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At a glance:
Research uncovers new details of communication between nervous and immune systems in endometriosis.
Findings in mice point to existing migraine medications as a potential treatment for the condition.
Team is now exploring a clinical trial and investigating whether other existing drugs could alleviate endometriosis symptoms.
Researchers have gained new insights into the basic biology of endometriosis — a common, mysterious, and often painful condition of the female reproductive system. In the process, the team identified an unexpected avenue toward alleviating symptoms of the condition, which has proven difficult to treat effectively.
The study, conducted in mice and led by scientists at Boston Children’s Hospital and Harvard Medical School, uncovered molecular details of how the nervous system and the immune system communicate in endometriosis.
Specifically, the researchers identified a small molecule called calcitonin gene-related peptide (CGRP) that plays an important role in this crosstalk.
The CGRP pathway is a target of several existing migraine medications, and when the team administered these drugs to lab mice, they seemed to reduce endometriosis pain and lesion size.
The researchers are now exploring partnerships with pharmaceutical companies, with the goal of launching a clinical trial to test the migraine drugs in patients with endometriosis.
The findings are published March 19 in Science Translational Medicine.
New endometriosis treatments needed
In patients with endometriosis, tissue similar to the uterine lining grows outside the uterus, forming lesions in the fallopian tubes, ovaries, or pelvis. These lesions can cause severe pain during periods, heavy menstrual bleeding, pelvic or abdominal pain, and painful bowel movements and urination.
Existing treatments for endometriosis have changed little in the past 30 years and are often ineffective or have undesired side effects. Options include nonsteroidal anti-inflammatory drugs and painkillers, which don’t always work, or hormones, which can interfere with getting pregnant. Surgery can remove some of the lesions, but they often return.
A decade ago, senior author Michael Rogers, HMS assistant professor of surgery at Boston Children’s, was pursuing cancer-related projects in the Vascular Biology Program when a friend with endometriosis urged him to study the condition.
Rogers discovered that while there is considerable overlap in the mechanisms that drive cancer and endometriosis, the entire U.S. federal budget for studying endometriosis at the time was less than $10 million.
“As a cancer biologist, I assumed there would be a similar research community working on endometriosis, [but] that turned out not to be true,” Rogers said.
Pulling double duty
In 2020, first author Victor Fattori, HMS instructor in medicine at Boston Children’s and a member of the Rogers Lab, led the development of a mouse model of endometriosis. For the new study, the team used the mouse model, along with samples from patients with endometriosis, to delve into the basic biology of the condition.
“We started thinking about how the nervous system can talk to immune cells and help shape immune cell function and inflammation in endometriosis,” Rogers said.
The researchers discovered that CGRP communicates with immune cells called macrophages, leading to increased growth of endometrial cells. They also found that endometriosis lesions contain nerve fibers with CGRP and its receptor, RAMP1.
Additional work suggested that CGRP reprograms macrophages to make them less able to clear debris, leading to inflammation that likely promotes endometriosis pain.
The team further found that the altered macrophages secrete molecules that help endometriosis lesions grow.
The researchers also used the mouse model to test existing drugs for potential effectiveness in endometriosis, prioritizing those that were commercially available and would be suitable for adolescents and young adults.
The candidates included several FDA-approved CGRP inhibitors for migraines, which also have a neuro-immune component. A 2018 study led by Amy DiVasta, HMS associate professor of pediatrics at Boston Children’s, found that migraines are especially common in adolescents with endometriosis.
The researchers gave four different CGRP/RAMP1 signaling inhibitors to mice with endometriosis lesions and found that all four reduced pain and lesion size. The results encouraged the team to move toward testing the drugs in human trials.
Based on mouse data, DiVasta and Marc Laufer, HMS professor of obstetrics, gynecology, and reproductive biology at Boston Children’s, are testing other existing drugs in patients with endometriosis, including the angiogenesis inhibitor cabergoline.
“Our patients and families are desperately looking for an alternative to hormonal treatments,” DiVasta said.
Adapted from a Boston Children’s blog post.
Authorship, funding, disclosures
Additional authors on the study include Tiago Zaninelli, Fernanda Rasquel-Oliveira, Olivia Heintz, Ashish Jain, Liang Sun, Maya Seshan, Daniëlle Peterse, Anne Lindholm, Raymond Anchan, and Waldiceu Verri Jr.
The research was supported by the J. Willard and Alice S. Marriott Foundation, the Marriott Daughters Foundation, and the Assistant Secretary of Defense for Health Affairs, endorsed by the Department of Defense through the Peer Reviewed Medical Research Program (HT9425-23-1-0040).
Fattori and Rogers are inventors on patent PCT/US2023/079238.
