The effect of intrauterine levonorgestrel use on the expression of c-JUN, oestrogen receptors, progesterone receptors and Ki-67 in human endometrium

The major regulators of endometrial function are oestrogen and progesterone, which act through binding their nuclear receptors and by activating transcription of their target genes. Interactions between steroid receptors and transcription proteins, e.g. c-JUN/AP-1, can modulate steroid action at the transcriptional level. The 19-nortestosterone-derived progestin, levonorgestrel, is used for contraception, treatment of menorrhagia and for endometrial protection during hormone replacement therapy, but the signaling pathways of its action are totally undefined. We examined the effect of an intrauterine system, releasing 20 mu g of levonorgestrel per 24 h (LNG-IUS), on immunoreactive oestrogen receptor, progesterone receptor, c-JUN and Ki-67 expression in 29 endometrial specimens, obtained from fertile women using the LNG-IUS for contraception. Moderate to strong immunostaining for oestrogen receptors was observed in the stromal cells in all specimens, in glandular epithelial cells in 26 cases and in flattened luminal epithelial cells in 17 specimens. Decidualized stromal cells showed no progesterone receptor immunoreactivity in 19 of the 29 specimens, and weak to moderate immunostaining in 10 cases. Luminal epithelial cells were negative for progesterone receptor in all samples. Intense nuclear staining for C-JUN was observed in epithelial cells in 26 and in decidualized stromal cells in all 29 of the samples. In 16 samples, Ki-67 immunoreactivity was evaluated as weak to moderate in decidualized stroma, and in 13 samples absent. Our data demonstrate that intrauterine release of LNG maintains constant: expression of C-JUN and exerts progestational effects in the endometrium in the absence of progesterone receptors. In contrast, LNG-IUS inhibits several cellular responses to oestrogen despite the presence of endogenous oestrogen and oestrogen receptors. These data suggest that the progestational effects induced by progesterone and levonorgestrel are mediated through different signalling pathways.