Why do primates menstruate

In the decidua of elephant shrews and three of the abovementioned bats M. These cells have periodic acid-Schiff PAS —positive granules, and it has been suggested that they could be similar to the uterine natural killer cells observed in humans. They have been detected both in pregnant and nonpregnant cycles especially at the basal lamina of the endothelial cells close to the generally predetermined implantation site [ 4 , 5 , 37 , 47 , 50 ]. In the induced mouse model of menstruation, an increased presence of inflammatory mediators and leukocytes, mainly neutrophils, has been also observed after progesterone removal and beginning of bleeding [ 60 ].

The presence of spiral arteries, a key structure in human and primate endometrial vasculature [ 61 , 62 ], is a feature present in a few of the species analyzed here. Indeed, the presence of these arteries has been observed only in the spiny mouse, in the elephant shrew, and in one species of bat: the black mastiff bat M. In the spiny mouse, the formation of spiral arteries has been observed during the late secretory phase.

Moreover, in this species, also the presence of the vascular endothelial growth factor VEGF has been investigated. VEGF has been detected especially in the stroma surrounding these spiral arteries suggesting its involvement in endometrial vascular regulation [ 34 ]. While in the spiny mouse, the presence of these spiral arteries has been detected also in nonpregnant cycles, in the elephant shrew, they have been observed only in the decidua of pregnant females.

Data about nonpregnant cycles are not available [ 47 ]. In bats, spiral arteries have been observed only in the black mastiff bat. However, it seems that they are not essential for menstruation in this species. Indeed, they are mostly located in the myometrium and in the endometrial lamina basalis, becoming straighter in their terminal segments in the lamina functionalis. Moreover, they do not show any increase in coiling during the progression of the menstrual cycle as observed in primates and humans [ 4 , 63 ].

In the long-tongued bat G. In the wild fulvous fruit bat R. Premenstrual spiral arteries remodeling has not been observed in the induced mouse model of menstruation [ 34 ].

Most of the examined menstruating animals in this study, as humans and apes, are characterized by invasive implantation, while one of them, the black mastiff bat M. Interestingly, the implantation site, in all the examined species, is predetermined and restricted to a specific uterine area, while in humans and primates there is not a restriction in this regard. However, in humans, it preferentially occurs in the upper and posterior end of the simplex uterus [ 65 ]. Information about implantation on the spiny mouse is not available since until now it has not been investigated.

In elephant shrews, implantation occurs only at the inferior end of the uterine horns. The presence of the embryo at the implantation site stimulates an extensive decidual reaction and a substantial expansion of the surrounding uterine glands [ 46 ].

In this species, implantation is invasive. Initially, the syncytiotrophoblast invasion is restricted to the basement membrane of the uterine epithelium. Then, after the amniotic cavity formation, the trophoblast invades the decidua to create anchoring points and remodel the maternal capillaries in preparation for the following placenta formation [ 50 , 52 ]. As said before, in bats, implantation is restricted to a specific portion of the uterus, but there are some species-specific differences.

For example, in C. Interestingly, in the case of post-implantation delays in embryo development, trophoblastic invasiveness highly increases, penetrating also the myometrium, oviducts, and other extrauterine tissues [ 66 ]. It has been observed that C. In the closely related long-tongued bat G. Decidualization is not spontaneous and occurs only at day 15 post-coitus after the trophoblastic penetration of the endometrial stroma, characterized by extensive destruction of maternal epithelium and trophoblast penetration of maternal basement membrane [ 40 ].

The black mastiff bat, M. The implantation site is restricted to the central area of the right uterine horn. After an initial spontaneous decidualization around the vascular tuft, during implantation, the decidual reaction continues to expand along the endometrial superficial lamina functionalis. However, no trophoblastic invasion of the endometrial stroma has been observed. The trophoblast is characterized by a single layer of flattened cells connecting the blastocyst and the endometrium [ 43 ].

Mice have rapid and invasive implantation. After embryo apposition, decidualization is stimulated, and the trophoblastic cells start penetrating through the uterine luminal basal lamina entering in contact with the maternal blood to form the hemochorial placenta [ 68 ]. Looking at the summary table Table 1 is clear that some species have more human-like characteristics than others, making them more suitable animal models.

Primates, being the closest related species to humans Figure 2 , share most of their features with them, and they would be the easiest choice as animal models to study menstrual cycle and reproductive processes. However, the use of non-primate animal models in research is often preferable due to ethical considerations and the possibility of maintaining big colonies with less effort in terms of space, money, and handling.

Overview of the menstrual cycle characteristics of the cited species in comparison with the human menstrual cycle. Using non-primate animal models developing spontaneously pathologies of the reproductive system like endometriosis would be advisable. It will be important for drug testing and pathology treatments but also for improvement of assisted reproductive technologies, ovarian stimulation, and endometrial receptivity.

Bats could be good animal models in reproductive research especially in their native countries where they are present in a considerable amount. They can also be caged and maintained in captivity. However, even though they have spontaneous ovulation and true menstruation for which they could be used to study menstrual dysfunction, they lack some other important features of human physiology.

For example, the short-tailed fruit bat C. The black mastiff bat M. However, the bat M. More research should be done in these two last species of bats to further determine their reproductive physiology and their use as animal models.

The elephant shrew seems to be less suitable than the bats as an animal model. Decidualization starts spontaneously, but the embryo presence is necessary for its further development. Decidualization and endometrial shedding are localized in the polyp-like outgrowth of the uterus, and there is no information about its endocrine profile. Moreover, the lack of cervix and true vagina and the consequent inability to detect estrus changes by vaginal smear technique add an additional problem to the use of this animal in research [ 46 ].

It is also the most distantly related species to humans analyzed here Figure 2 , adding extra concerns in its selection as a preferable animal model. The most promising animal to be used as non-primate animal model is the spiny mouse A.

It could be easily bred and kept in captivity, and it has several human-like characteristics even though no data are available regarding implantation. The fact of being a rodent, like the rat and the mouse, gives this species an additional advantage to be considered as a good animal model. There is plenty of literature about rat and mouse physiology that could be used as a starting point to further investigate the spiny mouse characteristics. Moreover, most of the laboratories will have the facilities to host this new rodent species already in place, being similar to other rodents.

However, further studies have to be done in this species to better characterize its menstruation. The colony at the Hudson Institute of Medical Research in Australia is the only colony in which menstruation, in this species, has been reported in scientific journals.

The induced mouse model of menstruation is easily maintained, menstruation induction is reproducible, and the immune response during menses seems to be similar to humans. However, it does not present spiral arteries remodeling, and the induced decidualization reaction is too destructive and extensive and does not resemble the physiological process observed in humans. Anyway, the absence of detailed genetic information, techniques, and reagents, particularly antibodies, that would allow routine use of the abovementioned menstruating animal models still renders the induced mouse model of menstruation a valid alternative.

The use of naturally menstruating animal models would be recommendable because, in addition to true menstruation, they present several other human-like characteristics like long gestation with the production of one single pup, invasive placentation, and spontaneous ovulation.

Their use and more detailed characterization will allow a more comprehensive overview of all the interconnected mechanisms that lead to the evolution of these features. Moreover, the study of factors involved in severe menstrual bleeding, endometriosis, or premenstrual syndrome will be more easily studied in animal models with physiological menstruation.

Unfortunately, until now, comparative studies of different models of menstruation have been done only between the spiny mouse and the induced mouse model of menstruation [ 34 ]. Indeed, in bats, most of the studies have been observational or morphological studies, and there is almost no molecular information about them. However, there is already information about care and handling and histology descriptions since most of them have used animal models in the studies of reproductive biology especially ovarian and placentation studies [ 69—71 ].

Information on handling and husbandry is available also for elephant shrews, but it seems that females do not menstruate in captivity but enter in an anestrous state [ 49 , 51 ]. The animals listed in this review are the ones that so far are known to menstruate. It seems menstruation appeared several times during the speciation of mammals, and it is not related to just one lineage Figure 2.

Several hypotheses have been proposed during the years for menstruation evolution, but no definitive answer has been found. The first theory suggested that menstruation evolved to clean the uterus from sperm-borne pathogens introduced during coitus [ 72 ]. Then it has been argued that menstruation was necessary to conserve energy, claiming that the cyclical renewal of the endometrium would be less costly than the maintenance of a continuous metabolically active endometrium which is required for implantation [ 73 ].

However, these first theories have been criticized in favor of a new theory that defines menstruation as a nonadaptative consequence of uterine—embryo coevolution and the development of decidualization.

Indeed, to balance the increased invasiveness of the embryo, the uterus evolved increasing its cellular growth and differentiation decidualization to protect itself [ 74 ]. Since in non-menstruating species decidualization is embryo induced while in most of the menstruating species it is spontaneous, the key to menstruation seems to be the evolution of spontaneous decidualization. In the most recent theory, spontaneous decidualization evolved by genetic assimilation of the decidualization reaction, which is induced by the fetus in non-menstruating species, driven by two possible selective forces: invasive embryos and high incidence of impaired embryos [ 2 ].

The reason why only a few species and not closely related to each other seems to have spontaneous decidualization and menstruation is still unknown but recently has been suggested that nutrition omnivorous diet and food availability could have played a role in species selection [ 75 ]. Researchers should keep investigating the possible presence of other menstruating animals that maybe have been overlooked not being closely related to known menstruating species or for their lack of clear macroscopical bleeding.

As can be deduced from this review, there is a need for more basic and comparative studies to better characterize these menstruating species. The information available for most of the different non-primate menstruating species is still not enough to render these species a competitive alternative to the use of primate or mouse models Table 2.

The spiny mouse seems to be the one with more potential to become a common and valid alternative to the models. Nevertheless, other menstruating species also deserve further studies to develop a more comprehensive view of menstruation and its evolution.

Moreover, comparative studies will be necessary to test the theory of genetic assimilation. Several experiments could be set up in the lab to test this theory comparing data from menstruating and non-menstruating species bringing new knowledge on how menstruation and spontaneous decidualization evolved [ 2 ].

The availably of genetically known menstruating animal models would be also very important to test the role and the importance of genes and proteins discovered thanks to the advancement of genomics and proteomics. Indeed, to develop new therapeutic targets would be important to understand the cellular and phenotypic changes that the selected genes may mediate, their interactions, and signaling pathways [ 77 ].

Laura Catalini: literature review, manuscript drafting. Jens Fedder: work conception, critical manuscript revision, final approval of the manuscript. Johnson MH.

Google Scholar. Google Preview. The evolution of menstruation: a new model for genetic assimilation: explaining molecular origins of maternal responses to fetal invasiveness. Bioessays ; 34 : 26 — First evidence of a menstruating rodent: the spiny mouse Acomys cahirinus.

Am J Obstet Gynecol ; : Rasweiler JJ. Spontaneous decidual reactions and menstruation in the black mastiff bat, Molossus ater.

Rasweiler JJ , de Bonilla H. Menstruation in short-tailed fruit bats Carollia spp. J Reprod Fertil ; 95 : — Wild fulvous fruit bats Rousettus leschenaulti exhibit human-like menstrual cycle. Biol Reprod ; 77 : — The menstrual cycle in Elephantulus. Martin RD. The evolution of human reproduction: a primatological perspective.

Am J Phys Anthropol ; 45 : 59 — Federhen S. The NCBI taxonomy database. Nucleic Acids Res ; 40 : D — D Finn CA , Pope M. Vascular and cellular changes in the decidualized endometrium of the ovariectomized mouse following cessation of hormone treatment: a possible model for menstruation.

For a start, women are more susceptible, not less, to infections such as chlamydia and gonorrhoea during menstruation, as the cervical mucus thins out.

The iron-rich blood also serves as an attractive food source for Staphylococcus aureus , of tampon-associated toxic shock syndrome notoriety. And there is no correlation between level of promiscuity in us and our close primate relatives and heaviness of bleeding, as the theory predicts. A more plausible explanation for menstruation is that it evolved to accommodate the peculiar way in which human embryos embed into the lining of the uterus — the endometrium — during pregnancy.

In some mammals with a placenta, a fertilised embryo attaches to the endometrium only superficially. In humans and other menstruating species, implantation is deep and invasive, and requires an especially luxurious lining to develop in preparation for implantation. While other mammals are able to reabsorb the lining that adorns their fertile womb, the volume of tissue in humans is too great, so if no pregnancy ensues, it is expelled instead.

In the evolutionary cost-benefit analysis, building up the lining only when a pregnancy is on the cards — only when we ovulate once a month — could be less costly than maintaining this expensive lining indefinitely. Another key difference between menstruators and non-menstruators is in the impetus for uterine thickening. Somewhere along the human evolutionary path, the dialogue between embryo and uterus shifted, so that the signals causing the endometrium to thicken came not from the embryo, but from the mother herself.

This was one of the first ideas about menstruation. Much of the research at the beginning of the 20 century was tainted with deeply rooted superstitions about menstruating women, some of which are still alive today. In , he conducted experiments in which menstruating and not menstruating women were to handle flowers.

Schick came to a conclusion that the former secrete a toxic substance from their skin, which causes the flowers to wilt. According to Schick, menotoxins stopped the yeast growth which prevented the dough from rising. It was impossible, though, to isolate those chemical compounds or to determine their chemical makeup.

Obviously, such claims were extremely harmful to women who were, from then on, treated as lesser or even disgusting. Attempts at studying the menotoxin were made until the 70s! In , Margie Profet, then from the University of California, Berkeley, suggested that menstruation functions as a defence mechanism against pathogens transported to the uterus with sperm.

In her view, menstruation was a means to reduce the chances of contracting venereal diseases. For the organism, it is much more efficient to get rid of the excess blood and rebuild the defects in the uterine wall.

Colin Finn, then from University of Liverpool, had a similar suggestion in This thick lining is able to host the embryo perfectly, but only for a couple of days. Deena Emera, from Yale University in New Haven, in her article has noticed that in the majority of mammals the changes in the uterus are prompted by signals coming from the embryo. As a result, the uterine lining thickens in response to pregnancy.

The uniqueness of menstruation to woman and a few other primates may not have been very apparent to early man. The animal most closely associated with him—and probably the only one with a reasonable possibility of having its vaginal discharges noticed—would have been the bitch, and this animal does periodically show a sanguinous discharge from the vagina.

In any case, in pre-Darwinian times man was not aware? All rights reserved. Nevertheless, it is interesting that Isodore of Seville [1] stated that "women are the only menstrual animal. Because of its occasionally putrescent appearance and smell and the attendant pain, it had been assumed since Hippocrates that the period was a form of detoxication of the blood poisoning that women encountered [3].

Isodore said that "the menstrual flow is woman's superfluous blood," and Trotula ofSalerno in the eleventh century [4], quoting no less an authority than Galen, gave very precise details for the treatment ofwomen who failed to menstruate: "If the menses are lacking and the woman is thin, the vein under the inner arch ofher foot, the internal saphenous, should be lanced. On the first day from one foot, on the following day from the other foot—the blood to be drawn as the case demands.