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The effects of hydroxyflutamide on action and production of androgens in rats induced to superovulate Yu, Frank Hong
In two experiments, immature female Sprague-Dawley rats treated with superovulatory doses of pregnant mare serum gonadotropin (PMSG) were used to study the effects of antiandrogen, hydroxyflutamide, on steroid production, particularly the biologically active androgens, testosterone, 5α-dihydrotestosterone, and androstenedione. In the first experiment, the animals were given either 5 mg hydroxyflutamide or vehicle alone at 30 and 36 h following 40 IU PMSG. Compared to the vehicle group, hydroxyflutamide treatment significantly reduced the percentage of degenerate oocytes recovered from oviducts (p<0.05). Serum levels of aromatizable androgens, testosterone and androstenedione, and their aromatized product, estradiol-17ß significantly decreased (p<0.05) in hydroxyflutamide-treated group; however, the serum concentrations of nonaromatizable androgen, 5α-dihydrotestosterone, was not statistically different between the two groups. In the second experiment, ovaries stimulated with 4 or 40 IU PMSG were obtained 48 h later and cultured in the presence and absence of hydroxyflutamide (10⁻⁵M) and/or testosterone (10⁻⁷ M) to study [4⁻¹⁴C] pregnenolone metabolism to major steroids. In 40 IU stimulated ovaries, hydroxyflutamide significantly decreased the metabolism of pregnenolone to progesterone (p<0.01) and androstenedione (p<0.01) while the production of estradiol-17ß increased significantly (p<0.05); however, pregnenolone conversions to testosterone and 5α-dihydrotestosterone were not statistically different between the untreated and hydroxyflutamide-treated cultures. Testosterone completely reversed the hydroxyflutamide-induced alteration of pregnenolone metabolism. In contrast, there was no difference in the pregnenolone conversion patterns between the untreated and hydroxyflutamide or hydroxyflutamide plus testosterone groups in the culture of ovaries stimulated with 4 IU PMSG. Present results confirm previous reports that antiandrogen, hydroxyflutamide, decreases the percentage of abnormal oocytes recovered from superovulating rats, and indicates that this hydroxyflutamide effect may be partly mediated by altered ovarian steroidogenesis, specifically the reduced hypersecretion of aromatizable androgens, testosterone and androstenedione, and/or estradiol-17ß.
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