Origin of plasma androstanediol glucuronide in men.

The role of testosterone (T) and dihydrotestosterone (DHT) as precursors of the peripheral metabolite androstanediol glucuronide (3 alpha diol G) in plasma from normal men was studied. An apparent steady state of both putative precursors and the steroid glucuronides were attained by 8-h constant iv infusions of 3H-labeled steroid after a loading dose. The unconjugated steroids and the steroid glucuronides (after beta-glucuronidase hydrolysis) with 14C indicator were purified by serial microcolumn and paper chromatography steps previously reported to achieve radiochemical purity. The specific activities of 3 alpha diol and 3 alpha diol G in plasma were widely different in each subject, confirming our earlier suggestion that the two peripheral metabolites are formed in different pools. The conversion ratios (CRPre-Prod BB) varied widely. The CRT-3 alpha diol G was generally less than 5%, while the CRDHT-3 alpha diol G was 10 times higher. These results are compatible with the expected model, T----DHT----3 alpha diol G. In some of the studies, T glucuronide (TG) and DHT glucuronide (DHTG) were isolated after T infusions, and DHTG was isolated after DHT infusion. The major conversion product of blood T was DHTG, not TG, and the major conversion product of DHT was 3 alpha diol G. This suggests that metabolism proceeds through a steroid reduction step and glucuronidation. The peripheral pathway to 3 alpha diol G may involve formation of DHTG and then 3 alpha-reduction to 3 alpha diol G. This may also explain why blood levels of unconjugated 3 alpha diol have not been helpful in elucidating disorders of androgen formation, as this androgen mostly arises from sites different from 3 alpha diol G.