Phosphodiesterase 3 inhibitors suppress oocyte maturation and consequent pregnancy without affecting ovulation and cyclicity in rodents.
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.
Wiersma
A
A
Department of Pharmacology, N.V. Organon, P.O. Box 20, 5340 BH Oss, The Netherlands. a.wiersma@organon.oss.akzonobel.nl
Hirsch
B
B
Tsafriri
A
A
Hanssen
R G
RG
Van de Kant
M
M
Kloosterboer
H J
HJ
Conti
M
M
Hsueh
A J
AJ
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D003271:Contraceptive Agents, Female / Q000494:pharmacology*; D000242:Cyclic AMP / Q000502:physiology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004971:Estrus / Q000187:drug effects*; D005260:Female; D005306:Fertilization / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D019271:Hypoxanthine / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008540:Meiosis / Q000187:drug effects*; D008596:Menotropins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D020105:Milrinone; D009866:Oogenesis / Q000187:drug effects*; D006080:Ovarian Follicle / Q000187:drug effects / Q000502:physiology; D010060:Ovulation / Q000187:drug effects*; D010062:Ovulation Induction; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011247:Pregnancy; D011688:Purinones / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram; D015290:Second Messenger Systems / Q000502:physiology*; D013379:Substrate Specificity; D013876:Thiophenes / Q000494:pharmacology
D003271:Contraceptive Agents, Female; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D011724:Pyridazines; D011728:Pyridones; D011760:Pyrrolidinones; D015363:Quinolones; D013876:Thiophenes; C097915:Org 9935; D019271:Hypoxanthine; C041648:pimobendan; C021294:cilostamide; D008596:Menotropins; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C011145:zaprinast; D020105:Milrinone; D020889:Rolipram; D015056:1-Methyl-3-isobutylxanthine