The Evidence Paradox: Healthcare Reformers Ignore Evidence Based Data
“Absence of evidence is not evidence of absence – but no more so than the remarkable capacity of healthcare reformers to alter service structure in the absence of evidence.”
It's puzzling to see healthcare reformers implement changes without sufficient evidence, only to disregard subsequent evidence and case studies that suggest a different approach. This paradox undermines the principles of evidence-based policy-making and raises questions about the commitment to safe and accurate healthcare reform. Endometriosis is just one example. It's essential to acknowledge the ongoing hindering of care because of outdated and inaccurate approaches.
A groundbreaking Class Action Investigation into Endometriosis Care in America is underway, fueled by a growing movement of over 3,000 supporters on change.org and 50 in-person signatures. This effort is backed by a compelling collection of:
40+ patient testimonials, exposing the human cost of inadequate care
Evidence-based research, highlighting the latest medical understanding
Independent studies, analyses, and patient cases, demonstrating systemic failures
The investigation aims to drive transformative change, from medical school education to revisions in the Americans with Disabilities Act (ADA).
By shedding light on decades of preventable suffering and mortality, it seems the movement to hold accountable those responsible for continued discriminatory practices and systemic failures in endometriosis care has begun.
There are 10 key factors discussed to be taking place everyday in the healthcare system, requesting an investigation into:
Preventable Mortality
Preventable Cancer Deaths
Spreading Cancer
Wrong Organ Surgeries
Discrimination in Funding
Discrimination in Med Schools
Life-threatening Bowel Obstructions & Kindey Failure
Harmful Medications
Illegal Denial of Care
Civil Rights Violations.
Endometriosis is a chronic, inflammatory, systemic, and estrogenic-dependent disease. This condition may manifest genitally or extragenitally. The prevalence of endometriosis ranges up to over a BILLION individuals globally. (Nezhat.2024) We’ve certainly come a long way since the days when Endometriosis was referred to as the ‘woman’s disease’ or ‘Eve’s Curse’ — developments and discoveries have slowly changed these outlooks, yet a staggering weight of institutionalized inertia stands in the way for genuine care.
For thousands of years, the crippling pain of endometriosis has been wrongly normalized, perpetuating a culture of silence and stigma. This misguided acceptance has been passed down through generations, with mothers teaching their daughters to endure the pain, and educators from high school to medical school reinforcing the misconception that it's 'just part of being a woman.' The consequences of this normalization are devastating — shamed into silence, discouraged from seeking medical care, and being subjected to subpar treatment. A branch to this problem lies in outdated medical theories, such as Sampson's Theory, which falsely attributes endometriosis to 'retrograde menstruation.' This debunked theory has been used to justify ineffective and harmful treatments, putting patients at greater risk.
The truth is, endometriosis is not a 'women's issue’ that needs minor treatment or limited recognition. Cases of men developing endometriosis lesions and experiencing abdominal pain have been documented, with these individuals receiving prompt medical attention — highlighting the gender care gap even deeper. Furthermore, endometriosis has even been found in the body of a developing fetuses in the womb and even in an array of animals. Its even shown transgender prevalence as significantly high and due to medical gaslighting, misgendering, and overall discrimination in healthcare it may lead to many patients not feeling safe to disclose certain information. It's time to shatter the myths surrounding endometriosis and demand evidence-based care that prioritizes ALL patients' well-being.
The current practice for endometriosis care involves an immediate use of reproductive hormonal medications and surgical surface area burning methods in an attempt to treat the disease. Some researchers even consider a few medications a type of chemical castration, and recognize the risks using such surgical ablation methods. This takes us into the leading cause of the estimated 600,000 hysterectomies performed each year in the U.S alone, as another supposed treatment for the disease. This does not include the numerous hospitalizations for the loss of other organs when Endometriosis is not recognized accurately or early enough. This leaves many patients with disease unnoticed and growing on organs, even reimplanting throughout the body. Everyday life for individuals can become damaged including careers, friends, mental health and even family. The gold standard is surgical precision excision disease intervention paired with individually tailored symptom management plans — which is hard to access and hard to find.
ESTROGEN DISCOVERIES
Endometriosis is its own thing, endometriotic tissue/cells – not endometrial tissue/cells – and can produce its own de-novo estrogen. This tissue also harbors numerous genetic mutations and abnormalities, particularly in hormone receptors. These flaws render hormone treatments, which have been used for millennia, largely ineffective in stopping the progression of the disease. In fact, despite 4,000 years of trying ancient and modern forms of hormone-based therapies, they have failed to halt endometriosis in the vast majority of patients. The reason lies in the tissue's broken hormone receptors, which render these treatments powerless. Hundreds of abnormalities are suspected or have been found in endometriotic cells compared to normal endometrium – endometrial tissue/cells – and debunk many current global approaches and policy making decisions.
Estrogen plays a crucial role in the development and growth of endometriosis. But what's surprising is that the enzyme responsible for producing estrogen, aromatase, is barely detectable in healthy endometrial tissue. In stark contrast, endometriosis lesions contain extremely high levels of aromatase, leading to a surge in estrogen production. This abnormal estrogen production is further fueled by prostaglandin E2, a key player in inflammation and pain. In a vicious cycle, estrogen also boosts the production of prostaglandin E2, creating a self-sustaining loop that exacerbates endometriosis symptoms.
Self-sustaining is important here. While external estrogen sources, such as natural circulating estrogen or added hormones, may trigger or worsen symptoms, they don't directly impact the tissue's self-produced estrogen. This means that blood tests measuring estrogen levels may not always reflect the true extent of the disease. In other words, even if test results show normal or low estrogen levels, endometriosis tissue may still be producing its own estrogen, driving the disease's progression single handedly.
Endometriosis has a unique ability to produce estradiol, a potent form of estrogen, from scratch using cholesterol and other hormone building blocks. At the same time, it's remarkably resistant to estrogen's usual regulatory mechanisms, with a significant decrease in estrogen receptor alpha (ERα). This resistance is further compounded by a stunning inability to respond to progesterone, a hormone that normally helps regulate estrogen's effects. This progesterone resistance stems from multiple factors, including a drastic reduction in progesterone receptors (PRα and PRβ) and severe impairment of other progesterone-related pathways, ultimately disrupting the delicate balance of hormonal regulation.
Newer research reveals that two orphan nuclear receptors, NR5A1 and NR2F2, are in a tug-of-war to control the production of steroid-synthesizing genes in endometriotic stromal cells. When NR5A1 dominates, it leads to an overproduction of estrogen. But that's not all - these cells also have an abnormal balance of estrogen receptors, with excessively high levels of ESR2. This imbalance triggers an estrogen-driven inflammatory response, producing prostaglandins that fuel the growth of endometriotic tissue. Furthermore, these cells are deficient in progesterone receptors, making them resistant to progesterone's regulating effects and disrupting retinoid synthesis.
Interestingly, the pattern of nuclear receptor expression in endometriotic stromal cells resembles that of uterine leiomyoma stem cells. This similarity suggests that endometriotic stromal cells may possess stem cell-like characteristics, which could contribute to the development and persistence of endometriosis. The consequences of these cellular abnormalities are far-reaching, leading to intense inflammation, defective cell differentiation, and enhanced survival of endometriotic tissue.
IMMUNE AND ENDOCRINE DISCOVERIES
The immune and endocrine systems are also intricately linked in the development of endometriosis, with mutual regulatory pathways and influences. This complex interplay is disrupted in endometriosis, leading to severely altered immunity-related pathways and endocrine dysfunction. Specifically, we see abnormal dendritic cells promoting angiogenesis and endothelial cell migration, rather than supporting beneficial immune functions. Epigenetic regulation is also aberrant, with DNA methylation changes in endometriotic cells contributing to the disease's pathogenesis. Dysregulated cytokines prevent apoptosis, allowing endometriotic lesions to survive and thrive.
The immune system's dysregulation is further evident in the increased secretion of pro-inflammatory factors, such as CCL5 and granulocyte-macrophage, which create a perfect inflammatory niche. Additionally, higher expression levels of the ESR2 gene and dysregulated immune cells exacerbate the condition. Mitochondrial mutations also play a role, highlighting the complex interplay of factors in endometriosis.
Research has also revealed that immune cells in endometriosis lesions are defective. Specifically, T cells are less activated, and the composition of natural killer cells is decreased, while monocytes/macrophages are increased. This imbalance contributes to the development and progression of endometriosis.
Endometriosis fibroblasts exhibit unique characteristics that enhance tumor growth. These cells express high levels of certain proteins, including C3, C7, StAR, and S100A10, which are associated with disease-related fibroblasts. Notably, StAR plays a crucial role in converting cholesterol to estrogen. S100A10, another protein highly expressed in endometriosis fibroblasts, activates the plasminogen activation pathway, leading to increased degradation of the extracellular matrix, angiogenesis, and invasion properties.
Subcluster analysis of endometriosis-associated fibroblasts revealed distinct functional characteristics. For instance, SC-FB-2 is associated with cytokine and inflammatory response, while SC-FBs-3 is relevant to fibroblast growth factor stimulus and immune response. Meanwhile, SC-FBs-10 is associated with extracellular matrix and cell adhesion, and SC-FBs-11 is correlated with angiogenesis and hypoxia response. These findings suggest that endometriosis-associated fibroblasts play a significant role in promoting the growth and spread of endometriosis.
Interestingly, the percentage of M cells was significantly higher in endometriosis lesions compared to eutopic endometrium and normal endometrium. This difference highlights the complex interplay of immune cells and fibroblasts in the development and progression of endometriosis.
Endometriotic lesions are also marked by an abundance of plasma cells, which produce high levels of IgM antibodies. Additionally, these lesions contain macrophages that secrete BLyS/BAFF/TNFSF13B, a protein belonging to the tumor necrosis factor (TNF) superfamily. Notably, this protein has been implicated in various autoimmune diseases, suggesting a potential link between endometriosis and autoimmune disorders.
Previous research has demonstrated that certain immune cells, such as CX3CL1 and IL6 monocytes, found in the peritoneal fluid, contribute to the development of fibrosis in endometriosis. Furthermore, the interaction between fractalkine (FKN) and its receptor, CX3CR1, plays a crucial role in peripheral hyperalgesia, or increased sensitivity to pain, by facilitating communication between macrophages and nerve cells. FKN is known to be involved in the immunopathogenesis of various inflammatory diseases, including endometriosis. Additionally, studies have shown that matrix metalloproteinase-9 (MMP-9) is overexpressed in endometriosis, enabling the degradation of the extracellular matrix and facilitating the invasion of endometrial tissue into surrounding areas.
NERVE AND BLOOD VESSEL DISCOVERIES
Endometriotic lesions have an unusual ability to promote the growth of new nerve and blood vessel pathways, a process called neuroangiogenesis. This leads to an increase in pain receptors, making the lesions even more painful. The nervous and blood vessel systems normally work together, sharing signals and receptors to guide their growth. However, endometriosis has its own unique way of reading these signals, allowing it to create its own network of nerves and blood vessels. In people with deep infiltrating endometriosis or bowel endometriosis, the lesions tend to be located in areas that are more closely linked to pelvic pain. These lesions and surrounding tissues have a higher concentration of nerve fibers, making them even more sensitive to pain.
OTHER MUTATION DISCOVERIES
Research has shown that decreased expression of CDH1 in epithelial cells is a hallmark of advanced peritoneal endometriosis. Notably, loss of CDH1 is also a characteristic of epithelial-to-mesenchymal transition, a process that increases the metastatic potential of malignant cells. Studies have also investigated the role of PTEN, a potent tumor suppressor, in endometriosis. Mutations in the PTEN gene have been implicated in various cancers, including ovarian endometriosis.
Decreased PTEN expression and increased PI3K/Akt activity have been observed in endometriosis, highlighting the pivotal role of PTEN loss in tumor development. The PTEN gene, located on chromosome 10q23.3, acts as a tumor suppressor. Mutations in this gene have been found in over 50% of endometrial carcinomas. Recent studies have also identified somatic missense mutations of PTEN in patients with endometriosis. Additionally, the gene CYP2C19 plays a crucial role in estrogen metabolism, including the conversion of estradiol to estrone. Abnormalities in this gene may contribute to the development of endometriosis.
Single-cell RNA sequencing (sc-RNA-seq) data has even revealed the expression of genes linked to endometriosis development, including those involved in key signaling pathways such as:
- TGF-ß (transforming growth factor beta)
- MAPK (mitogen-activated protein kinase)
- Rho-Rack (Ras homolog gene family, member A)
- NF-KB (nuclear factor kappa-light-chain-enhancer of activated B cells)
- JAK-STAT (Janus kinase/signal transducers and activators of transcription)
These pathways play critical roles in disease development, particularly in the process of epithelial-to-mesenchymal transition (EMT), a hallmark of endometriosis.
THE STATS
Evidence has presented patients with endometriosis face a 31% increased risk of early death, a 40% higher risk of ischemic heart disease, and even a 19% higher risk of cerebrovascular disease. This condition impacts a significant number of patients, encompassing up to 80% of those who experience pelvic pain. Endometriosis affects 47% of patients seeking gynecological care. The current prevalence of endometriosis in individuals with with unexplained infertility alone is reportedly 30–63.2%, while the occurrence of abnormal pathological discoveries is documented to reach up to 80.7% in unexplained fertility. A recent study also reported a low positive predictive value of visual diagnosis laparoscopically of 39% — this may in part be due to diagnostic issues of both stromal and glandular components on into the many alterations aforementioned.
5% of participants in an independent, global study expressed a positive experience when seeking a diagnosis – in contrast to the 89% feeling dismissed. 12% of that same study reported hearing over 6 misconceptions during their diagnosis or management of endometriosis — consisting of 67% being informed hormonal medications would cure or stop the growth of the disease; 43% being told to get pregnant; 33% told a complete hysterectomy was a cure; 32% even told they were cured with surgery removal and it wouldn't return.
INTO THE FUTURE
Moving forward in addressing the complex challenges of endometriosis, it is imperative that we prioritize evidence-based policy-making and reform. This requires a commitment to rigorous research, open-minded consideration of emerging evidence, and a willingness to adapt and refine our approaches accordingly. Current evidence tells us current standards of endometriosis care are outdated, inaccurate, and not beneficial for the massive amount of individuals who likely won't even receive adequate care in their lifetime – because of these questionably deliberate setbacks.
As we conclude the examination of this endometriosis paradox, it's clear that the need for reform is urgent. The Class Action Investigation into Endometriosis Care in America is a crucial step towards addressing the entrenched inequalities and discriminatory practices that have harmed countless individuals. By shedding light on the lived experiences of patients and highlighting the necessity of evidence-based care, we can work towards a future where everyone has access to safe, effective, and compassionate healthcare. Join us in demanding change and advocating for the rights of endometriosis patients everywhere.
Learn more about the Class Action Investigation and how you can get involved. The lives and well-being of billions around the world depend on our ability to get this right. Let us seize this opportunity to redefine the trajectory of healthcare reform and to ensure that evidence — rather than practicality — guides our pursuit of better care and better outcomes.
