase inhibitors represents a serious issue because, even if they are not currently included in the WADA Prohibited List as performance-enhancing drugs, they are confounding factors affecting several urinary steroid profile parameters: androsterone/etiocholanolone (A/Etio) and 5α-androstane-3α,17β-diol/5β-androstane-3α,17β-diol (5αAdiol/5βAdiol). This work is a preliminary study of the remarkable effects that Finasteride and Dutasteride have not only over these ratios but also over the isotopic fractionation of endogenous steroid hormones observed after GC-c-IRMS analyses.