Science is finally confirming the most mysterious symptoms of endometriosis

Julie Nash got her first period at 14. It was so painful that she vomited and spent hours in bed. More than a decade of similar symptoms later, she was finally diagnosed with endometriosis, a disease where tissue similar to the lining of the uterus takes root outside of the organ in the form of lesions and cysts. In recent years, Nash, now a 40-year-old real estate agent in Alvin, Texas, has suffered a bizarre list of additional symptoms—intense fatigue, constipation, the constant need to urinate, a burning sensation in her stomach, and pain in her hips, leg, and lower back—that didn’t seem related. 

For several years, “I was living on the couch, doing the bare minimum for my kids, ready to check out of life,” she recalls. Taking continuous birth control pills helped, but Nash only put her symptoms in the rear-view mirror after a comprehensive surgery last year. The doctor removed lesions not just around her pelvis but also on parts of her colon, back muscles, gastric nerves, and other areas. “I didn’t realize all these other problems were from the endometriosis,” Nash says.

Primary care doctors, gynecologists, and even patients too often view endometriosis as a reproduction-related illness that warrants treatment primarily when someone wants to conceive, says Megan Wasson, a minimally invasive gynecologic surgeon (MIGS) at the Mayo Clinic in Phoenix, who treats endometriosis patients. But in the operating room, she has removed endometrial lesions from the lungs, bowels, spleen, and even the pericardial sac surrounding the heart.

“The inflammatory process that is endometriosis can truly affect every single organ system,” Wasson says. “It can cause a host of symptoms that can significantly impact quality of life and make people miserable.”

In the last year, studies have validated patient experiences, finding a shockingly long list of symptoms and medical conditions in some women and exploring some of the far-flung impacts of the disease. Researchers have also uncovered a growing array of molecular signals in blood and saliva. All of this may ultimately lead to earlier diagnosis and a wider range of treatments. 

(Endometriosis is common, incredibly painful—and often misdiagnosed.)

Women can have hundreds of symptoms and conditions

For a study at University of California, San Francisco (UCSF), scientists used anonymous electronic health records from nearly forty thousand patients across six statewide university health systems to compare symptoms and diseases in women who have an endometriosis diagnosis to similar-aged women without one. 

Not surprisingly, those with the condition suffered more heavy periods, ovarian cysts, infertility, and other gynecological afflictions. But the scientists also identified numerous less-intuitive links, including asthma, autoimmune diseases, migraines, gastroesophageal reflux, and vitamin D deficiency. Ultimately, the group identified several hundred symptoms and medical conditions in women with the disease.

(Why do women get more migraines than men? Researchers have a few clues.)

The mechanisms behind the conditions were not studied, but experts point to a variety of likely explanations. Some may result from hypersensitivity to pain that can emerge when people live with any long-term, agonizing condition. Others may stem from the systemic inflammation or the excess estrogen that endometrial lesions are known to produce. Genes are also likely involved, as nearly a dozen other pain or inflammatory conditions share genetic expressions with endometriosis.

This real-world research makes clear that “endometriosis is a complicated disease” where a lot is going on across the body, says Marina Sirota, a pediatrician and data scientist at UCSF and senior author of the paper. As one example, her lab’s unpublished, unrelated work with cells removed from patient biopsies shows the disease can disrupt communication among immune cells and also dysregulate nerve pathways.

As labs dive further into endometriosis’ wide-ranging impacts, the results raise more questions. A study published last summer in the journal Hypertension tried to explore why it comes with an increased risk of cardiovascular disease. Blood pressure typically rises when people experience physical stressors such as uncomfortably cold temperatures, but in this study, it fell. How this altered response might contribute to heart disease risk is still a mystery.

New approaches may lead to faster diagnoses

Current estimates show endometriosis affects some 11 percent of American women, but many more likely remain undiagnosed, especially as it regularly takes up to a decade to get the label. 

Identifying seemingly unrelated conditions could change that, by flagging women who may warrant further evaluation earlier, Sirota says. If future studies were to confirm the links her research found, for example, neurologists who see a woman for migraine who also has reflux and pelvic pain might refer her for additional testing for endometriosis.

Today, endometriosis can only be definitively diagnosed after a tissue biopsy. Too few women get to this point, says Linda Giudice, the database study coauthor and a longtime reproductive endocrinologist at UCSF. “To have years of pain and not know why—to be dismissed, as many have, being told that severe menstrual cramps are normal or that it’s all in their head—it’s very disempowering,” she says.

On the horizon, a dozen biotech companies are currently developing tools to screen for or perhaps diagnose the condition. Their tests use saliva, blood, or menstrual blood to explore systemic markers linked to endometriosis. One test, for example, seeks out tiny gene regulators associated with endometriosis development. Another hunts for blood proteins associated with the disease. Some tests are already available in the U.S., but experts say more research is needed to assess their accuracy.

(Period pain has long been ignored. That’s changing.)

Wasson is eager for a time when such tests, once proven, catch people experiencing symptoms who currently fall through the cracks. “I think it would be phenomenal to put these in the hands of pediatricians and primary care doctors, to give them another tool to say there might be something going on,” Wasson says.

Potentially improving the range of treatments

Identifying unusual symptoms and conditions could also one day improve therapeutics, not just for endometriosis, but also for other conditions, Giudice says. Endometriosis is best treated using a multidisciplinary approach to care, with gynecologists working with neurologists, say, when patients have both endometriosis and migraines, she says.

Treating the systemic inflammation in a patient with endometriosis can improve other inflammatory-related diseases. As happened with Nash, Wasson has seen patients resolve numerous conditions once the endometrial lesions are removed. “When we get to the core source of the inflammation and we treat that, the rest of the body is naturally going to be able to heal itself,” she says.

Drugs prescribed for other diseases might also help alleviate endometriosis symptoms. Statin medicines to reduce high cholesterol and the anti-malarial primaquine have improved endometriosis pain in lab animals, according to Sirota’s unpublished research.

Any progress in endometriosis care is critical, since treatment today is largely subpar, according to researchers who evaluated a decade of U.S. insurance claims. Hormonal birth control is recommended as a first-line treatment for pain, but it’s often overlooked in favor of opioid drugs or surgical hysterectomy. The latter often fails to stop pain because lesions can exist away from the uterus.

Women with advanced forms of the disease need the same minimally invasive gynecologic surgery that Nash underwent, known as excision surgery. This “removes the endometriosis from its roots—taking the cells from the abdomen, pelvis, thoracic cavity—wherever it is located,” Wasson says (although microscopic cells can be overlooked that may trigger future flares). This surgery is most commonly performed by specialized MIGS surgeons, while gynecologists are more apt to burn, or ablate, the tissue. Removing it surgically is more likely to reduce chronic pain. 

Still more work is needed to fully understand all the ways endometriosis impacts women’s bodies. In the UCSF study, Giudice says she was surprised to see hundreds of comorbidities. “I was expecting maybe 10 or 15 max,” she says. “That’s interesting from the disease perspective, but also for the opportunities to be looking at the whole person, not just one part of the elephant.”