Journal List > Korean J Obstet Gynecol > v.54(9) > 1088326

TOOLS
Cheon, Sim, and Yang: The effect of udenafil (zydena) on the fertilization and early embryo development in mice
Original Article
Korean Journal of Obstetrics & Gynecology

Korean Journal of Obstetrics & Gynecology 2011; 54(9): 508-516.

Published online: 26 September 2011

DOI: https://doi.org/10.5468/KJOG.2011.54.9.508

The effect of udenafil (zydena) on the fertilization and early embryo development in mice

Keun Soo Cheon, MD, Jae Chul Sim, MD, Hoe Saeng Yang, MD

Department of Obstetrics and Gynecology, Dongguk University College of Medicine, Gyeongju, Korea.

Corresponding author: Hoe Saeng Yang, MD. Department of Obstetrics and Gynecology, Dongguk University College of Medicine, 1090-1 Seokjang-dong, Gyeongju 780-350, Korea. Tel: +82-54-770-8348, Fax: +82-54-770-8378, y31354@hotmail.com

Received 25 January 2011       Revised 27 April 2011       Accepted 18 July 2011

Copyright © 2011. Korean Society of Obstetrics and Gynecology

(open-access):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective

To determine the effect of udenafil, a cyclic monophosphate-specific type 5 phosphodiesterase inhibitor, on fertilization and early embryo cleavage of mice.

Methods

This mammal study included randomly assigned male and female mice. The females were sacrificed after mating to evaluate their oocytes and embryos in four different time intervals following the treatment. Female mice were injected intraperitoneally with 5 IU of gonadotropin and human chorionic gonadotropin to stimulate follicular growth and induce ovulation. They were separately caged with males that had been gavaged with udenafil (0.06 mg/0.05 mL) and allowed to mate. After 24, 48, 72, and 96 hours of time intervals, females were killed, their oviducts were dissected out, and retrieved embryos were assessed for blastomere number and quality. Fertilization rates and numbers of embryos were evaluated after treatment.

Results

Fertilization rates were reduced in females that were mated with udenafil gavaged males. Over days 2-4, the numbers of embryo that of the treated group were significantly fewer than in the control group. There was also a tendency of impaired cleavage rates with those embryos.

Conclusion

The impairments of fertility caused by udenafil have important implications for infertility centers and couples who are using this drug precoitally while attempting to conceive.

Keywords: Udenafil, Fertilization, Embryo cleavage

Figures and Tables

Fig. 1
Fertilization rate and early embyo development on each case (P <0.05).
kjog-54-508-g001
Fig. 2
Accumulated fertilization rate (P <0.05).
kjog-54-508-g002
Table 1
Rate of fertilization and early embryo development on day 1
kjog-54-508-i001

P =0.0175.

Table 2
Rate of fertilization and early embryo development on day 2
kjog-54-508-i002

P =0.0007.

Table 3
Rate of fertilization and early embryo development on day 3
kjog-54-508-i003

P =0.0114.

Table 4
Rate of fertilization and early embryo development on day 4
kjog-54-508-i004

P =0.0003.

References

1. Aldridge J, Measham F. Sildenafil (Viagra) is used as a recreational drug in England. BMJ. 1999. 318:669.
2. Smith KM, Romanelli F. Recreational use and misuse of phosphodiesterase 5 inhibitors. J Am Pharm Assoc (2003). 2005. 45:63–72.
3. Monga M, Bernie J, Rajasekaran M. Male infertility and erectile dysfunction in spinal cord injury: a review. Arch Phys Med Rehabil. 1999. 80:1331–1339.
4. McKinney KA, Lewis SE, Thompson W. Persistent effects of pentoxifylline on human sperm motility, after drug removal, in normozoospermic and asthenozoospermic individuals. Andrologia. 1994. 26:235–240.
5. Tournaye H, Van der Linden M, Van den Abbeel E, Devroey P, Van Steirteghem A. Effect of pentoxifylline on implantation and post-implantation development of mouse embryos in vitro. Hum Reprod. 1993. 8:1948–1954.
6. Yovich JL. Pentoxifylline: actions and applications in assisted reproduction. Hum Reprod. 1993. 8:1786–1791.
7. Lewis SE, Moohan JM, Thompson W. Effects of pentoxifylline on human sperm motility in normospermic individuals using computer-assisted analysis. Fertil Steril. 1993. 59:418–423.
8. Glenn DR, McVicar CM, McClure N, Lewis SE. Sildenafil citrate improves sperm motility but causes a premature acrosome reaction in vitro. Fertil Steril. 2007. 87:1064–1070.
9. Fisch JD, Behr B, Conti M. Enhancement of motility and acrosome reaction in human spermatozoa: differential activation by type-specific phosphodiesterase inhibitors. Hum Reprod. 1998. 13:1248–1254.
10. Lefièvre L, De Lamirande E, Gagnon C. The cyclic GMP-specific phosphodiesterase inhibitor, sildenafil, stimulates human sperm motility and capacitation but not acrosome reaction. J Androl. 2000. 21:929–937.
11. Cuadra DL, Chan PJ, Patton WC, Stewart SC, King A. Type 5 phosphodiesterase regulation of human sperm motility. Am J Obstet Gynecol. 2000. 182:1013–1015.
12. Tournaye H, Van der Linden M, Van den Abbeel E, Devroey P, Van Steirteghem A. Mouse in vitro fertilization using sperm treated with pentoxifylline and 2-deoxyadenosine. Fertil Steril. 1994. 62:644–647.
13. Scott L, Smith S. Human sperm motility-enhancing agents have detrimental effects on mouse oocytes and embryos. Fertil Steril. 1995. 63:166–175.
14. Tur-Kaspa I, Segal S, Moffa F, Massobrio M, Meltzer S. Viagra for temporary erectile dysfunction during treatments with assisted reproductive technologies. Hum Reprod. 1999. 14:1783–1784.
15. Donnelly ET, Lewis SE, McNally JA, Thompson W. In vitro fertilization and pregnancy rates: the influence of sperm motility and morphology on IVF outcome. Fertil Steril. 1998. 70:305–314.
16. Pomeroy KO, Dodds JF, Seidel GE Jr. Caffeine promotes in vitro fertilization of mouse ova within 15 minutes. J Exp Zool. 1988. 248:207–212.
17. Dodds JW, Seidel GE. Effects of caffeine, Ca++, capacifitation time, and strain on in vitro fertilization in mice. Gamate Res. 1984. 10:353–360.
18. Fort DJ, Stover EL, Propst TL, Faulkner BC, Vollmuth TA, Murray FJ. Evaluation of the developmental toxicity of caffeine and caffeine metabolites using the frog embryo teratogenesis assay: Xenopus (FETAX). Food Chem Toxicol. 1998. 36:591–600.
19. Kawahara M, Wakai T, Yamanaka K, Kobayashi J, Sugimura S, Shimizu T, et al. Caffeine promotes premature chromosome condensation formation and in vitro development in porcine reconstructed embryos via a high level of maturation promoting factor activity during nuclear transfer. Reproduction. 2005. 130:351–357.
20. Jacombs A, Ryan J, Loupis A, Pollard I. Maternal caffeine consumption during pregnancy does not affect preimplantation development but delays early postimplantation growth in rat embryos. Reprod Fertil Dev. 1999. 11:211–218.
21. Burdan F. Intrauterine growth retardation and lack of teratogenic effects of prenatal exposure to the combination of paracetamol and caffeine in Wistar rats. Reprod Toxicol. 2003. 17:51–58.
22. Petersen CG, Mauri AL, Ferreira R, Baruffi RL, Franco Júnior JG. Embryo selection by the first cleavage parameter between 25 and 27 hours after ICSI. J Assist Reprod Genet. 2001. 18:209–212.
23. Boostanfar R, Jain JK, Slater CC, Tourgeman DE, Francis MM, Paulson RJ. The prognostic significance of day 3 embryo cleavage stage on subsequent blastocyst development in a sequential culture system. J Assist Reprod Genet. 2001. 18:548–550.
24. Borini A, Lagalla C, Cattoli M, Sereni E, Sciajno R, Flamigni C, et al. Predictive factors for embryo implantation potential. Reprod Biomed Online. 2005. 10:653–668.
25. Lundin K, Bergh C, Hardarson T. Early embryo cleavage is a strong indicator of embryo quality in human IVF. Hum Reprod. 2001. 16:2652–2657.
26. Lieberman E, Ginsburg ES, Racowsky C. Rate of cell division and weight of neonates following IVF. Reprod Biomed Online. 2006. 12:315–321.
27. Lewin A, Schenker JG, Safran A, Zigelman N, Avrech O, Abramov Y, et al. Embryo growth rate in vitro as an indicator of embryo quality in IVF cycles. J Assist Reprod Genet. 1994. 11:500–503.
28. Zhu J, Meniru GI, Craft IL. Embryo developmental stage at transfer influences outcome of treatment with intracytoplasmic sperm injection. J Assist Reprod Genet. 1997. 14:245–249.
29. McKiernan SH, Bavister BD. Timing of development is a critical parameter for predicting successful embryogenesis. Hum Reprod. 1994. 9:2123–2129.
30. Bavister BD. Culture of preimplantation embryos: facts and artifacts. Hum Reprod Update. 1995. 1:91–148.
31. Hardarson T, Hanson C, Sjogren A, Lundin K. Human embryos with unevenly sized blastomeres have lower pregnancy and implantation rates: indications for aneuploidy and multinucleation. Hum Reprod. 2001. 16:313–318.
32. Whitaker M. Calcium at fertilization and in early development. Physiol Rev. 2006. 86:25–88.
33. Webb SE, Miller AL. Calcium signalling during embryonic development. Nat Rev Mol Cell Biol. 2003. 4:539–551.
34. Blancato JK, Seyler DE. Effect of calcium-modifying drugs on mouse in vitro fertilization and preimplantation development. Int J Fertil. 1990. 35:171–176.
35. Ghalayini IF. Nitric oxide-cyclic GMP pathway with some emphasis on cavernosal contractility. Int J Impot Res. 2004. 16:459–469.
36. Abramczuk JW, Lopata A. Resistance of human follicular oocytes to parthenogenetic activation: DNA distribution and content in oocytes maintained in vitro. Hum Reprod. 1990. 5:578–581.
37. Grealy M, Sreenan JM. Effect of adenylyl cyclase activation on intracellular and extracellular cAMP and cGMP in preimplantation cattle blastocysts. J Reprod Fertil. 1999. 116:355–361.
38. Souness JE, Hassall GA, Parrott DP. Inhibition of pig aortic smooth muscle cell DNA synthesis by selective type III and type IV cyclic AMP phosphodiesterase inhibitors. Biochem Pharmacol. 1992. 44:857–866.
39. Matousovic K, Tsuboi Y, Walker H, Grande JP, Dousa TP. Inhibitors of cyclic nucleotide phosphodiesterase isozymes block renal tubular cell proliferation induced by folic acid. J Lab Clin Med. 1997. 130:487–495.
40. Friedman DL. Role of cyclic nucleotides in cell growth and differentiation. Physiol Rev. 1976. 56:652–708.
41. Schiano MA, Sevin BU, Perras J, Ramos R, Wolloch EH, Averette HE. In vitro enhancement of cis-platinum antitumor activity by caffeine and pentoxifylline in a human ovarian cell line. Gynecol Oncol. 1991. 43:37–45.
42. Zeitlin PL. Future pharmacological treatment of cystic fibrosis. Respiration. 2000. 67:351–357.
43. Wang W, Masu K, Tamura G, Suzuki K, Ohwada K, Okuyama K, et al. Inhibition of eosinophil survival by a selective inhibitor of phosphodiesterase 4 via the induction of apoptosis. Biol Pharm Bull. 2005. 28:515–519.
44. Zhu B, Strada S, Stevens T. Cyclic GMP-specific phosphodiesterase 5 regulates growth and apoptosis in pulmonary endothelial cells. Am J Physiol Lung Cell Mol Physiol. 2005. 289:L196–L206.
45. Sarfati M, Mateo V, Baudet S, Rubio M, Fernandez C, Davi F, et al. Sildenafil and vardenafil, types 5 and 6 phosphodiesterase inhibitors, induce caspase-dependent apoptosis of B-chronic lymphocytic leukemia cells. Blood. 2003. 101:265–269.
46. Lewis SE, Donnelly ET, Sterling ES, Kennedy MS, Thompson W, Chakravarthy U. Nitric oxide synthase and nitrite production in human spermatozoa: evidence that endogenous nitric oxide is beneficial to sperm motility. Mol Hum Reprod. 1996. 2:873–878.
47. Lewis SE. Nitric oxide and human sperm. Assist Reprod Rev. 1998. 8:50–64.
48. Donnelly ET, Lewis SE, Thompson W, Chakravarthy U. Sperm nitric oxide and motility: the effects of nitric oxide synthase stimulation and inhibition. Mol Hum Reprod. 1997. 3:755–762.
49. Agarwal A, Gupta S, Sharma RK. Role of oxidative stress in female reproduction. Reprod Biol Endocrinol. 2005. 3:28.
50. Gouge RC, Marshburn P, Gordon BE, Nunley W, Huet-Hudson YM. Nitric oxide as a regulator of embryonic development. Biol Reprod. 1998. 58:875–879.
51. Li HY, Chang SP, Yuan CC, Chao HT, Ng HT, Sung YJ. Nitric oxide induces extensive apoptosis in endometrial epithelial cells in the presence of progesterone: involvement of mitogen-activated protein kinase pathways. Mol Hum Reprod. 2001. 7:755–763.
52. Novaro V, González E, Jawerbaum A, Rettori V, Canteros G, Gimeno MF. Nitric oxide synthase regulation during embryonic implantation. Reprod Fertil Dev. 1997. 9:557–564.
53. Biswas S, Kabir SN, Pal AK. The role of nitric oxide in the process of implantation in rats. J Reprod Fertil. 1998. 114:157–161.
54. Osborn BH, Haney AF, Misukonis MA, Weinberg JB. Inducible nitric oxide synthase expression by peritoneal macrophages in endometriosis-associated infertility. Fertil Steril. 2002. 77:46–51.
55. Kim KH, Oh DS, Jeong JH, Shin BS, Joo BS, Lee KS. Follicular blood flow is a better predictor of the outcome of in vitro fertilization-embryo transfer than follicular fluid vascular endothelial growth factor and nitric oxide concentrations. Fertil Steril. 2004. 82:586–592.
TOOLS
Similar articles