“The Curse”: A 21st Century Perspective of Models of Its Molecular Basis

“The Curse,” the “Period,” “Riding the Crimson Wave,” “Aunt Flo,” and “the Red Coats are Coming” (euphemisms for menstrual bleeding) capture the long history of taboo and mystery of menstruation, a critical component of reproductive capability that has had major effects on social structures and equality movements (1). With the advent of steroid hormone contraceptives, withdrawal bleeding seemingly mimicked the natural menstrual cycle with its predictable bleeding pattern, although unpredictable bleeding has limited their usefulness for long-term use for many women, depending on the preparation, dose, dosing schedule, and mode of delivery. Indeed, some have questioned the value of having menstruation at all, and in appropriate clinical situations, this can be of value. There is also a silent epidemic that prevails in women not on contraceptive steroids and who experience abnormal (“dysfunctional”) uterine bleeding, a major cause of hysterectomy (2). Despite millions of women over millennia experiencing the normal physiologic process of menstruation and abnormalities in uterine bleeding, models of menstruation and mechanisms underlying endometrial tissue desquamation and bleeding, repair and regeneration, and abnormal bleeding have had mixed results and applicability to human biology and pathophysiology. In this issue of Endocrinology (3), a unique approach using cultured human endometrial explants and advanced techniques of laser capture microscopy and whole-genome transcriptomics has contributed to our basic knowledge of initiation of menstrual bleeding. However, much remains for this and future generations to investigate to prevent and treat disorders of endometrial/uterine bleeding that affect millions of women worldwide. Menstruation is the shedding of most of the functionalis layer of the endometrium, accompanied by bleeding, that occurs at the end of each menstrual cycle during a woman’s reproductive life. The shedding is not uniform, it occurs at focal points, progressing over 4–5 d until most of the tissue is lost, and it repairs very rapidly. Scanning electron microscopy (4) reveals that small lesions are apparent in the luminal epithelium as early as d 28 of the normalized cycle. The very rapid degeneration of the functionalis layer exposes open blood vessels and glands. It can therefore be surmised that the primary event initiating menstruation is tissue destruction and that loss of blood vessel integrity is one consequence of this. Shedding and repair occur simultaneously at adjacent sites, making these processes exceedingly difficult to study. Menstruation differs from wounding of other tissues in that menstrual blood does not easily clot and that the repair occurs without scarring. Menstrual bleeding is initiated by the fall in circulating levels of estradiol (E2) and progesterone (P) that result from the demise of the corpus luteum. The key evidence that menstruation is triggered by a loss of steroid support of the tissue is that 1) if P levels are artificially maintained, menstruation does not occur; 2) administration of mifepristone, a P receptor (R) antagonist, during the secretory phase results in uterine bleeding; and 3) withdrawal of E2 and P, as in the case of cyclic contraceptive use, results in uterine bleeding. Importantly, menstruation occurs only in women, a few old world monkeys, the elephant shrew, and certain bats. In these species, differentiation (“decidualization”) of the endometrial stroma is initiated during each cycle,