Effect of Dose and 5α‐Reductase Inhibition on the Circulating Testosterone Metabolite Profile of Men Administered Oral Testosterone

Development of an oral testosterone therapy has proven extremely challenging because of extensive and variable first‐pass metabolism. We investigated the in vivo metabolism of testosterone with increasing oral doses of testosterone, both alone and with the co‐administration of dutasteride (5α‐reductase inhibitor) by liquid‐chromatography tandem mass spectrometry (LC‐MS/MS). In eugonadal men prior to dosing, the circulating concentration of testosterone, androstenedione, etiocholanolone‐glucuronide, and androsterone‐glucuronide was 8.6, 20.9, 9.1, and 55.3%, respectively, of the total testosterone‐related species, whereas testosterone‐glucuronide was ∼1%. When testosterone was dosed orally to men with experimental hypogonadism, a proportion of testosterone‐glucuronide increased to 13%. Dutasteride treatment significantly decreased levels of androsterone and its metabolites. This work reveals extensive metabolism of orally dosed testosterone to androsterone glucuronide via androstenedione, with testosterone‐glucuronide appearing to be the second most important metabolite. This information is of importance in the development of an effective oral testosterone therapy and may have implications for testosterone doping research.