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.
  
  
  METHODS
  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 100mg 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).
  
  
  CONCLUSIONS
  Oral dosing of cilostazol tablets during controlled ovarian stimulation protocols did not prevent oocyte maturation or embryo development in macaques.
  
  
  CONCLUSIONS
  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.
authors: Division of Reproductive and Developmental Science, Oregon National Primate Research Center, Beaverton, OR 97006, USA.
authors: Carol B
authors: CB
authors: Hanna
authors: Division of Reproductive and Developmental Science, Oregon National Primate Research Center, Beaverton, OR 97006, USA.
authors: Shan
authors: S
authors: Yao
authors: Division of Reproductive and Developmental Science, Oregon National Primate Research Center, Beaverton, OR 97006, USA.
authors: Cathy M
authors: CM
authors: Ramsey
authors: Division of Reproductive and Developmental Science, Oregon National Primate Research Center, Beaverton, OR 97006, USA; Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR 97239, USA.
authors: Jon D
authors: JD
authors: Hennebold
authors: Division of Reproductive and Developmental Science, Oregon National Primate Research Center, Beaverton, OR 97006, USA.
authors: Mary B
authors: MB
authors: Zelinski
authors: Division of Reproductive and Developmental Science, Oregon National Primate Research Center, Beaverton, OR 97006, USA; Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR 97239, USA. Electronic address: jensenje@ohsu.edu.
authors: Jeffrey T
authors: JT
authors: Jensen
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000187:drug effects; D006063:Chorionic Gonadotropin / Q000008:administration & dosage*; D000077407:Cilostazol; D005260:Female; D006801:Humans; D008253:Macaca mulatta; D008540:Meiosis; D051379:Mice; D023421:Models, Animal; D009865:Oocytes / Q000187:drug effects*; D009866:Oogenesis / Q000187:drug effects*; D058987:Phosphodiesterase 3 Inhibitors / Q000008:administration & dosage*; D011994:Recombinant Proteins / Q000008:administration & dosage; D013777:Tetrazoles / Q000008:administration & dosage*
chemical_list: D006063:Chorionic Gonadotropin; D058987:Phosphodiesterase 3 Inhibitors; D011994:Recombinant Proteins; D013777:Tetrazoles; D000077407:Cilostazol
keywords: Germinal vesicle; Meiosis; Nonhormonal contraception; Nonhuman primate; cAMP
references: Contraception. 2013 Apr;87(4):443-8
references: 23083529
references: Hum Reprod. 2002 Aug;17(8):2079-84
references: 12151440
references: Mol Cell Endocrinol. 2002 Feb 22;187(1-2):153-9
references: 11988323
references: Biol Reprod. 2003 Sep;69(3):1042-52
references: 12773402
references: Mol Reprod Dev. 1990 Nov;27(3):261-80
references: 2078341
references: J Clin Pharmacol. 1998 Feb;38(2):144-50
references: 9549645
references: Contraception. 2005 Jan;71(1):68-73
references: 15639077
references: Contraception. 2008 Apr;77(4):303-7
references: 18342656
references: Development. 2008 Oct;135(19):3229-38
references: 18776144
references: Development. 2009 Jun;136(11):1869-78
references: 19429786
references: PLoS One. 2012;7(1):e30649
references: 22292006
references: Nat Protoc. 2010 Jun;5(6):1138-47
references: 20539289
references: Contraception. 2010 Feb;81(2):165-71
references: 20103457
references: Cell Cycle. 2009 Sep 1;8(17):2741-7
references: 19717979