Study reveals why endometriosis pain persists after lesions are removed

Repeated menstrual cycles may do more than trigger endometriosis. They may rewire the brain.

That is the key finding from a new Washington State University study showing that recurring inflammation linked to the disease can sensitize the nervous system, driving lasting pain.

The work helps explain one of the most frustrating aspects of endometriosis, a condition in which tissue similar to the uterine lining grows outside the uterus. It affects more than 10 % of reproductive-aged women, or roughly 190 million people worldwide, and often causes severe pelvic pain and infertility.

In a paper published in the Journal of Clinical Investigation, WSU scientist Kanako Hayashi and collaborators found that repeated cycles of inflammation can trigger lasting changes in the brain, amplifying and sustaining pain over time.

"We're showing that this is not just a local gynecological disease," said Hayashi, a professor in WSU's School of Molecular Biosciences.

Once the system is sensitized, the brain keeps responding, even if the original lesions are gone."

Kanako Hayashi, Washington State University

Endometriosis has long puzzled researchers because pain does not reliably match the extent of disease. Some patients with widespread lesions report little discomfort, while others with minimal tissue growth experience debilitating symptoms.

"That mismatch tells us something more complex is happening," Hayashi said. "It's not just the lesions themselves. It's how the body and the nervous system respond over time."

To investigate, the research team designed a model that mimics repeated menstrual cycles. Most previous studies induced endometriosis-like conditions only once. Hayashi's group instead introduced multiple cycles, simulating the repeated backflow of menstrual tissue called retrograde menstruation, thought to contribute to the disease.

Mice exposed to repeated cycles showed heightened sensitivity and lasting changes in the nervous system. Inflammation increased in the pelvic region, and signals traveled along nerve pathways to the spinal cord and brain, where researchers observed clear signs of neuroinflammation.

"That repeated stimulation acts like turning up the volume again and again," Hayashi said. "Eventually, the system becomes hypersensitive. Even small signals can feel very painful."

To strengthen the findings, the team also analyzed tissue samples from rhesus macaques with naturally occurring endometriosis through a collaboration with the Oregon National Primate Research Center. No primate experiments were conducted at WSU.

The results help explain why pain can persist even after lesions are removed. Once the brain's pain-processing circuits are sensitized, they can continue to generate pain signals independently.

"It becomes a feedback loop," Hayashi said. "The body is sending signals to the brain, and the brain is reinforcing those signals back to the body."

The study also points toward new approaches for treatment. Rather than focusing only on removing lesions or suppressing hormones, therapies could target inflammation in the nervous system. In the study, both a commonly used hormonal drug and an immunomodulating compound reduced pain sensitivity and brain inflammation in the mouse model, even without shrinking lesions.

"We now have a system where we can follow the entire process from the beginning," Hayashi said. "That gives us a powerful way to develop better treatments and, hopefully, detect the disease earlier."