Studies on testosterone metabolism in subjects with testicular feminization syndrome P. Mauvais-Jarvis, … , O. Crepy, F. Gauthier J Clin Invest. 1970;49(1):31-40. https://doi.org/10.1172/JCI106219. Research Article 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 17β- hydroxy androstane steroids of labeled testosterone, according to its mode of administration. In normal males the yields of urinary 5α-androstane-3α,17β-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 5α-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 5α-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 17β-hydroxy-5α-androstan-3-one and androstanediol and also from the level of plasma binding for testosterone. This level was significantly higher (P < 0.05) in […] Find the latest version: https://jci.me/106219/pdf Studies on Testosterone Metabolism in Subjects with Testicular Feminization Syndrome P. MAuvAIS-JARvIs, J. P. BEmcovici, 0. CREPY, and F. GAUTIR From the Laboratoire de Chimie Biologique, C.H.U. La Pitie, Paris 13, France A B S T R A C T The metabolism of radioactive testoster- feminizing testes does not necessarily reflect an enzy- one simultaneously administered intravenously and matic impairment but might be related to an abnormal either orally or percutaneously has been studied in synthesis of plasma binding protein(s) under the effect seven patients with the syndrome of testicular feminiza- of circulating estrogens so that an abnormally small tion and compared with that of normal males and females. amount of unbound testosterone may be available in This investigation was carried out in order to determine target cells for 5a-reduction. the relative contribution to urinary 17-oxo and 17p- hydroxy androstane steroids of labeled testosterone, ac- cording to its mode of administration. In normal males INTRODUCTION the yields of urinary 5a-androstane-3a,17,-diol (andros- It is well known that the syndrome of testicular femini- tanediol) originating from either an intravenous or a zation develops in the presence of blood testosterone1 percutaneous dose of testosterone were respectively 3 levels sufficiently to cause virilization in normal indi- and 6 times higher than those arising from an oral dose viduals (1-3). This observation suggests that the clinical which perfuses the liver directly. These data indicate manifestations of the syndrome are related to a defect that in normal males, testosterone might be 5a-hydroge- in androgen action. Recently, we have reported that nated outside the liver. By contrast in patient with male sex differentiation is partly associated with a feminizing testes, because the contribution to androstane- stimulation of enzymes allowing the ring A reduction of diol of radioactive testosterone is identical whatever its testosterone to 17P-hydroxyandrostane steroids (Fig. 1) mode of administration, the extrahepatic 5a-reduction of (4, 5). When normal males and hirsute females are in- this substrate seems very unlikely. travenously injected with radioactive testosterone, the The metabolic abnormalities observed in patients with contribution of this precursor to urinary 5a- and 5P-an- testicular feminization syndrome may be reproduced in drostane-3a, 17f-diol is higher than in normal females normal males by estrogen treatment. Nevertheless, the and hypogonadal males with gonadotrophin deficiency. sensitivity of the patients to estrogen seems to be 10 The treatment of the latter patients by chorionic gonado- times greater than that of normal males. This sensi- trophin restores a normal male metabolic pattern. On tivity was appreciated from the reduction of radioactive the contrary, the administration of synthetic estrogens testosterone intravenously injected to urinary 17P-hy- to normal males decreases the excretion of urinary droxy-5a-androstan-3-one and androstanediol and also metabolites originating from the ring A reduction of from the level of plasma binding for testosterone. This testosterone (6). In all these situations the yield of uri- level was significantly higher (P < 0.05) in patients nary 17P-hydroxyandrostane steroids arising from testos- with feminizing testes than in normal males. The level terone is correlated with the concentration of this an- increased dramatically after administration of a low dose of estrogen whereas this effect was not observed 'The following trivial names have been used: T = testos- in normal males under the same experimental conditions. terone; androstanolone = 17#-hydroxy-Sa-androstan-3-one; androstenedione = androsta4-ene-3,17-dione; androstanedione In light of these results the defect of extrahepatic 5a- = 5a-androstane-3,17-dione; androsterone (A) = 3a-hy- reduction of testosterone observed in patients with droxy-5a-androstan-17-one; isoandrosterone = 3pi-hydroxy- 5a-androstan-17-one; 5f8-androsterone (5,8-A) = 3a-hydroxy- Part of this work has been published as a preliminary 5p-androstan-17-one; androstanediol (Adiol) = 5a-andro- communication (14). stane-3a,17fl-diol; Sp-androstanediol (5p-Adiol) = 5p-an- Received for publication 9 May 1969 and in revised form drostane-3a,17,B diol; androstanediols = diols = androstane- 22 August 1969. diol + 5,B-androstanediol. The Journal of Clinical Investigation Volume 49 1970 31 drogen in biological fluids. This is not the case in pa- sues of normal males and not in those of subjects with tients with testicular feminization syndrome in whom, feminizing testes. despite normal male testosterone secretion, the con- version of testosterone to androstanediols occurs at a METHODS very low rate (5, 7). Eight patients with testicular feminization syndrome were These clinical data are ascertained by the fact that investigated. There were seven postpubertal untreated cases labeled testosterone is not only taken up by accessory with the complete form of the syndrome. The symptoms are no axillary or pubic hair, no clitoris enlargement, and an XY sex tissues but is also quickly metabolized in these tis- karyotype. In addition a prepuberal 8 yr old subject (case sues, particularly to 17P-hydroxy-5a-androstane metabo- M. B.) was studied. lites (8, 9) which are known to be very potent andro- In six cases (five postpubertal cases and the prepuberal gens (10, 11). More recently, it has been reported that case), 1.0 /Ac of testosterone-4-"C (The Radiochemical Cen- tre, Amersham, specific activity (SA) 29.2 mc/mmole) was 17,8-hydroxy-5a-androstan-3-one (androstanolone) is the intravenously injected, and simultaneously, 10-12 Ac of tes- only metabolite present in the prostatic nuclei after in- tosterone-1,2-3H (Amersham, SA 1000 mc/mmole) were travenous administration of radiocative testosterone to orally administered. In the prepuberal case a combiped oral rats or after incubation of rat prostate with the same and intravenous dose of testosterone was also given after treatment with 1 mg of diethylstilbestrol daily for 10 days. precursor (12, 13). The presence of a highly tissue- The urine was collected for 3 days after the administration specific receptor for androstanolone in the prostatic nu- of labeled steroids. In three patients, 1.0 Asc of testosterone- clear chromatin indicates that this hydrogenated metabo- `C was injected, and simultaneously, 23-30 /Ac of testos- lite of testosterone might be an active form of androgen terone-3H dissolved in 100% ethanol were rubbed into the in the prostatic nuclei. skin as previously reported (14). The urine was collected over 3 days after the administration of tracers. All these Therefore, it was very important to determine whether experiments were done under the same experimental condi- the small conversion of circulating testosterone to uri- tions in normal males and females. In a postpubertal case nary androstanediols observed in patients with testicu- (J. Q.) an intravenous dose of testosterone-'4C was injected before and after castration. The first month was without lar feminization syndrome reflects an enzymatic im- hormonal treatment. After that, there was a daily injection pairment at the level of extrahepatic tissues. In this of 25 mg of testosterone propionate for 30 days and then an investigation data are presented which suggest that 5a- oral administration of 5 mg of diethylstilbestrol for 20 days. In addition, 0.5 gc of testosterone-j'C and 3.04.6 uc of hydrogenation of testosterone occurs in the target tis- testosterone-17a-8H, synthesized in the laboratory as previ- ously described (15), were injected into one patient with testicular feminization