Camille Berthelot: « Understanding the Origin of Menstruation Could Help Treat Endometriosis »

Rare are the animal species that menstruate. Camille Berthelot, Inserm research associate at Institut Pasteur, is comparing the genomes of different species to identify the genes responsible for menstruation and – potentially – the factors that cause endometriosis.

Menstruation is a characteristic of a few rare mammals: humans, some other primates, some bats, and one or two singular species such as the elephant shrew and spiny mouse. What is the evolutionary significance of menstruation and what are the genetic processes that govern it? Camille Berthelot would like to find out. In 2019, she was awarded European Research Council (ERC) funding for a project that just so happens to study the evolution of menstruation in primates. A subject that has its origins in her personal history.

« When I was in high school, discoveries about ancient DNA were in the news. I was fascinated by the fact that we could trace the history of species on a genetic level, and it was something that guided the biology studies I wanted to pursue. After a master’s degree at École Normale Supérieure (ENS) in Lyon, I joined ENS Paris to prepare a PhD on how genome structure has reorganized during evolution, » says the researcher. In 2016, she joined Inserm to carry out comparative genomics research and very quickly developed an interest in menstruation: « At the time, a friend of mine had just been diagnosed with endometriosis. » Endometriosis is a potentially very painful disease that develops when uterine cells in menstrual blood implant outside the uterus. « I wanted to explore what was known about this disease. But I realized that there were very little data beyond the purely clinical aspects. More broadly, it appeared to me that knowledge about the biological functions governing the female reproductive system is thin on the ground compared with what is known about the male reproductive system. For example, periods respond to mechanisms of which we actually know very little. »

Berthelot then decided to set up a project to apply her expertise in comparative genomics to this new field of investigation. Within a few months, her project, called Evomens, was awarded an ERC grant and then selected by Institut Pasteur in a recruitment call. « These 1.2 million euros in funding over 5 years is enough for me and the two postdoctoral fellows I recruited to conduct the experimental part of the project, which is particularly costly and involves collecting uterine tissue from primates. It will allow us to accelerate the pace of the findings. »

After collecting biological samples from different primate species, the researcher and her team are conducting comparative genomics research: through genetic analysis and computer processing of the data obtained, they are looking for differences in the genome and its expression between species that menstruate and those that do not.

Perfecting fetal development

« Menstruation depends on a mechanism related to progesterone, the so-called pregnancy hormone. Our hypothesis is that a modification of the tissue response to progesterone is involved in its appearance. We still need to understand the cellular mechanisms. To identify them, we will look at the genes that are modulated by the progesterone receptor in the different species studied.  » 

But what is the evolutionary utility of this modification and the cyclic bleeding it induces? « Historically, menstruation was thought to be a program to clean the uterus, which is obviously not true. Today, it is thought that it has no direct utility: it is just the consequence of the uterus getting a head start on a potential fertilization. The fetus of a species like ours consumes a lot of energy. In order to better control its implantation, and the investment of the mother’s energy, cells of the uterine mucosa differentiate into placental cells during the first part of the cycle.  » In the absence of fertilization, these cells are eliminated – meaning that the woman gets her period. « In non-menstruating species, the placenta is less voluminous and the interactions between the uterine mucosa and placental tissue are subject to much less control by maternal tissues. »

At the same time, this research could have medical implications: gene expression in uterine cells present in menstrual blood may make it possible to identify biological pathways that are activated differently in endometriosis, and that could promote implantation outside the uterine cavity. « It remains a subject that only few teams worldwide are interested in, » a surprising observation, when we know that endometriosis affects one in ten women. « But things have changed in the last few years, mainly due to the impetus of female researchers!  »

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* Comparative Functional Genomics group (UA12), Inserm/Institut Pasteur, Paris