Metabolism of 4-C14-Testosterone in Human Subjects. I. Distribution in Bile, Blood, Feces and Urine

Abstract

The metabolism of testosterone administered to human subjects was studied soon after the isolation and synthesis of the testicular steroid hormone. In 1939, Dorfman, Cook, and Hamilton (1) and Callow (2) almost simultaneously reported the isolation of androsterone and etiocholanolone in the urine of men receiving testosterone propionate. During the 1940's, Lieberman, Dobriner and their co-workers (3-5) published extensive studies on steroids in human urine related to the metabolism of testosterone. West and his colleagues (6, 7) not only studied the urinary metabolites following the intravenous administration of testosterone (in human serum albumin), but in addition reported studies on the clearance from blood of testosterone and its metabolites (17-ketosteroids). All of the investigations cited were performed following the administration of very large, and hence unphysiological, doses of testosterone.It was not until methods were developed for the synthesis of labelled testosterone that it became possible to study the metabolism of the hormone administered in physiological doses. Gallagher, Fukushima, Dobriner and their associates were the first to report observations on the metabolism of C14 and deuterium labelled testosterone (8-11). The amounts of testosterone administered by these investigators approximated, in most cases, the quantity of hormone calculated to be excreted by the testes. Fukushima, Dobriner, Gallagher, and Bradlow (10,11) reported that the preponderant part of the administered labelled testosterone ap peared in the urine with small amounts in the feces. The authors did not report on the radioactivity in blood.The biliary excretion of steroids in human subjects has not been studied extensively. Such studies are of importance in the elucidation of testosterone metabolism in man, since it has been

Studies on Phenolic Steroids in Human Subjects. II. The Metabolic Fate and Hepato-Biliary-Enteric Circulation of C14-Estrone and C14-Estradiol in Women1

“…Even though, in general, the importance of the biliary excretion of estrogens and their enterohepatic circulation had been accepted in the past to be true for animals, e.g., dogs, cows (6, 37), such has not been the case for human subjects. Our data demonstrate, however, that not only was more of the radioactivity of C4-estrone or C"-estradiol excreted in the bile than that seen following the injection of any other known steroid in human subjects (25,(28)(29)(30)38), but in addition more of the radioactivity appeared in the bile than in the urine of three of the bile-fistula subjects. This establishes the importance of biliary excretion in the metabolism of estrogens in women.…”

“…Radioactive estrone or estradiol was cleared from the plasma rapidly and at somewhat faster rates than the free steroid clearance following the administration of C"4-cortisol or Cl(-testosterone (25,29). In addition, there was no significant difference in the clearance of the free steroids among the various subjects studied.…”

“…Similar observations were made by Beer and Gallagher (17,18). Thus, following C14-labelled cortisol (27)(28)(29), testosterone (25,26), 1 1,8-hydroxyandrostenedione (31,36) or corticosterone (30) administration, over one-third of the radioactivity is excreted in the urine in the first four hours and over 60 to 70 per cent in the first 12 hours. On the other hand, following C14-estrone or C"-estradiol administration, only 12 per cent are excreted in the first four hours and about 33 per cent after 12 hours.…”

The in Vivo Glucuronide Conjugation of Radioactive Etiocholanolone and Androsterone by the Dog Kidney *

“…After conjugation, C1, glucuronides an(d sulfates are rapidly excreted by the kidneys (12)(13)(14)(15) …”

“…The rapid clearance of etiocholanolone and androsterone, after intravenous injection (12) and oral and intravenous administration of testosterone (13)(14)(15), suggests the possibility that these compounds may be conjugated by another organ besides the liver. The reports of Dutton (16), and Lipschitz and Bueding (17), that kidney slices synthesize glucuronide conjugates in vitro stimtulated an investigation to determine whether dog kidney could conjugate radioactive etiocholanolone and androsterone in 'vivo.…”