Production of Endometrial Matrix Metalloproteinases, but Not Their Tissue Inhibitors, is Modulated by Progesterone Withdrawal in an<i>in Vitro</i>Model for Menstruation¹

Abstract

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are implicated in normal menstruation, but the mechanism of their regulation is not yet clear. Human endometrial stromal cell cultures were established to mimic the events of the late luteal phase of the menstrual cycle: after 6 days of culture with estradiol 17beta (10 nmol/L) and progestin (P, 100 nmol/L), half the cells were subjected to P withdrawal, and medium was harvested on day 10. Decidualization of the cells was verified by PRL immunohistochemistry. Latent MMP-1, -2, -3, and -9 were detected by zymography and quantitated by densitometry, and production of all enzymes was increased on withdrawal of P. This increase 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 the 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 withdrawal. Thus, withdrawal of P alters the ratio of MMPs to TIMPs in this model in favor of MMPs and, hence, of tissue degradation. However, the 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.