Lab mice can now have periods like humans

Efforts to study the female reproductive system have long been set back by societal stigma—but also by the problematic fact that most laboratory animals don’t menstruate. Now, researchers have engineered mice that get a period in response to certain drugs, according to a preprint posted to bioRxiv this month. “The model is unique and takes a novel approach to inducing menstruation,” says Warren Nothnick, a reproductive scientist at the University of Kansas Medical Center not involved with the work, which has not been peer reviewed. The mice could be used to study reproductive health conditions such as endometriosis, Nothnick says. The team also plans to use the new model to better understand and treat heavy menstrual bleeding. Nearly all mammals support a pregnancy by thickening the lining of the uterus, or endometrium—specifically, its so-called functional layer, closest to the inside of the uterus. In most mammals, this process, called decidualization, only happens during pregnancy. But among the handful of animals that menstruate—which include large primates, four bat species, and the elephant shrew—the functional layer thickens before the release of an egg from the ovary. The layer then breaks down and is shed if no viable embryo appears. To study menstruation, researchers can “trick” mice into a pseudopregnant state by raising progesterone—a hormone that mounts during pregnancy—and by injecting fluid that, by pushing against the endometrium, is thought to mimic implantation. When progesterone treatment is withdrawn, the uterine cells are shed. But as a model for the real thing, that artificial period has limitations. The surprise discovery in 2016 that the African spiny mouse (Acomys cahirinus) has menstrual cycles offered researchers a natural way to study menstruation. But the animals require special care—they shed their skin when held, as a defense mechanism—and fewer genetic tools have been developed for them than for standard lab mice. In the new work, Harvard University reproductive biologist Kara McKinley and colleagues engineered standard lab mice’s endometrium to react to signals at work in menstruating animals. They equipped the cells with a receptor protein that, when activated by a drug, amplifies their sensitivity to calcium, a trigger of decidualization. When the researchers raised those animals’ progesterone levels and stimulated the receptors, the mice produced a 3- to 4-day period about 3 days later, with hallmarks of human menstruation including an enlarged uterus and expanded endometrial blood vessels. Analysis of the cells in the animals’ menstrual fluid revealed a 31% overlap in gene expression with human samples, compared with an expected 12% similarity if the processes were governed by distinct genetic pathways. Some features of human periods are missing in the mice, including the formation of spiral-shaped arteries that feed the endometrium, says Alison Swaims Kohlmeier of Emory University, who researches menstrual cycle regulation in pseudopregnant mice and was not involved in the preprint. “[It’s unclear how] the lack of these structures might influence the remodeling” of the endometrium, she says. Still, McKinley’s team has already used the new animals to explore aspects of menstruation that are out of reach in people. They found, for example, that before the functional layer is shed, the endometrial cells form rings made of different cell subtypes, with younger cells enclosing growing clusters of older, dying cells. The expanding rings of cells likely compress the surrounding tissue, helping cleave the functional layer from the rest of the endometrium, says the study’s first author, Çağrı Çevrim, a reproductive biologist at Harvard. “You can think of the uterus as preparing for menstruation from the inside-out,” Çevrim says. Kohlmeier suggests this ring structure might also protect the uterus from damage during shedding, because the younger cells may shield the endometrium from their dying counterparts, which can cause inflammation. Alterations to this arrangement of cells may contribute to female reproductive conditions, she adds. McKinley’s team now plans to use the new mice to probe the pathways that contribute to heavy menstrual bleeding. They hope the work will eventually inform treatments that use messenger RNA to disrupt those pathways, making periods less burdensome for people with the condition.