Effect of long-term progestin treatment on endometrial vasculature in normal cycling mice

The aim of this study was to develop a mouse model to investigate the effects of long-term progestin-only exposure on endometrial vascular structure. Normal cycling mice received Silastic implants containing either medroxyprogesterone acetate (MPA) or levonorgestrel (LNG) and were dissected after 1, 3 or 6 weeks. Endometrial vascular density increased significantly within 1 week of MPA (482 +/- 40.2 vessels/mm2) or LNG (440 +/- 26.5 vessels/mm2) treatment compared with normal cycling mice (293 +/- 10.5 vessels/mm2). MPA increased stromal cell density within 1 week of treatment (13813 +/- 1450 cells/mm2) compared with normal cycling mice (8256 +/- 928 cells/mm2). However, although LNG significantly increased stromal cell density overall, the increase did not reach significance within the individual weeks examined. There was no significant change in the ratio of vascular to stromal cell density among treated and normal cycling mice. Epithelial cell height significantly decreased within 1 week of LNG (17.6 +/- 1.3 microm) treatment compared with normal cycling mice (23.5 +/- 1.3 microm); epithelial cell height also decreased within 1 week of MPA treatment (16.6 +/- 2.1 microm), although this did not reach statistical significance. VEGF immunostaining increased significantly in luminal epithelium after MPA or LNG treatment, and in glandular epithelium after LNG treatment. These observations are similar to those reported in human endometrium, suggesting that this mouse model may facilitate further investigations into breakthrough bleeding due to long-term progestin use.