Gonadotropins (FSH and LH) are detectable in ovarian tumor fluid, suggesting a possible role for gonadotropins in ovarian carcinogenesis and progression. However, the molecular mechanisms behind the role of gonadotropins in ovarian cancer development are unknown. Cyclooxygenase (COX) enzymes, COX-1 and COX-2, play crucial roles in the pathogenesis of human malignancies. The purpose of the current study was to determine whether the effect of gonadotropins on ovarian cancer invasion is mediated by a COX-dependent mechanism. Here, we reported that FSH/LH can promote prostaglandin E(2) (PGE(2)) production in ovarian cancer cells via COX-1 and -2 up-regulation at the protein and mRNA level. The phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway was required for gonadotropin-mediated up-regulation of COX-1 and COX-2. Moreover, treatment with COX-1- and COX-2-specific inhibitors abrogated the stimulatory effect of gonadotropins on motility and invasive activity. Western blot and gelatin zymography showed that COX-1 and COX-2 were critical for gonadotropin-induced expression of metastasis-related proteinases, matrix metalloproteinase (MMP)-2 and MMP-9. In addition, our results showed that PGE(2) induced an increase in cell invasiveness and the expression of MMP-2 and MMP-9 in ovarian cancer cells. These data show that COX-1 and COX-2 play essential roles in gonadotropin-induced migration and invasion.