Harvard researchers have engineered mice that can menstruate — a key step in better under standing menstrual biology. Octavia Liku/ Staffwriter
At last, the women of Donner House can begin to empathize with their rodent cohabitants. Researchers at Harvard University have successfully engineered mice that can menstruate in response to the administration of specific drugs — an instrumental step in better understanding menstrual biology.
The accepted model of the endometrium, or uterine lining, can be traced back to 1923, when Dr. D. Seikba from the Pathology Institute of the University of Freiburg first outlined its bilayer structure. This model denotes two distinct layers: a functional layer that is cyclically shed and regenerated, and a deeper, basal layer that remains intact during menstruation. Over a century later, many of the underlying intracellular and genetic factors that inform menstruation remain poorly understood.
Progress in understanding menstruation has been limited by the absence of available animal models. Menstruation occurs in only 2 percent of mammals, most of which are unsuitable for usage in a laboratory setting due to practical and ethical limitations. Conversely, mammals that are widely used in laboratories, such as mice and rats, do not naturally menstruate.
Almost all mammals undergo decidualization — a process in which the uterine lining thickens in preparation for potential pregnancy. What separates menstruating and non-menstruating species is when this process occurs. In menstruating species, decidualization takes place before ovulation — if the released egg is not fertilized, the thickened tissue is then shed during menstruation. In non-menstruating animals, decidualization occurs only after the embryo is implanted. Thus, the uterine lining is never shed.
The female reproductive system has historically been underresearched due to the widespread belief that women’s bodies were “atypical” and unsuitable for scientific inquiry.
This, compounded with variations in individuals’ genetics and reproductive history, has led to a notable gap in our understanding of menstrual biology. The laboratory mouse presents a powerful, controlled model for studying the female reproductive system. Not only do mice and humans undergo comparable hormonal fluctuations, but they also share key reproductive structures.
Previously, researchers have attempted to induce menstruation in laboratory mice by creating a “pseudopregnancy.” First, researchers simulate the hormonal state of the uterus following fertilization by administering progesterone, a hormone that plays a key role in the menstrual cycle and pregnancy. Then, they mimic the physical and biochemical signals of embryo implantation by inflicting a localized injury on the uterine lining.
In the absence of a legitimate pregnancy, progesterone levels fall, and the endometrium is expelled by means of vaginal bleeding. While this model has been instrumental in advancing our understanding of menstrual biology, it ultimately fails to replicate the cyclical nature of menstruation — a key physiological feature of the human reproductive system.
To address this limitation, researchers transgenically engineered two different types of lab mice’s endometrium to react to chemical signals that mimic the hormonal triggers of menstruation. Previous research has established that signaling molecules such as calcium and cyclic adenosine monophosphate (cAMP) are paramount in mouse decidualization. Thus, the first strain was engineered such that calcium levels in their uterine walls would increase in response to the administration of targeted drugs. The second strain would operate under a similar mechanism, the only difference being that, instead of calcium, cAMP would be targeted.
Researchers created a pseudopregnancy in each respective strain by providing the mice with progesterone and then administering a drug that targeted the receptors. In both groups of mice, the amount of targeted signaling molecules present in the endometrium increased. Just four days later, as progesterone levels naturally dropped, the mice began to bleed vaginally.
Certain observed physiological changes — such as uterine expansion and vascular breakdown — were all consistent with human menstruation. Researchers determined that the induction process could be repeated as early as four days after the end of menstruation. The mice could also still become pregnant after the cycle, indicating that the uterine lining had been fully regenerated. In other words, the cyclical nature of the human menstrual cycle had, for the first time, been recreated within a laboratory mouse.
Researchers noted that in the cAMP-activated mice, decidualization patterns were dispersed throughout the uterine lining. Furthermore, hormonal control was consistent with progesterone signaling in humans. On the other hand, the calcium-activated mice displayed decidualization patterns and hormonal signaling that were more consistent with traditional rodent models.
To investigate the genetic factors underlying menstruation, researchers further analyzed the cAMP-activated mice and found that gene expression patterns during decidualization and shedding were strikingly similar to those observed in humans. Analysis of menstrual fluid revealed a 31 percent overlap in gene expression with human samples, dwarfing the anticipated 12 percent overlap.
Moreover, the analysis suggested that the mouse endometrium has a natural “maturation gradient” — multiple concentrated zones with cells at various maturity levels — rather than a cleanly cut bilayer. This gradient creates a natural cleavage point, allowing the upper layer to detach and be expelled during menstruation. These processes have yet to undergo peer review. However, if this model is successfully recreated and validated, it could redefine our understanding of reproductive biology. The study of women’s reproductive health has long been underfunded, underresearched, and stigmatized. The development of a recapitulated model of menstruation reaffirms the need to rigorously examine and inquire into processes that have historically been ignored. With this, researchers can explore how understudied menstrual conditions — such as endometriosis, uterine fibrosis, and infertility — function at the cellular level, transforming our understanding of the afflictions that have long threatened women’s health and quality of life.