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. 1998 Aug 1;102(3):532–537. doi: 10.1172/JCI2566

Phosphodiesterase 3 inhibitors suppress oocyte maturation and consequent pregnancy without affecting ovulation and cyclicity in rodents.

A Wiersma 1, B Hirsch 1, A Tsafriri 1, R G Hanssen 1, M Van de Kant 1, H J Kloosterboer 1, M Conti 1, A J Hsueh 1
PMCID: PMC508914  PMID: 9691090

Abstract

During each reproductive cycle, a preovulatory surge of gonadotropins induces meiotic maturation of the oocyte in the preovulatory follicle followed by ovulation. Although gonadotropins stimulate cAMP production in somatic cells of the follicle, a decrease in intra-oocyte cAMP levels is required for resumption of meiosis in oocytes. Based on the observed compartmentalization of the cAMP-degrading enzyme, phosphodiesterase, in follicular somatic and germ cells, inhibitors of phosphodiesterase 3 were used to block meiosis in ovulating oocytes in rodents. By this strategy, we demonstrated that fertilization and pregnancy could be prevented without disturbing follicle rupture and normal estrous cyclicity. In contrast to conventional contraceptive pills that disrupt ovarian steroidogenesis and reproductive cycles, the present strategy achieves effective contraception by selective blockage of oocyte maturation and development without alterations in ovulation and reproductive cyclicity.

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Selected References

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  1. Aberdam E., Hanski E., Dekel N. Maintenance of meiotic arrest in isolated rat oocytes by the invasive adenylate cyclase of Bordetella pertussis. Biol Reprod. 1987 Apr;36(3):530–535. doi: 10.1095/biolreprod36.3.530. [DOI] [PubMed] [Google Scholar]
  2. Beavo J. A. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev. 1995 Oct;75(4):725–748. doi: 10.1152/physrev.1995.75.4.725. [DOI] [PubMed] [Google Scholar]
  3. Bellen H. J., Gregory B. K., Olsson C. L., Kiger J. A., Jr Two Drosophila learning mutants, dunce and rutabaga, provide evidence of a maternal role for cAMP on embryogenesis. Dev Biol. 1987 Jun;121(2):432–444. doi: 10.1016/0012-1606(87)90180-1. [DOI] [PubMed] [Google Scholar]
  4. Bornslaeger E. A., Wilde M. W., Schultz R. M. Regulation of mouse oocyte maturation: involvement of cyclic AMP phosphodiesterase and calmodulin. Dev Biol. 1984 Oct;105(2):488–499. doi: 10.1016/0012-1606(84)90306-3. [DOI] [PubMed] [Google Scholar]
  5. Cho W. K., Stern S., Biggers J. D. Inhibitory effect of dibutyryl cAMP on mouse oocyte maturation in vitro. J Exp Zool. 1974 Mar;187(3):383–386. doi: 10.1002/jez.1401870307. [DOI] [PubMed] [Google Scholar]
  6. Conti M., Nemoz G., Sette C., Vicini E. Recent progress in understanding the hormonal regulation of phosphodiesterases. Endocr Rev. 1995 Jun;16(3):370–389. doi: 10.1210/edrv-16-3-370. [DOI] [PubMed] [Google Scholar]
  7. Dekel N., Lawrence T. S., Gilula N. B., Beers W. H. Modulation of cell-to-cell communication in the cumulus-oocyte complex and the regulation of oocyte maturation by LH. Dev Biol. 1981 Sep;86(2):356–362. doi: 10.1016/0012-1606(81)90193-7. [DOI] [PubMed] [Google Scholar]
  8. Downs S. M., Coleman D. L., Ward-Bailey P. F., Eppig J. J. Hypoxanthine is the principal inhibitor of murine oocyte maturation in a low molecular weight fraction of porcine follicular fluid. Proc Natl Acad Sci U S A. 1985 Jan;82(2):454–458. doi: 10.1073/pnas.82.2.454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Downs S. M., Daniel S. A., Bornslaeger E. A., Hoppe P. C., Eppig J. J. Maintenance of meiotic arrest in mouse oocytes by purines: modulation of cAMP levels and cAMP phosphodiesterase activity. Gamete Res. 1989 Jul;23(3):323–334. doi: 10.1002/mrd.1120230309. [DOI] [PubMed] [Google Scholar]
  10. Downs S. M. Purine control of mouse oocyte maturation: evidence that nonmetabolized hypoxanthine maintains meiotic arrest. Mol Reprod Dev. 1993 May;35(1):82–94. doi: 10.1002/mrd.1080350114. [DOI] [PubMed] [Google Scholar]
  11. Eppig J. J. The participation of cyclic adenosine monophosphate (cAMP) in the regulation of meiotic maturation of oocytes in the laboratory mouse. J Reprod Fertil Suppl. 1989;38:3–8. [PubMed] [Google Scholar]
  12. Hsueh A. J. Designer contraceptive pills. Hum Reprod. 1995 Aug;10(8):1997–2000. doi: 10.1093/oxfordjournals.humrep.a136223. [DOI] [PubMed] [Google Scholar]
  13. Hunter R. H., Cook B., Baker T. G. Dissociation of response to injected gonadotropin between the Graafian follicle and oocyte in pigs. Nature. 1976 Mar 11;260(5547):156–158. doi: 10.1038/260156a0. [DOI] [PubMed] [Google Scholar]
  14. Iwamatsu T., Chang M. C. Sperm penetration in vitro of mouse oocytes at various times during maturation. J Reprod Fertil. 1972 Nov;31(2):237–247. doi: 10.1530/jrf.0.0310237. [DOI] [PubMed] [Google Scholar]
  15. Kasuya J., Goko H., Fujita-Yamaguchi Y. Multiple transcripts for the human cardiac form of the cGMP-inhibited cAMP phosphodiesterase. J Biol Chem. 1995 Jun 16;270(24):14305–14312. doi: 10.1074/jbc.270.24.14305. [DOI] [PubMed] [Google Scholar]
  16. Magnusson C., Hillensjö T., Tsafriri A., Hultborn R., Ahrén K. Oxygen consumption of maturing rat oocytes. Biol Reprod. 1977 Aug;17(1):9–15. doi: 10.1093/biolreprod/17.1.9. [DOI] [PubMed] [Google Scholar]
  17. Manganiello V. C., Murata T., Taira M., Belfrage P., Degerman E. Diversity in cyclic nucleotide phosphodiesterase isoenzyme families. Arch Biochem Biophys. 1995 Sep 10;322(1):1–13. doi: 10.1006/abbi.1995.1429. [DOI] [PubMed] [Google Scholar]
  18. Manganiello V. C., Taira M., Degerman E., Belfrage P. Type III cGMP-inhibited cyclic nucleotide phosphodiesterases (PDE3 gene family). Cell Signal. 1995 Jul;7(5):445–455. doi: 10.1016/0898-6568(95)00017-j. [DOI] [PubMed] [Google Scholar]
  19. Nicholson C. D., Challiss R. A., Shahid M. Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes. Trends Pharmacol Sci. 1991 Jan;12(1):19–27. doi: 10.1016/0165-6147(91)90484-a. [DOI] [PubMed] [Google Scholar]
  20. Nicholson C. D., Shahid M., Bruin J., Barron E., Spiers I., de Boer J., van Amsterdam R. G., Zaagsma J., Kelly J. J., Dent G. Characterization of ORG 20241, a combined phosphodiesterase IV/III cyclic nucleotide phosphodiesterase inhibitor for asthma. J Pharmacol Exp Ther. 1995 Aug;274(2):678–687. [PubMed] [Google Scholar]
  21. Niwa K., Chang M. C. Fertilization of rat eggs in vitro at various times before and after ovulation with special reference to fertilization of ovarian oocytes matured in culture. J Reprod Fertil. 1975 Jun;43(3):435–451. doi: 10.1530/jrf.0.0430435. [DOI] [PubMed] [Google Scholar]
  22. Pang D. C. Tissue and species specificity of cardiac cAMP-phosphodiesterase inhibitors. Adv Second Messenger Phosphoprotein Res. 1992;25:307–320. [PubMed] [Google Scholar]
  23. Reinhardt R. R., Chin E., Zhou J., Taira M., Murata T., Manganiello V. C., Bondy C. A. Distinctive anatomical patterns of gene expression for cGMP-inhibited cyclic nucleotide phosphodiesterases. J Clin Invest. 1995 Apr;95(4):1528–1538. doi: 10.1172/JCI117825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rose-Hellekant T. A., Bavister B. D. Precocious oocyte maturation is induced by an inhibitor of cAMP-dependent protein kinase in the intact golden hamster. Mol Reprod Dev. 1996 Jun;44(2):250–255. doi: 10.1002/(SICI)1098-2795(199606)44:2<250::AID-MRD15>3.0.CO;2-6. [DOI] [PubMed] [Google Scholar]
  25. Sadler S. E. Inhibitors of phosphodiesterase III block stimulation of Xenopus laevis oocyte ribosomal S6 kinase activity by insulin-like growth factor-I. Mol Endocrinol. 1991 Dec;5(12):1947–1954. doi: 10.1210/mend-5-12-1947. [DOI] [PubMed] [Google Scholar]
  26. Sadler S. E. Type III phosphodiesterase plays a necessary role in the growth-promoting actions of insulin, insulin-like growth factor-I, and Ha p21ras in Xenopus laevis oocytes. Mol Endocrinol. 1991 Dec;5(12):1939–1946. doi: 10.1210/mend-5-12-1939. [DOI] [PubMed] [Google Scholar]
  27. Salustri A., Petrungaro S., De Felici M., Conti M., Siracusa G. Effect of follicle-stimulating hormone on cyclic adenosine monophosphate level and on meiotic maturation in mouse cumulus cell-enclosed oocytes cultured in vitro. Biol Reprod. 1985 Nov;33(4):797–802. doi: 10.1095/biolreprod33.4.797. [DOI] [PubMed] [Google Scholar]
  28. Schultz R. M., Montgomery R. R., Belanoff J. R. Regulation of mouse oocyte meiotic maturation: implication of a decrease in oocyte cAMP and protein dephosphorylation in commitment to resume meiosis. Dev Biol. 1983 Jun;97(2):264–273. doi: 10.1016/0012-1606(83)90085-4. [DOI] [PubMed] [Google Scholar]
  29. Thompson W. J. Cyclic nucleotide phosphodiesterases: pharmacology, biochemistry and function. Pharmacol Ther. 1991;51(1):13–33. doi: 10.1016/0163-7258(91)90039-o. [DOI] [PubMed] [Google Scholar]
  30. Tsafriri A., Chun S. Y., Zhang R., Hsueh A. J., Conti M. Oocyte maturation involves compartmentalization and opposing changes of cAMP levels in follicular somatic and germ cells: studies using selective phosphodiesterase inhibitors. Dev Biol. 1996 Sep 15;178(2):393–402. doi: 10.1006/dbio.1996.0226. [DOI] [PubMed] [Google Scholar]
  31. Tsafriri A., Lindner H. R., Zor U., Lamprecht S. A. In-vitro induction of meiotic division in follicle-enclosed rat oocytes by LH, cyclic AMP and prostaglandin E 2 . J Reprod Fertil. 1972 Oct;31(1):39–50. doi: 10.1530/jrf.0.0310039. [DOI] [PubMed] [Google Scholar]
  32. Tsafriri A., Lindner H. R., Zor U., Lamprecht S. A. In-vitro induction of meiotic division in follicle-enclosed rat oocytes by LH, cyclic AMP and prostaglandin E 2 . J Reprod Fertil. 1972 Oct;31(1):39–50. doi: 10.1530/jrf.0.0310039. [DOI] [PubMed] [Google Scholar]
  33. Usui N. Morphological differences in nuclear materials released from hamster sperm heads at an early stage of incorporation into immature oocytes, mature oocytes, or fertilized eggs. Mol Reprod Dev. 1996 May;44(1):132–140. doi: 10.1002/(SICI)1098-2795(199605)44:1<132::AID-MRD15>3.0.CO;2-6. [DOI] [PubMed] [Google Scholar]
  34. Vivarelli E., Conti M., De Felici M., Siracusa G. Meiotic resumption and intracellular cAMP levels in mouse oocytes treated with compounds which act on cAMP metabolism. Cell Differ. 1983 May;12(5):271–276. doi: 10.1016/0045-6039(83)90023-4. [DOI] [PubMed] [Google Scholar]

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