When Maria, a 32-year-old teacher from New Haven, endured sharp pelvic pain for years before being diagnosed with endometriosis, her scans showed only a few small lesions. Meanwhile, another patient had widespread tissue growth but no pain at all. This mystery—why some with minimal disease suffer terribly while others with more severe forms feel nothing—has long baffled doctors. Now, new research from Yale School of Medicine is uncovering the answer at the genetic level.
Endometriosis affects roughly 10% of women worldwide, yet diagnosis often takes up to 10 years, and treatments usually just mask pain rather than stop it at its source. But a study published September 10 in Molecular Human Reproduction analyzed tissue samples from 19 patients and found nearly 900 genes behaving differently in those who felt pain. These genes are mostly tied to inflammation, a key driver of discomfort.
The team, led by Dr. Hugh Taylor, compared biopsies from nine patients with painful endometriosis—three with severe pain, six with mild—to 10 asymptomatic patients whose condition was discovered during unrelated surgeries. Using RNA sequencing, they identified significant differences in gene activity. Most strikingly, levels of a protein called IL16 were much higher in painful cases. IL16 is a cytokine, a type of signaling molecule that turns on immune responses and can amplify inflammation.
"IL16 might be recruiting immune cells into endometriotic lesions and promoting the production of more inflammatory cytokines," says Ramanaiah Mamillapalli, Ph.D., the study’s first author. This chain reaction could be what makes certain cases so painful. The findings suggest that it’s not the size or number of lesions that matters most—it’s the biological environment around them.
Currently, many treatments focus on hormones or surgery, but they don’t always relieve pain. Some patients are even told their symptoms don’t match their scan results and aren’t taken seriously. This study offers hard evidence that pain is real and biologically rooted, even when visible disease seems minor.
The discovery opens the door to entirely new kinds of therapies. Researchers now plan to test drugs that block IL16 to see if they reduce pain in animal models and eventually humans. If successful, such treatments could target the actual cause of pain instead of just dulling it.
"Understanding what the source of the pain is and blocking it is likely to be much more effective," says Dr. Taylor. For millions living with this invisible illness, that shift could mean finally being believed—and finally finding relief.