Aline Van LangendonckEvery month, during menstruation, women shed the layer of cells that lines the inside of the uterus. This natural process is part of the reproductive cycle, occurring regularly throughout the fertile years. If an embryo does not implant and pregnancy does not occur, hormonal fluctuations cause the endometrium—the uterine lining—to break down and be expelled through the vagina along with some bleeding. Occasionally, however, fragments of the endometrial tissue that should be discarded migrate through the fallopian tubes and enter the abdominal cavity. When lodged outside the uterus, these tissue fragments provoke a chronic, painful, and often debilitating inflammatory disease. This condition, known as endometriosis, affects approximately 10–15% of women and trans men (individuals born biologically female but identifying as male). A study published in November in Science Translational Medicine sheds new light on the evolution of this disease.
The study, led by pharmacist Waldiceu Verri Junior from the State University of Londrina (UEL) and molecular biologist Michael Rogers from Harvard Medical School in the United States, presents a series of experiments conducted with human endometriosis samples, laboratory-cultured endometrial cells, and a mouse model simulating the human disease. After years of work, they concluded that the development, progression, and pain associated with endometriosis result from a complex, feedback-driven interaction between the lesion cells, the nervous system, and the immune system.
Endometrial cells located outside the uterus release compounds that activate pain-sensing neurons, which in turn release chemical signals that trigger macrophages, which are immune cells responsible for enveloping and digesting foreign or damaged cells—such as tumor cells, parasitic cells, or misplaced endometrial cells. In typical situations, macrophages would migrate to the misplaced endometrial cells and eliminate them, resolving the issue. However, in endometriosis, the chemical signals from the pain neurons instruct the macrophages to lose their cleaning function. Instead of removing the rogue endometrial cells, the macrophages inadvertently promote their proliferation. This process creates a vicious feedback loop, where additional injury activates more pain neurons, which recruit more impaired macrophages.
“In this study, we discovered that the very cells that should be combating the problem are, in fact, contributing to its persistence,” explains Brazilian pharmacist Victor Fattori, the lead author of the paper and an expert in the molecular mechanisms of pain and inflammation. The study, however, offers some hopeful news. “There are already FDA-approved medications that, at least in animal models, help reduce both the size of lesions and the associated pain of endometriosis,” adds the researcher, who is part of Rogers’s group and who developed the mouse model of endometriosis used in the group’s research.
Along with Brazilian biologist Tiago Zaninelli, currently a postdoctoral researcher at Washington University in St. Louis, and biomedical researcher Fernanda Rasquel Oliveira, a postdoctoral fellow with Verri, Fattori conducted the majority of the experiments described in the article.
The first task was to confirm that the composition of endometriosis lesions in women matched those observed in the animal model. It is already known that the ectopic endometrial tissue mirrors the uterine lining in many respects, functioning nearly autonomously. There are supportive and hormone-producing cells within the lesions, which are nourished by blood vessels and communicate with the rest of the body via nerves. However, the specific type of neuron responsible for innervation was previously unclear.
By comparing lesion samples from eight women with endometriosis to those from rodents, Fattori and colleagues found that both human and animal lesions are innervated by sensory neurons, which are responsible for transmitting pain signals to the brain. Specifically, these neurons produce calcitonin gene-related peptide (CGRP), a peptide (protein fragment) that serves as a chemical messenger between cells.
In laboratory experiments conducted with mice and cultured cells, the researchers discovered that two compounds released by the lesions—vascular endothelial growth factor (VEGF) and placental growth factor (PlGF)—activated these neurons. The neurons, in turn, began to produce CGRP while simultaneously transmitting pain signals to the brain. This finding was further validated when Fattori and colleagues created genetically modified mice that could not produce CGRP. These mice displayed smaller lesions and exhibited less pain compared to the control group, which produced the peptide.
In additional experiments, the researchers found that CGRP recruited macrophages to the injury site However, CGRP altered the function of these macrophages, preventing them from removing cellular debris or endometriosis cells. Instead, the macrophages began helping them multiply. In vitro tests showed that macrophages cultured with CGRP lost their ability to perform efferocytosis, the process of eliminating dead cells and their remains. At the same time, endometrial cells cultured with these macrophages proliferated more rapidly. The macrophages regained their ability to carry out efferocytosis when treated with a migraine medication that blocks CGRP. This treatment also prevented the macrophages from promoting the growth of endometriosis cells.
“The study highlights the important dual role of CGRP in endometriosis, showing that it both promotes pain and stimulates lesion growth,” comments pharmacologist Thiago Mattar Cunha, from the University of São Paulo (USP) in Ribeirão Preto, who was not involved in the research. A specialist in chronic pain, Cunha notes that it was once believed the immune system solely regulated the nervous system. “Today, we understand that neurons, cells within the nervous system, can release factors that alter the behavior of immune cells,” he explains.
In 2023, a study published in Nature Genetics by researchers at Oxford University in the UK found that individuals with endometriosis shared certain genetic traits with migraine sufferers, a condition in which CGRP also plays a key role. Inspired by this, Fattori decided to explore whether drugs blocking CGRP could alleviate the severity of endometriosis.
For the experiments, Fattori selected two monoclonal antibodies that neutralize CGRP—fremanezumab and galcanezumab—and two drugs that block the receptor to which CGRP binds on the surface of immune cells—rimegepant and ubrogepant, marketed as Nurtec and Ubrelvy respectively. These four migraine medications were tested individually on mice with a condition simulating human endometriosis.
Tiago Zaninelli / UELMicroscopy image showing macrophages (in red) next to the CGRP-producing neuron (in green) in a mouse’s endometriosis lesionTiago Zaninelli / UEL
Rodents treated with these medications exhibited lesions up to 50% smaller compared to those given an inert solution (placebo), although no differences were observed in the total number of lesions. Additionally, the animals in the treatment group showed fewer signs of pain—they licked their abdomens less and exhibited fewer contortions—than those in the control group. “All of these drugs have already been approved in the United States to treat migraines in humans, which makes it easier to test them for endometriosis as well,” notes Fattori.
“This proposed mechanism for controlling pain and reducing lesions is both intriguing and important because it targets a different pathway than current treatments,” says gynecologist Cristina Benetti Pinto from the University of Campinas (UNICAMP), who researches endometriosis therapies and their impact on patients’ quality of life. “Endometriosis is a chronic disease that requires further study and new therapeutic alternatives,” she adds.
Current treatments focus on pain management with analgesics and anti-inflammatories, as well as controlling lesion size with compounds that reduce estrogen activity. Produced by the ovaries, estrogen stimulates the growth and maturation of the endometrium throughout the reproductive cycle, preparing the uterus for pregnancy while also promoting lesion growth. The findings presented here suggest that estrogen and CGRP may interact synergistically, contributing to lesion progression. In some cases, when endometriosis affects the surface of certain organs, surgical intervention may be required to remove the lesions, although recurrence is not always preventable.
First described in medical journals in 1860 by Austrian pathologist Carl von Rokitansky (1804–1878), endometriosis appears to receive less attention than it warrants. A 2022 analysis published in Frontiers in Global Women’s Health revealed that, in that year, the US National Institutes of Health (NIH)—the world’s largest biomedical research organization—allocated just US$16 million to endometriosis research, amounting to only 0.04% of its US$41.7 billion budget. This figure seems disproportionately low given the disease’s widespread impact, which affects at least one in ten women and transgender men, their families, and their work. In Brazil, it is estimated that between 5 and 8 million women of reproductive age suffer from endometriosis. According to some estimates, in the United States alone, the condition is associated with annual expenditures ranging from US$78 billion to US$119 billion for care, treatment, and lost productivity.
“The research published in Science Translational Medicine advances our understanding of endometriosis and points to a promising therapeutic direction,” says gynecologist Mauricio Abrão, from USP, an international authority on the disease. “However, further studies are needed to validate the efficacy and safety of this approach in humans,” adds Abrão, who was not involved in the current study but is actively researching the causes, progression, and treatments of endometriosis.
In a 2023 study published in Reproductive Sciences, Abrão and his team evaluated the impact of pain on the quality of life of 1,129 individuals who had undergone surgery for endometriosis. The most commonly reported pain was severe dysmenorrhea (menstrual cramps), which affected 93.6% of participants. Pain significantly diminished the quality of life for all participants, especially those who reported pain intensity scores higher than 7 on a scale from 0 to 10.
One limitation of the study on CGRP’s role in endometriosis is that it was conducted using a mouse model. “While informative, these results may not capture all aspects of endometriosis in humans, particularly deep endometriosis, which is the main cause of pain,” cautions Abrão. Additionally, the duration of the effects of blocking the CGRP pathway remains uncertain, an important consideration in a chronic condition like endometriosis.
The story above was published with the title “How endometriosis worsens” in issue 346 of December/2024.
Scientific articles
FATTORI, V. et al. Nociceptor-to-macrophage communication through CGRP/RAMP1 signaling drives endometriosis-associated pain and lesion growth in mice. Science Translational Medicine. Nov. 6, 2024.
RAHMIOGLU, N. et al. The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions. Nature Genetics. Mar. 13, 2023.
ELLIS, K. et al. Endometriosis is undervalued: A call to action. Frontiers in Global Women’s Health. May 9, 2022.
ANDRES, M. P. et al. Visual analogue scale cut-off point of seven represents poor quality of life in patients with endometriosis. Reproductive Sciences. Dec. 6, 2023.
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