Endometriosis. Portuguese try to speed up diagnosis

I was always told it was normal. The pain became "a big obstacle" when Susana turned 12, and as time passed and among doctors and family members, the devaluation of her condition was constant. But it persisted. "The picture was progressing to the point of vomiting with pain, having a fever, missing classes, and not being able to stand up," she tells the Observer. Almost 12 years passed until she received confirmation of what she felt. The pains, the general malaise, and the numerous visits to hospital emergency rooms were a clear sign of endometriosis. Only at the age of 23 did the diagnosis arrive. It is estimated that there are thousands of women in Portugal who have gone through or are going through something similar to Susana Fonseca. "There was always a constant devaluation of the symptoms. I kept hearing that [the pain] was normal and the tests were always inconclusive. The ultrasounds gave normal results," she reports. To unravel why she suffered every day, Susana researched on the internet and recognized her symptoms under a description: endometriosis. From there, thorough clinical validation followed. "I had several tests: MRI, ultrasound, colonoscopy, and CT scan of the bladder, exactly to evaluate all the systems (urinary, gastric, etc.). I already had endometriosis everywhere, the disease was quite advanced. I had to undergo a surgery of about six hours, with bowel resection," she describes. "Habituated" to living with a "permanent pain," she went through two "stable" years after the operation. Appointments continued with some regularity to monitor her health, but she managed to recover "some quality of life." It was through testimonies like Susana's that SENSOPAD was born. The great objective of this European project—with research focuses in Portugal—is to reduce the eight years it takes, on average, to diagnose a person with endometriosis, to just a couple of months. In Athens, they seek to develop a system based on a hygienic pad to detect inflammation early through menstrual blood. In Braga, a diagnostic system is being designed with all the precision to detect the disease from an existing genetic alteration in the cells of people with endometriosis. With the two parts of the project in action, divided among a dozen partners in Europe, the idea is "to develop a technology that allows us, first, to detect endometriosis early and then to diagnose it accurately," describes Carlos Honrado, one of the researchers leading the project in Portugal. The pad, which has integrated sensors, serves for "screening," and is a kind of early warning, as it detects inflammation that may (or may not) be associated with the disease. If any irregularity is detected, menstrual blood is collected to be inserted into the analysis system developed in Portugal, to detect a specific mutation linked to endometriosis. "We would go from a diagnosis that takes eight years to perhaps one or two months," he reinforces. The laboratory where everything is on a "micro" scale and wants to fight "taboos" The prototypes of the diagnostic system are being tested in a corridor in the Iberian International Nanotechnology Laboratory (INL), where there are rows and rows of tables in an open space arrangement and, on the margins, dozens of laboratories. It is on the upper floor of that modern and curvilinear building, described by the hundreds of researchers who go through the facilities daily as "the comma of INL," that the microfluidics laboratory is located. The work is divided between the two benches of the room. The INL researchers are working on the development of the experimental method to detect the genetic mutation that gives rise to endometriosis. Therefore, on one side, the fluid to be analyzed is "cleaned" of the components that "are not of interest" through three-dimensional printed pieces and very thin tubes, and on the other, the necessary DNA is extracted to identify the gene of interest. It seems simple, but all this happens on a "micro" scale. In this laboratory, everything is done with extremely small volumes of samples to increase the speed, efficiency, precision, and control of all experimental variables. Hugo Silva, a doctoral student in that research group within the scope of his thesis in the field of microfluidics, shows the Observer how it all works. The explanation, technical and complex, is visually supported by the images transmitted on the large screen connected to the microscope where he works. "Menstrual blood is composed of both tissue and peripheral blood. It is basically the endometrium growing during the month, and then, during menstruation, all the tissue and cells that come from the endometrium, the stroma and the epithelium, along with immune cells and components of the peripheral blood, are in that sample," explains researcher Carlos Honrado. If in "normal" blood, centrifugation is enough to separate the different layers, in menstrual blood, the amount of elements is "much more complicated to process." It is also why "no one has ever seriously looked at menstrual blood" as a diagnostic tool. Through microfluidics, they can automatically "do a filtration." "This way, we remove the tissue and matrix that are not of interest, eliminate the red blood cells, and only enrich the nucleated cells to collect the DNA," the specialist in medical devices adds. "Since the sample is very complex, if they take a small sample of 500 microliters of this blood and want to extract the DNA, it will be a highly inefficient process. Our contribution is to make this process simple and efficient. If they were to take a sample of this kind to a laboratory, it would have to be a very manual process that would take many hours to unravel the sample," he continues. Milad Massoudifarid is an Iranian researcher who, after completing his studies in Tehran and spending seven years in South Korea working on his doctorate, came to Braga to work specifically on this project. It was Milad who set up the system to extract the DNA from the sample collected by Hugo. On the bench is an already automated system that injects four different substances, in different amounts, that allow isolating the genetic information of the "clean" blood. To illustrate the process to the Observer, Milad placed a dye in each of the tubes to identify the current of each liquid. The leader of the research group is the Galician Lorena Diéguez, who, sitting in conversation at a table overlooking the garden and the guesthouse that hosts researchers and guest professors within the INL perimeter, offers additional context for the difficulties associated with diagnosing endometriosis. Besides the lack of literacy, Lorena explains that the existence of "taboos" contributes to the lack of scientific articles focusing on the use of menstrual blood and its composition. "Little by little we are advancing so that people talk about this, but I guarantee that a large part of the population—and even the women themselves—does not know what endometriosis is," the researcher admits. "The disease conditioned my whole life" Susana's symptoms returned about two years after the laparoscopy. Only with laparoscopic surgery, which allows observation with a camera in the endometrium area, is it possible to remove the inflamed region and take a biopsy of the removed sample. Endometriosis is a disease associated with the abnormal growth of the layer that lines the inside of the uterus. But despite being a condition that starts localized, it ends up spreading to other regions, either the rest of the uterus or even the intestines. "If not treated in time, it can even evolve into endometrial cancer," explains Lorena Diéguez. At 27 years old, Susana had already been forced to "give up" what she had studied for multiple years. "In the midst of chaos," she managed to complete her degree in Education and became a primary school teacher. "When I started teaching, I was in the most critical phase of the disease and I ended up giving up the profession. I was always absent, I never knew when I could go to teach, and there were legitimate comments from colleagues and parents, as children need predictability," she tells the Observer. "I graduated as a teacher and gave up the career because of the diagnosis, as I could not compete to place myself in a distant place where there was no hospital nearby and where I had to live alone," she adds. "The disease conditioned my whole life." Having already, in theory, "repaired" the inflammation of the endometrium, it is common for the problem never to be fully resolved. "The doctor knew of my reproductive desire to be a mother and told me that the ideal would be to try to get pregnant at that time. He gave me six months to try naturally, otherwise I would have to go to Assisted Reproductive Technology," recalls Susana. During that post-surgical period, she was taking hormonal medication to suspend menstruation and reduce symptoms. But to try to get pregnant, she had to stop the treatment. "Every negative month was a torment, because the pains were incapacitating without medication. But, in the sixth month, I managed to get pregnant naturally," she celebrates. It was a pregnancy at risk that ended in a cesarean, where the endometriosis had to be intervened upon, as the doctors found her ovaries attached to the wall of the uterus. It is at these times, when therapeutic options that minimize symptoms are abandoned, that infertility is discovered. According to a study published in the Journal of Assisted Reproduction and Genetics, between 30% and 50% of women with endometriosis are infertile. And, two years after giving birth to her daughter, during a medical check-up, Susana realized she could not have children anymore. "Besides the very advanced endometriosis, I had developed an istmocele on the scar of the cesarean, that is, a blood sac in the uterus. The picture was very complex and, instead of a second child, I had to have a total hysterectomy," she describes. "Many young women start taking the pill very early to regulate hormonal symptoms. The problem is that the disease continues to evolve silently. When they stop the pill to try to get pregnant, the endometriosis returns with force and they discover that they are infertile because the damage has accumulated over the years," explains Carlos Honrado. The INL researcher says that these consequences of the disease are common because of the delays in diagnosis—either because the methods are inefficient or due to simple medical devaluation. "There are situations where the image shows nothing, which delays the diagnosis a lot. The person has the symptoms, has the imaging test, and sees nothing because certain locations of endometriosis are very difficult to detect," he continues. The genetic analysis proposed by the researchers based in Braga does not eliminate the need for laparoscopic surgery. "In an initial phase, surgery may not be ruled out immediately until it is confirmed that the results are identical, but it would greatly shorten the diagnostic time and help with postoperative monitoring," clarifies Lorena Diéguez. However, "it would be much cheaper, safer, and reach many more women because it is a non-invasive test with no side effects." "I waited 12 years for a diagnosis and to be constantly devalued. All the projects underway are excellent initiatives." The SENSOPAD project celebrated two years at the beginning of October. It was an initiative created at the National Technical University of Athens that, together with multiple European institutions, received a European grant of almost 7 million euros for four years of work. The design of the different prototypes that, together, will result in this hygienic pad with an inflammation sensor and a more effective diagnostic system, is proceeding "on track." "On our side, we have already managed to demonstrate several devices working to perform the different tasks: taking blood, unraveling it, and collecting DNA. Next year, our goal is to integrate all this automatically and optimally," describes Carlos Honrado. "Now, we need to test with real samples," points out the head of the research group. At the beginning of 2027, they hope to have formalized an agreement with the Academic Clinical Center of the Hospital of Braga to recruit patients and also healthy people to test the functionality of the developed diagnostic system. "So far, the tests have been done with peripheral blood or samples more similar to those of interest," refers Lorena Diéguez. "During most of 2027 we will do the integration and calibration of the sensors with control samples, and in 2028, we will do the complete clinical study," she completes. The project, in a general sense, also seeks the input of "already diagnosed people, collaboration with patient associations, and other research projects in the same area." As Susana, founder and president of Mulherendo—the Portuguese Association for Support to Women with Endometriosis—is fully familiar with this project. "I waited 12 years for a diagnosis and to be constantly devalued. All the projects currently underway are excellent initiatives. Everything that facilitates the diagnosis and improves the quality of life of the women is a good bet," she states. While a solution that facilitates the detection of the disease and simplifies the diagnostic process is not yet available, Susana organizes literacy sessions in schools for students from the 7th grade. "There are many young women who say, in the end, that they have all these symptoms, but that their mother says it is normal," she describes. "Even with all the access to information, myths and taboos are still perpetuated." In these cases, the only thing that can be done is to give out the Mulherendo brochure and wait for the parents to get in touch to help clarify questions about the condition. "Even so, sometimes our intervention is seen by some guardians as an invasion of parental work," she adds. Living with endometriosis is like having a "ticking time bomb" in the body, describes Susana, who, even after having surgically removed the uterus, continues to feel the effects of the late diagnosis. "A hysterectomy does not cure endometriosis. I underwent bowel resection years after the hysterectomy, still because of the endometriosis," justifies the association president. "There is a whole set of invisible consequences that continue to condition my daily life."