Women with endometriosis may be closer to finding relief from chronic inflammation and acute pain during menstruation after a group of international researchers have uncovered a new nonhormonal treatment target, neuropeptide S receptor 1 (NPSR1).

The first line of treatment for women with endometriosis is pain killers, and if that does not work, the next options are either surgery or hormonal treatment, shutting down a woman's cycle whereby she will not be able to have children.

"Surgery is needed to diagnose the disease properly by laparoscopy," Thomas Tapmeier, lead study author on a paper that was published in Science on August 25, 2021, told BioWorld Science. An endometriosis researcher at Monash University's Department of Obstetrics and Gynecology, he said that even surgery to remove the lesions does not always alleviate the pain.

It has been recognized since the 1980s that endometriosis runs in families, and that points to a genetic component, he said, noting that roughly 50% of cases of endometriosis are inherited.

Researchers began to gather data and samples from families in the 1990s to start to put together this puzzle of which genes might be connected to endometriosis.

"Genome-wide association studies (GWAS) have become available to sequence people's genomes and look at what genes are altered in women who have endometriosis, and that's how this work starts," he said, noting that the researchers relied on genetic analysis of humans and rhesus macaques.

Researchers sequenced five megabases from start to finish, and a number of genes came up that were aligned, and NPSR1 was one of them. There were more women that had differences in NPSR1 than the controls in comparison to other genes, Tapmeier said.

The group sequenced the DNA of 32 human families "contributing to genetic linkage signal on chromosome 7p13-15 and observed significant overrepresentation of predicted deleterious low-frequency coding variants in NPSR1, the gene encoding neuropeptide S receptor 1," the study said.

First time NPSR1 is identified as potential target

"This points to NPSR1 probably being the important gene here," Tapmeier said, noting that the study marks the first time this particular gene has been identified as a potential target for endometriosis.

"The NPSR1 variants that we found in the genetic screens are rare variants, so maybe 1-2% of women have them, and they tend to have endometriosis more than others," he said.

The study combined evidence from genetic analyses of endometriosis in humans and rhesus macaques "to identify a nonhormonal target for therapeutic intervention: the G protein-coupled cell surface receptor NPSR1," the study said, adding that this was the first such study that used parallel investigations in which human and nonhuman primate data were collected "to identify a genetically validated therapeutic target."

NPSR1 was originally identified as a risk factor for asthma and inflammatory bowel disease, he said. And, an NPS ligand was first identified in brain tissue, and this receptor is involved in psychosomatic disease such as stress and anxiety, which are also big components of the symptoms in endometriosis, because pain perception changes over time in chronic disease.

"You can see in the brain, structures adapting and changing in response to this recurrent pain," he said, which also pointed to NPSR1 as an important molecule.

Researchers then looked for expression of the receptor in the ligand and the tissues and followed up by looking at different immune cells and the level of the ligand in the peritoneal fluid "to see if it was sloshing around and which immune cells might express the receptor, and we found monocytes, which are cells recruited in inflammatory processes."

"When you have inflammation, monocytes come from the bone marrow and bloodstream, and they migrate into the tissue where the inflammation is taking place and then heal and ameliorate things there. That was very interesting that they expressed this receptor," Tapmeier said.

Because mice do not naturally menstruate, there is not a good animal model, he said, noting that menstruation only occurs in rhesus macaques, so they were important models in the study.

"We then asked what happens when we inhibit this receptor, and with our partners at Bayer in Berlin, we could then synthesize this inhibitor, and we did the assays to show we could inhibit the different functions of receptor signaling in a dose-dependent manner, and from there we went into animal models in mice."

The group used a mouse inflammatory model and then an endometriosis model by taking tissue from one mouse and then implanting it into another mouse as if the mouse had endometriosis. SHA 68R, which inhibits expression of NPSR1, was administered to mice in vitro.

Mice that received the inhibitor showed less pain behavior and had less inflammation, he said.

"That's as far as we got with this piece. The next step is to find a drug or compound that you can use in the clinic that has the same effect.

"We don't know the basic biology yet in how this receptor connects to endometriosis technically. But it shows the power of these genetic screening methods to identify potential targets.

"NPSR1 is important because it's not a hormonal target, and you could potentially do away with all this shutting down the cycle and women not being able to have children when they have endometriosis and undergo hormonal treatments."

Women wait for years until they get the correct diagnosis for endometriosis, and they often suffer through intense menstrual pain for years, and this finding could make it easier to diagnose rather than having to do laparoscopic surgery to diagnose the condition.

"This is why we need biomarkers to diagnose it more easily," he said, noting that doctors are often not aware of the symptoms and the variations in symptoms.

"There are big overlaps with other diseases of the pelvis, so it is difficult to diagnose, and surgery is not the first thing you do, but that makes it such a long journey until you have the correct diagnosis."

Understanding the heritability of the disease would also help progress the research, he said.