PRODUCTION OF ENDOMETRIAL MATRIX METALLOPROTEINASES, BUT NOT THEIR TISSUE INHIBITORS, IS MODULATED BY PROGESTERONE WITHDRAWAL IN AN IN-VITRO MODEL FOR MENSTRUATION

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) a re implicated in normal menstruation, but the mechanism of their regul ation is not yet clear. Human endometrial stromal cell cultures were e stablished to mimic the events of the late luteal phase of the menstru al cycle: after 6 days of culture with estradiol 17 beta (10 mmol/L) a nd progestin (P, 100 nmol/L), half the cells were subjected to P withd rawal, and medium was harvested on day 10. Decidualization of the cell s was verified by PRL immunohistochemistry. Latent MMP-1, -2, -3, and -9 were detected by zymography and quantitated by densitometry, and pr oduction of all enzymes was increased on withdrawal of P. This increas e was confirmed by enzyme-linked immunosorbent assay for MMP-1. TIMP-1 , -2, and -3 also were produced by the cells, with a mean ratio of 3.9 :1:1.2, respectively. There was no effect of P withdrawal on either th e amount of each TIMP or their relative concentrations. Expression of the messenger RNA for TIMP-1 or TIMP-2 also was not changed by P withd rawal. Thus, withdrawal of P alters the ratio of MMPs to TIMPs in this model in favor of MMPs and, hence, of tissue degradation. However, th e focal nature of menstruation-associated MMP activity suggests that P withdrawal is unlikely to be the only factor responsible for in vivo induction of MMPs at menstruation.