1. The phosphodiesterase 3 inhibitor ORG 9935 inhibits oocyte maturation during gonadotropin-stimulated ovarian cycles in rhesus macaques.
- Author
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Jensen JT, Zelinski-Wooten MB, Schwinof KM, Vance JE, and Stouffer RL
- Subjects
- Animals, Cyclic Nucleotide Phosphodiesterases, Type 3, Female, Gonadotropins physiology, Macaca mulatta, Menstrual Cycle drug effects, Menstrual Cycle physiology, Oocytes cytology, Oocytes growth & development, 3',5'-Cyclic-AMP Phosphodiesterases antagonists & inhibitors, Meiosis drug effects, Oocytes drug effects, Thiophenes pharmacology
- Abstract
To determine whether phosphodiesterase (PDE) 3 inhibitors prevent the resumption of meiosis by primate oocytes in vivo, rhesus macaques were stimulated to develop multiple preovulatory follicles by administering human recombinant gonadotropins, and follicles were aspirated 34 h after an ovulatory stimulus (human chorionic gonadotropin [hCG]). Monkeys received no further treatment (controls) or the PDE3 inhibitor ORG 9935 (a) exclusively in the periovulatory interval beginning 6-12 h prior to receiving hCG at 200 mg/kg every 12 h orally (PER200) or a 200 mg/kg oral loading dose followed by 50 mg/kg sc every 6 h (PER50) or (b) throughout the ovarian stimulation protocol with daily increases until a dose of 200 mg/kg bid was administered onward from the eighth day of ovarian stimulation (EXT200). The primary outcome was the number of oocytes that had resumed meiosis (germinal vesicle breakdown [GVBD]) at collection. At initial aspiration, 85% of oocytes recovered from control animals (n = 4) had progressed to GVBD compared with 53% (p<.01), 23% (p<.01), and 13% (p<.01) recovered from animals in the PER200 (n = 2), PER50 (n = 1) and EXT200 (n = 3) groups, respectively. Although spontaneous maturation of oocytes was observed during follow-up culture in the absence of ORG 9935, none of the oocytes in the PER50 or EXT200 underwent normal fertilization in vitro. These results demonstrate that the PDE3 inhibitor ORG 9935 blocks oocyte maturation during gonadotropin-stimulated ovarian cycles in rhesus macaques and suggest that PDE3 inhibitors have potential clinical use as contraceptives in women.
- Published
- 2005
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