Effects of ketoconazole on ovulatory changes in the rat: implications on the role of a meiosis-activating sterol.
In-vitro studies on mouse oocytes have shown that human follicular fluid and bull testes contain an activity which partially overrides the inhibitory action of hypoxanthine on meiosis. This activity was ascribed to two closely related sterols, subsequently named meiosis-activating sterols (MAS). We have used a potent inhibitor of sterol synthesis, ketoconazole, in order to test in vivo and in vitro whether MAS play a necessary physiological role in the resumption of meiosis in the rat. When administered systemically, ketoconazole (8.3-16.6 mg/rat) suppressed ovulation by 40%. Local unilateral administration of the drug into the ovarian bursa (1.25 mg/bursa) resulted in 75% inhibition of ovulation in comparison with the contralateral ovary. All the ovulated ova in the oviduct were mature. Histological examination of the ketoconazole-treated ovaries revealed mature oocytes trapped in follicles which failed to ovulate. Furthermore, extraction of oocytes from the large follicles of such ovaries revealed that 79% of them were mature. Addition of ketoconazole (0.0001-0.01 mM) to the culture medium did not affect significantly the spontaneous maturation of rat oocytes. However, ketoconazole at a higher concentration (0.1 mM) caused the degeneration of oocytes. Ketoconazole (0.01 mM) did not affect luteinizing hormone (LH)-stimulated oocyte maturation in explanted preovulatory follicles, even though it inhibited follicular progesterone production to levels below the hormone-free control follicles. At higher levels, ketoconazole caused the degeneration of follicles and the enclosed oocytes. In conclusion, using a potent inhibitor of MAS we have failed to confirm the suggested obligatory role of MAS in the resumption of meiosis in the rat both in vivo and in vitro.
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
A
A
Tsafriri
M
M
Popliker
R
R
Nahum
Y
Y
Beyth
D000818:Animals; D002478:Cells, Cultured; D002775:Cholestadienols / Q000037:antagonists & inhibitors*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D007654:Ketoconazole / Q000494:pharmacology*; D007986:Luteinizing Hormone / Q000494:pharmacology; D008540:Meiosis / Q000187:drug effects*; D009865:Oocytes / Q000187:drug effects; D009866:Oogenesis / Q000187:drug effects; D009924:Organ Culture Techniques; D006080:Ovarian Follicle / Q000187:drug effects; D010053:Ovary / Q000187:drug effects; D010060:Ovulation / Q000187:drug effects*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D058886:Sterol 14-Demethylase
C114832:4,4-dimethyl-5alpha-cholest-8,14,24-trien-3-ol; C114833:4,4-dimethyl-5alpha-cholest-8,24-dien-3-ol; C548418:CYP51A1 protein, human; D002775:Cholestadienols; C548417:Cyp51 protein, rat; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011374:Progesterone; D007986:Luteinizing Hormone; D010088:Oxidoreductases; C548415:Cyp51 protein, mouse; D058886:Sterol 14-Demethylase; D007654:Ketoconazole