A Key Migraine Mechanism Is Responsible for Endometriosis Pain

CGRP signaling from neurons to immune cells drives endometriosis pain and lesion growth, suggesting that CGRP-blocking drugs could be a potential treatment for the condition.

Endometriosis is an incredibly painful disorder affecting 10% to 15% of women in their reproductive years, even affecting fertility for some. Caused by the growth of tissue similar to uterine tissue outside of the uterus, endometriosis causes pain and a number of other symptoms, but its underlying pathophysiology remains unclear. How to treat it effectively also remains a steep challenge.

But now, building on evidence that endometriosis and migraine share some common mechanisms, researchers led by Michael Rogers, Harvard Medical School, Boston, US, show that interactions between neurons and immune cells in endometriotic lesions cause both pain and lesion growth.

CGRP signaling was the driving factor behind that pathophysiological process, with evidence from a mouse model of endometriosis, and from human samples from eight patients with endometriosis, indicating that CGRP released from neurons in the lesions activated macrophages, a type of immune cell, via the CGRP receptor, RAMP1. Blocking CGRP-RAMP1 signaling with different FDA-approved drugs not only reduced endometriosis pain but also diminished lesion size in mice.

“This paper elegantly shows that endometriosis pain is coupled to immune responses. This has implications not only for treating pain, but also [for understanding] whether pain fibers contribute to worsening of endometriosis. This study is also important because it shows we need to think about CGRP beyond its role in migraine, in particular its effects on the immune system,” said Isaac Chiu, an expert in immunology also at Harvard Medical School but who was not involved with the study.

The findings appeared November 6, 2024, in Science Translational Medicine.

Clues for a role of CGRP in endometriosis
Despite the prevalence of endometriosis, what causes it has remained a mystery, Rogers told Migraine Science Collaborative in an interview.

“It’s hard to overstate how little we know about endometriosis and its underlying pathophysiology,” he said. When discussing therapeutic options, Rogers said, “Endometriosis is badly understudied. Not much new has been discovered in the last 40 years. In part that’s because of underfunding of endometriosis-related research.”

That a painful condition like endometriosis lacks funding will likely resonate with migraine researchers, considering the field’s own funding gaps (migraine research funding reached only about $40 million in 2021, and a recent estimate for 2025 is for just $50 million). Total annual National Institutes of Health (NIH) funding for endometriosis research was as low as $6 million in 2017 and rose only to between $20 million and $29 million per year between 2021 and 2023. That is a very small slice of the $800 million to $1 billion annual pie for all pain research funding from NIH.

Considering the dearth of endometriosis research funding, perhaps it’s not surprising that the condition’s underlying causes remain unclear. What researchers do know is that during endometriosis, tissue resembling uterine tissue grows outside of the uterus. As in the uterus, this ectopic tissue, called endometriotic lesions, contains blood vessels, nerve fibers, and muscle and immune cells.

For the current study, the researchers were keen to learn about the lesion microenvironment – the specific cells and signaling molecules that are present in and around the lesions – and how the lesions grow or become painful. There were some breadcrumbs to follow. For one, many people with migraine also have endometriosis. Along with this comorbidity, a recent study found genetic links between the two diseases, indicating potential shared pathophysiology.

“We also know the immune environment in endometriosis patients is, for lack of a better term, messed up,” said Rogers, “but we don’t know if it’s a result of the disease or a driver of it.”

This altered immune environment was the focus of the new investigation. From his time working in the pain field, first author Victor Fattori knew that nociceptors – the sensory neurons that detect potentially harmful stimuli and send an electrical signal to the brain, ultimately resulting in the sensation of pain – can activate immune cells and exacerbate pain in many chronic pain conditions.

“But this link between nociceptors and immune communication had not been investigated in the context of endometriosis. From the genetic links [between endometriosis and migraine], we thought CGRP could be a key player,” said Fattori.

CGRP promotes endometriosis pain and lesion growth
The researchers first found that nerve fibers containing CGRP were present in endometriotic lesions in human tissue samples, and in tissue from a non-surgical mouse model of endometriosis.

The researchers also found that the CGRP-positive nociceptors from the dorsal root ganglion (DRG) of endometriosis mice showed more activation than DRG neurons from mice without lesions. (The DRG is a collection of the cell bodies of sensory neurons near the spinal cord, into which DRG neurons relay nociceptive signals from the periphery.)

In sum, the findings thus far had revealed that the lesions were innervated by activated nociceptive neurons that contain CGRP. The team then dug deeper into the cellular and molecular pathways that might drive endometriosis pain.

To that end, a series of experiments revealed that endometriotic lesions present in the animal model of endometriosis contained an abundance of chemical modulators. That included angiogenic factors, which affect endothelial cells that line blood vessels, among other functions. It also included chemokines, which promote inflammation and immune cell activation, and particularly chemokines made by macrophages, a type of white blood cell. The group further saw that angiogenic factors directly activated DRG neurons, which released CGRP in response.

A hypothesis emerges
These and other findings pointed to a potential mechanism driving endometriosis pain and lesions.

“Nociceptive neurons release CGRP, which binds to its receptor, RAMP1, expressed on macrophage immune cells. We thought that, once activated, these macrophages initiate a molecular cascade that drives endometriosis pain and also lesion growth,” said Fattori.

To test that hypothesis in the mouse model of endometriosis, the investigators bred mice in which they genetically removed particular nociceptors. These animals showed reduced mechanical pain in response to poking with thin filaments (a common experimental test in animal pain studies), and reduced spontaneous pain compared to animals with the normal presence of the neurons. Getting rid of the nociceptors also reduced the size of endometriotic lesions.

Other experiments showed that the nociceptors were causing trouble by recruiting monocytes, which are white blood cells that can differentiate into macrophages, into the lesions. Further, CGRP affected the function of the macrophages, decreasing their ability to clear debris from the lesions. Instead, the macrophages now had a pro-endometriosis phenotype, increasing the growth of endometrial cells.

In sum, the researchers had established a link between the nervous and immune systems in endometriosis, through effects of nociceptors on the functioning of macrophages.

“This means that we are not only dealing with pain, but also potentially dealing with endometriosis lesions and the underlying causes of the disease,” said Rogers.

Thinking bigger picture, Rogers said these findings help redefine endometriosis as a systemic disease with substantial dysfunction in the immune system and the pain system, “rather than just the presence of local lesions that are painful.”

Another use for anti-CGRP treatments?
So far, the experiments showed that interaction between the nervous system and the immune system, via CGRP from nociceptors signaling to its receptor, RAMP1, present on macrophages, regulated endometriosis pain and lesions. That suggested a logical next step for the study.

“This neuroimmune communication is CGRP driven, which led us to think that inhibitors of the CGRP pathway might be useful as therapeutics for endometriosis,” said Rogers.

So the researchers again turned to their mouse model of endometriosis, testing two monoclonal antibodies that block CGRP (fremanezumab or galcanezumab) or two small molecules that block RAMP1 (rimegepant or ubrogepant). All four anti-CGRP therapies reduced pain in the animal model. What’s more, ubrogepant also reduced lesion size. These findings have important clinical implications.

“Endometriosis causes infertility in an unknown fraction of the population. Probably the lesions disrupt the function of the reproductive system, but again we don’t know how. Our data shows that if we can shrink lesions [with CGRP-blocking drugs], maybe we can enable pregnancy, too,” said Rogers.

Is there any evidence that people who’ve taken CGRP-blocking drugs for migraine have a reduction in endometriosis pain, too? Rogers said there are no published data, but the researchers have asked around and now have a tiny bit of anecdotal evidence that this is the case.

“We’re up to four anecdotes where someone’s endometriosis symptoms improved after taking CGRP-blocking drugs. In one case, someone was scheduled for surgery [to remove endometriotic lesions] but cancelled because the pain went away,” he said.

“But if these drugs were curing every case of endometriosis, clinicians would have reported this by now. So it’s probably a subset of patients who would benefit,” he added.

Rogers also said he’s had a conversation with at least one company that makes CGRP-blocking drugs about testing their efficacy in patients with endometriosis. “But whether any of that will come to fruition, I can’t say,” he said.

If the trials were ever to go ahead and be successful, anti-CGRP drugs would be the first new class of endometriosis treatments in decades. Chiu, who agreed that the new study warrants controlled endometriosis clinical trials with CGRP-blocking drugs, said it would also be the first example where these drugs are effective for a pain condition other than migraine.

Chiu said that it’s very exciting that CGRP drugs could potentially be repurposed to target endometriosis, or to treat other diseases like cancer, where CGRP signaling can promote tumor growth. A recent study also found that CGRP is involved in helping immune cells facilitate wound healing, and Chiu thinks it would be interesting to know if similar mechanisms cause immune cells to drive the growth of endometriosis lesions.

But as more studies find broad effects of CGRP signaling around the body, they are highlighting that these drugs are non-specific, acting on more than one target.

“In some cases, blocking CGRP might have harmful effects, and one example is in the gut,” said Chiu, referring to recent work from his lab showing that blocking CGRP caused worsened GI infections and colitis. “You have to be careful when prescribing these drugs.”

Fred Schwaller, PhD, is a freelance science writer based in Germany.

Image credit: Noah Smith, CC BY-SA 4.0 via Wikimedia Commons.

Reference
Nociceptor-to-macrophage communication through CGRP/RAMP1 signaling drives endometriosis-associated pain and lesion growth in mice.
Fattori et al.
Sci Transl Med. 2024 Nov 6;16(772):eadk8230.