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

Abstract

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in normal menstruation, while MMP-1 and MMP-3 production by human endometrial stromal cells (HESCs) is repressed in vitro by progesterone. We postulated that the repression by synthetic progestins of MMP production from HESCs may not be fully maintained in the long term, and that this may account 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 analogues (ORG2058, medroxyprogesterone acetate, norethindrone acetate, levonorgestrel and drospirenone) on the production by these cells of MMP-1 and MMP-3 and TIMP-1. Zymographic and enzyme-linked immunosorbent analysis of culture 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 suppressed by all progestins, while TIMP production was increased. Thus, menstrual bleeding disturbances which occur during the use of synthetic progestins is not likely to result directly from changes in the effect of long-term progestin exposure on MMP-1 or MMP-3 or TIMP-1 production by HESCs.

Quantitative Analysis of Collagen Fibrillar Structure in Canine Uterus Exposed to Acetate of Medroxyprogesterone Using Second Harmonic Generation Microscopy

“…Progesterone inhibits the expression of MMP in endometrial cells in humans and rats (Marbaix et al, 1992;Hampton et al, 1999). Our results suggest the inhibitory effect described for the exogenous progestin MPA depends on the dose and dosage.…”

Down-Regulation of Endometrial Matrix Metalloproteinase-3 and -7 Expressionin Vitroand Therapeutic Regression of Experimental Endometriosisin Vivoby a Novel Nonsteroidal Progesterone Receptor Agonist, Tanaproget

“…Although NETA was as effective as P, MPA, and TNPR in normal cells in the absence of an IL-1␣ challenge, NETA was unable to suppress MMP expression in stromal cells challenged with IL-1␣ or within the organ cultures, even at doses similar to those used for P (data not shown). The failure of NETA to suppress MMPs is surprising, given its clinical effectiveness and other studies that suggest that this progestin is effective in the suppression of MMPs in vitro (22). Although the latter study examined isolated stromal cells from normal women, obtaining results similar to those presented in this report, this group did not examine cells from women with endometriosis or normal cells challenged with a proinflammatory cytokine.…”

Drospirenone induces decidualization in human eutopic endometrial stromal cells and reduces DNA synthesis of human endometriotic stromal cells

“…To investigate uterine bleeding in long-acting progestin users, Hampton et al found that drospirenone, similar to other progestins, reduced MMP-1 and MMP-3 expression (8). The aim of this study was to clarify the direct effect of drospirenone on endometrial and endometriotic stromal cells, especially whether it induces decidualization in the endometrium and the anti-DNA synthesis effect on endometriosis.…”