Progesterone modulation of cytokine-directed matrix metalloproteinase expression in the human endometrium: A potential mechanism for maintaining tissue integrity during implantation and placental development

Progesterone is the dominant circulating ovarian hormone at the time implantation normally occurs, and it is believed to play a key role in regulating endometrial maturation and receptivity. With embryo attachment and penetration of the uterine lining, progesterone-dependent stromal cell differentiation, known as decidualization, is amplified as the endometrium is transformed into the placenta, a unique organ of metabolic interchange between fetus and mother. The establishment and maintenance of pregnancy is dependent, therefore, on progesterone, and without adequate levels of this hormone there is an increased risk for failed implantation and spontaneous abortion.; Matrix metalloproteinases (MMPs), an extensive family of proteolytic enzymes, are routinely expressed in the endometrium during growth and remodeling, and in connection with tissue breakdown during menstruation. The majority of endometrial MMPs studied thus far are completely absent in the progesterone-dominated secretory endometrium at the time implantation normally occurs. While progesterone acts in an endocrine fashion to inhibit endometrial MMP expression, the release of local paracrine factors may also influence MMP expression. In particular, IL-1, TNF-α, and EGF are recognized for their potent stimulatory effects on MMPs, and are known to be released by endometrial epithelial cells and invasive trophoblasts. This project has examined the role of these cytokines in regulating the expression of the stromal cell-specific MMPs, −3 and −11, in an in vitro model of decidualization. Results have shown that, while the aforementioned cytokines do not appear to regulate MMP-11 expression in this model, secretory phase endometrium and progesterone treated stromal cells become insensitive to cytokine stimulation of MMP-3 in vitro. Therefore, while select endometrial MMPs may be stimulated during trophoblast invasion despite the suppressive environment of the secretory endometrium, progesterone actually prevents cytokine stimulation of MMP-3, and possibly others, thereby contributing to the overall stability of the endometrium.