One of the most significant barriers to care for people living with endometriosis is the amount of time it typically takes to reach a diagnosis after symptoms first appear. It isn’t uncommon for people to spend a decade or more struggling to arrive at a diagnosis, which can still only be reliably confirmed by laparoscopic surgery. While sometimes characterized as a relatively minor procedure, diagnostic laparoscopy is still a daunting prospect for anyone already struggling with the physical and psychological burdens of endometriosis. The financial burden of the surgical procedure is also one that many insurers won’t cover.
Part of the reason endometriosis takes so long to diagnose, and often proves so difficult to treat, is that its underlying causes are poorly understood and very few research groups have tackled the biological mechanisms that drive its progression with much success. Retrograde menstruation has been one of the prevailing explanations for how endometriosis begins. The lesions and adhesions that characterize the disease are thought to occur when some of the uterine lining that is sloughed off every cycle makes its way into the pelvic cavity via the fallopian tubes. While this might be the oldest proposed model for endometriosis, not everyone agrees that it’s the best one. It turns out that retrograde menstruation occurs in almost all people who menstruate, while only one in 10 of those same people will develop endometriosis. Understanding what contributes to the differences among people with and without endometriosis may be a key to spotting the disorder early and developing targeted treatments.
This is one of the major goals of the ROSE study, a large-scale interdisciplinary research effort which the Endometriosis Foundation of America provided critical seed funding for in 2013. A collaboration that was initiated by cofounder Dr. Tamer Seckin started at Northwell Health’s Feinstein Institutes for Medical Research and is led by Dr. Peter K. Gregersen, M.D., and Dr. Christine Metz, PhD., ROSE (Research Outsmarts Endometriosis) turns a molecular magnifying glass on the cells at the heart of endometriosis—those found in menstrual flow that are similar to those found in endometriosis lesions. Other work has focused on the composition of the endometrial lesions themselves, but the idea of retrograde menstruation suggested a more obvious source to Gregersen and Metz. “It seemed very logical to us to study menstrual effluent, and we were very surprised to find that very few labs around the world had ever studied menstrual effluent, specifically in the setting of endometriosis,” says Dr. Metz.
As of now, the ROSE study has enrolled over 1,700 participants. These participants fall into three categories: people whose endometriosis has been diagnosed and confirmed surgically, those whose chronic symptoms strongly suggest endometriosis but who have not been diagnosed yet, and another group who don’t report any of the symptoms associated with endometriosis and serve as unaffected controls. A robust diagnostic tool can not only tell a clinician that a patient has endometriosis, but it can just as definitively rule it out, making the inclusion of this third group is critical to the study.
“We began studying endometriosis here and actually went at it from a completely different angle than most people have in the past,” Dr. Metz says, “based on the premise that the endometrium of women with and without endometriosis is very different.” Doctors and surgeons may be able to see some of these differences if they look at the lesions of someone who has undergone excision surgery, and patients can certainly feel them as well. Dr. Gregersen, head of the Robert S. Boas Center for Genomics and Human Genetics, is a rheumatologist whose work focused on the genetics of autoimmune disease. He points out that a lot of these differences come down to genes. “The heritability is 50%,” he explains, “so that means that 50% of the reason why some people get it versus others is due to genetics.”
Dr. Gregersen and Dr. Metzare taking advantage of the rapidly expanding molecular toolkit available to research scientists over the last decade. Their unique approach has involved first isolating and refining specific cell types from the menstrual effluent samples, and then applying what’s known as single-cell RNA sequencing, a technique that generates a snapshot of how different genes are expressed in some cells versus others. They can then use this information to understand precisely what makes the menstrual effluent of people with endometriosis different from samples collected from those who do not. Currently, these kinds of experiments are costly and time-consuming, so one challenge the researchers face will be translating these techniques into an inexpensive, non-invasive diagnostic test or screening method that can be performed easily in a doctor’s office or even at home.
“The other aspect of this that we've wrestled with,” says Dr. Gregersen, “is how do you collect the menstrual effluent?” To approach this problem, they’ve come up with their own menstrual pad that study participants can then ship back to the lab for analysis. Gregersen and Metz note that considerable interest has built up in femtech around the development of menstrual products that could also act as easy in-home collection methods for diagnosing a variety of conditions.
Building on the foundation the data from the ROSE study has laid down so far, the team is planning to embark on a prospective clinical trial this year that would follow patients whose chronic symptoms are consistent with endometriosis and who are planning on getting diagnostic laparoscopy to confirm. They’ll compare their menstrual effluent to samples from individuals who aren’t symptomatic but have planned to undergo laparoscopy for unrelated reasons and they hope to zero in on a handful of factors revealed by their sequencing data that accurately correspond with either a positive or negative diagnosis or screening test. “We believe that that data for the first part of that trial would get us to an FDA application for the diagnostic,” says Dr. Metz, “so that's what our big goal is for 2022.” She adds that they’ll also be looking more closely at infertility and progesterone resistance, commonly associated with endometriosis.
So far, a few standout candidates for diagnostic markers of endometriosis have emerged from the study. One trait that very clearly differed in the cells of endometriosis versus controls was a defect in what’s called ‘decidualization’, which is a shift undergone by the endometrium to enrich the tissue with growth factors in preparation for a possible pregnancy. Samples taken from endometriosis patients also had far fewer uterine natural killer, or uNK, cells. uNK cells are cellular housekeepers, traveling to sites of infection or damage and clearing away unhealthy cells. This difference suggests an immune component within the endometrium in the setting of endometriosis that hasn’t been thoroughly studied until now.
Gregersen and Metz’s work also highlights the role of inflammation in endometriosis. Chronic, low-grade inflammation can be both a risk factor for, and a symptom of, an array of health conditions. It can be systemic, or it can be limited to certain tissue types. Chronic endometritis, marked by persistent, low-level inflammation of the endometrium, often evades diagnosis because it may not cause obvious or distressing symptoms. But over time, it significantly increases the likelihood that a patient will develop endometriosis. “Based on previous studies, people with chronic endometritis are almost three times more likely to get endometriosis than those without,” says Dr. Metz. “That aberrant inflammation within the endometrium, we believe, modifies the cells, so when they are retrograde transported into the pelvic cavity, they are already pathogenic and can wreak havoc.”
Finding a reliable set of biomarkers for endometriosis could not only dramatically remodel the landscape of endometriosis care, but also suggest more individualized treatment options than harsh hormonal interventions. In addition, it could possibly prevent disease progression that requires excision surgery. “When we talk to the women in our study, most of them are frustrated with all of these hormone therapies that address pain—not disease progression,” says Metz. She emphasizes that an overwhelming number of diagnosed patients who have submitted menstrual effluent samples for the ROSE study are not on a hormonal treatment regimen. “So what does that tell you? Some even say that the treatment is worse than the disease. So that's pretty bad.”
Hormonal treatments also aren’t a one-size-fits-all option. Progesterone is the current mainstay of hormone therapy for endometriosis, but a dosage that’s effective for one patient may not work for another. The sequencing data collected from this and future studies could also help identify factors that might make some patients more responsive to progesterone treatment, helping clinicians fine-tune doses based on the unique disease profile of an individual patient.
Managing endometriosis, or contending with its symptoms without a formal diagnosis, is a full-time job for many people. Its everyday impact is felt not only in acute physical ways, but in the emotional and mental fatigue that comes from managing relationships with medical providers who may dismiss or repeatedly misdiagnose their symptoms. Even under the best circumstances, relief is often temporary, costly, or accompanied by a host of unpleasant side-effects. “Many of these women have lost their employment because they missed two or three days of work a month,” says Metz. “We meet many women in our study who are having financial difficulties covering their healthcare bills.” Financial costs aside, many patients, especially young adults and teens, simply don’t want to proceed with diagnostic surgery if their treatment options are limited.
Dr. Metz says that in addition to refining treatment strategies and introducing an FDA-approved diagnostic tool, they’re also expanding the study to include teens. Menstrual effluent from younger patients hasn’t yet been studied, so this addition could generate exciting insights into early indicators of endometriosis and hopefully enable earlier intervention in very young patients. This combined with the access to genetic susceptibility factors unlocked by emerging sequencing technology holds enormous promise for enabling early non-invasive diagnosis and improving short- and long-term care. To learn more about the study, the research team, and how to participate, visit the ROSE at the Feinstein Institutes for Medical Research at Northwell Health.