Endometriosis: Latest Insights and Breakthroughs
🎗️March is Endometriosis Awareness Month🎗️
Endometriosis stands as a prevalent yet enigmatic condition affecting approximately 1 in 9 individuals with uteruses worldwide. The journey to an endometriosis diagnosis is often fraught with challenges. Despite its prevalence, the condition is frequently misunderstood and underdiagnosed, often taking an average of 7 to 10 years before individuals receive a conclusive diagnosis (1). This delay underscores the complex nature of the condition, characterised by the abnormal growth of endometrial-like tissue outside the uterus, leading to a spectrum of distressing symptoms and significant disruptions to daily life. The delay is often also attributed to the gender data gap and the fact that endometriosis, like many other female-specific diseases, remains elusive based on the lack of knowledge, data, funding and research. Fortunately, recent years have seen a dramatic increase in endometriosis research and innovative technologies stemming from newfound insights, which will help revolutionise healthcare for those affected by this condition, and ultimately the quality of their lives.
Understanding Endometriosis:
Endometriosis presents a multifaceted challenge, involving the implantation and growth of endometrial-like tissue in locations beyond the uterus. This tissue, mirroring the lining of the uterus, proliferates in areas such as the ovaries, fallopian tubes, and peritoneum, triggering inflammation, scarring, and adhesions. As a result, individuals with endometriosis often experience debilitating symptoms including pelvic pain, dysmenorrhea (painful periods), dyspareunia (pain during intercourse), and infertility (2).
Insights into Endometriosis Pathophysiology:
Research into the pathogenesis of endometriosis has uncovered various theories, with Sampson's theory of retrograde menstruation being the most widely accepted. This theory suggests that endometriosis occurs when endometrial cells flow backwards through the fallopian tubes during menstruation, leading to their implantation and the formation of lesions (3). However, it's puzzling that retrograde menstruation occurs in 90% of women, yet only 10% develop endometriosis. This hints that there are additional factors at play that allow for the development of endometriosis in only a subset of menstruators, and not all.
Genetic Underpinnings:
Recent advancements in genetic research have shed new light on the molecular underpinnings of endometriosis. Genome-wide association studies (GWAS) have identified specific genetic differences associated with an increased risk of endometriosis (4). Nineteen specific genetic markers, known as single-nucleotide polymorphisms (SNPs), have been pinpointed, with two particularly notable ones located at the ESR1 gene locus. This gene is responsible for encoding the estrogen receptor alpha (ESR1) protein, which plays a vital role in estrogen signalling and various reproductive functions. The discovery of these SNPs suggests a strong connection between hormonal influences, especially estrogen signalling, and the development and progression of endometriosis. It is speculated that these genetic variations at the ESR1 locus could disrupt the normal functioning or regulation of the ESR1 protein, leading to abnormalities in estrogen signalling and contributing to the pathophysiology of endometriosis. In essence, the identification of these 19 SNPs, particularly those at the ESR1 locus, sheds light on the pivotal role of estrogen signalling and provides potential targets for further exploration into the underlying molecular complexities of endometriosis (4).
Microbial Interactions:
Recent investigations into the microbiome have also unveiled a potential link between Fusobacterium bacteria and endometriosis development. Studies have revealed that 64% of individuals with endometriosis harbour members of the Fusobacterium genus in their uterine lining, compared to only 7% of those without the condition (5). Further experiments in cells and mice have demonstrated that Fusobacterium infection promotes the growth of endometriosis lesions, suggesting a novel avenue for therapeutic intervention (6). Excitingly, these findings open new avenues for understanding and potentially treating endometriosis. By elucidating the role of specific bacteria, and their metabolites in the development and progression of the disease, researchers may eventually develop targeted interventions to disrupt this process and alleviate pain.
Advancements in Endometriosis Research:
Moreover, pioneering research on lab-grown endometrial tissue, known as endometrial organoids, offers unprecedented opportunities to increase our understanding of endometriosis. These miniature replicas of endometrial tissue enable scientists to study disease mechanisms and test potential treatments in a controlled laboratory setting, providing invaluable insights into disease progression and therapeutic targets (7). To date, tissues and organoids have been cultured from numerous individuals with varying endometriosis types, severity and stages, therefore enabling therapeutic interventions to be tested across varying cases of endometriosis. Besides being obtained by invasive biopsies, endometrial organoids can also be obtained and grown from menstrual effluent during menstruation (8). Not only does this offer a non-invasive means to study endometriosis, but it could also increase our understanding of the earlier stages of endometriosis, and it’s initial development. Certain cells known as stem cells or progenitor cells have been identified in menstrual blood, in which are thought to be involved in the formation of lesions, following retrograde menstruation. The ability to now obtain such cells and culture endometrial organoids from menstrual blood enables researchers to gain more clarity surrounding the pathophysiology of menstruation, which could in turn aid with the development of novel prevention and therapeutic measures (9).
Innovative Diagnostic Approaches:
In addition to advances in understanding the pathophysiology of endometriosis, innovative diagnostic techniques are revolutionising endometriosis detection and management. One such innovation is the saliva diagnostic test, which is the first non-invasive, validated endometriosis diagnostic test (10). Based on detecting a salivary microRNA (miRNA) signature comprised of 109 miRNAs, this test holds promise for a sensitive and specific diagnostic tool that could help reduce the currently absurd diagnosis time from years to days. In addition to saliva diagnostic tests, menstrual blood is also being explored in terms of its potential use as a possible endometriosis diagnostic tool* (11). Cellular differences in menstrual effluent of those with endometriosis, compared to those without, may offer insights into the pathogenesis of endometriosis but may also provide the basis on which a menstrual blood diagnostic test can be built. Such non-invasive tests hold promise for early detection and personalised treatment strategies, and offer a paradigm shift in the diagnostic landscape, potentially mitigating diagnostic delays and improving patient outcomes.
*see (3) in Further Reading.
Innovative Approaches to Treatment
Innovative treatment strategies are also on the horizon, which could benefit those with endometriosis and improve the quality of their life, post diagnosis. Biotech start-up Gynica has recently announced a first-in-human clinical trial to evaluate its novel endometriosis treatment (12). The trial will assess the safety, tolerability, and pharmacokinetics of Gynica's IntraVag intra-vaginal drug delivery platform and two proprietary drug candidates, S-301 and S-302. Led by renowned endometriosis expert Professor Felice Petraglia, the trial aims to explore the potential of cannabinoids in alleviating endometriosis-associated pain and addressing the inflammatory microenvironment associated with the condition.
AMY109, an engineered antibody targeting interleukin-8 (IL-8) associated with inflammation, presents promising results in treating endometriosis. In a study involving macaques, monthly injections of AMY109 led to significant benefits, including a reduction in lesion size by half without adverse effects on health measures. Now undergoing clinical trials in humans in Japan and Taiwan, AMY109 holds potential as a non-invasive, disease-modifying therapy for endometriosis, offering hope for improved symptom management and enhanced quality of life for individuals with this complex condition. Compared to traditional treatments like hormone-suppressing drugs and surgery, AMY109 offers the advantage of being non-invasive and potentially more effective in reducing lesions without the side effects commonly associated with hormonal therapies or the risk of recurrence seen with surgery (13; 14).
Drug discovery initiatives are also being developed, to help discover novel therapeutic drugs for endometriosis. Professor Hugo Vankelecom is currently leading the CurE-me project aimed at revolutionising endometriosis treatment. The project harnesses the development of an organoid biobank into an endometriosis drug discovery and high-throughput screening platform. It will test targeted, repurposing, and unbiased compound libraries to identify and develop non-toxic therapeutics that directly impact the endometriotic ectopic lesions (15).
Conclusion:
Endometriosis represents a complex and multifaceted challenge in female health, necessitating concerted efforts across research, diagnosis, and treatment domains. The quality of life for those with endometriosis is negatively impacted, with the disease having an effect on a number of factors such as mental health, working capacity and relationships (16). A recent surge in awareness, funding, research and start-ups surrounding endometriosis has seen a pivotal turning point for the disease and the future of those with it. In addition to the innovative research, diagnostic and treatment approaches mentioned in this blog post, there are many more that were not mentioned. Together, these efforts are contributing to more data and knowledge on endometriosis, and paving the way for earlier detection, personalised interventions, and improved outcomes for individuals affected.
Despite these advancements, challenges remain in translating research findings into clinical practice and addressing the long-term impact of treatments on fertility and quality of life. Nevertheless, with continued investment in research and support for those affected by the disease, we can strive towards a future where endometriosis is not only better understood but effectively managed and, ultimately, prevented.
References:
Menstrual flow as a non-invasive source of endometrial organoids - PMC (nih.gov)
Validation of a Salivary miRNA Signature of Endometriosis — Interim Data | NEJM Evidence
Endometriosis could be controlled with monthly antibody injections | New Scientist
A long-acting anti–IL-8 antibody improves inflammation and fibrosis in endometriosis (science.org)
Further reading:
(2022). Molecular and Cellular Advances in Endometriosis Research. Available from: 10.3390/books978-3-0365-2802-1
