Aspects of human uterine creatine metabolism during the menstrual cycle and at term pregnancy†.

Creatine metabolism likely contributes to energy homeostasis in the human uterus, but whether this organ synthesizes creatine and whether creatine metabolism is adjusted throughout the menstrual cycle and with pregnancy are largely unknown. This study determined endometrial protein expression of creatine-synthesizing enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), creatine kinase (CKBB), and the creatine transporter (SLC6A8) throughout the menstrual cycle in fertile and primary infertile women. It also characterized creatine metabolism at term pregnancy, measuring aspects of creatine metabolism in myometrial and decidual tissue. In endometrial samples, AGAT, GAMT, SLC6A8, and CKBB were expressed in glandular and luminal epithelial cells. Except for SLC6A8, the other proteins were also located in stromal cells. Irrespective of fertility, AGAT, GAMT, and SLC6A8 high-intensity immunohistochemical staining was greatest in the early secretory phase of the menstrual cycle. During the proliferative phase, staining for SLC6A8 protein was greater (P = 0.01) in the primary infertile compared with the fertile group. Both layers of the term pregnant uterus contained creatine, phosphocreatine, guanidinoacetic acid, arginine, glycine, and methionine; detectable gene and protein expression of AGAT, GAMT, CKBB, and ubiquitous mitochondrial CK (uMt-CK); and gene expression of SLC6A8. The proteins AGAT, GAMT, CKBB, and SLC6A8 were uniformly distributed in the myometrium and localized to the decidual glands. In conclusion, endometrial tissue has the capacity to produce creatine and its capacity is highest around the time of fertilization and implantation. Both layers of the term pregnant uterus also contained all the enzymatic machinery and substrates of creatine metabolism.

Good things come to those who mate: analysis of the mating behaviour in the menstruating rodent, Acomys cahirinus.

BACKGROUND: The Egyptian spiny mouse (Acomys cahirinus) is the only known rodent to exhibit true, human-like menstruation and postpartum ovulation, and is an important new model for reproductive studies. Spiny mice do not produce a visible copulatory plug, and calculation of gestational age is therefore restricted by the need to use mated postpartum dams. The current inefficient method of monitoring until parturition to provide a subsequent estimate of gestational age increases study duration and costs. This study addressed this issue by comparing the mating behaviour of spiny mice across the menstrual cycle and proposes a more accurate method for staging and pairing animals that provides reliable estimates of gestational age. In experiment 1, mating behaviour was recorded overnight to collect data on mounting, intromission, and ejaculation (n = 5 pairs per stage) in spiny mice paired at menses and at early and late follicular and luteal phases of the menstrual cycle. In experiment 2, female spiny mice were paired at the follicular or luteal phases of the menstrual cycle to determine any effect on the pairing-birth interval (n = 10 pairs). RESULTS: We report a broad mating window of ~ 3 days during the follicular phase and early luteal phase of spiny mice. Males displayed a discrete 'foot twitch' behaviour during intromission and a brief copulatory lock during ejaculation. Litters were delivered after 40-43 days if pairing occurred during the mating window, compared with 46-48 days for spiny mice paired in the late luteal phase. When pairing occurred during the late luteal phase or menses no mating activity was observed during the recording period. CONCLUSION: This study clearly demonstrates an effect of the menstrual cycle on mating behaviour and pregnancy in the spiny mouse and provides a reliable and more effective protocol for estimating gestational age without the need for postpartum dams.

Reproductive aging and menopause-like transition in the menstruating spiny mouse (Acomys cahirinus).

STUDY QUESTION: Does the naturally menstruating spiny mouse go through menopause? SUMMARY ANSWER: Our study is the first to show a natural and gradual menopausal transition in a rodent. WHAT IS KNOWN ALREADY: Age-related depletion of the human ovarian reserve (OvR) leads to menopause, the permanent cessation of menstruation and reproduction. Current rodent models of menopause are inappropriate for inferences of the human condition, as reproductive senescence is abrupt or induced through ovariectomy. The spiny mouse is the only confirmed rodent with a naturally occurring menstrual cycle. STUDY DESIGN, SIZE, DURATION: Histological assessment of virgin spiny mice occurred in females aged 6 months (n = 14), 1 year (n = 7), 2 years (n = 13), 3 years (n = 9) and 4 years (n = 9). Endocrinology was assessed in a further 9 females per age group. Five animals per group were used for ovarian stereology with additional ovaries collected at prenatal Day 35 (n = 3), day of birth (n = 5), postnatal Days 35 (n = 5) and 100 (n = 5) and 15 months (n = 5). PARTICIPANTS/MATERIALS, SETTING, METHODS: Morphological changes in the reproductive system were examined using hematoxylin and eosin stains. Proliferating cell nuclear antigen immunohistochemistry assessed endometrial proliferation and sex steroids estradiol and testosterone were assayed using commercial ELISA kits. MAIN RESULTS AND THE ROLE OF CHANCE: The proportion of females actively cycling was 86% at 6 months, 71% at 1 year, 69% at 2 years, 56% at 3 years and 44% at 4 years. Uterine and ovarian weights declined steadily from 1 year in all groups and corresponded with loss of uterine proliferation (P < 0.01). Estradiol was significantly decreased at 1 and 2 years compared to 6-month-old females, before becoming erratic at 3 and 4 years, with no changes in testosterone across any age. Fully formed primordial follicles were observed in prenatal ovaries. Aging impacted on both OvR and growing follicle numbers (P < 0.001-0.0001). After the age of 3 years, the follicle decline rate increased more than 5-fold. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This is a descriptive study in a novel research rodent whereby reagents validated for use in the spiny mouse were limited. WIDER IMPLICATIONS OF THE FINDINGS: The gradual, rather than sudden, menopausal transition suggests that the spiny mouse is a more appropriate perimenopausal model than the current rodent models in which to examine the neuroendocrine pathways that encompass all hormonal interactions in the hypothalamic-pituitary-gonadal axis. The logistic, ethical and economic advantages of such a model may reduce our reliance on primates in menopause research and enable more thorough and invasive investigation than is possible in humans. STUDY FUNDING/COMPETING INTEREST(S): Hudson Institute is supported by the Victorian State Government Operational Infrastructure Scheme. The authors declare no competing interests.

Postpartum ovulation and early pregnancy in the menstruating spiny mouse, Acomys cahirinus.

Egyptian spiny mice are the only known species to have human-like menstruation and a postpartum ovulation. Unfortunately, no endocrine or morphological evidence has been provided for a postpartum ovulation in spiny mice, and while later stages of pregnancy have been well studied, early events including embryo implantation and spiral artery remodelling have not been reported. This study compared the sex steroid endocrinology and reproductive tract morphology of dams at eight timepoints (n = 40) postpartum to determine the timing of ovulation and the timing and invasiveness of embryo implantation in A. cahirinus. Reproductive tracts were fixed and stained for histology and immunohistochemistry, and plasma was prepared for enzyme-linked immunosorbent assay. Ovarian histology and estradiol-17B concentrations indicate ovulation within 48 h of parturition and then immediate resumption of follicular growth. Uterine histology and immunohistochemistry revealed progressive epithelial repair, endometrial growth and spiral artery assembly and remodelling in dams postpartum. Blastocysts were seen in the uterine lumen at day 4-5 postpartum and embryos had implanted superficially with minimal stromal invasion by day 5-6. This study provides further evidence for the unique, humanesque reproductive biology of spiny mice and for a postpartum ovulation using endocrine and morphological changes observed during early pregnancy. Taken together, our data suggest that spiny mice may act as appropriate models of human pregnancy disorders such as implantation failure or pre-eclampsia.

The Spiny Mouse-A Menstruating Rodent to Build a Bridge From Bench to Bedside.

Menstruation, the cyclical breakdown of the uterine lining, is arguably one of evolution's most mysterious reproductive strategies. The complexity and rarity of menstruation within the animal kingdom is undoubtedly a leading contributor to our current lack of understanding about menstrual function and disorders. In particular, the molecular and environmental mechanisms that drive menstrual and fertility dysregulation remain ambiguous, owing to the restricted opportunities to study menstruation and model menstrual disorders in species outside the primates. The recent discovery of naturally occurring menstruation in the Egyptian spiny mouse (Acomys cahirinus) offers a new laboratory model with significant benefits for prospective research in women's health. This review summarises current knowledge of spiny mouse menstruation, with an emphasis on spiral artery formation, inflammation and endocrinology. We offer a new perspective on cycle variation in menstrual bleeding between individual animals, and propose that this is indicative of fertility success. We discuss how we can harness our knowledge of the unique physiology of the spiny mouse to better understand vascular remodelling and its implications for successful implantation, placentation, and foetal development. Our research suggests that the spiny mouse has the potential as a translational research model to bridge the gap between bench to bedside and provide improved reproductive health outcomes for women.

A human-based assisted reproduction protocol for the menstruating spiny mouse, Acomys cahirinus.

The Egyptian or Common spiny mouse (A. cahirinus) is the first rodent species to show human-like menstruation and spontaneous decidualisation. We consider from these, and its other, human-like characteristics that this species will be a more useful and appropriate small animal model for human reproductive studies. Based on this, there is a need to develop specific laboratory-based assisted reproduction protocols including superovulation, in-vitro fertilisation, embryo cryopreservation and transfer to expand and make this model more relevant. Because standard rodent superovulation has not been successful in the spiny mouse, we have selected to test a human protocol. Female spiny mice will receive a subcutaneous GnRH agonist implant and be allowed to recover. Menstrual cycle lengths will then be allowed to stabilize prior to ovarian stimulation. After recovery, females will be injected IP once a day for 4 days with a FSH analogue, to induce follicular growth, and on day 5 will be injected IP with a hCG analogue to trigger ovulation. Females will either be culled 36hrs after trigger to collect oocytes or immediately paired with a stud male and two cell embryos collected 48hrs later. Mature oocytes will be inseminated using fresh spiny mouse spermatozoa and all in-vitro grown and in-vivo collected two cell embryos will be cryopreserved using methods developed in a close spiny mouse relative, the Mongolian gerbil. For embryo transfer, vitrified embryos will be rapidly warmed and non-surgically transferred to surrogate mice. Surrogates will be monitored until pregnancy is apparent (roughly 30 days) and then left undisturbed until birth, 38-40 days after transfer. By successfully developing robust assisted reproduction protocols in A. cahirinus we will be able to use this rodent as a more effective model for human reproduction.

Creatine metabolism in the uterus: potential implications for reproductive biology.

Creatine is an amino acid derivative synthesized from arginine, glycine and methionine. It serves as the substrate for the creatine kinase system, which is vital for maintaining ATP levels in tissues with high and fluctuating energy demand. There exists evidence that the creatine kinase system operates in both the endometrial and myometrial layers of the uterus. While use and regulation of this system in the uterus are not well understood, it is likely to be important given uterine tissues undergo phases of increased energy demand during certain stages of the female reproductive cycle, pregnancy, and parturition. This review discusses known adaptations of creatine metabolism in the uterus during the reproductive cycle (both estrous and menstrual), pregnancy and parturition, highlighting possible links to fertility and the existing knowledge gaps. Specifically, we discuss the adaptations and regulation of uterine creatine metabolite levels, cell creatine transport, de novo creatine synthesis, and creatine kinase expression in the various layers and cell types of the uterus. Finally, we discuss the effects of dietary creatine on uterine metabolism. In summary, there is growing evidence that creatine metabolism is up-regulated in uterine tissues during phases where energy demand is increased. While it remains unclear how important these adaptations are in the maintenance of healthy uterine function, furthering our understanding of uterine creatine metabolism may uncover strategies to combat poor embryo implantation and failure to conceive, as well as enhancing uterine contractile performance during labor.

Pseudopregnancy and reproductive cycle synchronisation cannot be induced using conventional methods in the spiny mouse (Acomys cahirinus).

The menstruating spiny mouse is the first rodent identified to exhibit natural spontaneous decidualisation, cyclical endometrial shedding and regeneration. While the spiny mouse shares several primate-like characteristics in its reproductive biology, it has not been established whether pseudopregnancy can be induced or if its cycles can be synchronised as in non-human mammals. Here we describe attempts to induce pseudopregnancy and synchronisation of menstrual cycles (i.e. Whitten effect) in spiny mice. Virgin females (n=3-8 per group) underwent one of the following procedures to induce pseudopregnancy: daily vaginal lavage only (control), progesterone injection, mechanical stimulation of the cervix and sterile mating. A separate cohort was also exposed to male-soiled bedding to assess the Whitten effect. Pseudopregnancy was deemed successful if females presented with extended (>12 consecutive days) leukocytic vaginal cytology. No female from any method of induction met this criterion. In addition, the menstrual cycles of a group of six females could not be synchronised, nor immediate ovulation induced via exposure to male-soiled bedding. These responses indicate that the spiny mouse does not behave as a typical rodent. Like higher-order primates, the spiny mouse exhibits a relatively rare reproductive strategy, of failure to show pseudopregnancy or cyclical synchronisation. This is further endorsement of the use of this species as a versatile animal model for translational studies of menstruation and fertility.

Monkeys, mice and menses: the bloody anomaly of the spiny mouse.

The common spiny mouse (Acomys cahirinus) is the only known rodent to demonstrate a myriad of physiological processes unseen in their murid relatives. The most recently discovered of these uncharacteristic traits: spontaneous decidual transformation of the uterus in virgin females, preceding menstruation. Menstruation occurring without experimental intervention in rodents has not been documented elsewhere to date, and natural menstruation is indeed rare in the animal kingdom outside of higher order primates. This review briefly summarises the current knowledge of spiny mouse biology and taxonomy, and explores their endocrinology which may aid in our understanding of the evolution of menstruation in this species. We propose that DHEA, synthesised by the spiny mouse (but not other rodents), humans and other menstruating primates, is integral in spontaneous decidualisation and therefore menstruation. We discuss both physiological and behavioural attributes across the menstrual cycle in the spiny mouse analogous to those observed in other menstruating species, including premenstrual syndrome. We further encourage the use of the spiny mouse as a small animal model of menstruation and female reproductive biology.

Altered exploratory behaviour and increased food intake in the spiny mouse before menstruation: a unique pre-clinical model for examining premenstrual syndrome.

STUDY QUESTION: Does the newly discovered menstruating spiny mouse exhibit behavioural and metabolic changes in correlation with premenstrual phases of the menstrual cycle? SUMMARY ANSWER: This is the first report of cycle variability in the exploratory and interactive behaviour, and food consumption in menstruating spiny mice, and demonstrates that physiological changes are also dependent on within-subject variation. WHAT IS KNOWN ALREADY: Premenstrual syndrome (PMS) is a prominent cyclic disorder that affects millions of women worldwide. More than 70% of women endure symptoms of impending menstruation, such as bloating, abdominal cramping and nausea to some degree. Consequently, ~8% of women experience recurrent physical and emotional symptoms which are extreme enough to disrupt daily life and seek intervention. Due to a lack of an appropriate animal model, the mechanisms underlying PMS are poorly understood, and subsequently, effective treatments are limited. STUDY DESIGN, SIZE, DURATION: This study analyses the changes in behavioural responses to the investigator during vaginal lavage (n = 14), exploratory behaviour (n = 11) and metabolism (n = 20) across the menstrual cycle in the spiny mouse (Acomys cahirinus). PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed vaginal lavages on virgin spiny mice (6-8 months of age) and subjected each cohort of females to repeated measures for vaginal lavage, exploratory behaviour and metabolism. Stages of the menstrual cycle were designated as early follicular, late follicular, early luteal, late luteal, early menstrual and late menstrual, with the late luteal and early menstrual phases considered as premenstrual phases and analysed using generalized estimating equations. For vaginal lavage, the behavioural responses to researcher handling were scored on an increasing scale of severity during the lavage process (e.g. restraint, frequency of vocalizations, total handling time). For exploratory behaviour, exploration, memory and sociability were assessed through subjection to Open Field (OF), Novel Object Recognition (NORT), Social Novelty (SN) and Elevated Plus Maze (EPM) tests. For metabolism, physiological changes were measured over a 24-h period in metabolic cages. Results are mean ± SD with statistical significance set to P < 0.05. MAIN RESULTS AND THE ROLE OF CHANCE: Qualitative behavioural assessment showed that compared to early follicular controls, during premenstrual phases, cycling females had significantly increased probability of: manifesting difficulties during restraint (4×, P < 0.01), vocalizing (8×, P < 0.01) and exhibiting isolation in the cage (40×, P = 0.041). We saw significant increases in handling time during the premenstrual phase in cycling females (76 ± 16 s) compared to controls (55 ± 7 s, P < 0.001). For exploratory behaviour, cycling females in their early menstrual phase travelled significantly less distance in the outer zone of the OF arena (13.3 ± 9.0 m) than females in their early luteal phase (22.3 ± 9.9 m, P = 0.038) and at significantly reduced velocities (40.2 ± 10.5 mm/s and 78.8 ± 31.0 mm/s, respectively, P = 0.006). These females also had fewer entries into the EPM open arms during the same phases (9.6 ± 6.1 and versus 20.0 ± 7.2, respectively, P = 0.030) and travelled less distance (3.2 ± 2.8 m versus 7.0 ± 5.5 m, respectively, P = 0.026). No differences were observed in NORT or SN across the cycle. In the metabolism studies, spiny mice demonstrated a significant increase in food consumption (percentage of body weight) during the early follicular and late luteal phases (3.9 ± 2.4% and 3.8 ± 2.1%, respectively) compared to the late follicular phase (2.3 ± 2.6%, P = 0.015). LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This is an observational study to determine fundamental changes in behaviour and metabolism in a novel species, and as such, lacks commercially available laboratory reagents and protocols specific to the spiny mouse. WIDER IMPLICATIONS OF THE FINDINGS: The timing of these behavioural and physiological changes suggests that spiny mice exhibit symptoms analogous to PMS in higher order primates, thus providing a pre-clinical model for testing novel interventions to alleviate premenstrual symptoms and overcoming many limitations associated with this research area. STUDY FUNDING/COMPETING INTEREST(S): N.B. is supported by a Research Training Program stipend through Monash University. J.E. is supported by a Fellowship awarded by the Peter Fielding Foundation. The Hudson Institute of Medical Research is supported by the Victorian Government Operational Research Infrastructure Support. The authors declare no conflicts of interest.

Characterization of human-like menstruation in the spiny mouse: comparative studies with the human and induced mouse model.

STUDY QUESTION: Is the newly discovered menstruating rodent, the spiny mouse, a valid model for studying endometrial morphology and menstruation? SUMMARY ANSWER: Our study is the first to demonstrate a primate-like pattern of natural menstruation in a rodent, with decidualization, spiral arteriole remodeling and piece-meal endometrial shedding. WHAT IS KNOWN ALREADY: The spiny mouse has a naturally occurring menstrual cycle. This unique feature has the potential to reduce the heavy reliance on primates and provide a more appropriate small animal model for menstrual physiology research. STUDY DESIGN, SIZE, DURATION: This study compares morphological changes in the endometrium during early, mid and late menstruation of the spiny mouse (n = 39), human (n = 9) and the induced mouse model of menstruation (n = 17). PARTICIPANTS/MATERIALS, SETTING, METHODS: We assessed tissue morphology with hematoxylin and eosin and erythrocyte patterns with Mallory's trichrome. We conducted staining for neutrophil gelatinase associated lipocalin (NGAL), cytokeratin and interleukin-11 (IL-11) in all species. We used double immunofluorescence staining for vascular endothelial growth factor and alpha-smooth muscle actin to detect vasculature remodeling and western immunoblot to detect interleukin-8 (IL-8) and macrophage migration inhibitory factor (MIF) in the menstrual fluid of spiny mice. MAIN RESULTS AND THE ROLE OF CHANCE: Menstruation occurs in the spiny mouse over a 72-h period, with heaviest menstrual breakdown occurring 24 h after initial observation of red blood cells in the vaginal cytology. During menstruation, the endometrium of the spiny mouse appeared to resemble human menstrual shedding with focal epithelial breakdown observed in conjunction with lysis of underlying stroma and detection of IL-8 and MIF in menstrual fluid. The mouse exhibits extensive decidualization prior to induced menses, with transformation of the entire uterine horn and cytokeratin expression absent until initiation of repair. Decidualization occurred spontaneously and was less marked in the spiny mouse, where epithelial integrity remained intact. In all species, the decidua was positive for IL-11 secretion and neutrophil recruitment was similar in each. Spiral arteriole formation was confirmed in the spiny mouse. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This is a descriptive study comparing primarily morphological traits between the spiny mouse, the mouse and the human. Reagents specific to the spiny mouse were limited and resources for global use of this novel species are few. WIDER IMPLICATIONS OF THE FINDINGS: Our work supports the spiny mouse as a viable model, sharing many attributes of physiological menstruation with humans. The strength of a natural as opposed to an artificial model is validated through the striking similarities observed between the spiny mouse and human in uterine breakdown. The spiny mouse may be highly useful in large-scale investigations of menstruation and menstrual disorders. STUDY FUNDING/COMPETING INTEREST(S): N.B. and S.R. are each recipients of a Research Training Program scholarship supported by Monash University. This work was supported by the Victorian Government Operational Infrastructure and laboratory funds to H.D. The authors declare no competing interests.

A missing piece: the spiny mouse and the puzzle of menstruating species.

We recently discovered the first known menstruating rodent. With the exception of four bats and the elephant shrew, the common spiny mouse (Acomys cahirinus) is the only species outside the primate order to exhibit menses. There are few widely accepted theories on why menstruation developed as the preferred reproductive strategy of these select mammals, all of which reference the evolution of spontaneous decidualisation prior to menstrual shedding. Though menstruating species share several reproductive traits, there has been no identifiable feature unique to menstruating species. Such a feature might suggest why spontaneous decidualisation, and thus menstruation, evolved in these species. We propose that a ≥3-fold increase in progesterone during the luteal phase of the reproductive cycle is a unique characteristic linking menstruating species. We discuss spontaneous decidualisation as a consequence of high progesterone, and the potential role of prolactin in screening for defective embryos in these species to aid in minimising implantation of abnormal embryos. We further explore the possible impact of nutrition in selecting species to undergo spontaneous decidualisation and subsequent menstruation. We summarise the current knowledge of menstruation, discuss current pre-clinical models of menstruation and how the spiny mouse may benefit advancing our understanding of this rare biological phenomenon.

First evidence of a menstruating rodent: the spiny mouse (Acomys cahirinus).

BACKGROUND: Advances in research relating to menstruation and associated disorders (eg, endometriosis and premenstrual syndrome) have been hindered by the lack of an appropriate animal model. Menstruation, the cyclical shedding of the decidualized endometrium in the absence of pregnancy, is believed to be limited to 78 higher-order primates (human beings and Old World monkeys), 4 species of bat, and the elephant shrew. This represents only 1.5% of the known 5502 mammalian species and <0.09% of these are nonprimates. Thus, many aspects of menstruation remain poorly understood, limiting the development of effective treatments for women with menstrual disorders. Menstruation occurs as a consequence of progesterone priming of the endometrial stroma and a spontaneous decidual reaction. At the end of each infertile cycle as progesterone levels decline the uterus is unable to maintain this terminally differentiated stroma and the superficial endometrium is shed. True menstruation has never been reported in rodents. OBJECTIVE: Here we describe the first observation of menstruation in a rodent, the spiny mouse (Acomys cahirinus). STUDY DESIGN: Virgin female spiny mice (n = 14) aged 12-16 weeks were sampled through daily vaginal lavage for 2 complete reproductive cycles. Stage-specific collection of reproductive tissue and plasma was used for histology, prolactin immunohistochemistry, and enzyme-linked immunosorbent assay of progesterone (n = 4-5/stage of the menstrual cycle). Normally distributed data are reported as the mean ± SE and significant differences calculated using a 1-way analysis of variance. Nonnormal data are displayed as the median values of replicates (with interquartile range) and significant differences calculated using Kruskal-Wallis test. RESULTS: Mean menstrual cycle length was 8.7 ± 0.4 days with red blood cells observed in the lavages over 3.0 ± 0.2 days. Cyclic endometrial shedding and blood in the vaginal canal concluding with each infertile cycle was confirmed in all virgin females. The endometrium was thickest during the luteal phase at 322.6 µm (254.8, 512.2), when plasma progesterone peaked at 102.1 ng/mL (70.1, 198.6) and the optical density for prolactin immunoreactivity was strongest (0.071 ± 0.01 arbitrary units). CONCLUSION: The spiny mouse undergoes spontaneous decidualization, demonstrating for the first time menstruation in a rodent. The spiny mouse provides a readily accessible nonprimate model to study the mechanisms of menstrual shedding and repair, and may therefore be useful in furthering studies of human menstrual and pregnancy-associated disorders.