Prostaglandin (PG) production by intrauterine tissues plays a key part in the control of pregnancy and parturition. The present study was to investigate the role of placenta-derived CRH and CRH-related peptides in the regulation of PG synthesis and metabolism. We found that placental trophoblasts expressed both CRH-R1 and CRH-R2. Treatment of cultured placental cells with either a CRH or urocortin I (UCNI) antibody resulted in a significant decrease in PGE₂ release. Both CRH and UCNI antibodies significantly decreased mRNA and protein expression of synthetic enzymes cPLA₂ and COX-2 whilst increased mRNA and protein expression of PGDH, the key enzyme of PG metabolism. CRH-R1/-R2 antagonist astressin and CRH-R1 antagonist antalarmin significantly inhibited PGE₂ release whereas CRH-R2 antagonist astressin2b had no effect on PGE₂ release. Administration of astressin decreased expression of cPLA₂ but had no effect on COX-2 expression. Antalarmin reduced cPLA₂ and COX-2 expression whereas astressin2b did not alter cPLA₂ expression but increased COX-2 expression. PGDH expression was enhanced by these three antagonists. Cells treated with exogenous CRH and UCNI showed an increase in PGE₂ release and expression of cPLA₂ and COX-2 but a decrease in PGDH expression. UCNII and UCNIII had no effect on PGE₂ release but decreased COX-2 and PGDH expression. Our results suggested CRH and CRH-related peptides act on CRH-R1 and CRH-R2 to exert different effects on PG biosynthetic enzymes cPLA₂ and COX-2, and thereby modulate output of PGs from placenta, which would be important for controlling pregnancy and parturition.