A B S T R A C T The metabolism of radioactive testosterone simultaneously administered intravenously and either orally or percutaneously has been studied in seven patients with the syndrome of testicular feminization and compared with that of normal males and females. This investigation was carried out in order to determine the relative contribution to urinary 17-oxo and 17p-hydroxy androstane steroids of labeled testosterone, according to its mode of administration. In normal males the yields of urinary 5a-androstane-3a,17,-diol (androstanediol) originating from either an intravenous or a percutaneous dose of testosterone were respectively 3 and 6 times higher than those arising from an oral dose which perfuses the liver directly. These data indicate that in normal males, testosterone might be 5a-hydrogenated outside the liver. By contrast in patient with feminizing testes, because the contribution to androstanediol of radioactive testosterone is identical whatever its mode of administration, the extrahepatic 5a-reduction of this substrate seems very unlikely.The metabolic abnormalities observed in patients with testicular feminization syndrome may be reproduced in normal males by estrogen treatment. Nevertheless, the sensitivity of the patients to estrogen seems to be 10 times greater than that of normal males. This sensitivity was appreciated from the reduction of radioactive testosterone intravenously injected to urinary 17P-hydroxy-5a-androstan-3-one and androstanediol and also from the level of plasma binding for testosterone. This level was significantly higher (P < 0.05) in patients with feminizing testes than in normal males. The level increased dramatically after administration of a low dose of estrogen whereas this effect was not observed in normal males under the same experimental conditions.In light of these results the defect of extrahepatic 5a-reduction of testosterone observed in patients with Part of this work has been published as a preliminary communication (14).