No abstract

Administration spironolactone at a dosage of 400 mg/day to healthy male volunteers for 5 days resulted in a significant rise in plasma progesterone and 17alpha-hydroxyprogesterone which persisted throughout the study. A transient increase in plasma FSH and LH concentration was observed after the second but not the third or fifth days of drug administration. There was no change in plasma concentration of testosterone, 17beta-estradiol, or prolactin. These findings are consistent with a previously-reported spironolactone-induced destruction of the microsomal enzyme cytochrome P-450, an enzyme necessary for 17-hydroxylase and desmolase activity. The results do not explain the decrease of libido, the impotence, and the gynecomastia frequently associated with spironolactone therapy in males.

The daily administration of spironolactone caused a 40-90% decrease in the level of microsomal cytochrome P-450 in the testes of rat, guinea pig, rabbit, mouse and dog, but no reduction was detected in the amount of cytochrome b 5 . The loss of microsomal cytochrome P-450 was concomitant with a similar loss of both the microsomal heme associated with cytochrome P-450 and the activity of the microsomal 17a-hydroxylase. In contrast to its effects on the 17a-hydroxylase, spironolactone administration slightly increased the enzyme activity of the microsomal 17/3-dehydrogenase. The extent of the destruction of cytochrome P-450 by spironolactone was dependent upon the dose given and upon the duration of the treatment.The decline in androgen formation in the testis resulted in a 30-35% decrease in the activity of hepatic 3,4-benzpyrene hydroxylase in the rat, but an 80% increase in the guinea pig. The decrease in the 3,4-benzpyrene hydroxylase activity in the rat could be prevented by the administration of androgens, such as 17-methyltestosterone. In contrast to the decline in 3,4-benzpyrene hydroxylase activity in the male rat, spironolactone administration enhanced the activity of both ethylmorphine N-demethylase and NADPH cytochrome c reductase in the liver of the male rat and guinea pig. Other steroids such as progesterone and testosterone, given at a dose similar to that of spironolactone, also lowered the content of cytochrome P-450 in the testis. However, in contrast to the rapid destruction of cytochrome P-450 by spironolactone, the decrease in the level of cytochrome P-450 by testosterone or progesterone is probably caused by a decline in the level of LH resulting from a steroidfeedback inhibition on the release of LH from the pituitary gland. (Endocrinology 94: 1628(Endocrinology 94: , 1974 V ARIOUS steroids including spironolgjetone have been reported by Selye (1) to protect rats against the toxic effects of a number of foreign compounds such as drugs, carcinogens, and insecticides. Subsequent studies have revealed that the protective action of these steroids is associated with an increased clearance of the toxicants from the blood rather than an increased tolerance to the toxicant (2). Moreover, Solymoss et al. (3), Feller and Gerald (4), and Stripp et al. (5) have demonstrated that the mode of protection afforded by spironolactone results from the stimulation of drug metabolism by the mixed function oxidases in liver.