The levonorgestrel releasing intrauterine system (LNG-IUS) provides a novel contraceptive method. Intrauterine LNG induces a dramatic transformation of the endometrium, characterized by extensive decidualization. This is associated with strong expression of local factors associated with decidualization, including prolactin receptor and insulin-like growth factor binding protein-1. A striking discovery was the down-regulation of oestrogen and progesterone receptors in all components of the endometrium after insertion of the LNG-IUS, with a gradual return between 6 and 12 months post-insertion. Preliminary findings suggest that androgen receptors are expressed during this time. Elevated leukocyte infiltrate is observed 1 month after insertion of the device, comprising large granular lymphocytes and macrophages. We examined a number of local mediators implicated in menstruation and breakthrough bleeding episodes. Expression of the chemokine interleukin-8 was enhanced after insertion of the device, with a notable decrease apparent 6 months post-insertion. Cyclooxygenase-2 was similarly strongly expressed in the first months after LNG-IUS insertion, in contrast to an initial suppression of prostaglandin dehydrogenase activity. By deduction it appears that higher local concentrations of prostaglandins are present in the initial period of local LNG exposure. Taken together these data suggest that in the first months following LNG-IUS insertion steroid receptor content is significantly decreased, resulting in the altered expression of many locally acting mediators which may be involved in breakthrough bleeding episodes.