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 17beta-hydroxy
androstane steroids of labeled
testosterone, according to its mode of administration. In normal males the yields of urinary 5alpha-androstane-3alpha,17beta-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 5alpha-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 5alpha-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
17beta-hydroxy-5alpha-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 5alpha-reduction of
testosterone observed in patients with feminizing testes does not necessarily reflect an enzymatic impairment but might be related to an abnormal synthesis of plasma
binding protein(s) under the effect of circulating
estrogens so that an abnormally small amount of unbound
testosterone may be available in target cells for 5alpha-reduction.