The mechanisms underlying the menstrual lysis leading to shedding of the human endometrium and its accompanying bleeding are still largely unknown. In particular, whether breakdown of the endometrial fibrillar extracellular matrix that precedes bleeding depends on aspartic-, cysteine-, serine-, or metalloproteinases remains unclear. In the present study, menstrual regression of the human endometrium was mimicked in organ culture. Whereas sex steroids could preserve tissue integrity only in nonperimenstrual explants, matrix breakdown upon sex steroid deprivation was completely and reversibly inhibited at all stages of the menstrual cycle by specific inhibitors of matrix metalloproteinases, but not by inhibitors of the other classes of proteinases. Matrix metalloproteinases are thus identified as the key class of proteinases involved in the initiation of menstruation.In his pioneering studies on menstruation using intraocular endometrial transplants in Rhesus monkeys, Markee constantly observed a major shrinking of the tissue within the few days preceding menstrual bleeding (1). Bleeding, which characterizes primates and a limited number of other species, has been linked to hypoxia/reperfusion secondary to spasm or compression of their unique coiled arteries upon tissue collapse (1). Regression of the endometrium also occurs in nonbleeding mammals: in cycling rats, both endometrial wet weight and collagen content decrease during metestrus to 20% of their proestrus value (2), indicating that proteolysis of the extracellular matrix (ECM) takes part in the process (3).An extensive argyrophilic network of so-called "reticular fibers," containing both type III and type I collagen (4), but whose argyrophilic staining properties are not completely understood (5), is built up in the ECM of human endometrium during the proliferative and early secretory phases of the menstrual cycle. When progesterone concentration declines at the end of the secretory phase, this embryonic-like interstitial fibrillar matrix shows focal breakdown that develops into extensive lysis at menstruation, concomitantly with more restricted sites of basement membrane disruption around vessels and glands. The shrunken tissue remnants then undergo piecemeal shedding (reviewed in ref. 6).The frequent localization of collagen fibers inside stromal cells just before and during menstruation has been interpreted as lysosomal digestion (7). The lysosomal concept of endometrial bleeding was supported by (i) the high specific activities of several acid hydrolases in this tissue (8); (ii) the increase of the nonsedimentable fraction of lysosomal enzymes during the late secretory phase (9); and (iii) the cytochemical demonstration of extracellular acid phosphatase in perimenstrual endometria (10). These observations are compatible with a role of lysosomal hydrolases, but do not prove their involvement in the ECM breakdown at menstruation.Plasmin and plasminogen activators could also be involved. The human endometrium contains both urokinase and tissue pl...