Hormonal effects of ketoconazole in vivo in the male rat: Mechanism of action

Shalender Bhasin, S. Sikka, T. Fielder, U. Sod-Moriah, H. B. Levine, R. S. Swerdloff, J. Rajfer

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Ketoconazole, an antifungal agent, has been shown to lower serum testosterone (T) in man. Measurements of circulating precursors of T suggest that ketoconazole may inhibit 17,20-desmolase activity in the testis. To further elucidate its mechanism of action in vivo, we studied its effects on the pituitary-gonadal axis in the male rate. Two groups of normal male Sprague-Dawley rats were treated with either oil or 25 mg ketoconazole in oil by im injection every 8 h for 21 days. Serum ketoconazole concentrations in the rat 2 h after the 25-mg dose were similar to those after oral administration of a much lower (l/33rd) dose to man. Ketoconazole treatment led to 50% suppression of serum T and prostate and seminal vesicle weights. Testis weights were not significantly affected. Intratesticular T concentrations showed a 50% decrease below the control level. Testicular 17α-hydroxylase, 17,20-desmolase, and 17β-hydroxysteroid dehydrogenase activities in the ketoconazole-treated animals were significantly decreased in proportion to the decreases in serum and intratesticular T concentrations. Elevations of serum LH and FSH concentrations in the ketoconazole-treated rats were not proportionate to the decline in serum T concentration. Therefore, to exclude an additional inhibitory effect of ketoconazole at the pituitary level, we treated two groups of castrated male Sprague-Dawley rats with the same dose of ketoconazole or oil for 3 days. Serum LH and FSH concentrations were not significantly different in the two groups. In separate experiments, combined treatment of intact rats with GnRH agonist and ketoconazole for 21 days led to lower mean serum T concentrations and accessory organ weights than those achieved with either agent alone. We conclude that 1) ketoconazole inhibits T synthesis, primarily by inhibiting the activity of multiple enzymes in the T biosynthetic pathway and has no direct effect at the pituitary level; 2) ketoconazole metabolism in the rat is considerably different from that in man; and 3) ketoconazole enhances the inhibitory effects of GnRH agonist.

Original languageEnglish
Pages (from-to)1229-1232
Number of pages4
Issue number3
StatePublished - 1 Jan 1986
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology


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