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Testosterone and Dihydrotestosterone in Normal Subjects, During Pregnancy, and in Hyperthyroidism

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Testosterone and Dihydrotestosterone in Normal Subjects, During Pregnancy, and in Hyperthyroidism Metabolic Clearance Rate and Blood Production Rate of Testosterone and Dihydrotestosterone in Normal Subjects, during Pregnancy, and in Hyperthyroidism J. M. SAEz, M. G. FOREST, A. M. MoRErm, and J. BRnTND From the Unite' de Recherches Endocriniennes et Metaboliques chez l'Enfant (Institut National de la Sante et de la Recherche Medicale), H6pital Debrousse, Lyon 5', France A B S T R A C T The metabolic clearance rate (MCR) and (an adult with hyperthyroidism and two children) these blood production rate (BP) of testosterone (T) and dihy- two MCRs were greatly reduced compared to the normal drotestosterone (DHT), the conversion of plasma testos- females, but the conversion of testosterone into dihy- terone to plasma dihydrotestosterone, and the renal clear- drotestosterone was in the limits of normal male range ance of androstenedione, testosterone, and dihydrotestos- In the normal subjects the renal clearance of andros- terone have been studied in man. In eight normal men, the tenedione was greater than that of testosterone and di- MCRT (516±108 [SD] liters/m/day) was significantly hydrotestosterone. Less than 20% of the dihydrotestos- greater than the MCRDIT (391±71 [SD] liters/m'/day). terone and less than 10% of the androstenedione in the In seven females, the MCRT (304±53 [SD] liters/m'/day) urine is derived from the plasma dihydrotestosterone and was also greater than the MCRDET (209±45 [SD] liters/ androstenedione. m2/day) and both values were less than their respective values in men (P <0.001). In men the conversion of testosterone into dihydrotestosterone at 2.8±0.3% (SD) INTRODUCTION was greater than that found in females, 1.56±0.5% (SD) During the past few years increased attention has been (P < 0.001). In five pregnant females the MCRT (192± focused on dihydrotestosterone (DHT)1 as the result 36 [SD] liters/m/day), the MCRDHT (89±30 [SD] liters/ of the discovery that testosterone (T) is converted m'/day) and the conversion of testosterone into dihydro- mainly into dihydrotestosterone at the site of its target testosterone (0.72±0.15%) (SD) were significantly less tissues (1-2) and the fact that part of the biological than the values found in nonpregnant women. In five actions of testosterone could be produced by dihydro- females with hyperthyroidism, the MCR for testosterone testosterone (3). More recently, it has been shown that and dihydrotestosterone were similar to those observed the plasma concentration of dihydrotestosterone is higher in pregnant females, but the conversion of testosterone in males than in females, and in both sexes its concen- into dihydrotestosterone (2.78±1.7%) (SD) was greater, tration is far lower than testosterone (4-6). At present and similar to that found in men. In men the production our knowledge of production, origin and metabolism of of dihydrotestosterone was 0.39±0.1 (SD) mg/day, 50% dihydrotestosterone is small. being derived from the transformation of plasma testos- This paper presents a study of the metabolic clearance terone. In women the production of DHT was 0.05± rate (MCR) of dihydrotestosterone, the conversion of 0.028 (SD) mg/day, only 10% coming from testosterone. testosterone into dihydrotestosterone, and the production During pregnancy, the production of testosterone and 1 Trivial names and abbreviations used in this paper: an- dihydrotestosterone are similar to that in normal women. drostenedione (A), 4-androstene-3,17-dione; BP, blood pro- In three patients with testicular feminization syndrome duction rate; dehydroepiandrosterone (DHA), 3 85-hydroxy- 5-androstene-17-one; dihydrotestosterone (DHT), 5 a-an- A preliminary report of this work was presented at the drostan-17 fi-ol-3-one; MCR, metabolic clearance rate; 52nd Meeting of the Endocrine Society, June 1970. TeBG, testosterone-estradiol binding protein; testosterone Received for publication 24 August 1971 and in revised (T), 17 fi-hydroxy-4-androstene-3-one; TLC, thin-layer form 20 December 1971. chromatography. 1226 The journal of Clinical Investigation Volume 51 1972 of dihydrotestosterone in normal subjects and during (E) Silica gel TLC: hexane: acetone (200: 35). pregnancy. The majority of these parameters were also Gas-liquid chromatography was performed with an F. & measured in five women with hyperthyroidism and in M. apparatus model 402 (Hewlett-Packard Co., Avondale Div., Avondale, Pa.) using 2% SE-30 packing (Applied three cases of testicular feminization syndrome. The renal Science Laboratories Inc., State College, Pa.) and an ion- clearances of androstenedione, testosterone, and dihydro- ization flame detector. testosterone were measured in normal subjects of both Radioactivity on paper and thin-layer plates was detected sexes. by scanning with a windowless flow counter (Packard radiochromatogram scanner, model 7200; Packard Instru- METHODS ment Co., Inc., Downers Grove, Ill.). The radioactivity was Subjects measured in a Packard Tri-Carb liquid scintillation spec- trometer, model 3003, at a tritium and carbon-14 efficiencies 15 normal persons, eight men (subjects 1-8) and seven of 38% and 60%, respectively. 16% of the 14C was counted women (subjects 9-15), aged 22-36 yr were studied. Five in the tritium channel. women were studied during the first trimester of pregnancy (8-11 wk) on the day of a therapeutic abortion for medico- Plasma concentration of nonradioactive testoster- social reasons (subjects 16-20). Five females with hyper- one and dihydrotestosterone thyroidism (subjects 21-25) were studied before giving any treatment. Three patients with a testicular feminization The concentration of these steroids was measured by the syndrome were studied. The first (subject 26), was 60 yr double isotopic dilution method (6-8). old and had developed hyperthyroidism 10 months previ- Infusions. In all subjects but pregnant women the studies ously. The other two were children aged 4 and 1 yr; one were commenced between 8 and 9 a.m. The subject had been of them (subject 28) had been studied under basal condi- lying down for 40-60 min before commencing the test. A tions (first study) and 15 days after treatment with di- blood sample was taken to measure the plasma testosterone ethylstilbestrol, 2.5 mg/day. and dihydrotestosterone concentration. The priming dose (about a quarter of the total dose of each isotope) was Steroids then injected. 20 min later, an i.v. infusion of testosterone- 4C and dihydrotestosterone-8H was continued and run at a Testosterone-4-14C (SA 50 mCi/mmole), dihydrotestos- constant rate for 220 min. 30-40 ml samples of blood were terone-4-14C (SA 50 mCi/mmole), androstenedione-1,2-8H taken at 130, 160, 190, and 220 min after starting the in- (SA 42 Ci/mmole) (A), and dihydrotestosterone-1,2-8H fusion. The subject voided urine 120 min after starting the (SA 30 Ci/mmole) were obtained from CEA Saclay, infusion and once again at the end of the infusion. The France. All these compounds were purified by paper chro- urine formed between the 120th and 220th min was collected. matography using systemA (seebelow) before each infusion. In the pregnant women, the infusion was commenced be- With the exception of the dihydrotestosterone-1,2-3H, the tween 5 and 6 a.m. The duration of the infusion varied purity was over 98%. The first lot (No. 568-569) of the between 210 and 310 min. Blood samples were taken at dihydrotestosterone was more than 98% pure after paper various times after start of infusion: subject 16 at 150, 210, chromatography and was verified by recrystallization. A 280, and 310 min; subject 17 at 160, 180, 200, and 210 min; second lot of this compound (No. 568-270) appeared to be subject 18 at 140, 160, 180, and 210 min; subject 19 at more than 98% pure after chromatography in the system 160, 190, 230, and 260 min; subject 20 at 140, 160, 180, and A, as the scanning of the paper after chromatography only 210 min. demonstrated a single radioactive peak with the same Rf In three normal males in addition to the infusion of as nonradioactive dihydrotestosterone. However, after study- testosterone-Y4C and dihydrotestosterone--H another study ing the MCR in five subjects (three men and two women) comprising testosterone-m4C and androstenedione-8H was and obtaining results far higher than those found previ- made a few days later. The protocol of this second study ously, the purity of this compound was examined by re- was identical to the first. crystallization and was found to be only 60%.' Subsequently, dihydrotestosterone-1,2-8H was always purified by chroma- Analyses of the plasma. 200 ,ug of testosterone, andro- in stenedione, and dihydrotestosterone were added to each tography the systems A and B, and the purity verified sample of plasma. The plasma was extracted three times by recrystallization was over 98%. with 2 vol of ether. The extracts were then chromato- graphed in the A system. Testosterone and androstenedione Chromatographic systems (dihydrotestosterone had the same Rf as androstenedione in The following systems were used: this system) were located using a 254 nm ultraviolet light (A) Paper chromatography: hexane: methanol: water and eluted separately. The dried extracts containing tes- (100:90: 10). tosterone and the complex androstenedione + dihydrotes- (B) Alumina thin-layer chromatography (TLC): ben- tosterone were rechromatographed in the B system for 2 zene: ethyl acetate (60: 40). hr. In this system, dihydrotestosterone is well separated (C) Silica gel TLC: chloroform: ethanol (98: 2). from androstenedione and etiocholanolone. The testosterone, (D) Silica gel TLC: benzene: dichloromethane: meth- dihydrotestosterone, and androstenedione spots were eluted anol (150: 150: 6). separately and the solvent evaporated. The sample contain- ing androstenedione was dissolved in a mixture of pyridine: A summary of the results obtained with the second lot acetic anhydride (1: 1) and kept at room temperature over- of impure dihydrotestosterone-1,2-8H has been published night.
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