When chlormadinone acetate, an anti-androgenic agent, is administered to rats and humans, a significant fall in plasma testosterone levels is demonstrated during the treatment. In connection with the decrease of plasma testosterone the biosynthesis of testosterone in the testes and metabolism of testosterone in the liver was investigated in rats treated with chlormadinone acetate. When 100 mg/kg of chlormadinone acetate were administered to rats for 3 and 5 weeks, conversion ratios of testosterone to 5α-dihydrotestosterone and 5a-androstandediol in the liver were 2-3.5 fold greater than the control. While, under similar conditions hydroxylation of testosterone (2α-, 6β-, 16α-hydroxylation) decreased to the extent of 50% of the control. Further, the 5α-reductase activity rose to about 3 fold by the treatment of estradiol 3-benzoate (0.4 mg/kg) for 5 weeks. On the other hand, no effects of chlormadinone acetate on hepatic 5α-reduction and hydroxylation of testosterone were observed by the removal of pituitary gland. These findings indicated an essential role of the pituitary gland in androgenic control of hepatic enzyme.
While, the homogenate of testes from rats treated with chlormadinone acetate for different periods was incubated with progesterone-4-14C and cholesterol-4-14C, and assayed for conversion rate of the substrates to testosterone. Biosynthesis of testosterone from cholesterol-4-14C in rat testes treated with chlormadinone acetate for 4 weeks showed a marked inhibition depending on the dose of chlormadinone acetate, varying from 40% to 50% with 20 mg/kg to 100 mg/kg of chlormadinone acetate. While the conversion rate of progesterone-4-14 C to testosterone was inhibited to the extent of 16% by chlormadinone acetate treatment (100 mg/kg) for 4 weeks, no effects with 20 mg/kg of chlormadinone acetate and 3β-hydroxy chlormadinone acetate, one of the main metabolites in human and rat.
It is possible that reduction of plasma testosterone levels observed during chlormadinone acetate treatment is ascribed to suppression of biosynthesis of testosterone in the testes and to stimulation of the metabolism in the liver.
