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 flu id and bull testes contain an activity which partially overrides the i nhibitory action of hypoxanthine on meiosis. This activity was ascribe d to two closely related sterols, subsequently named meiosis-activatin g 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) suppre ssed ovulation by 40%. Local unilateral administration of the drug int o the ovarian bursa (1.25 mg/bursa) resulted in 75% inhibition of ovul ation in comparison with the contralateral ovary. All the ovulated ova in the oviduct were mature. Histological examination of the ketoconaz ole-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. Addit ion of ketoconazole (0.0001-0.01 mM) to the culture medium did not aff ect significantly the spontaneous maturation of rat oocytes. However, ketoconazole at a higher concentration (0.1 mM) caused the degeneratio n of oocytes. Ketoconazole (0.01 mM) did not affect luteinizing hormon e (LH)-stimulated oocyte maturation in explanted preovulatory follicle s, even though it inhibited follicular progesterone production to leve ls below the hormone-free control follicles. At higher levels, ketocon azole caused the degeneration of follicles and the enclosed oocytes. I n conclusion, using a potent inhibitor of MAS we have failed to confir m the suggested obligatory role of MAS in the resumption of meiosis in the rat both in vivo and in vitro.