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Uterine prostaglandin (PG) levels and cellular reaction in response to IUDs were elevated in sixty women. Short-term users (n = 30) were studied in a control cycle and 3 months after IUD insertion, and long-term users (n = 30) were studied at least 2 years after device insertion. A uterine wash was performed in the proliferative and luteal phase of each investigated menstrual cycle; the cellular components were counted and levels of PGE2, PGF2 alpha and their 13,14-dihydro-15-keto metabolites measured. A significant rise in PG levels was observed in the uterine wash shortly after IUD insertion, particularly in the luteal phase. However, there was a significant reduction in PG levels among long-term users, though the cellular reaction showed a continued increment. The absence of correlation between the biochemical and biological responses indicated that neither of them was totally dependent on the other. The decreased PG levels among long-term users does not support the concept of a key role for these substances in the mechanism of action of IUDs. The temporary post-insertion rise in PG levels coincides with the phase of increased bleeding and pain.