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Normal Human Adrenals * Journal of Clinical Investigation Vol. 44, No. 1, 1965 C.902 Steroids and Some of Their Precursors in Blood from Normal Human Adrenals * RALPH G. WIELAND, CONSTANCE DE COURCY, RICHARD P. LEVY, ANTONIA P. ZALA, AND H. HIRSCHMANN (From the Department of Medicine, Western Reserve University and University Hospitals, Cleveland, Ohio) The ready response of the main urinary 11- Methods deoxy- 17-ketosteroids to adrenal suppression and Patients. The subjects studied were five women (I.A., adrenal stimulation leaves no doubt that a con- M.R., C.B., M.M., and R.R.) and three men (J.J., L.W., siderable fraction of urinary androsterone (3a- and F.B.). Their ages and serial numbers are given in hydroxy-5a-androstan-17-one), 5,8-androsterone Table III. R.R. had hirsutism but normal ovulatory (3ca-hydroxy-5/8-androstan-17-one), and andros- menses and F.B. had diabetes. There was no other evi- dence of endocrinologic disease or hepatic dysfunction in tenolone (3,8-hydroxyandrost-5-en-17-one, dehy- any of these subjects. The patients fasted on the morn- droepiandrosterone) must be derived from adrenal ing of the procedure. Secobarbital (100 mg orally) was precursors. However, when adrenal vein blood given at 8 a.m., and 50 mg meperidine hydrochloride was was examined for such compounds, no consistent given subcutaneously just before the catheterization,' pattern emerged (3-9) ; therefore the identity of which was usually done between 10 a.m. and noon es- sentially in the manner performed by Cranston (5). the precursors remained in doubt. The presence The location of the catheter was ascertained by veno- of androstenedione (androst-4-ene-3,17-dione), gram. In most patients this produced sufficient pain to which was tentatively identified by Pincus and require additional meperidine. This was unnecessary Romanoff (3), was not confirmed by Lombardo, with L.W. and F.B., who had minimal discomfort. Blood and Hudson who examined 12 was collected after the iv injection of 100 mg of heparin. McMorris, (6), The adrenal blood sample (usually about 100 ml) was samples of human adrenal blood. In fact, these collected during a measured interval. This was followed investigators (6) obtained from only one indi- by the withdrawal of a similar volume of peripheral vidual a substance, androstenolone, that could be blood. Thereafter, corticotropin was administered to classed as an efficient precursor of the urinary R.R. and F.B., and a second sample was taken from the adrenal vein. In the case of R.R. this collection was be- 11-deoxy-17-ketosteroids. The scope of the in- gun 10 minutes after the completion of an iv infusion (11 vestigation widened when Baulieu (8) reported minutes) of 25 U of corticotropin and of F.B. 16 min- that in two instances, adrenal tumors secreted utes after the rapid injection of 40 U of corticotropin. but no free androstenolone. Radioactivity measurements. Radioactivity was de- androstenolone sulfate termined by scintillation counting with a two-channel The purpose of this communication is to document spectrometer. Free steroids were dissolved in 5 ml of and extend the findings of our preliminary re- scintillator solution (toluene containing 20 mg of 2,5- ports (1, 2) and to show that the normal human diphenyloxazole and 0.5 mg of 1,4-bis-2-(5-phenyloxa- zolyl)benzene), sulfates in 0.3 ml of methanol before 5 ml adrenal consistently secretes androstenolone sul- of the scintillator solution was added. When methanol fate, androstenolone, and androstenedione. These was present, corrections for the diminished efficiency of three compounds appear to be the principal pre- counting were determined by internal standards. cursors of the urinary 1 1-deoxy-17-ketosteroids. In calculating the isotope ratios C"2/HI,, we used the equation, C"2/H'L = [(N2/N1) - a] /[1 - (1/b) (N2/N1) ]. In this expression, the N values are the observed rates of * Submitted for publication July 13, 1964; accepted scintillation corrected for background; the subscripts 1 October 1, 1964. Supported by U. S. Public Health Service grant 1 A. more detailed description will be given elsewhere C-1679, a research fellowship under training grant by Levy and Katz. 2A-5293, and a research career award K6-AM-14,367. 2 Tricarb, Packard Instrument Co., La Grange, Ill. Preliminary accounts of some of our findings have Samples from Patients 1 to 5 were analyzed on a model been given (1, 2). 314 AX, the others on a model 314 EX. 159 160 WIELAND, DE COURCY, LEVY, ZALA, AND HIRSCHMANN TABLE I and 17-hydroxypregnenolone-7-H3 (3,8,17-dihydroxypregn- Test for radiochemical purity of 5-en-20-one) were the same preparations as we described androstenolone-7-H3 sulfate* before (9) and were generally used in the same amounts. They were periodically tested for purity by paper chro- Fraction Solvent Weight matography and scanning4 for radioactivity. Cortexo- lone-1,2-H' (17,21-dihydroxypregn-4-ene-3,20-dione) was mg cpm/lmole a commercial sample -that was purified by Girard sepa- Mother liquor 4.8 1,375 ration and chromatography on paper in system 1. An- Methanol Crystals 8.2 1,318 drostenediol-4-C"4 (androst-5-ene-3,3,17p8-diol) was pre- pared from commercial testosterone-4-C" by a procedure Mother liquor 0.8 1,347 essentially like the one subsequently published by Gut and 95%aO Ethanol Crystals 6.8 1,305 Uskokovic (13). The resulting androstenediol diace- tate melted at 161.5 to 1630 C; 5 the free diol melted at Sample solvolyzed 181 to 183° C and showed a single symmetrical peak when and recrystallized Methanol Crystals 0.3 1,391 chromatographed in system 7. Androstenolone-7-H3 sulfate 6 was prepared from the free steroid (1.9 Ag, 1.1 X * Nonradioactive androstenolone sulfate (13 mg) was 106 cpm N3) in 1 ml of chloroform with 50 mg of pyridine- added before recrystallization. Samples were assayed for sulfur trioxide according to the method of McKenna and radioactivity and for steroid content by the Zimmermann Norymberski (15). The product was converted to the reaction. potassium salt by treatment with aqueous potassium hy- and 2 refer to the two channels of the spectrometer. droxide. The solution was then washed with ether and The symbol C"2, therefore, signifies the number of disinte- extracted with n-butanol, which was washed with water grations of C" that are registered in channel 2 per unit and taken to dryness in vacuo. The product was chro- time. The efficiency ratios, a and b, equal the N2/N, matographed on paper in system 6. The radioactive zone ratios of reference samples that contain only a single that had the same Rr as a recrystallized unlabeled refer- isotope, H' or C", respectively. Spectrometer 2 model ence sample (mp, 219 to 2210 C, mp in reference 16, 219 314 AX was operated at settings that resulted in efficiency to 2230 C) was eluted and used as tracer [7,000 cpm N. ratios a 0.2 and b 5.1; model 314 EX gave a 0.05 (corrected) /sample]. Its purity was tested by dilution of a sample with cold carrier, recrystallization, and sol- and b _- 11.8. Color reactions and spectroscopy. The Zimmermann volysis (16) followed by recrystallization. The results are reaction was carried out essentially according to the shown in Table I. At its last use as tracer the prepara- modification described by Wilson (10). In Cases 1 to 5, tion was still in its conjugated state, since only 1%o of the Porter-Silber reaction was done on the neutral water- the radioactivity could be extracted from water with soluble ketonic plasma fraction as described (9); in the benzene. others, on 5-ml samples of plasma by the method of The preparations of acetic anhydride were commercial Peterson, Karrer, and Guerra (11). Infrared spectra samples that had been diluted with benzene. Unless noted were measured with a double beam spectrometer 3 with otherwise the one containing H' introduced about 250 cpm beam condenser on samples (ca. 17o) embedded in KBr HW, into 1 ms.mole of a monohydroxysteroid; the one disks (1.5 mm). with C", about 180 cpm C"2 into 1 mumole. Precise Chromatography. Systems for chromatographic sepa- counts were determined by acetylation of reference com- rations were prepared from mixtures of the following pounds of known weight that contained the same amounts solvents in the volume ratios specified: 1) toluene, iso- of steroid tracer as the unknowns. These reference ace- 6ctane, n-heptane, methanol, and water, 10: 5: 5:16: 4; tates were prepared at the same time and purified in the 2) iso6ctene, methanol, and water, 5: 4: 1; 3) benzene, same manner as the acetates from blood. The amount of iso6ctane, methanol, and water, 10: 20: 12: 3; 4) ligroin, steroid in the test sample (s ,ug) was calculated by the methanol, and water, 10: 9:1; 5) isopropyl ether, t-bu- following equation, s = t [ (H31/C"2)unk. ( C142/H31) ref. tanol, and 2.8% aqueous ammonia, 3: 2: 5; 6) toluene, - 1], when t ,ug of a C"4-labeled steroid tracer had been n-butanol, and 2.8% aqueous ammonia, 1: 1: 2; and 7) added to the plasma or plasma fraction. The subscripts toluene, iso6ctane, methanol, and water, 15: 5: 16: 4. unk. and ref. relate to the tritiated acetates from blood We have previously described solvent systems 1 to 4 (9); and from the pure steroid tracer, respectively. When Schneider and Lewbart (12) described systems 5 and 6 tritiated steroid tracers of negligible weight were used, for the fractionation of steroid sulfates.
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