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Considering it affects half the population directly, and much of the other half indirectly, menstruation is remarkably poorly investigated, let alone understood. Why humans menstruate – while most mammals do not – has been the subject of a longstanding and often esoteric debate. Günter Wagner and colleagues recently rekindled this debate by emphasizing the evolutionary basis of menstruation. More accurately, they focused on “spontaneous” decidualization, a process that precedes the shedding of the endometrium in all known menstruating species (i.e. higher primates, some bats, and the elephant shrew) 1.

Decidualization denotes the differentiation of endometrial stromal cells (ESCs) into epitheloid decidual cells 2. Among other functions, decidualization confers maternal immunotolerance to the semi-allogeneic embryo, rendering it an obligatory process for successful pregnancy in all species with invading placentae. A rise in cellular cAMP levels initiates this differentiation process whereas maintenance of the decidual phenotype is strictly dependent on continuous progesterone signaling. The Wagner lab elegantly demonstrated that the decidual response is evolutionarily hardwired by transposable elements (TEs) found only in placental mammals. These TEs introduced cAMP- and progesterone-responsive regulatory elements that modulate the expression of large gene networks essential for controlled invasion of fetal trophoblast. In most mammals, embryonic signals drive the rise in endometrial cAMP levels, thus ensuring that decidualization is strictly coupled to pregnancy. Wagner and colleagues argued that, through a process termed genetic assimilation, maternal signals acquired control of the endometrial cAMP pathway in menstruating species. Consequently, the decidual process is now “spontaneous”, meaning it is now initiated in each cycle.

Differentiating ESCs first mount an acute inflammatory response, which in turn renders the uterus transiently receptive to implantation. Continuous progesterone signaling then drives an anti-inflammatory response essential for post-implantation embryo. Decidual cells are exquisitely adapted to respond to embryonic signals, indicating that they function as biosensors that fine-tune the maternal response to individual embryos. In the absence of pregnancy, a fall in ovarian progesterone production reactivates the expression of inflammatory mediators, triggering apoptosis, influx of immune cells, extracellular matrix breakdown, and menstrual shedding. This intrinsic ability to self-destruct implies that “spontaneous” decidualization also serves as a mechanism for prompt rejection of an unwanted conceptus. It has been estimated that between 30% and 60% of all human embryos are disposed of this way before any telltale signs of pregnancy.

Reproductive success in menstruating species depends on deeply invading hemochorial placentas that support one or two offspring per pregnancy. Human pre-implantation embryos display intrinsic genomic instability, carrying segmental imbalances and aneuploidies found otherwise only in cancer cells. Thus, it seems axiomatic that “spontaneous” decidualization emerged as the maternal riposte to invasive and often chromosomally chaotic embryos. This notion is supported by recent studies indicating that recurrent miscarriage is caused by an aberrant decidual response, which facilitates out-of phase implantation of poor quality embryos and compromises post-implantation development of high-quality embryos 2.

Thus – argues Wagner and colleagues – menstruation per se is nothing more than the price for a beneficial reproductive trait, i.e. spontaneous decidualization. This misses an important point. Menstruation imposes the need for constant recruitment of mesenchymal stem cells to regenerate and renew the endometrium each cycle. Endometrial mesenchymal stem cells are immuno-privileged compared to other types of adult stem cells. They are recruited to the endometrium in response to hypoxic and inflammatory stimuli, which in most mammals only happens after parturition. Arguably, the process of constant renewal in menstruating species may bestow extraordinary plasticity on the endometrium, enabling it to respond to highly variable embryos, to learn from previous reproductive events, and to adapt to changing ecology. This innate adaptability explains why most women suffering miscarriage, whether sporadic or several consecutive losses, will achieve a successful pregnancy. Harnessing the mechanisms underpinning uterine plasticity may equally hold the key to preventing obstetrical disorders associated with impaired placentation, such as pre-eclampsia, fetal growth restriction, and preterm birth.

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