Phosphodiesterase 3 (PDE3) inhibition with cilostazol does not block in vivo oocyte maturation in rhesus macaques (Macaca mulatta)

Carol Hanna, Shan Yao, Cathy M. Ramsey, Jon Hennebold, Mary Zelinski, Jeffrey Jensen

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Objective: Studies in mice suggest that cilostazol, an FDA-approved phosphodiesterase 3 (PDE3) inhibitor, might have a contraceptive effect within the approved dose range. We sought to evaluate the potential contraceptive effects of cilostazol in a nonhuman primate model. Study design: Adult female rhesus macaques were stimulated to develop multiple preovulatory follicles by administering human recombinant gonadotropins, and oocytes were collected by follicle aspiration 36 h after an ovulatory stimulus (human chorionic gonadotropin). Monkeys received no further treatment (controls) or the PDE3 inhibitor cilostazol at the maximum approved human dose of 100 mg twice daily starting 6 days prior to follicle aspiration. Recovered oocytes were scored for meiotic stage [germinal vesicle (GV) intact, GV breakdown], and metaphase II stage oocytes were fertilized in vitro and observed for normal embryo development. Results: Similar proportions of GV stage oocytes were recovered from control (27% ± 4%) and cilostazol (27% ± 9%)-treated females, and the proportion of embryos that developed into blastocysts was also similar for both groups (7% ± 5% control vs. 15% ± 8% cilostazol). Conclusion: Oral dosing of cilostazol tablets during controlled ovarian stimulation protocols did not prevent oocyte maturation or embryo development in macaques. Implications: Since administration of the maximum approved human dose of cilostazol (an FDA-approved PDE3 inhibitor) to macaques did not prevent oocyte maturation or fertilization, it is not likely that this dose would be contraceptive in women.

Original languageEnglish (US)
Pages (from-to)418-422
Number of pages5
JournalContraception
Volume91
Issue number5
DOIs
StatePublished - May 1 2015

Fingerprint

Phosphoric Diester Hydrolases
Macaca mulatta
Oocytes
Phosphodiesterase 3 Inhibitors
Contraceptive Agents
Macaca
Embryonic Development
Ovulation Induction
Blastocyst
Chorionic Gonadotropin
Metaphase
cilostazol
Gonadotropins
Fertilization
Primates
Tablets
Haplorhini
Embryonic Structures

Keywords

  • cAMP
  • Germinal vesicle
  • Meiosis
  • Nonhormonal contraception
  • Nonhuman primate

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology

Cite this

Phosphodiesterase 3 (PDE3) inhibition with cilostazol does not block in vivo oocyte maturation in rhesus macaques (Macaca mulatta). / Hanna, Carol; Yao, Shan; Ramsey, Cathy M.; Hennebold, Jon; Zelinski, Mary; Jensen, Jeffrey.

In: Contraception, Vol. 91, No. 5, 01.05.2015, p. 418-422.

Research output: Contribution to journalArticle

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title = "Phosphodiesterase 3 (PDE3) inhibition with cilostazol does not block in vivo oocyte maturation in rhesus macaques (Macaca mulatta)",
abstract = "Objective: Studies in mice suggest that cilostazol, an FDA-approved phosphodiesterase 3 (PDE3) inhibitor, might have a contraceptive effect within the approved dose range. We sought to evaluate the potential contraceptive effects of cilostazol in a nonhuman primate model. Study design: Adult female rhesus macaques were stimulated to develop multiple preovulatory follicles by administering human recombinant gonadotropins, and oocytes were collected by follicle aspiration 36 h after an ovulatory stimulus (human chorionic gonadotropin). Monkeys received no further treatment (controls) or the PDE3 inhibitor cilostazol at the maximum approved human dose of 100 mg twice daily starting 6 days prior to follicle aspiration. Recovered oocytes were scored for meiotic stage [germinal vesicle (GV) intact, GV breakdown], and metaphase II stage oocytes were fertilized in vitro and observed for normal embryo development. Results: Similar proportions of GV stage oocytes were recovered from control (27{\%} ± 4{\%}) and cilostazol (27{\%} ± 9{\%})-treated females, and the proportion of embryos that developed into blastocysts was also similar for both groups (7{\%} ± 5{\%} control vs. 15{\%} ± 8{\%} cilostazol). Conclusion: Oral dosing of cilostazol tablets during controlled ovarian stimulation protocols did not prevent oocyte maturation or embryo development in macaques. Implications: Since administration of the maximum approved human dose of cilostazol (an FDA-approved PDE3 inhibitor) to macaques did not prevent oocyte maturation or fertilization, it is not likely that this dose would be contraceptive in women.",
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