Leukocyte iniltration is considered key to both endometrial extracellular matrix breakdown and repair of the functionalis layer. The term "inflammatory tightrope" refers to the ability of macrophages to assume phenotypes that vary from proinflammatory and phagocytic to immunosuppressive and reparative. These are likely relevant to menstruation, in which tissue breakdown and restoration occur simultaneously (Evans, 2012; Maybin, 2015). Invading leukocytes secrete enzymes that are members of the matrix metalloprotease (MMP) family. These add to the proteases already produced by endometrial stromal cells and efectively initiate matrix degradation. During menses as tissue shedding is completed, microenvironment-regulated changes in macrophage phenotype then promote repair and resolution (Evans, 2012; Thiruchelvam, 2013).
The classic study by Markee (1940) described tissue and vascular alterations in endometrium before menstruation. With endometrial regression, spiral artery coiling becomes suiciently severe that resistance to blood flow rises to cause endometrial hypoxia. Resultant stasis is the primary cause of endometrial ischemia and tissue degeneration. Intense spiral artery vasoconstriction precedes menstruation and also serves to limit menstrual blood loss.
Prostaglandins playia key role in the events leading to menstruation that include vasoconstriction, myometrial contractions, and upregulation of proinflammatory responses (Abel, 2002).
Large amounts of prostaglandins are present in menstrual blood. Painful menstruation is common and likely caused by myometrial contractions and uterine ischemia. This response is believed to be mediated by prostaglandin F2a (PGF2a)-induced spiral artery vasoconstriction, which render the uppermost endometrial zones hypoxic. The hypoxic environment is a potent inducer of angiogenesis and vascular permeability factors such as VEGF.
Progesterone withdrawal increases expression of cyclooxygenase 2 (COX-2), also called prostaglandin synthase 2, to synthesize prostaglandins. Withdrawal also lowers expression of 15-hydroxyprostaglandin dehydrogenase (PGDH), which degrades prostaglandins (Casey, 1980, 1989). The net result is higher prostaglandin production by endometrial stromal cells and greater prostaglandin-receptor density on blood vessels and surrounding cells.
Actual menstrual bleeding follows rupture of spiral arterioles and consequent hematoma formation. With a hematoma, the superficial endometrium is distended and ruptures. Subsequently, fissures develop in the adjacent functionalis layer, and blood and tissue fragments are sloughed. Hemorrhage stops with arteriolar constriction. Changes that accompany partial tissue necrosis also serve to seal vessel tips.
he endometrial surface is restored by growth of langes, or collars, that form the everted free ends of the endometrial glands (Markee, 1940). These flanges rapidly grow in diameter, and epithelial continuity is reestablished by fusion of the edges of these sheets of migrating cells.