Endometriosis, a debilitating condition characterized by the growth of uterine-like tissue outside the uterus, affects a significant portion of women and individuals assigned female at birth, estimated to be at least 11% globally. This chronic inflammatory disease not only imposes a substantial burden on individual sufferers but also on society as a whole. Despite being recognized for over a century and a half, endometriosis remains shrouded in mystery, with considerable gaps in our understanding, particularly concerning its exact causes. Alarmingly, research into endometriosis is severely underfunded, receiving a mere 0.038% of the National Institutes of Health (NIH) 2022 health budget, despite impacting 6.5 million women in the US alone and over 190 million worldwide.
A critical challenge in managing endometriosis is the often-delayed diagnosis. Currently, histological confirmation, requiring surgery, is the standard diagnostic procedure. This delay exacerbates symptom severity, increases the risk of central and peripheral sensitization, and escalates the overall costs associated with the disease for both patients and healthcare systems. Current treatment approaches, primarily conservative, focus on pain management and hormonal birth control. However, these methods often fall short, proving ineffective in alleviating suffering or improving work capacity, and failing to address critical issues such as infertility and the heightened risk of certain cancers linked to endometriosis. The sheer prevalence, impact, and economic repercussions of endometriosis necessitate a significant increase in research funding and focused attention. Such investment is crucial for developing less invasive, more timely diagnostic tools, and effective treatments, potentially including innovative biomarkers, nanomedicine, and microbiome-based therapies.
Understanding Endometriosis: A Chronic Inflammatory Condition
Endometriosis is recognized as a chronic inflammatory condition that leads to significant illness and affects between 10% and 15% of women during their reproductive years across the globe. In the United States and Australia, conservatively, about 1 in 9 women of reproductive age are affected by endometriosis. The hallmark of this disease is the migration and implantation of uterine tissue in areas outside the uterus. This misplaced tissue disrupts various bodily systems, including the endocrine, musculoskeletal, vascular, reproductive, and nervous systems, resulting in a wide array of painful symptoms and physiological changes.
Endometriosis is broadly categorized into three main types: superficial peritoneal endometriosis, ovarian endometriosis, and deep infiltrating endometriosis. Peritoneal endometriosis is the most common form, while ovarian endometriosis affects a considerable percentage of patients (17–44%) and is characterized by the formation of ovarian endometriomas, cysts filled with dark endometrial fluid. Deep infiltrating endometriosis, affecting approximately 20% of endometriosis patients, is considered the most severe form of the disease. While each subtype is believed to have distinct pathogenic mechanisms, the definitive cause of endometriosis remains elusive, with no single etiology fully explaining its diverse manifestations.
The Significant Burden of Endometriosis Symptoms
Diverse and Debilitating Symptoms
Endometriotic tissue outside the uterus can trigger a broad spectrum of symptoms. These include chronic pelvic pain, dysmenorrhea (painful menstruation), dyspareunia (painful sexual intercourse), dysuria (painful urination), dyschezia (painful bowel movements), metrorrhagia (bleeding between periods), diarrhea, constipation, infertility, and myofascial pain, among others. Notably, gastrointestinal symptoms in endometriosis patients are often more severe compared to those without the condition, frequently leading to overlap and misdiagnosis with irritable bowel syndrome (IBS).
As endometriosis progresses, patients are at risk of developing adhesions, which are fibrous scar tissue bands that can abnormally connect pelvic and abdominal organs. Endometriosis is a leading cause of adhesions in women, commonly affecting areas such as the anterior abdominal wall, bladder, and uterus. These adhesions can cause anatomical distortions, contributing to infertility, rectal constriction, and dyspareunia. Studies have demonstrated that endometriosis-related adhesions significantly impair a patient’s quality of life.
The cumulative effect of these persistent pain symptoms places a substantial burden on individuals with endometriosis. A significant majority, around 70%, experience ongoing, unresolved pain that impacts all aspects of their lives. Research indicates that endometriosis patients also have a higher incidence of co-occurring health conditions compared to those without the disease. Pain, in particular, contributes to increased rates of chronic stress, anxiety, depression, and a diminished quality of life among endometriosis patients.
A significant diagnostic delay, ranging from 4 to 11 years from symptom onset, is a well-documented issue in endometriosis. Several factors contribute to this delay, including the lack of a specific symptom profile, the variability of symptoms, and long wait times for laparoscopies, the surgical procedure used for definitive diagnosis. Many patients resort to seeking multiple medical opinions to find a healthcare provider who will support their pursuit of an endometriosis diagnosis. Studies have shown that a significant percentage of endometriosis patients consult at least five doctors before receiving a diagnosis or referral. This may be partly attributed to a lack of sufficient knowledge about endometriosis among general practitioners, as highlighted in studies where a considerable proportion of general practitioners felt inadequately informed about the condition for their clinical practice. Misdiagnosis is also common, with conditions like intolerances, appendicitis, irritable bowel syndrome, and pelvic inflammatory disease frequently being mistaken for endometriosis.
The Role of Sensitization in Endometriosis Pain
Beyond the direct pain from endometriotic lesions, patients can also experience central and peripheral sensitization. Central sensitization involves abnormal processing of sensory signals, leading to an amplified perception of both painful and non-painful stimuli through heightened pelvic nerve sensitivity. Peripheral sensitization lowers the threshold for pain receptor activation due to repetitive and prolonged stimulation, a characteristic feature of endometriosis. The combined effect of these sensitization processes means that over time, even normally non-painful stimuli can trigger intense pain in sensitized individuals.
Women with chronic pelvic pain, whether diagnosed or not, exhibit significantly lower pain tolerances compared to those without pelvic pain. The extent of reduced pain tolerance is correlated with the duration of symptoms, supporting the idea that delayed diagnosis can worsen patient sensitization. Studies have found that endometriosis patients experience significantly higher functional pain disability, meaning pain interferes with daily activities such as sleep, relationships, and work, compared to women without endometriosis. Furthermore, biological differences contribute to women generally having a higher pain sensitivity than men, influenced by complex interactions of anatomical, hormonal, physiological, and psychological factors.
Cancer and Infertility Risks Associated with Endometriosis
While endometriosis itself is not cancerous, it is considered a non-neoplastic invasive disease. However, research suggests a potential link between endometriosis and ovarian cancer. Molecular evidence indicates that endometriotic lesions can undergo transformation into certain types of ovarian cancers, specifically clear cell and endometrioid ovarian cancers. This connection remains a subject of ongoing research and debate, requiring further investigation to fully understand the underlying mechanisms. Current data suggests that endometriosis may slightly increase the risk of ovarian cancer, from 1.3% in the general female population to 1.8% among women with endometriosis.
In addition to pain, infertility is a major concern for endometriosis patients. Approximately half of women with endometriosis experience fertility problems. In fact, endometriosis is found in up to half of women with unexplained infertility or subfertility. The mechanisms by which endometriosis impairs fertility are multifactorial and may include anatomical distortions, reduced ovarian reserve, chronic inflammation, and impaired endometrial receptivity.
Image alt text: Laparoscopic view illustrating characteristic endometriosis lesions on the pelvic peritoneum, highlighting the visual diagnostic challenges and the need for enhanced clinical diagnosis of endometriosis.
The Critical Issue of Underfunding for Endometriosis Research
Endometriosis has far-reaching consequences, affecting not only individuals but also their families, workplaces, and society as a whole. The current challenges in diagnosis, treatment, and funding for endometriosis are rooted in a historical lack of understanding and prioritization of women’s health issues. Increased funding for endometriosis research is essential to improve our understanding of the disease, address knowledge gaps, shorten diagnostic delays, expand treatment options, enhance pain management, and give long-overdue emphasis to women’s experiences of illness.
The National Institutes of Health (NIH), a major global source of biomedical research funding, allocates billions of dollars annually. However, in 2022, endometriosis research is estimated to receive a meager $16 million, representing only 0.038% of the NIH budget. Considering that endometriosis conservatively affects 11% of women in the US during their lifetime, this translates to a mere $2.00 per patient per year allocated for research. In stark contrast, diabetes, affecting approximately 12% of US women, receives significantly more funding. Even assuming only half of the diabetes research budget is directed towards female sufferers, the per-woman funding for diabetes research is over 1,500% higher than that for endometriosis.
Comparing endometriosis funding to that of Crohn’s disease, another chronic inflammatory condition, further highlights the disparity. Crohn’s disease, affecting a much smaller percentage of the US population (0.21%), receives significantly more research funding per patient than endometriosis. This comparison is not to argue for reduced funding for Crohn’s disease, but to emphasize the serious underfunding of endometriosis research relative to its prevalence and impact.
The Significant Economic Burden of Endometriosis
The burden of endometriosis on individual patients is substantial, both before and after diagnosis. The persistent pain associated with endometriosis can lead to job loss and relationship difficulties. Moreover, the financial strain is considerable. Endometriosis patients incur significantly higher healthcare resource utilization, resulting in greater direct and indirect healthcare costs compared to those without the condition. In the US, endometriosis patients spend significantly more on healthcare expenses in the years surrounding their diagnosis. In the year following diagnosis, endometriosis patients spend, on average, 3.5 times more on healthcare compared to controls.
Direct costs associated with endometriosis include outpatient and inpatient treatments, surgeries, and prescription medications, averaging thousands of dollars per patient annually in the US. Indirect costs, encompassing lost workdays and reduced work productivity, are even higher. Studies across multiple countries show that lost productivity costs are generally double the healthcare costs. Endometriosis patients often experience reduced effectiveness at work, losing significant work hours per week due to presenteeism (being at work but functioning at a reduced capacity). Since endometriosis typically begins at a young age, during a highly productive phase of life, the cumulative effects of fatigue, productivity loss, and time away from work and education create significant barriers to career advancement and financial security for patients.
The total economic burden of endometriosis in the US is estimated to be in the tens to over a hundred billion dollars annually. In Australia, the annual cost per woman with endometriosis is also substantial, with the majority attributed to productivity losses. Delays in endometriosis diagnosis not only worsen symptoms but also increase emergency room visits, hospitalizations, and overall healthcare costs. Longer diagnostic delays are associated with significantly higher healthcare expenditures in the years leading up to diagnosis.
Lost workdays are also significantly higher among endometriosis patients compared to the general population. In countries like Australia, endometriosis patients utilize a significant portion of their sick leave to manage chronic pain. Studies have shown that a large percentage of endometriosis patients use unpaid leave to manage their symptoms, experience workplace judgment due to their condition, and some even report job loss as a result of endometriosis.
Furthermore, productivity losses due to fatigue are substantial, even when women with endometriosis are at work. Studies have consistently shown that endometriosis patients experience significant work impairment due to fatigue and other endometriosis-related symptoms. These findings are echoed across different countries, highlighting the global impact of endometriosis on women’s work lives and economic well-being.
When comparing the economic burden of endometriosis to diabetes in the US, the per-patient burden of endometriosis is estimated to be comparable to or even higher than that of diabetes. This underscores the immense financial strain not only on individuals with endometriosis but also on national economies due to increased healthcare utilization and reduced workforce participation. If endometriosis research were funded at a level commensurate with its economic burden, similar to diabetes, funding would need to increase dramatically.
Limitations of Current Endometriosis Treatment Options
The lack of adequate research funding for endometriosis hinders the development of effective diagnostic and treatment options. Consequently, current treatments for endometriosis are limited, and recurrence rates for both symptoms and the disease itself are high. Non-surgical treatments like birth control and pain management offer only temporary symptom relief, not a cure, and are ineffective for endometriosis-related infertility. Effective, non-invasive, non-hormonal treatments are urgently needed for the millions of women worldwide affected by endometriosis.
Birth Control and Pain Management: Symptom Suppression, Not Solutions
Birth control is a commonly prescribed treatment for endometriosis, including intrauterine progesterone devices, progestin injections, and combined hormone pills. However, these hormonal treatments come with potential side effects. Combined treatments can increase the risk of thromboembolism, nausea, and breast tenderness, while progestin injections may cause weight gain, decreased bone density, acne, and depression. Birth control is also unsuitable for women who cannot tolerate the side effects or who are trying to conceive.
Pain management is a central aspect of endometriosis care, given pain is the most prevalent symptom. However, effective pain management is complex. Evidence for the effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) is inconclusive. Opioids, while not recommended for endometriosis, are frequently used by patients to manage severe pain, highlighting the intensity of pain experienced. Chronic opioid use, however, carries risks of addiction and adverse side effects, and can increase healthcare costs. Long-term opioid use for chronic non-cancer pain like endometriosis is controversial due to the high rate of adverse events and the development of tolerance, requiring increasingly higher doses for pain relief.
Surgery: Invasive and Not Always Permanent
Laparoscopic surgery is considered the gold standard for both diagnosing and treating endometriosis, providing histological confirmation of the disease. However, surgery is not a permanent solution for many patients. Recurrence of symptoms and lesions is common, with a significant percentage of patients requiring multiple surgeries over time. Repeated surgical interventions can exacerbate pain and fertility issues. Furthermore, surgery itself is a physical trauma that can trigger biological responses that may paradoxically promote endometriosis recurrence.
Promising Avenues for Future Endometriosis Research and Diagnosis
Despite the challenges, ongoing research offers hope for improved diagnosis and treatment of endometriosis. While the earliest descriptions of endometriosis date back centuries, fundamental aspects of the disease, such as its cause and the biology of both healthy and endometriotic tissues, remain poorly understood. The limited progress despite extensive research publications underscores the complexity of endometriosis and the need for increased global funding. Nevertheless, dedicated researchers are exploring promising new directions.
Biomarkers: Towards Non-Invasive Diagnosis
A major obstacle in endometriosis management is the lack of non-invasive diagnostic tools. Biomarkers offer a potential solution for non-invasive diagnosis. However, many previously investigated biomarkers have only been able to detect advanced stages of the disease, highlighting the need for research to identify biomarkers capable of diagnosing milder cases. Recent studies have identified distinct microbial communities in the peritoneal fluid and feces of endometriosis patients compared to controls. Specific microorganisms, such as Ruminococcus in the gut and Pseudomonas in peritoneal fluid, show promise as potential auxiliary diagnostic markers for endometriosis, warranting further investigation into the complex interactions between microorganisms and endometriosis.
Follicular fluid, obtained during oocyte retrieval, is another area of biomarker research. Studies have revealed dysregulated cytokine profiles in the follicular fluid of endometriosis patients, with elevated levels of pro-inflammatory cytokines and decreased levels of anti-inflammatory cytokines. Specifically, measuring the level of IL-10 in follicular fluid has shown potential in differentiating between endometriosis patients and controls.
Nanomedicine: Targeted Therapy and Imaging
Nanomedicine, utilizing nanoparticles, is an emerging field with potential for endometriosis imaging, targeted treatment, and drug delivery. While the unknown etiology and pathogenesis of endometriosis present challenges, nanoparticles have shown the ability to accumulate in endometriotic lesions, offering potential for improved imaging and targeted drug delivery. Nanoparticles could be used to deliver anti-inflammatory, antioxidant, anti-angiogenic, and immunomodulating molecules directly to lesions, potentially reducing lesion size or eliminating them altogether, rather than just suppressing symptoms. However, extensive pre-clinical and clinical research is needed to validate the use of nanomedicine for endometriosis.
Microbiome Modulation: A Novel Therapeutic Target
Imbalances in gut microbiota composition have been linked to the immune system dysfunction associated with endometriosis. Animal studies consistently demonstrate the interplay between the gut microbiome and endometriosis. Beyond biomarkers, the gut microbiome itself may be a target for novel treatments. Studies in mice with induced endometriosis have shown that antibiotic therapy can reduce lesion size and inflammation. Furthermore, fecal microbiota transplantation experiments suggest a role for the gut microbiome in endometriosis progression. Conversely, beneficial bacterial metabolites, such as n-butyrate, a short-chain fatty acid, have shown protective effects against endometriosis progression in animal models. Therapies aimed at modulating the gut microbiota hold significant potential for reducing lesion growth and inflammation in endometriosis patients.
Discussion: A Call for Increased Funding and Action
Despite advancements in endometriosis research, critical knowledge gaps persist, presenting significant opportunities for expanding our understanding of this important women’s health issue. The authors strongly believe that endometriosis warrants significantly more attention and research investment to address these fundamental gaps. The current level of research activity in this critical area is insufficient, likely due to inadequate funding. If endometriosis research were funded at even half the level of diabetes, the budget would need to increase dramatically.
The current funding levels for endometriosis research are not commensurate with the immense pain suffered by patients, the lengthy diagnostic delays, the limitations of current treatments, the significant knowledge gaps, the substantial economic burden, and the profound personal costs incurred by individuals with this condition. Beyond research funding, investment is also needed in translating research findings into clinical practice, understanding the diverse epidemiological aspects of the disease, increasing public awareness of endometriosis, and improving healthcare practitioner training to better manage and support endometriosis patients.
Promising research avenues, including non-invasive biomarker diagnostics, nanoparticle-based drug delivery, and microbiome-targeted therapies, offer the potential for significant positive impacts on patient care. Advancing our understanding and treatment of endometriosis is challenging but achievable. Increased and more representative funding for endometriosis research is crucial to accelerate the development of non-invasive diagnostic and treatment methods, leading to long-term benefits for patients and society.
Data Availability Statement
The original data supporting this study is available within the article; further inquiries can be directed to the corresponding author.
Author Contributions
KE conceived and collected literature as the primary author. DM and JC contributed equally through critical revision and editing. All authors contributed to and approved the submitted manuscript.
Conflict of Interest
The authors declare no commercial or financial conflicts of interest.
Publisher’s Note
The views expressed in this article are solely those of the authors and do not necessarily represent the views of their affiliated organizations, or those of the publisher, editors, and reviewers. No endorsement of evaluated products or manufacturer claims is implied.
Acknowledgments
The authors acknowledge the Biomolecular Interaction Centre (BIC) for their support and financial contribution to the Engineering Endometriosis Research Program at the University of Canterbury.
References
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Keywords: endometriosis, funding, women’s health, quality of life, chronic pain
