Comparative analysis of pharmacologic and/or genetic disruption of cyclooxygenase-1 and cyclooxygenase-2 function in female reproduction in mice

Cyclooxygenase (COX)-derived prostaglandins are critical in female reproduc tion. Gene targeting studies show that ovulation, fertilization, implantati on, and decidualization are defective in COX-2 deficient mice. We used gene tic and pharmacologic approaches to perturb COX function and examine the di fferential and synergistic effects of inhibition of COX-1, COX-2, or of bot h isoforms on reproductive outcomes during early pregnancy in mice. The res ults demonstrate that simultaneous inhibition of COX-1 and COX-2 produces m ore severe effects on early pregnancy events than inhibition of either isof orm alone. The effects of pharmacological inhibition of COX-2 on female rep roductive functions were less severe than the null mutation of the COX-2 ge ne. A combined approach showed that COX-2 inhibition in COX-1(-/-) mice ind uced complete reproductive failure, suggesting a lack of alternative source s of prostaglandin synthesis. This investigation raises caution regarding t he indiscriminate use of COX inhibitors and shows for the first time the di stinct and overlapping pathways of the cyclooxygenase systems in female rep roduction.