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Researchers optimistic about potential new treatment for endometriosis

UK trial of first non-hormonal drug for condition may lead to ‘long overdue’ innovation in relieving often debilitating pain

  • ‘Worse than childbirth’: women with endometriosis call for better treatments

Women will be given a potential new treatment for endometriosis in a groundbreaking clinical trial that doctors hope will pave the way for the first new class of drug for the condition in 40 years.

The trial will involve 100 women in Edinburgh and London and will assess whether the drug, dichloroacetate, helps relieve pain. If successful, it would be the first non-hormonal, non-surgical treatment for endometriosis, which affects roughly one in 10 women of reproductive age.

“We know women with endometriosis desperately want more treatment options and better ways to manage the often-debilitating pain that it causes,” said Dr Lucy Whitaker, a clinical lecturer in obstetrics and gynaecology at the University of Edinburgh, who is leading the research. “Our research so far shows promising results that dichloroacetate can make a huge difference. I hope our new trial will confirm this and give women hope that new treatments and a better quality of life are on the horizon.”

Endometriosis affects 1.5 million women in the UK and occurs when tissue similar to the lining of the womb grows elsewhere in the body. During a woman’s period, these cells bleed, causing inflammation, pain and the formation of scar tissue. A lack of awareness of the condition, compounded by the requirement for a diagnostic laparoscopy, means that women in the UK typically wait eight years for a diagnosis after first experiencing symptoms.

Current treatment options include conventional pain relief, hormonal contraceptives and surgery. However, hormone-based treatments – typically the pill or a contraceptive implant – have side-effects and are not suitable for everyone, including those trying to conceive. Surgery carries risks and is not always effective in the long term, with studies showing that about half of those who have surgery experience a return of symptoms within five years.

Janet Lindsay, the chief executive of Wellbeing of Women, a women’s health charity that is funding the trial with the Scottish government, said that progress in treating endometriosis was “long overdue”.

“It is completely unacceptable that there have been no new treatments for endometriosis in 40 years,” she said. “Too many women and girls are suffering from debilitating symptoms, such as chronic pelvic pain, fatigue and even fertility problems, and current hormonal and surgical treatments aren’t suitable for everyone.”

The latest trial builds on previous research showing that cells from the pelvic wall of women with endometriosis produce higher amounts of lactate, a potentially harmful waste product that is normally produced by muscles and red blood cells when the body is running low on oxygen during exercise. In endometriosis, lab-based experiments suggested the lactate was creating an environment that fuelled the development and growth of endometrial tissue.

When cells were treated with dichloroacetate, in the lab and in mouse experiments, lactate production decreased to normal levels and the size of the endometriosis lesions was reduced. The drug is already licensed as a medicine to treat rare childhood metabolic disorders and various cancers, meaning that it has an established safety profile. In a pilot study, with 30 women, the main side-effects were a slightly upset stomach on starting the medication and a tingling sensation in the fingers.

In the latest trial, which will start recruiting this autumn, half of the women will receive dichloroacetate and half will be given a placebo and they will take the tablets for 12 weeks. The participants will complete a series of questionnaires and give blood samples over the course of two-and-a-half years, to determine whether the treatment is effective for relieving pain and other symptoms.

Dr Ranee Thakar, the president of the Royal College of Obstetricians and Gynaecologists, welcomed the trial. “We know current endometriosis treatment options don’t work well for everyone, leaving many women with symptoms that can have a serious impact on their quality of life, affecting their physical and mental health,” she said. “We look forward to the results of this trial and it’s potential to improve the day-to-day lives of women and people living with endometriosis.”

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New therapeutic targets for endometriosis could be on the horizon

Immunoperoxidase histochemistry was used to localize nerve growth factor (NGF).

Microscopic photo of endometrium showing brown staining in many of the tissue’s stromal cells, along with blue glands essentially devoid of brown staining. The brown pigment indicates the presence of BDNF (brain-derived neurotrophic factor), a potent growth factor protein that stimulates nerves to proliferate and migrate through the tissue, increasing the transmission of pain. 

UB study reveals how neurotrophins and their receptors could be novel therapeutic targets for pelvic pain in endometriosis

By Ellen Goldbaum

Release Date: August 9, 2023

Robert N. Taylor MD PhD; Professor of Obstetrics and Gynecology; Department of Obstetrics and Gynecology; Assistant Dean and Director of the MD-PhD Program; Jacobs School of Medicine and Biomedical Sciences; University at Buffalo; 2020.

BUFFALO, N.Y. – New research on the connection between endometrial lesions and pain in endometriosis could lead to new therapies for this chronic, painful and poorly understood condition that affects 5-10% of women worldwide and costs an estimated $69 billion in medical and surgical expenses. Endometriosis is a condition where tissue similar to uterine tissue develops and grows outside of the uterus, causing chronic pain that can be severe.

Published online in May in the American Journal of Pathology and featured on the cover of the journal this month, the work was led by researchers in the Department of Obstetrics and Gynecology in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, in collaboration with researchers at the University of Michigan.

Robert N. Taylor, MD, PhD, senior author on the paper and professor of obstetrics and gynecology and pathology and anatomical sciences in the Jacobs School, describes the drawbacks of current endometriosis treatments.

“Laparoscopic surgical removal of endometriosis lesions remains a primary mode of treatment, but it can be expensive, with attendant risks of complications, and often is associated with recurrence,” he says. “Hormonal medications have been useful but their long-term use is associated with menopausal symptoms and side effects.”

Cover of the August 2023 issue of The American Journal of Pathology featuring a graphic from a study by UB researchers.

The new research focuses on the potential connection between the presence of nerves in endometriosis lesions and pain. “The association of pain with endometriosis has been known for a hundred years,” Taylor says, “but the relationship between the volume of lesions and the degree of pain symptoms is poorly correlated.”

To determine how lesions and pain are related, the UB researchers teamed up with researchers at the University of Michigan, who Taylor says are experts in the brain’s perception of pain and central sensitization or nociplastic pain, which is a quality of pain that does not arise from an identifiable injury or lesion.

The UB team of scientists has studied the biology of the uterus and endometriosis lesions for decades and now focuses on how nerves present in those tissues are peripheral generators of pelvic pain.

Only in the past 20 years has it been established that the density of nerves in endometriosis lesions and the endometrium (the inner lining of the uterus) is higher in women with endometriosis.

“This led us to propose that this phenomenon might be explained by the excessive expression of neurotrophins, proteins that stimulate the growth and migration of neurons,” Taylor says. “This paper addresses the molecular pathways that are activated in endometriosis and offer new targets for therapy.”

Using established neural biomarkers isolated from endometrial tissue biopsies obtained from eight adult women (four patients with endometriosis and four without), the researchers were looking to identify biochemical mediators of endometriosis-associated pelvic pain. They used immunofluorescence histochemistry, a technique that visualizes parts of a cell with fluorescently labeled antibodies, to confirm that neurons are present in human endometrial tissue. Endometrial stromal cells isolated from the issue expressed neurotrophins and their receptors.

The researchers propose that IL-1β, a potent inflammatory protein, activates a membrane receptor in endometrial stromal cells, predominantly through the c-Jun N-terminal kinase (JNK) pathway, to promote neurotrophin and neurotrophin receptor production and signaling. That increase, in turn, activates the development of new neurons in the brain, which can potentially create a vicious cycle of inflammation and perceived pelvic pain.

The researchers also found that tropomyosin receptor kinase A/B expression, one of the main neurotrophin receptors in endometrium, was almost twice as high in cells from patients with endometriosis than in those from control subjects, an increase that also is mediated through the JNK pathway.

“We therefore postulate that clinical trials using JNK inhibitors have the potential to reduce neuroinflammation in women with endometriosis,” says Taylor.

“It is our hope that by identifying and correlating peripheral and central generators of pain, we can come up with new pharmacological approaches for treating endometriosis symptoms,” Taylor says. 

“Targeted therapies of the future have the promise of blocking nerve growth and pain transmission, ideally without compromising endocrine function,” he says. “This is the ultimate goal of our research.”

UB co-authors include Sarah L. Berga, MD, chair of the Department of Obstetrics and Gynecology in the Jacobs School and Jie Yu, research associate professor in the department. 

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Ellen Goldbaum News Content Manager Medicine Tel: 716-645-4605 [email protected]

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Researchers identify genetic cause of endometriosis and potential drug target

Endometriosis is a painful, chronic condition in which tissue from the uterus inappropriately grows outside the uterus. 

Current treatments are limited and include surgery and hormone therapy, which can involve unwanted side effects. New research conducted by the University of Oxford, Baylor College of Medicine, the University of Wisconsin-Madison and Bayer AG, offers new insight into how to treat this debilitating disease.

The researchers performed genetic analyses of humans and rhesus macaques to identify a specific gene, NPSR1 , that increases risk of suffering from endometriosis. The results reveal a potential new nonhormonal drug target that may lead to improved therapy. Their results are published in Science Translational Medicine .

The Oxford team, led by Dr. Krina T. Zondervan, had previously found a genetic linkage to endometriosis on chromosome 7p13-15 by analysing DNA from families containing at least three women diagnosed with endometriosis. The Baylor team, led by Dr. Jeffrey Rogers, verified this genetic linkage in the DNA of rhesus monkeys with spontaneous endometriosis at the Wisconsin National Primate Research Center at the University of Wisconsin-Madison. This validation justified further research through in-depth sequencing analysis of the endometriosis families at Oxford, which narrowed down the genetic cause to rare variants in the NPSR1 gene.

Most of the women carrying these rare variants had stage III/IV disease. The Baylor researchers similarly sequenced rhesus monkeys and again showed suggestive evidence also in this species. Finally, an Oxford study of more than 11,000 women, including patients with endometriosis and healthy women, identified a specific common variant in the NPSR1 gene also associated with stage III/IV endometriosis.

Jeffrey Rogers, associate professor at the Human Genome Sequencing Center at Baylor, says: 'This is one of the first examples of DNA sequencing in nonhuman primates to validate results in human studies and the first to make a significant impact on understanding the genetics of common, complex metabolic diseases. The primate research really helped to provide confidence at each step of the genetic analysis in humans and gave us motivation to carry on chasing these particular genes.'

The insights revealed in this genetic analysis point to a potential new drug target. As part of this collaboration, researchers at Bayer, in scientific partnership with Oxford University, used an NPSR1 inhibitor to block protein signaling of that gene in cellular assays and then in mouse models of endometriosis. They found this treatment led to reduced inflammation and abdominal pain, thus identifying a target for future research in treating endometriosis.

Krina Zondervan, professor of reproductive and genomic epidemiology, head of the Department of Women’s and Reproductive Health at the University of Oxford and co-director of the Endometriosis CaRe Centre at Oxford says: 'This is an exciting new development in our quest for new treatments of endometriosis, a debilitating and underrecognized disease affecting 190 million women worldwide. We need to do further research on the mechanism of action and the role of the genetic variants in modulation of the gene’s effects in specific tissues.

'However, we have a promising new nonhormonal target for further investigation and development that appears to address directly the inflammatory and pain components of the disease.'

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  • 1 Department of Mechanical Engineering, University of Canterbury, Christchurch, New Zealand
  • 2 Faculty of Health, University of Canterbury, Christchurch, New Zealand

Endometriosis is an inflammatory chronic pain condition caused by uterine tissue growing outside of the uterus that afflicts at least 11% of women (and people assigned female at birth) worldwide. This condition results in a substantial burden to these women, and society at large. Although endometriosis was first identified over 160 years ago, substantial knowledge gaps remain, including confirmation of the disease's etiology. Research funding for endometriosis is limited, with funding from bodies like the National Institutes of Health (NIH) constituting only 0.038% of the 2022 health budget—for a condition that affects 6.5 million women in the US alone and over 190 million worldwide. A major issue is that diagnosis of endometriosis is frequently delayed because surgery is required to histologically confirm the diagnosis. This delay increases symptom intensity, the risk of central and peripheral sensitization and the costs of the disease for the patient and their nation. Current conservative treatments of presumed endometriosis are pain management and birth control. Both of these methods are flawed and can be entirely ineffective for the reduction of patient suffering or improving ability to work, and neither addresses the severe infertility issues or higher risk of certain cancers. Endometriosis research deserves the funding and attention that befits a disease with its substantial prevalence, effects, and economic costs. This funding could improve patient outcomes by introducing less invasive and more timely methods for diagnosis and treatment, including options such as novel biomarkers, nanomedicine, and microbiome alterations.

Introduction

Endometriosis is a chronic inflammatory disease ( 1 ) that causes significant morbidity ( 2 ), and affects 10–15% of women of reproductive age globally ( 3 – 5 ). Conservatively, 1 in 9 women of reproductive age has endometriosis in the United States (US) ( 6 ) and Australia ( 7 ). Endometriosis causes tissue from the uterus to migrate and implant in other regions of the body ( 8 , 9 ). This tissue interacts with the body's endocrine, musculoskeletal, vascular, reproductive, and nervous systems ( 10 ) causing numerous painful symptoms and physiological changes. There are three key types of endometriosis: superficial peritoneal, ovarian, and deep infiltrating ( 11 ). While peritoneal is the predominant presentation of the disease, ovarian affects 17–44% of endometriosis patients ( 12 ) and is characterized by the development of ovarian endometriomas, cystic lesions filled with dark endometrial fluid ( 13 ). Deep infiltrating endometriosis affects ~20% of endometriosis patients ( 14 ) and is considered the most severe form ( 15 ). Each endometriosis subtype is thought to have a different pathogenesis ( 16 ), but no etiology is confirmed ( 17 ) that explains all disease manifestations ( 18 ).

Symptom Burden

Misplaced endometriotic tissue causes a wide range of symptoms, including chronic pelvic pain, dysmenorrhea (menstrual pain), dyspareunia (painful sex), dysuria (painful urination), dyschezia (painful defecation) ( 19 ), metrorrhagia (mid-cycle bleeding), diarrhea, constipation, infertility ( 20 ), and myofascial pain, among others ( 1 ). Furthermore, the gastrointestinal symptoms of endometriosis patients are more severe than those of controls ( 21 ), which often results in both coexistence and misdiagnosis of irritable bowel syndrome ( 22 ). As the disease progresses, patients risk developing adhesions, fibrous scar tissue bands that can abnormally bind pelvic and abdominal organs ( 9 ). Endometriosis is the most frequent cause of adhesions in women and common areas for endometriosis adhesions include the anterior abdominal wall, bladder, and uterus ( 23 ). Adhesions can cause anatomical distortion, which can hinder fertility, cause rectal constriction, and be a cause of dyspareunia. In a 2019 study, the presence of endometriosis-associated adhesions was shown to significantly negatively impact quality of life ( 23 ).

The cumulative effect of these chronic pain symptoms is a substantial burden on sufferers ( 20 ) and 70% of patients live with unresolved pain ( 2 ), with impacts to all aspects of their quality of life ( 24 ). Research shows that endometriosis patients also have significantly higher rates of co-morbidities than control populations ( 25 ). The symptoms of endometriosis, particularly those associated with pain, increase the rates of chronic stress, anxiety, depression and decreased quality of life among endometriosis patients compared with those without the disease ( 26 ).

There is a well-established delay from symptom onset to diagnosis of 4–11 years for endometriosis patients ( 1 ). There are many reasons for this delay, including the lack of a unique symptom profile ( 27 ), the variety of symptoms ( 28 ) and large waitlists for the laparoscopies used to diagnose endometriosis ( 2 ). Many patients find it necessary to “doctor shop” to find a medical practitioner who will support their efforts to obtain an endometriosis diagnosis. In a 2004 study, 47% of endometriosis patients had seen at least five doctors before getting an endometriosis diagnosis or referral ( 29 ). This may be partially explained by the results of a 2021 French study, where 25% of general practitioners did not think they knew enough about endometriosis for their clinical practice ( 30 ). In a 2012 study of 173 endometriosis patients in Austria and Germany, 74.3% had experienced a misdiagnosis. These misdiagnoses included intolerances, appendicitis, irritable bowel syndrome, and pelvic inflammatory disease ( 31 ).

In addition to painful symptoms, patients can be subject to central and peripheral sensitization ( 10 ). Central sensitization is the abnormal processing of sensory signals ( 32 ) that results in exaggerated experiences of painful and non-painful stimuli ( 10 ) through enhanced pelvic nociception. Peripheral sensitization lowers the body's threshold for nociceptor activation with repetitive and prolonged stimulation, as occurs in endometriosis ( 10 ). The combined effect of these phenomena is that over time non-painful stimuli can produce incredibly painful signals in sensitized patients.

Women with chronic pelvic pain, with or without a confirmed diagnosis, show significantly lower pain tolerances than controls ( 33 ). The severity of the decrease in pain tolerance corresponds to the duration of symptoms ( 33 ) supporting the theory that delayed diagnosis increases patient sensitization. An Australian study found endometriosis patients have significantly higher functional pain disability (pain interference with daily activities like sleep, relationships and work) than women without endometriosis ( 34 ). Furthermore, women have higher pain sensitivity than men ( 35 , 36 ) as a result of complex interactions in women of anatomical, hormonal, physiological, and psychological factors ( 37 ).

Cancer Associations

Endometriosis is a non-neoplastic invasive disease ( 38 ), although there is evidence to suggest a positive association between endometriosis and ovarian cancer ( 39 ). There is molecular evidence to suggest endometriotic lesions can undergo a transformation to clear cell and endometrioid ovarian cancers ( 40 ). This connection is controversial, and like many aspects of endometriosis, requires much more study to fully outline the potential mechanisms involved. The indication is that endometriosis increases ovarian cancer risk ( 19 ) from 1.3% in the general female population to 1.8% of endometriosis patients ( 41 ).

Infertility

In addition to the extensive pain symptoms endometriosis patients experience, endometriosis patients have a high prevalence of infertility and sub-fertility among their cohort. Half of endometriosis patients suffer from fertility issues ( 42 ), and up to half of women with unexplained infertility or sub-fertility are subsequently found to have endometriosis ( 43 , 44 ). The high rates of endometriosis interfering with fertility may relate to factors including anatomical distortions ( 45 ), diminished ovarian reserve, chronic inflammation and compromised endometrial receptivity ( 42 ).

Lack of Funding

Endometriosis is a condition that impacts not only patients, but their families, jobs, societies, and countries. The authors believe the present issues with diagnosing, treating and funding endometriosis result from many years of misunderstanding and ignoring important female health topics. Improving funding for endometriosis research could improve the understanding of the condition, eliminate knowledge gaps, reduce time to diagnosis, expand available treatment options, improve pain management and place a long-overdue emphasis on predominantly female experiences of illness.

The National Institutes of Health (NIH) is the largest source of biomedical research funding globally, allocating $41.7 billion USD annually ( 46 ). In 2022, the expected funding allocation for endometriosis is $16 million ( 47 ), 0.038% of the budget. Since the conservative estimate is that endometriosis affects 11% of US women in their lifetime, only $2.00 per patient per year is allocated. As a comparison, 12% of US women are expected to suffer from diabetes in their lifetime ( 48 ). If it is assumed that half of the allocated diabetes research budget was for female sufferers, there is a funding allocation of $31.30 per woman, over 1,500% more than for endometriosis.

Crohn's disease, like endometriosis, is a chronic inflammatory condition ( 49 ). Crohn's disease affects the digestive tract lining, resulting in abdominal pain, weight loss, diarrhea, and fatigue ( 50 ). There are over 690,000 people with Crohn's disease in the US, or 0.21% of the population ( 51 ). In 2022, Crohn's disease research will receive $90 million in funding, $130.07 per patient, over 65 times more per patient than for endometriosis. This comparison is not to suggest Crohn's disease is overfunded, but that endometriosis is seriously underfunded.

Economic Burden of Endometriosis

The burden of endometriosis on individual patients is substantial ( 20 ) both before and after diagnosis ( 52 ). The impact of ongoing pain can cause some patients to lose their jobs or their partners ( 53 ). Additionally, the financial burden is significant. Endometriosis patients have significantly higher healthcare resource utilization, and direct and indirect healthcare costs than controls. Endometriosis patients in the US spend $26,305 USD more than controls on healthcare expenses in the 5 years before and after diagnosis ( 52 ). In the year after diagnosis patients with endometriosis spend on average 3.5 times the amount on healthcare than controls do ( 25 ). The direct costs of endometriosis include in and outpatient treatment, surgery, and prescription costs, which in the US average $12,118 per patient, per year ( 54 ). Indirect costs, including days of work lost and reduced quality of work, were almost $16,000 per patient per year ( 54 ). In a study across ten countries lost productivity costs were generally double those of healthcare costs ( 55 ) as the average patient loses 6.4 h of work a week to presenteeism (reduced effectiveness while working) ( 56 ). Endometriosis patients begin to suffer from their condition at a young age, during a very productive period of their lives. The additive effects of fatigue, productivity loss, and time removed from the workforce, schooling and training create an immense barrier to patients being able to effectively progress in life, take up career opportunities, and in their capacity to save their earnings.

The total US endometriosis economic burden is estimated to be as high as $78–119 billion annually ( 54 , 57 ). In Australia, the annual cost of endometriosis was estimated to be $16,970–20,898 per woman, per year, with 75–84% of the total due to productivity losses ( 58 ). Delays until endometriosis diagnosis increase not only the number of pre-diagnosis endometriosis symptoms but also emergency visits, hospitalizations, and overall healthcare costs ( 59 ). Compared to short delays of less than a year, long delays of 3–5 years from first symptom presentation to diagnosis, increased the cost of healthcare in the 5 years prior to diagnosis by $12,971–34,460 ( 59 ).

Lost workdays are also higher among endometriosis patients than control populations ( 25 ). In Australia, where the annual economic burden of endometriosis is estimated to be $6.5 ( 58 ) to $7.4 billion ( 60 ), endometriosis patients used on average 60% of their sick leave to treat their chronic pain ( 60 ). In a 2022 study, 65% of an Australian cohort of endometriosis patients used unpaid leave to manage their endometriosis symptoms, 64% felt judged in the workplace for their symptoms, and one in seven reported being fired as a result of their condition ( 61 ).

Furthermore, research shows there are immense productivity losses due to endometriosis for women in the workforce, even while at work. Fatigue is more common among endometriosis patients, than in control populations ( 62 ). In a 2021 Canadian study on fatigue, endometriosis patients reported substantial impairments to their work productivity with 46.5% overall work impairment due to endometriosis-related symptoms ( 63 ). These findings were like a 2013 Danish study that found that patients with endometriosis had significantly more pain than controls, were in more pain when using their sick days and used more sick days ( 64 ). This study also found that many women were embarrassed by their symptoms, felt obligated to use their sick days and often felt unable or too tired to do a satisfying job ( 64 ).

In the US, the diabetes economic burden is $327 billion ( 65 ), and with 37.3 million Americans with diabetes ( 48 ), that accounts for $8,767 of burden per patient. By comparison, the estimated economic burden of endometriosis in the US would account for $9,754–14,881 per patient, 11–70% higher than for diabetes. Thus, it is evident to the authors there is an immense financial burden not only on endometriosis patients but on nations with patients who then require high levels of healthcare utilization. These patients frequently cannot participate in their workplaces and economies to the degree they wish because of symptoms, incurring a further cost to patients and society. If endometriosis was funded by the NIH at the same level as diabetes with respect to the annual economic burden, endometriosis funding would need to increase to $298.8–455.3 million, rather than the current $16 million.

The Present Options

Low research funding for endometriosis research means knowledge gaps are not being filled, making the development of effective diagnosis and treatment options more complicated, more time consuming, and less enticing for researchers. As a consequence, presently available options to treat endometriosis are severely limited. There are also high recurrence rates of symptoms and disease for current interventions ( 66 ). Recurrence of symptoms for non-surgical therapies, such as birth control and pain management, are rapid ( 18 ), because non-surgical treatments reduce or repress symptoms, but do not cure the disease. Furthermore, these methods are entirely inefficacious for endometriosis-associated fertility issues ( 19 ). Effective, non-invasive, non-hormonal treatments are required but are not currently available to the over 190 million global endometriosis patients ( 67 ).

Birth Control

Birth control is a standard endometriosis treatment ( 68 ). Endometriosis birth control methods include intrauterine progesterone devices, progestin injections and combined hormone pills ( 69 ). Combined treatments increase the risk of thromboembolism, nausea and breast tenderness. Progestin injections can cause weight gain, decreased bone density, worsened acne, and depression ( 69 ). Birth control is also a limited treatment for endometriosis, as many women cannot use birth control because the side effects are too severe or because of a desire to get pregnant.

Pain Management

Pain is the most common symptom of endometriosis ( 70 ). However, endometriosis pain management is complex. There is inconclusive evidence that non-steroidal anti-inflammatory drugs provide greater relief than placebos ( 71 ). Opioids are not a recommended treatment for endometriosis ( 72 ); however, in a cohort of 113,506 endometriosis patients in the US, 89% were utilizing opioids to manage their pain ( 25 ). Chronic opioid use can significantly increase healthcare costs for endometriosis patients compared to non-chronic users ( 73 ). Long-term opioid use for non-cancerous chronic pain, such as endometriosis, is controversial and results in an absolute adverse event rate of 78% ( 74 ). The high use of opioids among this cohort is indicative of the intensity of the pain experienced, but this approach can lead to addiction and side effects, including constipation, nausea, confusion and drowsiness ( 75 ). The required dosage to manage pain also increases with chronic use as the body becomes habituated to it ( 76 ).

Laparoscopic surgery is considered the “gold-standard” for diagnosing and treating endometriosis ( 18 ) and is the only method available to “confirm” endometriosis histologically ( 77 ) which provides a clear and unambiguous diagnosis for patients that is often essential for practitioners to provide the best treatment plan. According to one study, 42% of patients have undergone at least three surgeries ( 2 ). Surgery is thus an impermanent solution for many patients, with recurrence of both symptoms and lesions ( 19 ) expected for 40–50% of patients within 5 years ( 78 ), and this repeated intervention can exacerbate pain and fertility issues ( 79 ). Furthermore, surgery is a trauma to the body that activates adrenergic signaling, suppresses cell-mediated immunity and promotes angiogenesis ( 80 ). In mice with induced endometriosis, subsequent surgery increased lesion weight and microvessel density ( 80 ), which is counteractive to the intent of surgery for endometriosis.

Evolving Possibilities

Earliest descriptions of endometriosis date back to 1860 ( 81 ) and 1920 ( 82 ). However, we still do not understand its etiology ( 70 ), the biology and function of both healthy female and endometriotic peritoneum, or the actions of endometrial stem cells ( 83 ). A substantial amount of knowledge still needs to be collected, collated, and applied to patient care. The lack of progress despite the relatively high volume of papers published about endometriosis indicates the complexity of endometriosis and the limited global funding available ( 83 ). Despite these issues, endometriosis research has been undertaken by talented researchers, and there are many promising avenues for further endometriosis research.

New Biomarker Analysis

One of the key aspects impacting the diagnosis and treatment of endometriosis is the lack of non-invasive diagnostic tools. Biomarkers present an appealing option for non-invasive diagnosis of endometriosis. However, many biomarkers that have been assessed previously could only discern advanced disease, indicating a need for more research to locate biomarkers that can diagnose “milder” cases of the disease ( 84 ). In a 2021 study, the researchers found patients with endometriosis had distinct microbial communities in their peritoneal fluid and feces compared to the control group. In the peritoneal fluid of endometriosis patients, there were more pathogens, while there was a loss of protective microbes in feces samples ( 85 ). The authors concluded that Ruminococcus in the gut and Pseudomonas in the peritoneal fluid may be able to act as auxiliary diagnostic tools for endometriosis with further investigation into the interactions of micro-organisms and endometriosis required ( 85 ).

Follicular fluid can be obtained from follicles by fine-needle aspiration following oocyte removal ( 5 ). Researchers have found endometriosis patients have dysregulated cytokine profiles in their follicular fluid with significant upregulation of IL-1β and IL-6 ( 86 ). Conversely, the concentration of IL-12, an anti-inflammatory cytokine, inflammatory cytokine IL-10 and E-cadherin levels were lower among endometriosis patients compared to controls ( 5 ). In a 2021 study, the measurement of IL-10 in follicular fluid was able to perfectly differentiate between endometriosis patients and controls ( 5 ).

Nanomedicines

One technology in its infancy for the treatment of endometriosis is the use of nanoparticles to aid in the imaging of, directly treating or delivering drugs to treat endometriosis ( 87 ). The key limitation for this emerging technology is that the etiology and pathogenesis of endometriosis are unknown ( 87 ). Despite this, investment in nanomedicines for endometriosis could substantially augment the capacity to diagnose and treat endometriosis. Nanoparticles have shown a capacity to accumulate in endometriotic lesions ( 87 ), which could improve the use of imaging technologies to diagnose endometriosis. This technology could also provide a method for targeting endometriotic lesions without the requirement of surgery. Potential drugs that could be delivered by nanotechnological methods could be anti-inflammatory, antioxidant, anti-angiogenic and immunomodulating molecules ( 88 ), which may have the capacity to reduce the size of or eliminate endometriosis lesions, rather than just suppress symptoms. However, much more pre-clinical and clinical research is required to support the use of this emerging technology for endometriosis ( 88 ).

Alterations to the Microbiome

Imbalances to gut microbiota composition have been connected to the compromised immunosurveillance and altered immune profiles associated with endometriosis ( 89 ), with animal studies consistently showing the impact of the gut microbiota on endometriosis and endometriosis on gut microbiota ( 90 ). In addition to being a potential site for novel biomarkers, the gut microbiota may be a target site for new treatments. In a 2019 study by Chadchan et al., mice with induced endometriosis were subjected to antibiotic therapies ( 91 ). Broad-spectrum antibiotics were shown to significantly reduce lesion size and inflammatory response. Furthermore, the authors showed that fecal transfer from mice with endometriosis restored lesion growth and inflammation in mice treated with the antibiotic metronidazole ( 91 ). Conversely, metronidazole-treated mice that received fecal transfers from mice without endometriosis had significantly smaller lesions, suggesting a role for the gut microbiome in the progression of endometriosis ( 91 ). The effect of gut microbiota on endometriosis is not solely negative. The bacteria-derived metabolite n-butyrate is a short-chain fatty acid that is significantly downregulated in mice with induced endometriosis. In a 2021 study, n-butyrate treatment significantly reduced lesion growth and inflammatory cell infiltration in a mouse model ( 92 ). Therapies that address endometriotic alterations to the gut microbiota could have immense potential to reduce the growth of lesions and the effects of inflammation for endometriosis patients.

Despite progress, critical gaps remain in the fundamental understanding of endometriosis. This means there are opportunities to substantially expand and improve our core understanding of this important health topic. The authors feel endometriosis warrants more attention to fill these fundamental knowledge gaps. There are not enough people working in this vital space, likely due to insufficient funding. If endometriosis was funded by the NIH at half the level of diabetes, the budget would increase almost 16 times to over $250.4 million annually. It is the belief of the authors that present levels of endometriosis funding do not reflect the immense pain of patients, long delays in diagnosis, the ineffectiveness of common treatment options, massive knowledge gaps, substantial economic burdens or the immense costs borne by individual patients. Unexplored in the scope of this paper, but vital, is the investment into structures to translate research findings into clinical care, understanding of the epidemiological underpinnings of patient diversity, increased awareness through public education about endometriosis so affected patients are better aware, and into healthcare practitioner training about how best to treat and support endometriosis patients.

There is a lot of promising research underway that could create substantial positive ramifications for patients. These include the chance for non-invasive biomarker auxiliary diagnosis methods, the application of nanoparticle drug delivery and treatments targeting the microbiome. An area of immense potential for developing new non-invasive diagnostic and treatment options may be the application of nanoparticles to deliver therapies directly to endometriotic lesions.

Advancement in the identification and treatment of endometriosis is challenging but entirely possible. It is the opinion of these authors that if endometriosis had more representative funding, the rate of advancement of non-invasive diagnostic and treatment methods could be significantly increased, with long-term benefits for patients and society.

Data Availability Statement

The original contributions presented in the study are included in the article; further inquiries can be directed to the corresponding author.

Author Contributions

KE is the first author of this paper through conception and literature collection. DM and JC have contributed equally to this work by critically revising and editing the article. All authors contributed to the article and approved the submitted version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Acknowledgments

The authors would like to acknowledge the Biomolecular Interaction Centre (BIC) for their support and financial contribution to the Engineering Endometriosis Research Program at the University of Canterbury.

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Keywords: endometriosis, funding, women's health, quality of life, chronic pain

Citation: Ellis K, Munro D and Clarke J (2022) Endometriosis Is Undervalued: A Call to Action. Front. Glob. Womens Health 3:902371. doi: 10.3389/fgwh.2022.902371

Received: 23 March 2022; Accepted: 19 April 2022; Published: 10 May 2022.

Reviewed by:

Copyright © 2022 Ellis, Munro and Clarke. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Deborah Munro, debbie.munro@canterbury.ac.nz

This article is part of the Research Topic

The Impact of Endometriosis

ScienceDaily

Researchers identify genetic cause of endometriosis and reveal potential drug target

Endometriosis is a painful, chronic condition in which tissue from the uterus inappropriately grows outside the uterus. Current treatments are limited and include surgery and hormone therapy, which can involve unwanted side effects. New research conducted by Baylor College of Medicine, the University of Oxford, the University of Wisconsin-Madison and Bayer AG, offers new insight into how to treat this debilitating disease.

The researchers performed genetic analyses of humans and rhesus macaques to identify a specific gene, NPSR1, that increases risk of suffering from endometriosis. The results reveal a potential new nonhormonal drug target that may lead to improved therapy. Their results are published in Science Translational Medicine .

The Oxford team, led by corresponding author Dr. Krina T. Zondervan, had previously found a genetic linkage to endometriosis on chromosome 7p13-15 by analyzing DNA from families containing at least three women diagnosed with endometriosis. The Baylor team, led by senior author Dr. Jeffrey Rogers, verified this genetic linkage in the DNA of rhesus monkeys with spontaneous endometriosis at the Wisconsin National Primate Research Center at the University of Wisconsin-Madison. This validation justified further research through in-depth sequencing analysis of the endometriosis families at Oxford, which narrowed down the genetic cause to rare variants in the NPSR1 gene. Most of the women carrying these rare variants had stage III/IV disease. The Baylor researchers similarly sequenced rhesus monkeys and again showed suggestive evidence also in this species. Finally, an Oxford study of more than 11,000 women, including patients with endometriosis and healthy women, identified a specific common variant in the NPSR1 gene also associated with stage III/IV endometriosis.

"This is one of the first examples of DNA sequencing in nonhuman primates to validate results in human studies and the first to make a significant impact on understanding the genetics of common, complex metabolic diseases," said Rogers, associate professor at the Human Genome Sequencing Center at Baylor. "The primate research really helped to provide confidence at each step of the genetic analysis in humans and gave us motivation to carry on chasing these particular genes."

The insights revealed in this genetic analysis point to a potential new drug target. As part of this collaboration, researchers at Bayer, in scientific partnership with Oxford University, used an NPSR1 inhibitor to block protein signaling of that gene in cellular assays and then in mouse models of endometriosis. They found this treatment led to reduced inflammation and abdominal pain, thus identifying a target for future research in treating endometriosis.

"This is an exciting new development in our quest for new treatments of endometriosis, a debilitating and underrecognized disease affecting 190 million women worldwide. We need to do further research on the mechanism of action and the role of the genetic variants in modulation of the gene's effects in specific tissues. However, we have a promising new nonhormonal target for further investigation and development that appears to address directly the inflammatory and pain components of the disease," said Zondervan, head of the department of women's and reproductive health, professor of reproductive and genomic epidemiology and co-director of the Endometriosis CaRe Centre at Oxford.

Dr. Thomas Tapmeier, now at Monash University, is co-corresponding author of the study. 

  • Personalized Medicine
  • Gene Therapy
  • Human Biology
  • Diseases and Conditions
  • Personalized medicine
  • Rhesus Macaque
  • Gene therapy
  • Stem cell treatments
  • Vector (biology)
  • Adult stem cell
  • COX-2 inhibitor

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Materials provided by Baylor College of Medicine . Note: Content may be edited for style and length.

Journal Reference :

  • Thomas T. Tapmeier, Nilufer Rahmioglu, Jianghai Lin, Bianca De Leo, Maik Obendorf, Muthuswamy Raveendran, Oliver M. Fischer, Cemsel Bafligil, Manman Guo, Ronald Alan Harris, Holger Hess-Stumpp, Alexis Laux-Biehlmann, Ernesto Lowy, Gerton Lunter, Jessica Malzahn, Nicholas G. Martin, Fernando O. Martinez, Sanjiv Manek, Stefanie Mesch, Grant W. Montgomery, Andrew P. Morris, Jens Nagel, Heather A. Simmons, Denise Brocklebank, Catherine Shang, Susan Treloar, Graham Wells, Christian M. Becker, Udo Oppermann, Thomas M. Zollner, Stephen H. Kennedy, Joseph W. Kemnitz, Jeffrey Rogers, Krina T. Zondervan. Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis . Science Translational Medicine , 2021; 13 (608): eabd6469 DOI: 10.1126/scitranslmed.abd6469

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Science Update: NIH-funded researchers develop non-surgical method to treat endometriosis

Technique adapted from cancer treatment shows promise in mouse study.

A woman speaks with her healthcare provider during a checkup.

Magnetic hyperthermia—a procedure that uses heat to remove disease-causing tissues—may work as a treatment for endometriosis, according to a mouse study conducted by NIH-funded researchers. Endometriosis is a common gynecological condition that has no cure.

The work is supported by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development. The findings are published in the journal Small ,and the team is led by Oleh Taratula, Ph.D., of Oregon State University, and Ov. D. Slayden, Ph.D., of Oregon Health & Science University.

Endometriosis occurs when tissue that is similar to the lining of the uterus grows in other places in the body. It frequently causes debilitating pain and infertility, and treatments include hormone therapy and surgery to remove the patches of endometriosis tissue. However, hormone therapy cannot be used by those desiring near-term fertility, and surgery comes with the risk of complications. In addition, new endometriosis tissue may grow again in the future, requiring multiple surgical procedures.

As a result, researchers are developing non-surgical approaches to remove endometriosis tissue. Their goal is to increase efficacy and ease of treatments while reducing the unwanted side effects of surgery.

In the new study, the team adapted an experimental therapy called nanoparticle-mediated magnetic hyperthermia, which is used to remove cancerous tissue. The team delivered the magnetic nanoparticles via intravenous injection, an improvement over current methods that require direct injection into tumors. These nanoparticles generate heat when exposed to an alternating magnetic field, which is created through a medical device. If the temperature reaches above 46 degrees Celsius, the tissue dies. Studies so far indicate that this method is well-tolerated in people and in animal models. However, it was never applied to endometriosis until now.

The study team developed hexagon-shaped magnetic nanoparticles, which can generate heat more efficiently than sphere-shaped particles and thus reach the desired high temperatures. The team also modified the surfaces of their nanoparticles with a peptide that targets a receptor (vascular endothelial growth factor receptor 2, also called KDR) that is found at high levels in endometriosis tissue.

Using a mouse model of endometriosis, the researchers showed that their nanoparticles can accumulate in endometriosis tissues. They also identified a timeframe, about five days after injection, when the nanoparticles are cleared from other organs, such as the liver and spleen. During this time, the researchers administered the alternating magnetic field and found they could safely remove all the endometriosis tissue within 20 minutes. The team also showed that the magnetic field can be applied locally, to one part of the body, to further ensure that other tissues are not affected. They also show that the nanoparticles are not toxic and are eliminated from the body. Overall, the technique appears safe and effective, but more work is needed before it can be used in people.

Significance

This study identifies a new experimental therapy for endometriosis that does not require surgery. While the findings are early-stage, they offer a potentially safe and efficient method to remove endometriosis tissue.

Park Y et al. Targeted nanoparticles with high heating efficiency for the treatment of endometriosis with systemically delivered magnetic hyperthermia . Small DOI: 10.1002/smll.202107808 (2022)

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  • 14 June 2023

Could endometriosis be caused by bacteria? Study offers fresh clues

  • Heidi Ledford

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Infection by a particular group of bacteria could be linked to endometriosis, a painful condition that affects up to 10% of women and girls of reproductive age.

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New research shows potential to reduce pain in women suffering from endometriosis

by Elsevier

New research shows potential to reduce pain in women suffering from endometriosis

Pelvic pain in women with endometriosis is attributed to neuroinflammation. Researchers have investigated biochemical mediators of endometriosis-associated pelvic pain to provide a foundation to identify new drugs to improve symptoms and quality of life.

They postulated that novel therapeutic targets for pelvic pain in endometriosis are regulated by interleukin-1β (IL-1β) via the c-Jun N-terminal kinase (JNK) signaling pathway. IL-1β has been a popular focus of translational research in the field of endometriosis. Their results are published in The American Journal of Pathology published by Elsevier.

Lead investigator Robert N. Taylor, MD, Ph.D., Departments of Obstetrics and Gynecology and of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, explains, "Endometriosis is common and complex and likely to develop via multiple etiological mechanisms. As a result, multiple therapeutic targets are needed. Strategies over the past five decades have focused on surgical and endocrine approaches. New drugs aimed to block neuroinflammation may be promising future interventions for endometriosis-associated pain."

This collaborative research effort sought to identify biochemical mediators of endometriosis-associated pelvic pain using established neural biomarkers isolated from endometrial tissue biopsies obtained from eight adult women undergoing hysterectomy (four patients with endometriosis; four without). Immunofluorescence histochemistry confirmed the presence of neurons in human endometrial tissue, and isolated endometrial stromal cells (ESCs) expressed neurotrophins and their receptors. Peritoneal fluid samples were analyzed from 14 participants with and 26 participants without endometriosis.

New research shows potential to reduce pain in women suffering from endometriosis

Tropomyosin receptor kinase A/B (TrkA/B) expression in stimulated ESCs was almost twice as high in endometriosis cases than ESCs from control subjects, an effect mediated via the c-Jun N-terminal kinase (JNK) pathway. Investigators therefore postulate that JNK inhibitors have the potential to reduce neuroinflammation in women with endometriosis.

Nerve fibers were identified in the human uterus more than 80 years ago, but only in the past decade has their association with endometriosis pain been appreciated. The main findings of this study are that despite functioning through at least five different post-receptor signal cascades, the IL-1β pathway in ESC that engages JNK regulates a coordinated program of neurogenic factors, their receptors and other related nerve proteins that investigators identified in the uterus and ectopic lesions of women with endometriosis. They also found that JNK inhibitors may have the potential to reduce neuroinflammation in women with endometriosis.

The results revealed that many of the dominant mediators of inflammation, nerve growth, and pain sensation are predominantly communicated via a selective signaling node of the JNK pathway. The most significant implication of this finding is the potential for drugs targeting that common pathway to impact and ameliorate the multifaceted aspects of endometriosis -associated pelvic pain .

Dr. Taylor comments, "Our research and that of others lay a foundation to identify new drugs to block painful stimuli emanating from the pelvis to the brain, opening opportunities to improve symptoms and quality of life in women not well served by the limited therapeutics currently available. Drugs of the future that target JNK specifically, but do not interfere with ovarian hormone production, might supplant current hormone-disrupting agents, many of which have adverse side effect profiles."

Endometriosis is a disease in which tissue similar to the lining of the uterus grows outside the uterus. It can cause severe pain in the pelvis and infertility. It affects 5% to 10% of women of reproductive age worldwide.

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  • Open access
  • Published: 16 February 2024

Assessing the relationship between gut microbiota and endometriosis: a bidirectional two-sample mendelian randomization analysis

  • Chunxiao Dang 1   na1 ,
  • Zhenting Chen 2   na1 ,
  • Yuyan Chai 3 ,
  • Pengfei Liu 1 ,
  • Xiao Yu 4 ,
  • Yan Liu 5 &
  • Jinxing Liu 1  

BMC Women's Health volume  24 , Article number:  123 ( 2024 ) Cite this article

162 Accesses

Metrics details

An increasing body of observational studies have indicated an association between gut microbiota and endometriosis. However, the causal relationship between them is not yet clear. In this study, we employed Mendelian randomization method to investigate the causal relationship between 211 gut microbiota taxa and endometriosis.

Independent genetic loci significantly associated with the relative abundance of 211 gut microbiota taxa, based on predefined thresholds, were extracted as instrumental variables. The primary analytical approach employed was the IVW method. Effect estimates were assessed primarily using the odds ratio and 95% confidence intervals. Supplementary analyses were conducted using MR-Egger regression, the weighted median method, the simple mode and the weighted mode method to complement the IVW results. In addition, we conducted tests for heterogeneity, horizontal pleiotropy, sensitivity analysis, and MR Steiger to assess the robustness of the results and the strength of the causal relationships.

Based on the IVW method, we found that the family Prevotellaceae , genus Anaerotruncus , genus Olsenella , genus Oscillospira , and order Bacillales were identified as risk factors for endometriosis, while class Melainabacteria and genus Eubacterium ruminantium group were protective factors. Additionally, no causal relationship was observed between endometriosis and gut microbiota. Heterogeneity tests, pleiotropy tests, and leave-one-out sensitivity analyses did not detect any significant heterogeneity or pleiotropic effects.

Conclusions

Our MR study has provided evidence supporting a potential causal relationship between gut microbiota and endometriosis, and it suggests the absence of bidirectional causal effects. These findings could potentially offer new insights for the development of novel strategies for the prevention and treatment of endometriosis.

Peer Review reports

Introduction

Endometriosis (EMs) is a chronic, estrogen-dependent inflammatory condition characterized by the presence of endometrial tissue outside the uterus [ 1 ]. Approximately 6–10% of women of reproductive age are affected by EMs, and about 50% of infertile women have EMs [ 2 , 3 ]. Due to the secretive and diverse nature of EMs symptoms, and the lack of reliable non-invasive methods for detecting endometriosis, it often goes unnoticed. In recent years, the gut microbiota has emerged as a research hotspot, with scholars [ 4 , 5 , 6 ] discovering its associations with various diseases such as gastrointestinal disorders, cardiovascular diseases, respiratory diseases, and more. Research on the relationship between gut microbiota and endometriosis has spanned over two decades, starting as early as the 1990s and continuing to the present day. Many scholars have observed significant differences in the types, distribution, and abundance of gut microbiota between patients with EMs and healthy women [ 7 , 8 ]. Additionally, up to 90% of EMs patients experience gastrointestinal issues such as nausea, vomiting, diarrhea, and bloating [ 9 ], suggesting a potential imbalance in the gut microbiota. In fact, in a large-scale study, EMs patients were found to have a 50% increased risk of developing inflammatory bowel disease (IBD) compared to the general population [ 10 ]. Furthermore, ecological imbalances in the gut, vagina, or uterus in EMs patients may impact estrogen metabolism, immune system balance, and exacerbate the condition [ 11 , 12 ]. However, in observational studies, the relationship between gut microbiota and endometriosis can be influenced by confounding factors (such as age and surgical history) and reverse causality, making it uncertain whether these associations are causal in nature.

Randomized controlled trials (RCTs) are considered the gold standard in epidemiology for inferring causal relationships. However, due to ethical constraints, implementing RCTs can be challenging [ 13 ]. Mendelian randomization (MR) utilizes single nucleotide polymorphism (SNP) loci as instrumental variables to infer causal associations between exposures and outcomes. It does so by adhering to the genetic principle of “random allocation of parental alleles to offspring,” achieving similar randomization effects without being influenced by external environmental factors, thus compensating for the limitations of observational studies [ 14 ].

Currently, there are no MR reports regarding a causal relationship between gut microbiota and endometriosis. Although previous observational studies have suggested an association between gut microbiota and the incidence and progression of endometriosis, the causal relationship is not yet clear. This study is the first application of a two-sample Mendelian randomization approach to explore the causal association between gut microbiota and endometriosis. It aims to provide new insights into the treatment and prevention of endometriosis.

Materials and methods

Research design.

In a scenario where the genome wide association study (GWAS) summary data for the exposure variable and the GWAS summary data for the outcome variable are mutually independent, this study employed the TwoSampleMR package in R programming language to conduct a two-sample bidirectional Mendelian randomization analysis. The objective was to investigate the causal association between gut microbiota and endometriosis, with the specific design as shown in Fig.  1 . MR analysis adheres to three crucial assumptions [ 15 ]: First, the instrumental variables are strongly correlated with the exposure variable. Second, the instrumental variables are independent of observed or unobserved confounding factors. Third, the instrumental variables affect the outcome solely through the exposure.

figure 1

Flowchart of instrumental variable screening for MR method analysis

Data source

The GWAS summary data for endometriosis were obtained from the Finngen database, which includes data from 77,257 European participants and covers 16,377,306 SNPs ( https://gwas.mrcieu.ac.uk/datasets/finn-b-N14_ENDOMETRIOSIS/ ). The statistical data on gut microbiota were derived from the research conducted by the MiBioGen Consortium ( http://www.mibiogen.org/ ), which incorporated 18,340 individuals from 24 cohorts, mainly from Europe [ 16 ]. Microbial composition was analyzed using three distinct variable regions of the targeted 16 S rRNA gene, namely V4 (10,413 samples, 13 cohorts), V3-V4 (4,211 samples, 6 cohorts), and V1-V2 (3,716 samples, 5 cohorts). Supplementary File 1 shows a description of the participants in each cohort in a dataset of gut microbiota. Both gut microbiota and endometriosis were selected as exposure and outcome variables, respectively, for the MR analysis. As our study is based on publicly available databases, ethical committee approval was not required.

Instrumental variable selection

(1) IVs Selection: To obtain strongly related exposure data, SNPs with a significance level of P  < 5 × 10 − 8 were selected as conditions. Given that gut microbiota SNPs rarely have P  < 5 × 10 − 8 , gut microbiota SNPs were selected with a threshold of P  < 1 × 10 − 5 . (2) Independence Criterion: The PLINK aggregation method was used to calculate linkage disequilibrium (LD) between each risk factor’s SNPs. SNPs with an LD coefficient r 2  > 0.001 and a physical distance of less than 10,000 kb were removed to ensure that the SNPs were mutually independent and to eliminate the influence of genetic pleiotropy on the results [ 17 , 18 ]. (3) Statistical Strength Criteria: The strength of the instrumental variables was calculated using the F-statistic, with the formula: F = β 2 / SE 2 (where β is the allele effect size and SE is the standard error). Instrumental variables with F < 10 were removed to ensure that the instrumental variables were unrelated to unmeasured confounding factors [ 19 ]. Finally, the “harmonise_data” function from the TwoSampleMR package was used to align the direction of alleles between exposure and outcome, remove palindromic and incompatible SNPs [ 20 ], and exclude SNPs with confounding factors through the PhenoScanner database ( http://www.phenoscanner.medschl.cam.ac.uk/ ).

Mendelian randomization analysis

In this study, the inverse variance weighted (IVW) method [ 21 ] was employed as the primary analytical approach for establishing causal relationships. This method, assuming the validity of all instrumental variables, calculates weighted estimates by taking the reciprocal of their variances as weights. It provides the most accurate results when there is no heterogeneity or horizontal pleiotropy present. Additionally, MR-Egger regression, the weighted median (WME) method, the simple mode (SM) and the weighted mode (WM) method were used as supplementary analyses to complement the IVW results. MR-Egger regression method performs weighted linear regression of the exposure and outcome effect estimates, providing a causal effect assessment even when all SNPs are invalid instruments. The WME method leverages the intermediate effects of all available genetic variations, estimating them by weighting each SNP by the inverse variance of its correlation with the outcome. SM and WM are mode-based methods. The mode-based estimation model clusters SNPs with similar causal effects and returns causal effect estimates for the majority of clustered SNPs. Specifically, WM weights the influence of each SNP on the cluster by the inverse variance of its outcome effect. These methods complement the IVW results and provide additional insights into the causal relationships between exposure and outcome variables. Finally, we conducted reverse MR analysis for EMs and gut microbiota. The methods and settings used in these reverse MR analysis were consistent with those of forward MR.

Sensitivity analysis

Heterogeneity testing [ 22 ] assesses the presence of differences among various IVs. It utilizes the P -value from Cochran’s Q test to evaluate heterogeneity, with P  > 0.05 indicating the absence of heterogeneity. If heterogeneity is detected, the MR pleiotropy residual sum and outlier (MR-PRESSO) test is employed to assess potential outliers [ 23 ], eliminate them, and then reanalyze the data. Multiplicity testing [ 24 ] verifies the reliability of MR analysis results. MR-Egger intercept is used to detect horizontal pleiotropy, with P  > 0.05 indicating the absence of horizontal pleiotropy and, thus, the reliability of the MR analysis results. Sensitivity testing [ 25 ] is conducted using a “leave-one-out” approach, sequentially removing each SNP. If the MR results derived from the remaining SNPs do not exhibit significant differences from the overall result, it demonstrates the robustness of the MR results. Furthermore, the MR Steiger directional test was employed to further assess the correlation between the exposure and the outcome.

Causal effect of gut microbiota on EMs

In this study, 211 gut microbiota relative abundances were selected as the exposure variable from gut microbiota GWAS data involving 18,340 participants. These 211 taxa include 9 phylums, 16 classes, 20 orders, 35 families, and 131 genuses. As both heterogeneity and pleiotropy tests yielded negative results, the IVW analysis results were considered the primary reference indicator. The MR analysis results indicate that seven different gut microbiota at various taxonomic levels (1 class, 1 order, 1 family, and 4 genuses) may be associated with endometriosis, as shown in Fig.  2 . The main MR analysis results for the association between all gut microbiota and the risk of EMs, as well as the results of heterogeneity and pleiotropy tests, can be found in Supplementary File 2 .

We identified associations between endometriosis and five microbial taxonomic groups with positive correlations: family Prevotellaceae (OR = 1.19, 95%CI 1.02  ∼  1.40, P  = 0.026), genus Anaerotruncus (OR = 1.25, 95%CI 1.03  ∼  1.53, P  = 0.025), genus Olsenella (OR = 1.11, 95%CI 1.01  ∼  1.22, P  = 0.036), genus Oscillospira (OR = 1.21, 95%CI 1.01  ∼  1.46, P  = 0.035), order Bacillales (OR = 1.11, 95%CI 1.00  ∼  1.22, P  = 0.042). Simultaneously, two microbial taxonomic groups showed negative associations with endometriosis: class Melainabacteria (OR = 0.86, 95%CI 0.75  ∼  0.99, P  = 0.036), genus Eubacterium ruminantium group (OR = 0.88, 95%CI 0.79  ∼  0.98, P  = 0.015) (Figs.  2 , 3 and 4 ). For detailed results of all SNPs related to these seven gut microbiota (including specific chromosomes, F values, and R 2 ), please refer to Supplementary File 3 .

figure 2

Forrest plot for summary causal effects of gut microbiota on EMs risk based on IVW method for the primary analysis

figure 3

Scatter plots of five taxa of gut microbiota positively associated with EMs. ( A ) family Prevotellaceae ( B ) genus Anaerotruncus ( C ) genus Olsenella ( D ) genus Oscillospira ( E )order Bacillales

figure 4

Scatter plots of two taxa of gut microbiota negatively associated with EMs. ( A ) class Melainabacteria ( B ) genus Eubacterium ruminantium group

As indicated in Supplementary File 3 , we noted that the contribution of total variation (R 2 values) for the 7 gut microbiota ranged from 0.13 to 0.21%, with F values spanning from 18.27 to 29.81. This range effectively rules out the possibility of weak genetic instrumental variables. Heterogeneity testing was conducted with a distribution = 10,000 setting. The Cochran’s Q test for both IVW and MR-Egger regressions indicated the absence of heterogeneity among the SNPs of each microbial taxonomic group. Multiple-effect tests revealed that the MR-Egger regression intercepts were all less than 0.05, and their P -values were greater than 0.05, suggesting the absence of horizontal pleiotropy. Furthermore, all MR Steiger directional tests consistently indicated that the direction from gut microbiota to endometriosis was robust for all outcomes (Table  1 ). Sensitivity analysis was performed using a “leave-one-out” test, and a forest plot was generated. The results indicated that removing any single SNP did not significantly influence the remaining SNP results, all remained on the same side of the null line. This suggests that the MR results in this study are robust. Refer to Fig.  5 for visualization of the sensitivity analysis results.

figure 5

Results of a leave-one-out analysis of the association of gut microbiota with EMs MR. ( A ) class Melainabacteria ( B ) family Prevotellaceae ( C ) genus Anaerotruncus ( D ) genus Eubacterium ruminantium group ( E ) genus Olsenella ( F ) genus Oscillospira ( G ) order Bacillales

Reverse-direction MR analyses

Finally, a reverse mendelian randomization analysis was conducted, with endometriosis as the exposure factor and gut microbiota as the outcome variables. The results of each SNP of endometriosis and 7 gut microbiota are shown in Supplementary File 4 . Heterogeneity and multiple-effect tests yielded negative results. The IVW analysis revealed that there is no causal relationship between endometriosis and the seven different gut microbiota at various taxonomic levels. The MR Steiger directional tests for the 7 gut microbiota with respect to endometriosis yielded TRUE results. Detailed results can be found in Table  2 .

Main findings and interpretation

In this study, we assessed for the first time the potential relationship between gut microbiota and endometriosis by a bidirectional MR method, and identified the presence of specific microbial groups at the level of phylum, order, family, and genus that are closely related to EMs, family Prevotellaceae , genus Anaerotruncus , genus Olsenella , genus Oscillospira and order Bacillales had a risk effect on endometriosis, and class Melainabacteria , genus Eubacterium ruminantium group was a protective factor against endometriosis. Sensitivity analyses showed no horizontal pleiotropy, indicating that our MR analyses were not affected by confounding factors, and “leave-one-out” analyses confirmed the robustness of the study.

During menstruation, when endometrial tissue retrogrades into the peritoneal cavity and implants into surrounding tissues, such as the intestines or peritoneum, it leads to the formation of endometriotic lesions [ 26 ]. In approximately 10% of women, the immune system fails to clear these ectopic endometrial cells, leading to the activation of macrophages, secretion of pro-inflammatory cytokines and growth factors, and the spread of the lesions [ 27 , 28 ]. The gut microbiota is a crucial component of the human immune system, with immunomodulatory functions mediated through interactions with stromal cells and epithelial cells. Research has shown that microbial metabolites act as messengers between the gut microbiota and immune functions [ 29 , 30 , 31 ]. In studies involving mice with endometriosis, alterations in microbial metabolites were observed. The consumption of gut microbiota suppressed inflammation related to endometriosis [ 32 ] and influenced immune cell populations, suggesting that gut microbiota can influence endometriosis through immune pathways.

The abnormal endocrine microenvironment within EMs lesions is considered a key characteristic of endometriosis. Estrogen [ 33 ] has a direct cell anti-apoptotic and proliferative effect on EMs lesions and promotes the formation of a pro-inflammatory microenvironment, contributing to the chronic progression of the disease. Estrogen is a major regulatory factor for gut microbiota, and the gut microbiome’s genetic repertoire involved in estrogen metabolism is often referred to as the “estrobolome” [ 34 ]. It participates in estrogen regulation by secreting beta-glucuronidase [ 35 ], forming the estrogen-gut microbiota axis. Research has shown significant differences in the expression of 17β-estradiol, 16-keto-17β-estradiol, 2-hydroxyestrone, and 2-hydroxyestradiol in individuals with EMs. Additionally, there is a clear positive correlation between the gut microbiota of EMs patients and urinary estrogen levels [ 36 ]. Family Prevotellaceae belongs to the Bacteroidetes phylum , and a meta-analysis [ 37 ] found that the abundance of Bacteroidetes is positively correlated with estrogen levels. When the Firmicutes/Bacteroidetes ratio in the gut decreases, there is an increase in the secretion of beta-glucuronidase in the intestine, leading to elevated estrogen levels. High estrogen levels are directly associated with the development of EMs, and our study provides similar findings.

Multiple studies have indicated [ 7 , 33 ] that individuals with endometriosis experience dysbiosis in their gut microbiota. The gut microbiota, when fermenting carbohydrates, produces short-chain fatty acids (SCFAs) that can activate G protein-coupled receptors. This activation has beneficial effects by reducing food intake, improving insulin sensitivity, inhibiting fat accumulation, and reducing systemic inflammation [ 38 ]. However, in cases of gut microbiota dysbiosis, there is a reduction in SCFA production. Simultaneously, certain neuroactive metabolites, such as glutamate and butyric acid, increase in level. These metabolites can stimulate brain neurons and, through the hypothalamus-pituitary-ovary axis, increase ovarian estrogen secretion, exacerbating the condition of patients [ 39 , 40 ].

It is noteworthy that PERROTTA et al. [ 41 ] established an EM classification model based on random forest, revealing that the vaginal microbiota could predict the severity of endometriomas (EMs), with Anaerococcus identified as the most crucial factor, while the gut microbiota lacked corresponding accuracy. Furthermore, CHEN et al. [ 42 ] built a model based on the female reproductive tract microflora, which can distinguish whether infertility is caused by EMs. Considering the potential influences on the gut microbiota from factors such as diet, antimicrobial drugs, and psychological stress, relying on it as a tool for early diagnosis and screening of EMs is unreliable. Similarly, the reproductive tract microbiota can be affected by different physiological stages and diseases like vaginal infections. Therefore, exploration of non-invasive diagnostic methods for EMs is still needed, and using saliva for diagnosis may be more helpful [ 43 ]. However, what can be confirmed is the causal association between gut microbiota and endometriosis, with a dynamic interplay between the two, which holds potential implications for future bacteria-based therapies.

However, our study has several limitations: (1) Human behavior is complex, and while understanding the genetic risk of a disease can help prevent its occurrence to some extent, environmental factors also play a role in the development of the disease [ 44 ], and MR can only partially eliminate the interference of confounding factors such as the environment [ 45 ]. (2) The current study may not comprehensively explore the entire spectrum of the gut microbiota, from phylum to genus level, potentially missing other microbial taxa that could have a causal relationship with endometriosis, especially those associated with increased risk. (3) The outcome data used in the study is derived from European populations, and caution should be exercised when extrapolating the results to other populations with different lifestyles, cultural backgrounds, and genetic backgrounds, as specific traits may vary across different racial and ethnic groups driven by their distinct living environments and genetic backgrounds. Efforts should be made to include populations of all ethnicities globally in genetic studies of this nature. (4) Although we have demonstrated a causal relationship between gut microbiota and endometriosis, the underlying mechanism is still unclear and requires further research.

The study collected data from GWAS databases and used a two-sample bidirectional MR approach to confirm the potential causal relationship between gut microbiota and endometriosis, providing new insights into the pathogenesis and treatment of endometriosis. Future research should aim to further elucidate the underlying mechanisms by which these microbial communities influence endometriosis, explore potential treatment strategies targeting gut microbiota.

Data availability

All data generated or analysed during this study are included in this published article and its supplementary information files.

Abbreviations

Mendelian randomization

  • Endometriosis

Randomized controlled trials

Single nucleotide polymorphisms

Instrumental variables

Genome wide association study

Linkage disequilibrium

Inverse variance weighted

Weighted median

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Acknowledgements

This work benefited from the publicly available statistics of GWAS. We thank the contributors to the original GWAS database.

This work was supported by the Natural Science Foundation of China (No.82104917), the Natural Science Foundation of Shandong Province (No.ZR2021MH079).

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Chunxiao Dang and Zhenting Chen contributed equally to this work.

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First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong, China

Chunxiao Dang, Pengfei Liu & Jinxing Liu

Department of eugenic genetics, Dongying People’s Hospital (Dongying Hospital of Shandong Provincial Hospital Group), Dongying, 257091, Shandong, China

Zhenting Chen

Department of obstetrics, The People’s Hospital of Dongying Distric, Dongying, 257091, Shandong, China

Department of gynaecology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250000, Shandong, China

National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Department of Cardiology, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250000, Shandong, China

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Pengfei Liu and Jinxing Liu conceived the study. Chunxiao Dang and Yuyan Chai provided the design of the study. Zhenting Chen and Pengfei Liu collected the data. Xiao Yu and Yan Liu conducted the main analyses of the study. Chunxiao Dang and Zhenting Chen wrote the body of the manuscript. Yan Liu and Jinxing Liu revised the manuscript. All authors reviewed the the manuscript.

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Dang, C., Chen, Z., Chai, Y. et al. Assessing the relationship between gut microbiota and endometriosis: a bidirectional two-sample mendelian randomization analysis. BMC Women's Health 24 , 123 (2024). https://doi.org/10.1186/s12905-024-02945-z

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Endometriosis Is Undervalued: A Call to Action

Katherine ellis.

1 Department of Mechanical Engineering, University of Canterbury, Christchurch, New Zealand

Deborah Munro

Jennifer clarke.

2 Faculty of Health, University of Canterbury, Christchurch, New Zealand

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The original contributions presented in the study are included in the article; further inquiries can be directed to the corresponding author.

Endometriosis is an inflammatory chronic pain condition caused by uterine tissue growing outside of the uterus that afflicts at least 11% of women (and people assigned female at birth) worldwide. This condition results in a substantial burden to these women, and society at large. Although endometriosis was first identified over 160 years ago, substantial knowledge gaps remain, including confirmation of the disease's etiology. Research funding for endometriosis is limited, with funding from bodies like the National Institutes of Health (NIH) constituting only 0.038% of the 2022 health budget—for a condition that affects 6.5 million women in the US alone and over 190 million worldwide. A major issue is that diagnosis of endometriosis is frequently delayed because surgery is required to histologically confirm the diagnosis. This delay increases symptom intensity, the risk of central and peripheral sensitization and the costs of the disease for the patient and their nation. Current conservative treatments of presumed endometriosis are pain management and birth control. Both of these methods are flawed and can be entirely ineffective for the reduction of patient suffering or improving ability to work, and neither addresses the severe infertility issues or higher risk of certain cancers. Endometriosis research deserves the funding and attention that befits a disease with its substantial prevalence, effects, and economic costs. This funding could improve patient outcomes by introducing less invasive and more timely methods for diagnosis and treatment, including options such as novel biomarkers, nanomedicine, and microbiome alterations.

Introduction

Endometriosis is a chronic inflammatory disease ( 1 ) that causes significant morbidity ( 2 ), and affects 10–15% of women of reproductive age globally ( 3 – 5 ). Conservatively, 1 in 9 women of reproductive age has endometriosis in the United States (US) ( 6 ) and Australia ( 7 ). Endometriosis causes tissue from the uterus to migrate and implant in other regions of the body ( 8 , 9 ). This tissue interacts with the body's endocrine, musculoskeletal, vascular, reproductive, and nervous systems ( 10 ) causing numerous painful symptoms and physiological changes. There are three key types of endometriosis: superficial peritoneal, ovarian, and deep infiltrating ( 11 ). While peritoneal is the predominant presentation of the disease, ovarian affects 17–44% of endometriosis patients ( 12 ) and is characterized by the development of ovarian endometriomas, cystic lesions filled with dark endometrial fluid ( 13 ). Deep infiltrating endometriosis affects ~20% of endometriosis patients ( 14 ) and is considered the most severe form ( 15 ). Each endometriosis subtype is thought to have a different pathogenesis ( 16 ), but no etiology is confirmed ( 17 ) that explains all disease manifestations ( 18 ).

Symptom Burden

Misplaced endometriotic tissue causes a wide range of symptoms, including chronic pelvic pain, dysmenorrhea (menstrual pain), dyspareunia (painful sex), dysuria (painful urination), dyschezia (painful defecation) ( 19 ), metrorrhagia (mid-cycle bleeding), diarrhea, constipation, infertility ( 20 ), and myofascial pain, among others ( 1 ). Furthermore, the gastrointestinal symptoms of endometriosis patients are more severe than those of controls ( 21 ), which often results in both coexistence and misdiagnosis of irritable bowel syndrome ( 22 ). As the disease progresses, patients risk developing adhesions, fibrous scar tissue bands that can abnormally bind pelvic and abdominal organs ( 9 ). Endometriosis is the most frequent cause of adhesions in women and common areas for endometriosis adhesions include the anterior abdominal wall, bladder, and uterus ( 23 ). Adhesions can cause anatomical distortion, which can hinder fertility, cause rectal constriction, and be a cause of dyspareunia. In a 2019 study, the presence of endometriosis-associated adhesions was shown to significantly negatively impact quality of life ( 23 ).

The cumulative effect of these chronic pain symptoms is a substantial burden on sufferers ( 20 ) and 70% of patients live with unresolved pain ( 2 ), with impacts to all aspects of their quality of life ( 24 ). Research shows that endometriosis patients also have significantly higher rates of co-morbidities than control populations ( 25 ). The symptoms of endometriosis, particularly those associated with pain, increase the rates of chronic stress, anxiety, depression and decreased quality of life among endometriosis patients compared with those without the disease ( 26 ).

There is a well-established delay from symptom onset to diagnosis of 4–11 years for endometriosis patients ( 1 ). There are many reasons for this delay, including the lack of a unique symptom profile ( 27 ), the variety of symptoms ( 28 ) and large waitlists for the laparoscopies used to diagnose endometriosis ( 2 ). Many patients find it necessary to “doctor shop” to find a medical practitioner who will support their efforts to obtain an endometriosis diagnosis. In a 2004 study, 47% of endometriosis patients had seen at least five doctors before getting an endometriosis diagnosis or referral ( 29 ). This may be partially explained by the results of a 2021 French study, where 25% of general practitioners did not think they knew enough about endometriosis for their clinical practice ( 30 ). In a 2012 study of 173 endometriosis patients in Austria and Germany, 74.3% had experienced a misdiagnosis. These misdiagnoses included intolerances, appendicitis, irritable bowel syndrome, and pelvic inflammatory disease ( 31 ).

In addition to painful symptoms, patients can be subject to central and peripheral sensitization ( 10 ). Central sensitization is the abnormal processing of sensory signals ( 32 ) that results in exaggerated experiences of painful and non-painful stimuli ( 10 ) through enhanced pelvic nociception. Peripheral sensitization lowers the body's threshold for nociceptor activation with repetitive and prolonged stimulation, as occurs in endometriosis ( 10 ). The combined effect of these phenomena is that over time non-painful stimuli can produce incredibly painful signals in sensitized patients.

Women with chronic pelvic pain, with or without a confirmed diagnosis, show significantly lower pain tolerances than controls ( 33 ). The severity of the decrease in pain tolerance corresponds to the duration of symptoms ( 33 ) supporting the theory that delayed diagnosis increases patient sensitization. An Australian study found endometriosis patients have significantly higher functional pain disability (pain interference with daily activities like sleep, relationships and work) than women without endometriosis ( 34 ). Furthermore, women have higher pain sensitivity than men ( 35 , 36 ) as a result of complex interactions in women of anatomical, hormonal, physiological, and psychological factors ( 37 ).

Cancer Associations

Endometriosis is a non-neoplastic invasive disease ( 38 ), although there is evidence to suggest a positive association between endometriosis and ovarian cancer ( 39 ). There is molecular evidence to suggest endometriotic lesions can undergo a transformation to clear cell and endometrioid ovarian cancers ( 40 ). This connection is controversial, and like many aspects of endometriosis, requires much more study to fully outline the potential mechanisms involved. The indication is that endometriosis increases ovarian cancer risk ( 19 ) from 1.3% in the general female population to 1.8% of endometriosis patients ( 41 ).

Infertility

In addition to the extensive pain symptoms endometriosis patients experience, endometriosis patients have a high prevalence of infertility and sub-fertility among their cohort. Half of endometriosis patients suffer from fertility issues ( 42 ), and up to half of women with unexplained infertility or sub-fertility are subsequently found to have endometriosis ( 43 , 44 ). The high rates of endometriosis interfering with fertility may relate to factors including anatomical distortions ( 45 ), diminished ovarian reserve, chronic inflammation and compromised endometrial receptivity ( 42 ).

Lack of Funding

Endometriosis is a condition that impacts not only patients, but their families, jobs, societies, and countries. The authors believe the present issues with diagnosing, treating and funding endometriosis result from many years of misunderstanding and ignoring important female health topics. Improving funding for endometriosis research could improve the understanding of the condition, eliminate knowledge gaps, reduce time to diagnosis, expand available treatment options, improve pain management and place a long-overdue emphasis on predominantly female experiences of illness.

The National Institutes of Health (NIH) is the largest source of biomedical research funding globally, allocating $41.7 billion USD annually ( 46 ). In 2022, the expected funding allocation for endometriosis is $16 million ( 47 ), 0.038% of the budget. Since the conservative estimate is that endometriosis affects 11% of US women in their lifetime, only $2.00 per patient per year is allocated. As a comparison, 12% of US women are expected to suffer from diabetes in their lifetime ( 48 ). If it is assumed that half of the allocated diabetes research budget was for female sufferers, there is a funding allocation of $31.30 per woman, over 1,500% more than for endometriosis.

Crohn's disease, like endometriosis, is a chronic inflammatory condition ( 49 ). Crohn's disease affects the digestive tract lining, resulting in abdominal pain, weight loss, diarrhea, and fatigue ( 50 ). There are over 690,000 people with Crohn's disease in the US, or 0.21% of the population ( 51 ). In 2022, Crohn's disease research will receive $90 million in funding, $130.07 per patient, over 65 times more per patient than for endometriosis. This comparison is not to suggest Crohn's disease is overfunded, but that endometriosis is seriously underfunded.

Economic Burden of Endometriosis

The burden of endometriosis on individual patients is substantial ( 20 ) both before and after diagnosis ( 52 ). The impact of ongoing pain can cause some patients to lose their jobs or their partners ( 53 ). Additionally, the financial burden is significant. Endometriosis patients have significantly higher healthcare resource utilization, and direct and indirect healthcare costs than controls. Endometriosis patients in the US spend $26,305 USD more than controls on healthcare expenses in the 5 years before and after diagnosis ( 52 ). In the year after diagnosis patients with endometriosis spend on average 3.5 times the amount on healthcare than controls do ( 25 ). The direct costs of endometriosis include in and outpatient treatment, surgery, and prescription costs, which in the US average $12,118 per patient, per year ( 54 ). Indirect costs, including days of work lost and reduced quality of work, were almost $16,000 per patient per year ( 54 ). In a study across ten countries lost productivity costs were generally double those of healthcare costs ( 55 ) as the average patient loses 6.4 h of work a week to presenteeism (reduced effectiveness while working) ( 56 ). Endometriosis patients begin to suffer from their condition at a young age, during a very productive period of their lives. The additive effects of fatigue, productivity loss, and time removed from the workforce, schooling and training create an immense barrier to patients being able to effectively progress in life, take up career opportunities, and in their capacity to save their earnings.

The total US endometriosis economic burden is estimated to be as high as $78–119 billion annually ( 54 , 57 ). In Australia, the annual cost of endometriosis was estimated to be $16,970–20,898 per woman, per year, with 75–84% of the total due to productivity losses ( 58 ). Delays until endometriosis diagnosis increase not only the number of pre-diagnosis endometriosis symptoms but also emergency visits, hospitalizations, and overall healthcare costs ( 59 ). Compared to short delays of less than a year, long delays of 3–5 years from first symptom presentation to diagnosis, increased the cost of healthcare in the 5 years prior to diagnosis by $12,971–34,460 ( 59 ).

Lost workdays are also higher among endometriosis patients than control populations ( 25 ). In Australia, where the annual economic burden of endometriosis is estimated to be $6.5 ( 58 ) to $7.4 billion ( 60 ), endometriosis patients used on average 60% of their sick leave to treat their chronic pain ( 60 ). In a 2022 study, 65% of an Australian cohort of endometriosis patients used unpaid leave to manage their endometriosis symptoms, 64% felt judged in the workplace for their symptoms, and one in seven reported being fired as a result of their condition ( 61 ).

Furthermore, research shows there are immense productivity losses due to endometriosis for women in the workforce, even while at work. Fatigue is more common among endometriosis patients, than in control populations ( 62 ). In a 2021 Canadian study on fatigue, endometriosis patients reported substantial impairments to their work productivity with 46.5% overall work impairment due to endometriosis-related symptoms ( 63 ). These findings were like a 2013 Danish study that found that patients with endometriosis had significantly more pain than controls, were in more pain when using their sick days and used more sick days ( 64 ). This study also found that many women were embarrassed by their symptoms, felt obligated to use their sick days and often felt unable or too tired to do a satisfying job ( 64 ).

In the US, the diabetes economic burden is $327 billion ( 65 ), and with 37.3 million Americans with diabetes ( 48 ), that accounts for $8,767 of burden per patient. By comparison, the estimated economic burden of endometriosis in the US would account for $9,754–14,881 per patient, 11–70% higher than for diabetes. Thus, it is evident to the authors there is an immense financial burden not only on endometriosis patients but on nations with patients who then require high levels of healthcare utilization. These patients frequently cannot participate in their workplaces and economies to the degree they wish because of symptoms, incurring a further cost to patients and society. If endometriosis was funded by the NIH at the same level as diabetes with respect to the annual economic burden, endometriosis funding would need to increase to $298.8–455.3 million, rather than the current $16 million.

The Present Options

Low research funding for endometriosis research means knowledge gaps are not being filled, making the development of effective diagnosis and treatment options more complicated, more time consuming, and less enticing for researchers. As a consequence, presently available options to treat endometriosis are severely limited. There are also high recurrence rates of symptoms and disease for current interventions ( 66 ). Recurrence of symptoms for non-surgical therapies, such as birth control and pain management, are rapid ( 18 ), because non-surgical treatments reduce or repress symptoms, but do not cure the disease. Furthermore, these methods are entirely inefficacious for endometriosis-associated fertility issues ( 19 ). Effective, non-invasive, non-hormonal treatments are required but are not currently available to the over 190 million global endometriosis patients ( 67 ).

Birth Control

Birth control is a standard endometriosis treatment ( 68 ). Endometriosis birth control methods include intrauterine progesterone devices, progestin injections and combined hormone pills ( 69 ). Combined treatments increase the risk of thromboembolism, nausea and breast tenderness. Progestin injections can cause weight gain, decreased bone density, worsened acne, and depression ( 69 ). Birth control is also a limited treatment for endometriosis, as many women cannot use birth control because the side effects are too severe or because of a desire to get pregnant.

Pain Management

Pain is the most common symptom of endometriosis ( 70 ). However, endometriosis pain management is complex. There is inconclusive evidence that non-steroidal anti-inflammatory drugs provide greater relief than placebos ( 71 ). Opioids are not a recommended treatment for endometriosis ( 72 ); however, in a cohort of 113,506 endometriosis patients in the US, 89% were utilizing opioids to manage their pain ( 25 ). Chronic opioid use can significantly increase healthcare costs for endometriosis patients compared to non-chronic users ( 73 ). Long-term opioid use for non-cancerous chronic pain, such as endometriosis, is controversial and results in an absolute adverse event rate of 78% ( 74 ). The high use of opioids among this cohort is indicative of the intensity of the pain experienced, but this approach can lead to addiction and side effects, including constipation, nausea, confusion and drowsiness ( 75 ). The required dosage to manage pain also increases with chronic use as the body becomes habituated to it ( 76 ).

Laparoscopic surgery is considered the “gold-standard” for diagnosing and treating endometriosis ( 18 ) and is the only method available to “confirm” endometriosis histologically ( 77 ) which provides a clear and unambiguous diagnosis for patients that is often essential for practitioners to provide the best treatment plan. According to one study, 42% of patients have undergone at least three surgeries ( 2 ). Surgery is thus an impermanent solution for many patients, with recurrence of both symptoms and lesions ( 19 ) expected for 40–50% of patients within 5 years ( 78 ), and this repeated intervention can exacerbate pain and fertility issues ( 79 ). Furthermore, surgery is a trauma to the body that activates adrenergic signaling, suppresses cell-mediated immunity and promotes angiogenesis ( 80 ). In mice with induced endometriosis, subsequent surgery increased lesion weight and microvessel density ( 80 ), which is counteractive to the intent of surgery for endometriosis.

Evolving Possibilities

Earliest descriptions of endometriosis date back to 1860 ( 81 ) and 1920 ( 82 ). However, we still do not understand its etiology ( 70 ), the biology and function of both healthy female and endometriotic peritoneum, or the actions of endometrial stem cells ( 83 ). A substantial amount of knowledge still needs to be collected, collated, and applied to patient care. The lack of progress despite the relatively high volume of papers published about endometriosis indicates the complexity of endometriosis and the limited global funding available ( 83 ). Despite these issues, endometriosis research has been undertaken by talented researchers, and there are many promising avenues for further endometriosis research.

New Biomarker Analysis

One of the key aspects impacting the diagnosis and treatment of endometriosis is the lack of non-invasive diagnostic tools. Biomarkers present an appealing option for non-invasive diagnosis of endometriosis. However, many biomarkers that have been assessed previously could only discern advanced disease, indicating a need for more research to locate biomarkers that can diagnose “milder” cases of the disease ( 84 ). In a 2021 study, the researchers found patients with endometriosis had distinct microbial communities in their peritoneal fluid and feces compared to the control group. In the peritoneal fluid of endometriosis patients, there were more pathogens, while there was a loss of protective microbes in feces samples ( 85 ). The authors concluded that Ruminococcus in the gut and Pseudomonas in the peritoneal fluid may be able to act as auxiliary diagnostic tools for endometriosis with further investigation into the interactions of micro-organisms and endometriosis required ( 85 ).

Follicular fluid can be obtained from follicles by fine-needle aspiration following oocyte removal ( 5 ). Researchers have found endometriosis patients have dysregulated cytokine profiles in their follicular fluid with significant upregulation of IL-1β and IL-6 ( 86 ). Conversely, the concentration of IL-12, an anti-inflammatory cytokine, inflammatory cytokine IL-10 and E-cadherin levels were lower among endometriosis patients compared to controls ( 5 ). In a 2021 study, the measurement of IL-10 in follicular fluid was able to perfectly differentiate between endometriosis patients and controls ( 5 ).

Nanomedicines

One technology in its infancy for the treatment of endometriosis is the use of nanoparticles to aid in the imaging of, directly treating or delivering drugs to treat endometriosis ( 87 ). The key limitation for this emerging technology is that the etiology and pathogenesis of endometriosis are unknown ( 87 ). Despite this, investment in nanomedicines for endometriosis could substantially augment the capacity to diagnose and treat endometriosis. Nanoparticles have shown a capacity to accumulate in endometriotic lesions ( 87 ), which could improve the use of imaging technologies to diagnose endometriosis. This technology could also provide a method for targeting endometriotic lesions without the requirement of surgery. Potential drugs that could be delivered by nanotechnological methods could be anti-inflammatory, antioxidant, anti-angiogenic and immunomodulating molecules ( 88 ), which may have the capacity to reduce the size of or eliminate endometriosis lesions, rather than just suppress symptoms. However, much more pre-clinical and clinical research is required to support the use of this emerging technology for endometriosis ( 88 ).

Alterations to the Microbiome

Imbalances to gut microbiota composition have been connected to the compromised immunosurveillance and altered immune profiles associated with endometriosis ( 89 ), with animal studies consistently showing the impact of the gut microbiota on endometriosis and endometriosis on gut microbiota ( 90 ). In addition to being a potential site for novel biomarkers, the gut microbiota may be a target site for new treatments. In a 2019 study by Chadchan et al., mice with induced endometriosis were subjected to antibiotic therapies ( 91 ). Broad-spectrum antibiotics were shown to significantly reduce lesion size and inflammatory response. Furthermore, the authors showed that fecal transfer from mice with endometriosis restored lesion growth and inflammation in mice treated with the antibiotic metronidazole ( 91 ). Conversely, metronidazole-treated mice that received fecal transfers from mice without endometriosis had significantly smaller lesions, suggesting a role for the gut microbiome in the progression of endometriosis ( 91 ). The effect of gut microbiota on endometriosis is not solely negative. The bacteria-derived metabolite n-butyrate is a short-chain fatty acid that is significantly downregulated in mice with induced endometriosis. In a 2021 study, n-butyrate treatment significantly reduced lesion growth and inflammatory cell infiltration in a mouse model ( 92 ). Therapies that address endometriotic alterations to the gut microbiota could have immense potential to reduce the growth of lesions and the effects of inflammation for endometriosis patients.

Despite progress, critical gaps remain in the fundamental understanding of endometriosis. This means there are opportunities to substantially expand and improve our core understanding of this important health topic. The authors feel endometriosis warrants more attention to fill these fundamental knowledge gaps. There are not enough people working in this vital space, likely due to insufficient funding. If endometriosis was funded by the NIH at half the level of diabetes, the budget would increase almost 16 times to over $250.4 million annually. It is the belief of the authors that present levels of endometriosis funding do not reflect the immense pain of patients, long delays in diagnosis, the ineffectiveness of common treatment options, massive knowledge gaps, substantial economic burdens or the immense costs borne by individual patients. Unexplored in the scope of this paper, but vital, is the investment into structures to translate research findings into clinical care, understanding of the epidemiological underpinnings of patient diversity, increased awareness through public education about endometriosis so affected patients are better aware, and into healthcare practitioner training about how best to treat and support endometriosis patients.

There is a lot of promising research underway that could create substantial positive ramifications for patients. These include the chance for non-invasive biomarker auxiliary diagnosis methods, the application of nanoparticle drug delivery and treatments targeting the microbiome. An area of immense potential for developing new non-invasive diagnostic and treatment options may be the application of nanoparticles to deliver therapies directly to endometriotic lesions.

Advancement in the identification and treatment of endometriosis is challenging but entirely possible. It is the opinion of these authors that if endometriosis had more representative funding, the rate of advancement of non-invasive diagnostic and treatment methods could be significantly increased, with long-term benefits for patients and society.

Data Availability Statement

Author contributions.

KE is the first author of this paper through conception and literature collection. DM and JC have contributed equally to this work by critically revising and editing the article. All authors contributed to the article and approved the submitted version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Acknowledgments

The authors would like to acknowledge the Biomolecular Interaction Centre (BIC) for their support and financial contribution to the Engineering Endometriosis Research Program at the University of Canterbury.

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Introduction, case presentation, conflict of interest statement, a rare case of invasive endometriosis causing intestinal obstruction.

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Sathish K Thirumurthy, Mahsheena Mohammed, A rare case of invasive endometriosis causing intestinal obstruction, Journal of Surgical Case Reports , Volume 2024, Issue 2, February 2024, rjae082, https://doi.org/10.1093/jscr/rjae082

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A 35-year-old woman presented to the emergency department with severe right iliac fossa pain with features of subacute intestinal obstruction and recurrent episodes of similar pain in the past. CT scan showed a mass with fluid collection with no trace of the appendix in the right iliac fossa. The patient was taken up for a diagnostic laparoscopy and proceeded. Operative findings were that of a mass in the lumen of the terminal ileum just 6 inches from the ileocaecal junction. Normal pelvis with normal uterus and ovaries. The patient underwent a laparoscopic resection of the terminal ileum and limited resection of the ascending colon with an ileo-colic anastomosis. The patient recovered well and was discharged. The biopsy was reported as invasive endometriosis involving the muscularis layer of the terminal ileum with stricture of the terminal ileum with transmural inflammation. The case is being presented for the rarity of invasive endometriosis causing bowel obstruction with a normal pelvis.

Incidence of invasive endometriosis is a rare entity. Endometriosis usually occurs in menstruating women up to 15% [ 1 ]. Most common gastrointestinal involvement of endometriosis is found in the sigmoid colon, rectum, and terminal ileum in 3%–37% of women [ 2 ]. Proliferation and infiltration of the intestinal wall with endometrial implants may cause fibrotic reaction with formation of strictures and adhesions, probably from the effect of cyclical hormonal influences of menstruation. Eventually, this may lead to bowel obstruction and recurrent abdominal pain [ 3 ]. We are presenting an interesting case of invasive terminal ileum endometriosis required surgical resection.

This is a case reported in line with SCARE criteria [ 4 ].

This 35-year-old nulliparous woman has been suffering from a long-standing undiagnosed abdominal pain that started 2 years earlier. The pain was colicky, localized in the right iliac fossa and seldom associated with nausea and vomiting. NO association with menstrual cycle. The previous episode was 3 months back when she was diagnosed at a center outside as a case of appendicitis with appendicular mass formation. The patient was treated conservatively at that time. This visit to the ER she presented with severe abdominal pain and subacute intestinal obstruction. The laboratories evaluations were normal. Patient had abdominal pain, nausea, vomiting, and constipation, but passing flatus for 2 days. She was vitally stable. Her abdomen was mildly distended with tenderness over the right lower quadrant but no signs of peritonitis. Patient was resuscitated and a CT scan with contrast was done to determine the nature of the obstruction ( Fig. 1 ).CT scan showed a complex cystic lesion in the ileo caecal area with no proper delineation of the appendix. A clinical diagnosis of appendicular mass was made based on the CT findings and the patient was treated conservatively. But the patient did not respond well to conservative management and had persistent pain. She was planned for surgical intervention with a diagnostic laparoscopy and proceeded. A mass involving about 4 cm of the terminal ileum was found just about 4 inches away from the ileo caecal junction ( Fig. 2 ). The serosa of the ileum looked normal. Appendix was found to be normal. Proximal to this intestinal lesion, there was another ileal stricture about 6 inches proximal to the ileal mass. Remaining part of the ileum and jejunum looked normal. The uterus, both ovaries, and fallopian tubes were normal ( Fig. 2 ). Giving its close proximity to the ileocecal valve, decision was made to proceed with laparoscopic resection of the ileum including both the lesions and a limited resection of the ascending colon ( Fig. 3 ) as discussed previously with patient.

CT images showing the lesion in the right iliac fossa.

CT images showing the lesion in the right iliac fossa.

Intraoperative laparoscopic pictures showing normal uterus, ovaries, and the ileal lesion.

Intraoperative laparoscopic pictures showing normal uterus, ovaries, and the ileal lesion.

(A) Received partially cut opened limited hemicolectomy specimen. Ileum measuring 17 cm in length, 2 cm in diameter. Caecum dilated measuring 7.5 × 4.5 × 0.5 cm. Appendix identified measuring 4.0 × 0.4 cm. (B) Ileum shows already cut opened mass measuring 2.5 × 2.0 × 1.0 cm. Protruding into lumen. Cut surface showing cystic change with mucoid material. (C) Ileal end shows stricture for length 5 cm with serosa showing reddish hemorrhagic spots. (D) Ileocaecal valve shows congestion with brownish area. Caecum dilated wall thinned out with loss of mucosal rugosity. Representative sections submitted.

(A) Received partially cut opened limited hemicolectomy specimen. Ileum measuring 17 cm in length, 2 cm in diameter. Caecum dilated measuring 7.5 × 4.5 × 0.5 cm. Appendix identified measuring 4.0 × 0.4 cm. (B) Ileum shows already cut opened mass measuring 2.5 × 2.0 × 1.0 cm. Protruding into lumen. Cut surface showing cystic change with mucoid material. (C) Ileal end shows stricture for length 5 cm with serosa showing reddish hemorrhagic spots. (D) Ileocaecal valve shows congestion with brownish area. Caecum dilated wall thinned out with loss of mucosal rugosity. Representative sections submitted.

Biopsy report came as invasive endometrioma of the ileum involving the muscularis layer and also additional stricture of the ileum. There was an involvement of the ileocecal junction as well ( Fig. 4 ).

(A, B) Ileum with cystic structure showing submucosal endometrial glands and stroma plus hemosiderin extending to deeper layers of intestine surrounded by smooth muscle layer. (B) Ovarian tissue with diffuse areas of hemorrhage and necrosis. (C, D) Multiple mural and serosal foci of endometriosis noted corresponding to area of ileal stricture.

(A, B) Ileum with cystic structure showing submucosal endometrial glands and stroma plus hemosiderin extending to deeper layers of intestine surrounded by smooth muscle layer. (B) Ovarian tissue with diffuse areas of hemorrhage and necrosis. (C, D) Multiple mural and serosal foci of endometriosis noted corresponding to area of ileal stricture.

Final diagnosis given as ILEUM WITH ENDOMETRIOMA WITH MULTIPLE MURAL AND SEROSAL FOCI OF ENDOMETRIOSIS. NEGATIVE FOR MALIGNANCY. MARGINS OF RESECTION UNREMARKABLE. TWO BENIGN LYMPH NODES.

Endometriosis is characterized by the presence of functional endometrial tissue consisting of glands and stroma outside the uterus. Intestinal obstruction could be the presentation of ilial involvement. However, this is very rare up to 23% of all cases with ileum involvement [ 1 ]. Sampson’s retrograde menstruation theory is the most widely accepted theory. Endometrial tissue refluxes through the fallopian tubes, implanting on the serosal surface of abdominal and pelvic organs which commonly occurs during menstruation [ 5 ]. However, other theories and factors, immunological, genetic, and familial, could be involved in the pathogenesis of this disease [ 6 ]. Endometriosis presents usually with pelvic pain, infertility, and dyspareunia [ 7 ], but it may often be nonspecific. Because of terminal ileum involvement, our patient had recurrent pelvic pain with associated nausea and vomiting as a picture of partial small bowel obstruction.

Our patient is not married and her symptoms were not associated with menses and relapsed irregularly. Many GI diseases including small bowel obstruction, inflammatory bowel disease, and neoplasm make preoperative diagnosis more elusive because of clinical similarities [ 7 ]. Relapsing symptoms are the hallmark of this disease [ 7 ]. Endometriosis of the distal ileum is an infrequent cause of intestinal obstruction, ranging from 7% to 23% of all cases with intestinal involvement [ 8 ]. The incidence of intestinal resection for bowel obstruction is 0.7% among patients undergone surgical treatment for abdomino-pelvic endometriosis [ 9 ]. However, endometriosis of the small bowel should be suspected in young, nulliparous patients with abdominal pain, in conjunction with signs of obstruction as this is the case in our patient [ 3 ].

Imaging work up may be inconclusive. Endoscopy and barium enema are not helpful because the disease does not involve the mucosa. CT scan and MRI may be helpful in diagnosis of the condition [ 10 ]. Diagnostic laparoscopy is considered gold standard. The diagnosis can be confirmed only on histology. Gastrointestinal endometriosis is usually found as an incidental finding on abdominal exploration. Asymptomatic and mildly symptomatic cases may be treated using hormonal treatment.

Suspicion of malignancy as well as acute obstructive cases may warrant a radical resection [ 7 ]. The management should include hormonal therapy and surgery. The former treatment with danazol or gonadotrophin-releasing hormone analogs may be used in patients without obstruction. However, resection of the involved bowel remains the choice of treatment for complicated or unresolved cases [ 11 ]. In our case, our patient had a prolonged history of relapsing symptoms for years with picture of recurrent partial small bowel obstruction in addition to an image showing possible mass causing small bowel stenosis and obstruction. Because of those reasons, we elected to perform diagnostic laparoscopy and found this ileal and performed limited right hemicolectomy. The diagnosis was proven with histopathology ( Fig. 3 ). Postoperatively, she has fully recovered with no abdominal complaints. She is on regular follow-up visits for assessment.

Small bowel endometriosis is a rare entity. Clinical picture is similar to other gastrointestinal diseases and careful assessment is warranted. Surgical resection is sometimes indicated for diagnosis or failing medical management. High suspicious of index is warranted in these cases.

None declared.

Bratu D . A rare case of ileus caused by ileum endometriosis . Int J Surg Case Rep 2016 ; 26 : 24 – 6 .

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Watch CBS News

Fertility treatment costs are out of reach for many Americans, even with insurance

By Michelle Andrews

February 22, 2024 / 5:00 AM EST / KFF Health News

Mary Delgado's first pregnancy went according to plan, but when she tried to get pregnant again seven years later, nothing happened. After 10 months, Delgado, now 34, and her partner, Joaquin Rodriguez, went to see an OB-GYN. Tests showed she had endometriosis , which was interfering with conception. Delgado's only option, the doctor said, was in vitro fertilization.

"When she told me that, she broke me inside," Delgado said, "because I knew it was so expensive."

Delgado, who lives in New York City, is enrolled in Medicaid, the federal-state health program for low-income and disabled people. The roughly $20,000 price tag for a round of IVF would be a financial stretch for lots of people, but for someone on Medicaid — for which the maximum annual income for a two-person household in New York is just over $26,000 — the treatment can be unattainable.

Expansions of work-based insurance plans to cover fertility treatments , including free egg freezing and unlimited IVF cycles , are often touted by large companies as a boon for their employees. But people with lower incomes, often minorities, are more likely to be covered by Medicaid or skimpier commercial plans with no such coverage. That raises the question of whether medical assistance to create a family is only for the well-to-do or people with generous benefit packages.

"In American health care, they don't want the poor people to reproduce," Delgado said. She was caring full-time for their son, who was born with a rare genetic disorder that required several surgeries before he was 5. Her partner, who works for a company that maintains the city's yellow cabs, has an individual plan through the state insurance marketplace, but it does not include fertility coverage.

Some medical experts whose patients have faced these issues say they can understand why people in Delgado's situation think the system is stacked against them.

"It feels a little like that," said Elizabeth Ginsburg , a professor of obstetrics and gynecology at Harvard Medical School who is president-elect of the American Society for Reproductive Medicine , a research and advocacy group.

Whether or not it's intended, many say the inequity reflects poorly on the U.S.

"This is really sort of standing out as a sore thumb in a nation that would like to claim that it cares for the less fortunate and it seeks to do anything it can for them," said Eli Adashi , a professor of medical science at Brown University and former president of the Society for Reproductive Endocrinologists.

Yet efforts to add coverage for fertility care to Medicaid face a lot of pushback, Ginsburg said.

Over the years, Barbara Collura , president and CEO of the advocacy group Resolve: The National Infertility Association, has heard many explanations for why it doesn't make sense to cover fertility treatment for Medicaid recipients. Legislators have asked, "If they can't pay for fertility treatment, do they have any idea how much it costs to raise a child?" she said.

"So right there, as a country we're making judgments about who gets to have children," Collura said.

The legacy of the eugenics movement of the early 20th century, when states passed laws that permitted poor, nonwhite, and disabled people to be sterilized against their will, lingers as well.

"As a reproductive justice person, I believe it's a human right to have a child, and it's a larger ethical issue to provide support," said Regina Davis Moss, president and CEO of In Our Own Voice : National Black Women's Reproductive Justice Agenda, an advocacy group.

Mary Delgado with her children, Joaquin and baby Emiliana

But such coverage decisions — especially when the health care safety net is involved — sometimes require difficult choices, because resources are limited.

Even if state Medicaid programs wanted to cover fertility treatment, for instance, they would have to weigh the benefit against investing in other types of care, including maternity care, said Kate McEvoy , executive director of the National Association of Medicaid Directors. "There is a recognition about the primacy and urgency of maternity care," she said.

Medicaid pays for about 40% of births in the United States. And since 2022, 46 states and the District of Columbia have elected to extend Medicaid postpartum coverage to 12 months, up from 60 days.

Fertility problems are relatively common, affecting roughly 10% of women and men of childbearing age, according to the National Institute of Child Health and Human Development .

Traditionally, a couple is considered infertile if they've been trying to get pregnant unsuccessfully for 12 months. Last year, the ASRM broadened the definition of infertility to incorporate would-be parents beyond heterosexual couples, including people who can't get pregnant for medical, sexual, or other reasons, as well as those who need medical interventions such as donor eggs or sperm to get pregnant.

The World Health Organization defined infertility as a disease of the reproductive system characterized by failing to get pregnant after a year of unprotected intercourse. It terms the high cost of fertility treatment a major equity issue and has called for better policies and public financing to improve access.

No matter how the condition is defined, private health plans often decline to cover fertility treatments because they don't consider them "medically necessary." Twenty states and Washington, D.C., have laws requiring health plans to provide some fertility coverage, but those laws vary greatly and apply only to companies whose plans are regulated by the state.

In recent years, many companies have begun offering fertility treatment in a bid to recruit and retain top-notch talent. In 2023, 45% of companies with 500 or more workers covered IVF and/or drug therapy, according to the benefits consultant Mercer.

But that doesn't help people on Medicaid. Only two states' Medicaid programs provide any fertility treatment: New York covers some oral ovulation-enhancing medications, and Illinois covers costs for fertility preservation, to freeze the eggs or sperm of people who need medical treatment that will likely make them infertile, such as for cancer. Several other states also are considering adding fertility preservation services.

In Delgado's case, Medicaid covered the tests to diagnose her endometriosis, but nothing more. She was searching the internet for fertility treatment options when she came upon a clinic group called CNY Fertility that seemed significantly less expensive than other clinics, and also offered in-house financing. Based in Syracuse, New York, the company has a handful of clinics in upstate New York cities and four other U.S. locations.

Though Delgado and her partner had to travel more than 300 miles round trip to Albany for the procedures, the savings made it worthwhile. They were able do an entire IVF cycle, including medications, egg retrieval, genetic testing, and transferring the egg to her uterus, for $14,000. To pay for it, they took $7,000 of the cash they'd been saving to buy a home and financed the other half through the fertility clinic.

She got pregnant on the first try, and their daughter, Emiliana, is now almost a year old.

Delgado doesn't resent people with more resources or better insurance coverage, but she wishes the system were more equitable.

"I have a medical problem," she said. "It's not like I did IVF because I wanted to choose the gender."

One reason CNY is less expensive than other clinics is simply that the privately owned company chooses to charge less, said William Kiltz, its vice president of marketing and business development. Since the company's beginning in 1997, it has become a large practice with a large volume of IVF cycles, which helps keep prices low.

At this point, more than half its clients come from out of state, and many earn significantly less than a typical patient at another clinic. Twenty percent earn less than $50,000, and "we treat a good number who are on Medicaid," Kiltz said.

Now that their son, Joaquin, is settled in a good school, Delgado has started working for an agency that provides home health services. After putting in 30 hours a week for 90 days, she'll be eligible for health insurance.

One of the benefits: fertility coverage.

KFF Health News , formerly known as Kaiser Health News (KHN), is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF — the independent source for health policy research, polling, and journalism.

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  12. Mapping endometriosis: A vast cellular atlas is created

    Aug. 25, 2021 — New research offers insight into how to treat endometriosis. The researchers performed genetic analyses of humans and rhesus macaques to identify a specific gene, NPSR1, that ...

  13. Endometriosis: How new treatment 'changed my life'

    9 March 2021 By Sarah Campbell BBC News Watch: Jessica says she was in constant agony before the trial Taking the dog for a walk is a routine task for most people. But Jessica Rafferty would often...

  14. Endometriosis cellular mapping could aid diagnosis, treatment

    New research analyzing almost 400,000 cells has revealed a detailed molecular profile of endometriosis, which may help improve diagnostic and therapeutic options for people with the condition.

  15. Researchers identify genetic cause of endometriosis and reveal

    New research offers insight into how to treat endometriosis. The researchers performed genetic analyses of humans and rhesus macaques to identify a specific gene, NPSR1, that increases risk of ...

  16. Endometriosis: A Review of Clinical Diagnosis, Treatment, and

    All research articles published between 1960 and 2021 were included in the search. The findings were then categorized to summarize the evidence. There was a total of 29 instances of endometriosis discovered. The patients' ages varied from 20 to 45 years old, with a median of 28.8 years and a mean of 29.4±7.7 years.

  17. The first endometriosis drug in four decades is on the horizon

    He blames it on a lack of research and awareness, driven by funding shortages. Things are starting to change. A clinical trial of the first non-hormonal, non-surgical treatment for endometriosis ...

  18. Research and treatments

    Latest news on clinical and scientific research in endometriosis. Pages: 1 2 3 4 5 6 7 8 » Global study shows the experience of endometriosis is rooted in a person's genetics 12 April 2023 DNA from 60,600 women with endometriosis reveals evidence of shared genetic basis for endo and other causes of pain.

  19. Science Update: NIH-funded researchers develop non-surgical ...

    However, hormone therapy cannot be used by those desiring near-term fertility, and surgery comes with the risk of complications. In addition, new endometriosis tissue may grow again in the future, requiring multiple surgical procedures. As a result, researchers are developing non-surgical approaches to remove endometriosis tissue.

  20. Could endometriosis be caused by bacteria? Study offers fresh clues

    Infection by a particular group of bacteria could be linked to endometriosis, a painful condition that affects up to 10% of women and girls of reproductive age. In a study of 155 women in Japan ...

  21. New research shows potential to reduce pain in women suffering from

    New research shows potential to reduce pain in women suffering from endometriosis. Diagram of neuroinflammation in endometriosis. Researchers propose that IL-1β activates IL-1 type 1 membrane ...

  22. Assessing the relationship between gut microbiota and endometriosis: a

    The study collected data from GWAS databases and used a two-sample bidirectional MR approach to confirm the potential causal relationship between gut microbiota and endometriosis, providing new insights into the pathogenesis and treatment of endometriosis. Future research should aim to further elucidate the underlying mechanisms by which these ...

  23. Endometriosis Is Undervalued: A Call to Action

    Research funding for endometriosis is limited, with funding from bodies like the National Institutes of Health (NIH) constituting only 0.038% of the 2022 health budget—for a condition that affects 6.5 million women in the US alone and over 190 million worldwide.

  24. Revolutionizing Endometriosis Treatment: The Robotic Surgery

    The Dawn of a New Surgical Era. Endometriosis, a condition marked by the growth of tissue similar to the lining of the uterus in other parts of the body, has tormented women with its debilitating pain and significant health complications. Traditional surgical methods, while effective to some degree, often fell short of providing lasting relief.

  25. rare case of invasive endometriosis causing intestinal obstruction

    Introduction. Incidence of invasive endometriosis is a rare entity. Endometriosis usually occurs in menstruating women up to 15% [].Most common gastrointestinal involvement of endometriosis is found in the sigmoid colon, rectum, and terminal ileum in 3%-37% of women [].Proliferation and infiltration of the intestinal wall with endometrial implants may cause fibrotic reaction with formation ...

  26. White House commits $100M for women's health research

    Photo: Steph Solis/Axios. The Biden administration pledged to invest $100 million for women's health research, First Lady Jill Biden announced. Driving the news: The first lady announced the commitment during an ARPA-H forum on women's health Wednesday in Cambridge. ARPA-H will oversee the women's health research as part of its "Sprint for ...

  27. Fertility treatment costs are out of reach for many Americans, even

    Medicaid pays for about 40% of births in the United States. And since 2022, 46 states and the District of Columbia have elected to extend Medicaid postpartum coverage to 12 months, up from 60 days ...