The hallmark of the menstrual cycle is extensive steroid-dependent tissue turnover. Estrogen mediates endometrial cell growth and structural remodeling, whereas progeserone suppresses estrogen-dependent proliferation and promotes cellular differentiation. In nonfertile cycles, tissue degradation and menstruation occur as a consequence of steroidal deprivation as the ovarian corpus luteum fails. Stromalepithelial interactions are recognized as a necesary component in mediating steroid-induced endometrial turnover. Specific mRNAs for metalloproteinases of the stromelysin family are expressed during endometrial growth and menstrual breakdown but are absent in the progestin-dominated secretory phase. This expression pattern suggss involvement of stromelysins in remodeling the extracellular matrix of the endometrium during tissue growth and breakdown and implicates progesteronE in the suppression of these enzymes. We examined the regulation of endometrial stromelysins in explant cultures and found no acute effect ofestradiol on their expression, whereas progesterone was a potent inhibitor of stromelysin expression. Progesterone also suppressed stromelysin expression in cultures ofisolated stromal cells, but epithelial cells were progesterone insensitive. Coculture ofrecombined stromal and epithelial cells restored steroidal suppression of the epithelial-specific metalloproteinase. Our data confirm that progesterone inhibits endometrial stromelysins and further demonstrate the necessity for a stromalderived factor(s) as a mediator of steroid suppression of an epithelial metalloproteinase.The human endometrium undergoes extensive estradiolinduced growth and remodeling during the proliferative phase of the menstrual cycle, followed by secretory maturation in response to postovulatory progesterone (1). This rapid and extensive degree of steroid-mediated tissue development, which rivals that of many neoplasias, appears to be a necessary component of providing an environment suitable for sustaining hemochorial placentation (2). In the absence of implantation and the continued progestational environment of pregnancy, the superficial functionalis region of the endometrium undergoes degradation and is expelled with menstrual blood flow. Several laboratories have recently described the expression of matrix metalloproteinases (MMPs) in the normal, cycling human endometrium (3-6). These enzymes degrade many components of the extracellular matrix, including proteoglycans, glycoproteins, and basement membrane collagens (7). Our studies (5, 6) identified a cell type-specific expression pattern of mRNAs coding for members of the stromelysin family only during the proliferative and premenstrual/menstrual stage of the cycle; none of the enzymes were identified during the progesterone-dominated secretory menstrual interval. This pattern of expression suggests an active role for stromelysins during growth-associated structural remodeling as well as during the extensive tissue breakdown associated with menstruation.MMPs of the st...

Unlike most normal adult tissues, cyclic growth and tissue remodeling occur within the uterine endometrium throughout the reproductive years. The matrix metalloproteinases (MMPs), a family of structurally related enzymes that degrade specific components ofthe extracellular matrix are thought to be the physiologically relevant mediators of extracellular matrix composition and turnover. Our laboratory has identified MMPs of the stromelysin family in the cycling human endometrium, implicating these enzymes in mediating the extensive remodeling that occurs in this tissue. While the stromelysins are expressed in vivo during proliferation-associated remodeling and menstruation-associated endometrial breakdown, none of the stromelysins are expressed during the progesterone-dominated secretory phase of the cycle. Our in vitro studies of isolated cell types have confirmed progesterone suppression of stromal MMPs, but a stromalderived paracrine factor was found necessary for suppression of the epithelial-specific MMP matrilysin. In this report, we demonstrate that transforming growth factor (3 (TGF-13) is produced by endometrial stroma in response to progesterone and can suppress expression of epithelial matrilysin independent of progesterone. Additionally, we find that an antibody directed against the mammalian isoforms of TGF-P abolishes progesterone suppression of matrilysin in stromal-epithelial cocultures, implicating TGF-j8 as the principal mediator of matrilysin suppression in the human endometrium.

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