The phosphodiesterase 3 inhibitor ORG 9935 inhibits oocyte maturation during gonadotropin-stimulated ovarian cycles in rhesus macaques

Jeffrey Jensen, Mary Zelinski, Kristine M. Schwinof, Jessica E. Vance, Richard Stouffer

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 (B = 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.

Original languageEnglish (US)
Pages (from-to)68-73
Number of pages6
JournalContraception
Volume71
Issue number1
DOIs
StatePublished - Jan 2005

Fingerprint

Phosphodiesterase 3 Inhibitors
Menstrual Cycle
Macaca mulatta
Gonadotropins
Oocytes
Ovulation Induction
Meiosis
Chorionic Gonadotropin
Fertilization in Vitro
Contraceptive Agents
Primates
Haplorhini

Keywords

  • Contraception
  • Meiosis
  • Oocyte
  • Phosphodiesterase 3
  • Primate

ASJC Scopus subject areas

  • Medicine(all)
  • Obstetrics and Gynecology

Cite this

The phosphodiesterase 3 inhibitor ORG 9935 inhibits oocyte maturation during gonadotropin-stimulated ovarian cycles in rhesus macaques. / Jensen, Jeffrey; Zelinski, Mary; Schwinof, Kristine M.; Vance, Jessica E.; Stouffer, Richard.

In: Contraception, Vol. 71, No. 1, 01.2005, p. 68-73.

Research output: Contribution to journalArticle

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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 (B = 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.",
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