In honor of International Women’s Day and Endometriosis Awareness Month, we recognize researchers’ efforts to understand the unique mechanisms behind the mysterious disease and offer hope in the form of promising research and clinical trials in the medical world. Learn more about the disease 1 out of every 10 women suffers from in an article by Medint’s analyst Or Degany.

How do endometrial cells end up in various places in the body?

Even in the writings of Hippocrates (who may or may not have written them himself), dating back 2,500 years, the uterus was perceived as a unique organ that would start “wandering” if it did not fulfill its purpose (that is to say, pregnancy). This perception reflects some of the insights gained over the years into – among other things – the dispersal of endometrial cells in various areas of the body, and curative effects of pregnancy. 

While various hypotheses were proposed on the pathophysiology of endometriosis, the dominant theory, published back in 1927, suggests that during menstruation, tissue segments, cells and blood flow through the fallopian tubes in a retrograde manner (“retrograde menstruation”). This was compounded by the “seed and soil” theory, reminiscent of those theories that we have elaborated on in our blog post regarding cancer microenvironments. According to this perception, changes in the nature of cells (the “seeds”, endometrial cells), in addition to changes in the nature of the environment (the “soil”, or, say, the peritoneal environment) enable the cells to proliferate in various locations (Part A, Part B).

In 2021,”Reproductive BioMedicine Online” published a study by an Australian group with evidence of endometrial stem cells migrating in a retrograde manner during menstruation in women. However, stem cells were found to have a similar prevalence in both the menstrual fluid and the peritoneal fluid of women with and without endometriosis, which indicates that further factors are required in order to understand the development of the disease. The researchers suggest that the presence of additional stem cells (epithelial and mesenchymal, present in both the menstrual fluid and the peritoneal fluid), which were more frequently found in women with endometriosis even after menstruation, may indicate that a tolerant peritoneal and immune environment in women with endometriosis enables their survival in these areas.

Sounds familiar? As you are no doubt well aware, a tolerant environment also enables the survival of cancerous cells. Another study from 2023 demonstrated that cancer-driving genetic mutations (in the KRAS gene) are associated with more severe endometriosis. These are somatic mutations, identified in endometriosis lesions sampled from about 122 patients who underwent surgery. The mutations were correlated with a more severe (deeper, harder to operate on) disease.

Hope for treatment

Treatments currently on offer for women who suffer from endometriosis are primarily hormonal therapies, surgery in suitable cases, and painkillers. 

Current studies stress the importance of the bacterial flora in the uterus and propose a surprising therapeutic approach – antibiotics, or dietary changes. In a study from 2023, a Japanese group demonstrated a high prevalence of Fusobacterium bacteria in the endometrium and endometrial lesions in patients with endometriosis. The researchers demonstrated that bacterial infection promotes the secretion of TGF-b by cells in the environment, leading to a change in the activity of fibroblasts – from “dormant” fibroblasts to myofibroblasts with increased proliferation and adherence capabilities. The researchers showed that antibiotic treatment (administered vaginally) with Flagyl or Chloramphenicol reduced the number and size of endometriosis lesions in patients. Clinical trials (1, 2) are currently being conducted in order to confirm this. 

Additionally, pre-clinical trials in female mice demonstrated that bacterial gut flora has an effect on pain sensitivity in general and on the development of endometriosis in particular. This may affect future treatments, focusing on diet and probiotics. However, it is important to remember that mouse trials are limited in this context, as female mice do not menstruate, nor do they develop endometriosis without intervention.

Endometriosis remains a mysterious illness, encompassing genetic, immune, microbiological, hormonal, and other factors. An in-depth understanding of the mechanisms and the development of groundbreaking diagnosis and treatment methods may lead to a revolution that would benefit many women. Until that time, it is important to raise awareness for endometriosis, so that patients can receive full medical treatment for their pain.