New Study Helps Explain How Endometriosis Causes Pain

One of the puzzling aspects of endometriosis—a gynecologic condition in which tissue similar to that lining the uterus grows outside of it—is that the extent of the disease doesn’t determine the severity of its symptoms. New Yale research may help explain why some patients with a small number of growths experience debilitating pain, while others with more widespread disease do not have symptoms.

To learn more about how endometriosis causes pain at the molecular level, Yale School of Medicine researchers studied biopsies from patients with either symptomatic or asymptomatic endometriosis. Their analyses revealed genetic differences that distinguish cases of endometriosis with pain.

The findings, published Sept. 10 in Molecular Human Reproduction, point to a possible explanation for the variability in symptom severity that patients experience. Furthermore, many existing treatments for endometriosis simply mask pain without addressing its underlying source. The researchers hope these insights could lead to new treatments that directly target the mechanisms driving pain.

“This gives us a window to potentially understand why some endometriosis causes pain, and it will be the starting point for investigations that help us treat that pain in a better way,” says Hugh Taylor, MD, Anita O’Keeffe Young Professor of Obstetrics, Gynecology, and Reproductive Sciences and the study’s principal investigator.

While the exact cause of endometriosis is unknown, many scientists believe that the disease arises as a result of retrograde menstruation, in which cells typically contained in menstrual blood flow backwards and implant themselves outside the uterus. The disease can cause a wide range of symptoms, including painful periods, chronic pelvic pain, heavy or abnormal menstrual bleeding, and infertility.

For some, symptoms can be debilitating. But other patients, even those with widespread implants, may not even realize that they have the disease. “It has never made complete sense why people could have extensive disease and not have pain,” Taylor says.

Taylor’s team studied biopsies from nine patients with painful disease and 10 asymptomatic patients. Across the symptomatic patients, three reported their pain as severe and six as mild. Biopsies of asymptomatic endometriosis were obtained during laparoscopic surgeries for conditions unrelated to pelvic pain, which also led to the discovery of the disease.

The researchers analyzed the tissue samples using RNA sequencing to understand how gene expression differed between the two groups. Their analyses revealed almost 900 genes that were expressed differently in symptomatic and asymptomatic disease. Many of these differences involved genes that play important roles in inflammation.

They also measured the protein levels in the biopsies and confirmed that the changes in gene expression corresponded with increases in inflammatory molecules that might contribute to painful symptoms. In particular, the team found that the elevation of a molecule called IL16 was linked to pain severity. IL16 is an inflammatory cytokine, or a small protein that acts as a chemical messenger to regulate inflammation.

“IL16 might be recruiting immune cells into endometriotic lesions and promote producing more inflammatory cytokines,” says Ramanaiah Mamillapalli, PhD, research scientist in obstetrics, gynecology & reproductive sciences and the study’s first author. “This cascade might heighten pain and inflammation.”

In future studies, the researchers will explore the cytokine as a target for new drugs.

“More research will be needed to determine if IL16 indeed is a driver of painful symptoms,” Mamillapalli says. “We plan to study whether the use of drugs that block this protein can reduce pain associated with endometriosis.”

“The things we use typically to treat pain now don’t really get at the root cause of pain,” Taylor says. “Understanding what the source of the pain is and blocking it is likely to be much more effective.”

Even today, the pain that some patients with endometriosis experience is commonly dismissed by doctors. This can especially be true for individuals with less extensive tissue growth, says Taylor, despite the lack of correlation between disease stage and pain.

“People need to know that even a little bit of disease can actually cause a lot of pain and to not let anybody dismiss those concerns,” he says.