Progesterone analogues similarly modulate endometrial matrix metalloproteinase-1 and matrix metalloproteinase-3 and their inhibitor in a model for long-term contraceptive effects

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are in volved in normal menstruation, while MMP-1 and MMP-3 production by human en dometrial stromal cells (HESCs) is repressed in vitro by progesterone. We p ostulated that the repression by synthetic progestins of MMP production fro m HESCs may not be fully maintained in the long term, and that this may acc ount for the disturbed uterine bleeding patterns in women using long-acting progestins. In this study, a long-term HESC culture model was established to compare the effects of natural progesterone and a number of synthetic an alogues (ORG2058, medroxyprogesterone acetate, norethindrone acetate, levon orgestrel and drospirenone) on the production by these cells of MMP-1 and M MP-3 and TIMP-1. Zymographic and enzyme-linked immunosorbent analysis of cu lture medium after 2 weeks showed that both natural progesterone and all of the synthetic progestins tested maintained a significant inhibition of MMP -1 and MMP-3 production. Production of mRNA for MMP-1 and MMP-3 was also su ppressed by all progestins, while TIMP production was increased. Thus, mens trual bleeding disturbances which occur during the use of synthetic progest ins is not likely to result directly from changes in the effect of long-ter m progestin exposure on MMP-1 or MMP-3 or TIMP-1 production by HESCs.