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Pharmacological Inhibition of Phosphodiesterase 4 Triggers Ovulation in Follicle-Stimulating Hormone-Primed Rats

Serono Reproductive Biology Institute (S.D.M., M.P., A.C., D.F., D.K., B.B., S.P.), Rockland, Massachusetts 02370; Istituto di Ricerche Biomediche "A Marxer" (E.G.T.), LCG Bioscience, 10010 Colleretto Giacosa, Italy; and Department of Obstetrics, Gynecology, and Reproductive Sciences (P.J.C.), College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 0W8

Address all correspondence and requests for reprints to: Sean D. McKenna, Serono Reproductive Biology Institute, One Technology Place, Rockland, Massachusetts 02370. E-mail: sean.mckenna{at}serono.com.

Phosphodiesterases (PDEs) are a family of enzymes that hydrolyze cyclic nucleotides to render them biologically inactive. As such, these enzymes are critical regulators of signal transduction pathways that use cyclic nucleotides as second messengers. PDE4 is one such member that has been identified in ovarian tissue and purported to have a role in the regulation of gonadotropin action. In the present study, selective PDE4 inhibitors enhanced intracellular signaling in a human LH receptor-expressing granulosa cell line. In vivo, PDE4 inhibition in FSH-primed rats resulted in ovulation, indicating that the PDE4 inhibitors can substitute for LH and human chorionic gonadotropin (hCG) in this process. Moreover, when coadministered with a subeffective dose of hCG, PDE4 inhibitors acted synergistically to enhance the ovulation response. Inhibitors of PDE3 or PDE5 had no ovulatory effect under similar conditions. Oocytes that were ovulated after PDE4 inhibition could be fertilized in vitro at a rate similar to that of oocytes from hCG-induced ovulation. Moreover, such oocytes were fully capable of being fertilized in vivo and developing into normal live pups. These results indicate that small molecule PDE4 inhibitors may be orally active alternatives to hCG as part of a fertility treatment regimen.