Sex‐Dependent Differences in Derangements of Biliary‐Steroid‐Excretion Patterns Produced by Cyanoketone in Rats

Intramuscular injections of 25 mg/kg body weight of 2α cyano 4,4,17α trimethyl 5 androsten 17β ol 3 one (cyanoketone) produces an immediate cessation of excretion of practically all corticosteroid metabolites (3α,11β,15α,21 tetrahydroxy 5α pregnan 20 one and 3α and 3β,11β,21 trihydroxy 5α pregnan 20 one) in bile from female rats. Instead, large amounts of 3β hydroxy 5 pregnen 20 one, 3β,16α dihydroxy 5 pregnen 20 one and 5 pregnene 3β,20α diol are excreted. The total daily excretion of steroids in bile from treated female animals is 2580±580 μg compared to 850 μg in a female rat injected with solvent only. When ovariectomized rats are treated with cyanoketone, the principal biliary metabolites are 3β hydroxy 5 pregnen 20 one and 3β,16α dihydroxy 5 pregnen 20 one and the total daily excretion of steroids measured is 1186±197 μg indicating that ovaries contribute about 50% of the total output of 3β hydroxy Δ⁵ steroids in treated, intact female rats. As late as 28 days after a single injection of cyanoketone 3β hydroxy Δ⁵ steroids (44 μg/24 h) are excreted in bile and the total excretion of corticosteroid metabolites is still low (72 μg/24 h) at this time. 130 days after a single dose, no 3β hydroxy Δ⁵ steroids can be identified in bile but the total corticosteroid excretion is still less than 2 standard deviations below values of untreated intact animals (315 μg/24 h). Thus, in females cyanoketone has both an immediate enzyme inhibiting effect reflected by rapid onset of action after administration and, in addition, a longterm depressing action on enzyme biosynthesis manifested by low total steroid excretion values measured at least as long as 130 days after injection of inhibitor. Administration of cyanoketone to male rats gives rise to a small biliary excretion of 3β hydroxy Δ⁵ steroids (3β,16α dihydroxy 5 pregnen 20 one, 5 pregnene 3β,17α,20α triol and 5 pregnene 3β,20α diol) and a decrease in corticosteroid (mainly 3β,11β,21 trihydroxy 5α pregnan 20 one) excretion. Corticosteroid output reaches normal values about 24 h after injection of inhibitor. Testectomy eliminates biliary 3β hydroxy Δ⁵ steroids. These findings indicate that cyanoketone produces biliary 3β hydroxy Δ⁵ steroids mainly of testicular origin. Moreover, it appears that the 3β hydroxy Δ⁵ steroid oxidoreductase system in the adrenals and testes of the male rat is inhibited by cyanoketone considerably less efficiently and for a shorter duration than that in the adrenals and ovaries of the female.