Neuroendocrinological effects of ketoconazole in rats

Abstract

The effect of ketoconazole on steroid synthesis was studied in intact (sham-operated) and castrated male and ovariectomized female rats. Rats were given 25 mg/kg ketoconazole twice a day im for 5 days. The influence of ketoconazole was also investigated on hormone release altered by GnRH, estradiol and haloperidol. The following hormones were measured: serum LH, PRL, testosterone, corticosterone, 17-OH-progesterone, estradiol, and dopamine content of the tubero-infundibular area. Ketoconazole treatment resulted in a significant decrease of testerone level (from 7.93 \m=+-\1.99 to 3.83 \m=+-\0.94 nmol/l), whereas LH, PRL, corticosterone and 17-OH\x=req-\ progesterone remained unchanged in the male rat. The effect of castration on LH level was reduced by ketoconazole in male (from 590 \m=+-\35 to 390 \m=+-\25 \g=m\g/l ) and female rats (from 468 \m=+-\22 to 346 \m=+-\39 \g=m\g/l ), but the GnRH-stimulated LH release in castrated and ovariectomized animals was unchanged. The suppressive action of estradiol on LH in ovariectomized rats was enhanced (from 160 \ m=+-\41 to 64.6 \m=+-\12.9 \g=m\g/l ),and its priming effect on PRL release was diminished by ketoconazole (from 598 \ m=+-\ 81 to 281 \ m=+-\ 66 \g=m\g/l ). Ketoconazole failed to modify the tubero-infundibular dopamine content and haloperidol-induced PRL release. It can be assumed that in addition to its inhibitory role of steroid biosynthesis ketoconazole has an influence on central mechanisms underlying LH and PRL release. Ketoconazole (KZ) is an äntifungal agent with a marked effect on steroidogenesis in humans and in animals, inhibiting the enzyme activity of the cho¬ lesterol side-chain cleavage enzyme, 17-hydroxylase, 11-hydroxylase, and mostly the 17-20-desmolase activity (1-6). Schurmeyer & Nieschlag (7) suggested that a phenylated side chain of the imidazole molecule is responsible for the inhibition of testosterone biosynthesis. Some data show that the substance is able to reduce ovarian aromatase ac¬ tivity in the rat (8,9). Basal aldosterone and cortisol levels are not necessarily altered by KZ, presumably because the inhibitory process is partial, and can be unequivocally demonstrated when the synthesis of these steroids is stimulated (10-13). The androgen steroid production is more sensitive to KZ suppres¬ sion, and with long-term treatment a 50 per cent decrease of testosterone level can be achieved (14,15). According to Santen et al. (16) and Bhasin et al. (17) the low serum testosterone concentrations were not accompanied by the expected rate of in¬ crease in LH and FSH release. It was assumed that KZ might have a direct effect at the pituitary level, but this has not been confirmed on castrated male rats (17). The present work was devoted to studying the actions of KZ on hypothalamic and pituitary mech¬ anisms in the rats, and to investigating the suppressive effect of the drug on the stimulated LH release in vivo. Materials and MethodsAnimals and treatment protocol Adult male and regularly cycling female rats of the Wistar strain were used....

Effect of Fluconazole on the Fertility of Male Rabbits

“…This could be a plausible explanation for the decline in serum testosterone level encountered in animal species used in the present study. Similar findings have been reported by other investigators [21]. Furthermore, it was claimed that the drug displaces testosterone from its binding globulin to allow for its rapid metabolism [22].…”

Immunohistochemical localization and biological activity of the steroidogenic enzyme cytochrome P450 17α‐hydroxylase/C17, 20‐lyase (P450C17) in the frog brain and pituitary

“…In the rat brain and in glial tumour cells, the involvement of P450 C17 in the formation of DHEA is still a matter of debate (Prasad et al 1994;Cascio et al 1998Cascio et al , 2000. Here, we show that ketoconazole, a P450 C17 inhibitor (Irsy and Koranyi 1990) reduced in a concentration-dependent manner the biosynthesis of 17OH-D 5 P, 17OH-P, DHEA and D 4 . These Fig.…”

“…1998, 2000). Here, we show that ketoconazole, a P450 C17 inhibitor (Irsy and Koranyi 1990) reduced in a concentration‐dependent manner the biosynthesis of 17OH‐Δ 5 P, 17OH‐P, DHEA and Δ 4 . These results indicate that the P450 C17 ‐immunoreactive material detected in the frog brain and pituitary actually corresponds to an active form of the enzyme, that possesses both 17α‐hydroxylase and C17, 20‐lyase activities.…”

Effects of ketoconazole on the acquisition of intravenous cocaine self-administration under different feeding conditions in rats

“…This study also showed that ketoconazole had no effect on baseline levels of cortisol in humans. Furthermore, ketoconazole has been found to have no effect on plasma corticosterone in ad libitum fed rats (Irsy and Koranyi 1990). In a recent study of the effects of ketoconazole on i.v.…”