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New therapeutic targets for endometriosis could be on the horizon

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

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.”

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. 

Media Contact Information

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

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Mapping endometriosis: A vast cellular atlas is created

Cedars-sinai investigators produced data from 400,000 patient cells to better understand the disease.

Investigators at Cedars-Sinai have created a unique and detailed molecular profile of endometriosis to help improve therapeutic options for the millions of women suffering from the disease.

The study is published today in the journal Nature Genetics .

"Endometriosis has been an understudied disease in part because of limited cellular data that has hindered the development of effective treatments. In this study we applied a new technology called single-cell genomics,which allowed us to profile the many different cell types contributing to the disease," said Kate Lawrenson, PhD, an associate professor in the Department of Obstetrics and Gynecology at Cedars-Sinai, and co-senior and corresponding author of the study.

Endometriosis is a condition in which cells of the uterine lining, or ones similar to endometrial tissue, are found growing in the wrong places, most commonly on the ovaries, fallopian tubes and in the abdominal cavity. The disease impacts about 10% of women, usually during their reproductive years. Patients with the disorder can experience chronic pain, infertility, headaches, fatigue, and bowel and bladder dysfunction.

Currently, there are few good treatment options for women diagnosed with endometriosis. Lawrenson and her co-investigators were able to profile endometriosis using state-of-the-art methods permitting them to gather an immense amount of data from the cells of just 21 patients, some of whom had the gynecological disorder and others who were disease-free.

"We generated a cellular atlas of endometriosis after analyzing nearly 400,000 individual cells from these patients. We were able to identify the molecular differences between the major subtypes of endometriosis, including peritoneal disease and ovarian endometrioma," said Lawrenson, who is also an associate professor in the Department of Biomedical Sciences.

Investigators expect this critical new database will lead to improved care.

"Identifying these cellular differences at such a detailed level should allow us to better understand the origins, natural progression, and potential therapeutic targets for treatment. We are currently limited to hormonal therapy and surgical excision, with variable success and frequent recurrence of disease," said Matthew Siedhoff, MD, MSCR, vice chair of Gynecology at Cedars-Sinai and a co-author of the study.

Endometriosis has been associated with a slightly elevated risk for developing certain cancers. Medical scientists have often observed similarities in the way the disorders operate.

"The disease can travel throughout the body, so in many ways it behaves like cancer. But why does endometriosis behave like cancer while rarely becoming cancer? Large-scale next generation sequencing projects have been incredibly helpful in understanding how cancer works and in designing targeted therapeutics. We expect it can do the same for endometriosis," said Lawrenson, co-director of the Women's Cancer Research Program at Cedars-Sinai Cancer.

Investigators at Cedars-Sinai have already begun using the new cellular atlas of endometriosis to test therapeutic targets in a mouse model of the disease.

"This resource can now be used by researchers all throughout the world to study specific cell types that they specialize in, which will hopefully lead to more efficient and effective diagnosis and treatment for endometriosis patients. It really is a game changer," said Lawrenson.

Funding was provided by the Leon Fine Translational Science Award from Cedars-Sinai. Additional support came from the National Institutes of Health, the American Cancer Society, the Canadian Cancer Society Research Institute, the Canadian Institutes of Health Research, and the Michael Smith Foundation for Health Research.

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Story Source:

Materials provided by Cedars-Sinai Medical Center . Note: Content may be edited for style and length.

Journal Reference :

• Fonseca, M.A.S., Haro, M., Wright, K.N. et al. Single-cell transcriptomic analysis of endometriosis . Nat Genet , 2023 DOI: 10.1038/s41588-022-01254-1

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Strange & offbeat.

Endometriosis is a condition that occurs when patches of the endometrium, a layer of tissue lining the uterus, travel throughout the body and attach to other organs, like the ovaries or intestines. Unfortunately, 1 in 10 women experiences pain and even infertility due to this disorder. Current treatments include surgery to remove the mislocated tissue and drug treatment to suppress ovarian activity, which can lead to weight gain, mood changes and headaches. 

After decades of study, a team of researchers, including Wisconsin National Primate Research Center scientists, discovered a possible new therapy for endometriosis that zeroes in on a particular region of chromosome 7 as the responsible gene. 

A thorough study of the DNA of women in 32 families with deep-rooted histories of endometriosis helped researchers narrow in on this single gene variant – neuropeptide S receptor 1 ( NPSR1) – which they found in many, but not all, of the women with more severe cases of endometriosis.  

To learn more about this complex disease, researchers simulated endometriosis in mice by injecting bits of bacteria or uterine lining into their abdomens while attempting to silence the culprit gene. The researchers saw positive results with the rodents experiencing less inflammation and abdominal pain.  

As a next step, researchers will study this same treatment in monkeys, which have been an animal model for endometriosis studies for several decades. Joseph Kemnitz, former director of the Wisconsin National Primate Research Center, explains, “We documented the similarities of endometriosis in our monkeys compared to affected women in collaboration with Stephen Kennedy at Oxford.” The teams recognized the Wisconsin monkeys offered an excellent opportunity to examine endometriosis and have continued building on early results that revealed a familial pattern, suggesting a genetic risk.

As genomic tools continue to advance and analysis costs decrease, the rate of testing treatments stands to increase. Such comprehensive scientific progress is excellent news for the pursuit of improved human health. 

Source: Science Translational Medicine on Aug. 25, 2021.  

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Endometriosis

• Related content
• Peer review
• Louie Ye , RANZCOG trainee/clinical fellow 1 2 ,
• Lucy H R Whitaker , NES/CSO clinical lecturer in obstetrics and gynaecology 3 ,
• Rebecca L Mawson , GP and academic training fellow 4 ,
• Martha Hickey , Professor of Obstetrics and Gynaecology 1 2
• 1 The Royal Women’s Hospital, Melbourne, Victoria, Australia
• 2 Department of Obstetrics and Gynaecology, University of Melbourne and the Royal Women’s Hospital, Victoria, Australia
• 3 MRC Centre for Reproductive Health, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
• 4 The Academic Unit of Primary Medical Care, The University of Sheffield, Sheffield, UK
• Correspondence to M Hickey hickeym{at}unimelb.edu.au

What you need to know

Consider endometriosis when women of reproductive age present with abdomino-pelvic pain associated with menstruation, sexual intercourse, urination, defecation, and/or infertility

Consider gynaecology referral if three months of simple analgesia (with or without combined oral contraceptive pill) is ineffective for suspected endometriosis

A normal pelvic exam and/or pelvic ultrasound does not exclude endometriosis

A 24 year old woman presents to a new GP with three years of pain during sexual intercourse and increasingly painful periods affecting her mood, relationships, and work. Simple analgesia was ineffective and pelvic ultrasound within three months was normal. She has presented five times in the past two years but has received no diagnosis or effective management.

What is endometriosis?

Endometriosis is a condition defined by the presence of endometrial-like tissue outside the uterus. 1 It typically occurs in women of reproductive age but prepubertal endometriosis has been reported. Endometriosis is also reported in women after menopause but is thought to have developed prior to menopause. 2 3 Globally, it affects 190 million women and those assigned female at birth, but a UK survey in 2017 reported that only 20% of the general public had ever heard of it. 4 Subtypes 5 include superficial peritoneal (as visualised at laparoscopy, and the most common type); deep (depth of penetration ≥5 mm); and ovarian (ovarian cysts with endometriosis content, also known as endometriomas). In women with endometriosis, 17-44% have an ovarian endometrioma. 6 7 Less frequently, endometriosis occurs at other anatomical locations such as the thorax or previous surgical incision sites. 1

Long term consequences include impaired quality of life, anxiety, depression, and self-harm. 8 9 Central pathway sensitisations may also lead to chronic pain syndromes. 10 Symptom severity is frequently discordant between disease subtype and extent 1 and data pertaining to natural history are limited, particularly when disease is found incidentally at laparoscopy.

Prevalence estimates vary widely ( box 1 ) because of inconsistent presentation and reliance on laparoscopy for diagnosis, access to which varies globally. 15 16

How common is it?

Prevalence estimates.

A 2017 cross sectional survey of nearly 60 000 women in the US estimated the prevalence of confirmed endometriosis at 6.1%, 11 with symptom burden greatest in those aged 18-29.

A 2021 population based survey in Australia reported that 6.3% of women aged 40-44 have clinically confirmed endometriosis. 12

Population prevalence is estimated at 10%, based on prevalence estimates of pelvic pain and infertility in the general population. 13

Prevalence in certain patient groups 14 15

In 2% to 11% of women, endometriosis is an incidental finding during surgery for other indications

Up to 50% of women presenting with infertility 15 and 24-40% of those with chronic pelvic pain have endometriosis 14 15

Although endometriosis can coexist with other causes of pelvic pain, explicit discussion of these comorbidities, as well as infertility associated with endometriosis, is beyond the scope of this paper,

Why is it missed?

Clinical diagnosis is difficult, partly because the symptoms are often non-specific 17 18 and may be attributed to other conditions. For example, endometriosis may mimic or cause irritable bowel syndrome. 19 Symptoms may also be misdiagnosed as functional or psychosomatic 20 21 or dismissed or normalised (for example, as painful periods). 22 23 Women consistently report difficulties in convincing doctors about the severity of their symptoms; 22 however, some women may also believe that their menstrual symptoms are normal. 17 Despite increased public awareness and clinical education, early recognition of endometriosis remains uncommon, possibly as a result of gaps in evidence about the clinical relevance of mild disease at laparoscopy, poor correlation between symptoms and extent of disease, the need for histological confirmation, limited laparoscopy access, and/or laparoscopy cost. 24

The average diagnostic delay has been reported as seven years from symptom onset to definitive diagnosis, with variation between countries 5 17 20 21 25 (approximately eight years in both the UK and Australia). 22 26 Retrospective data analysis in the UK showed that one third of patients had consulted their GP six times or more before referral, with 39% having two or more gynaecological referrals before receiving a definitive diagnosis. 25 Diagnostic delay is even more common in adolescents, 27 possibly because of the unfounded belief that endometriosis takes time to cause symptoms after menarche. 28

Cultural barriers to discussing menstruation and sexual symptoms still exist and may cause reluctance or difficulty in reporting them. 22 23 The lack of reliable non-invasive tests likely also contributes to delays. 29 30 This is intensified by the variation and methodological quality of endometriosis guidelines, which suggest different diagnostic criteria. 31

Why does it matter?

Although it is unknown whether earlier treatment affects the course of endometriosis or reduces the incidence of chronic pain syndromes, 4 22 endometriosis, and associated delays in diagnosis, can cause considerable suffering, distress, impaired quality of life, economic hardship, reduced productivity, and reduced workforce participation. 8 10 11 22 32 33

In the UK, work absenteeism and healthcare costs related to endometriosis cause economic losses of around £8.2bn a year (direct treatment costs are comparable to those for type 2 diabetes and rheumatoid arthritis). 34 Earlier diagnosis and prompt treatment might reduce psychosocial and economic burdens. 17 20 35

According to retrospective population linked data, delayed diagnosis was associated with a reduced chance of pregnancy by 33% in those who required assisted reproductive technology. 35

How is it diagnosed?

Endometriosis poses a diagnostic dilemma in primary care settings, and uncertainty at initial consultations is common. 36

Definitive diagnosis is only possible with laparoscopy in secondary care. However, we encourage GPs to empower patients to advocate for themselves by having early, open discussions about endometriosis as a possible or likely cause of their symptoms, and about consequences and treatment options. Some women may wish to avoid definitive diagnosis with laparoscopy for mild symptoms or when their symptoms are controlled on hormonal therapies.

Improving diagnosis and non-invasive screening tools are among the top 10 research priorities for endometriosis in the UK. 4

Clinical features

No consensus exists about how to diagnose endometriosis clinically; however, typical gynaecological presentations include painful periods and infertility. 1 37 Other common symptoms include pelvic pain (which may be cyclical) that occurs with sex, defecation, or urination, gastrointestinal symptoms which may be associated with menstruation, and systemic manifestations such as fatigue. 1 37 38 39 Some patients have no pain symptoms, particularly those with infertility, which may be the presenting complaint or primary concern for some women.

Guidance from the National Institute for Health and Care Excellence (NICE) 37 suggests considering a diagnosis of endometriosis in women and girls presenting with one or more of the following symptoms or signs:

Chronic pelvic pain

Period related pain (dysmenorrhoea) affecting daily activities and quality of life

Deep pain during or after sexual intercourse

Period related or cyclical gastrointestinal symptoms, in particular, painful bowel movements or rectal pain

Period related or cyclical urinary symptoms, in particular, blood in the urine or pain passing urine

Infertility in association with one or more of the above.

Isolated pelvic examination in primary care is often uninformative 38 but, especially in deep disease, may reveal masses or signs such as reduced organ mobility and enlargement, tender nodularity in the posterior vaginal fornix, or visible vaginal lesions. Pelvic floor spasm might also be present.

Investigations

No relevant biomarkers.

Although it is an active area of research, there are no biomarkers with adequate specificity or sensitivity to identify endometriosis 29 40 (including CA125), according to NICE 37 and the European Society of Human Reproduction and Embryology (ESHRE). 41

NICE recommends transvaginal ultrasound (TVUS) as the first line investigation. 37 TVUS is often normal in those who are subsequently diagnosed with superficial or deep endometriosis; however, it can reliably identify those with endometriomas and exclude differentials such as non-endometriotic cysts and adenomyosis. Advanced TVUS specialists might assess for subtle features of endometriosis such as loss of mobility of the ovaries and, within the pouch of Douglas, site specific tenderness and nodularity (a sensitivity of 79% and specificity of 94% has been reported for the identification of deep endometriosis with TVUS by experienced sonographers). 42 The sensitivity of 3D ultrasound for deep endometriosis is 87%. 30 43 However, access to specialist ultrasonography is limited in most settings. When TVUS is declined, inappropriate, or unavailable, offer trans-abdominal ultrasound (although sensitivity and specificity is lower). 37 Ovarian and deep endometriosis may be visible on magnetic resonance imaging (MRI), but normal MRI does not exclude endometriosis. 30

Laparoscopy with histological confirmation

NICE and ESHRE guidance suggests that laparoscopy with histology is the gold standard for diagnosis 21 37 ; however, many researchers and clinicians believe that clinical and radiographical features (as above) are sufficient for diagnosis, particularly for ovarian and deep subtypes. 23 44 Similarly, some guidelines (including those from ESHRE 41 ) suggest that laparoscopy may not be indicated for patients with symptoms controlled by medical treatment if the patient is in agreement with a working diagnosis of endometriosis. 44

How is it managed?

Primary care management.

NICE recommends an initial three month trial of paracetamol or non-steroidal anti-inflammatory drugs (alone or with a combined oral contraceptive pill or continuous progestogen) in primary care for pain suggestive of endometriosis. 37 45 In parallel, offer holistic management for symptoms and psychological support, individualised to patient wishes and fertility priorities, and, after asking about experience with hormonal treatment, the need for contraception, and future pregnancy planning, make shared decisions about trialling hormonal treatment (combined oral contraceptive pill or continuous oestrogen). 37 Patient decision aids can support choice of hormonal preparation. 46

When to refer

NICE recommends not excluding the possibility of endometriosis if abdominal/pelvic examination, ultrasound, or MRI are normal. When clinical suspicion remains, symptoms persist, or initial management with analgesia or hormonal treatments is ineffective or contraindicated, consider gynaecology referral for further assessment and investigation. When patients have severe or recurrent symptoms, endometriomas >3 cm on ultrasound, deep endometriosis with urinary tract or bowel symptoms, or infertility with symptoms of endometriosis, consider referral to gynaecology specialists (if available, a specialist endometriosis centre). 37

Secondary and tertiary care management

Medical treatments such as gonadotrophin releasing hormone agonists and antagonists, alone or in addition to surgery (pre and post-operatively), may be considered to manage pain and reduce recurrence. 41 47 48 Laparoscopic excisional/ablative surgery is the mainstay of surgical treatment. Complex surgery for deep endometriosis involving the bowel, bladder, or ureter is best managed within a specialist endometriosis centre. 49 Surgery may not be definitive and up to 50% of patients who have had surgery report persistent symptoms at five years. 45 50 51 Clinical trials are examining the risks and benefits of subtype specific surgery to improve pain, quality of life, and fertility further to inform evidence based and shared decision making.

Case continued

The GP suspects endometriosis and discusses this with the patient. A TVUS scan shows no pathology and a three month trial of analgesia with a combined oral contraceptive leads to little improvement, so a gynaecology referral is offered. Subsequent laparoscopy reveals superficial peritoneal endometriosis and the patient opts for concurrent excisional surgery with insertion of a levonorgestrel releasing intrauterine system, a choice which reflects her current contraceptive requirements.

How patients were involved in the creation of this article

We asked two people living with endometriosis in the UK for comments on an early draft of this paper. In response to their comments, we revised the case to highlight that it often takes several years and many doctor visits for endometriosis to be suspected and investigated. We also sought to highlight the impact of endometriosis on quality of life and the recurrence/ongoing impact after surgical excision. Based on comments from an external patient reviewer arranged by The BMJ , we strengthened several paragraphs, including those mentioning cultural barriers to discussing menstruation, imaging availability in different settings, how endometriosis affects some patients’ mental wellbeing, and the importance of doctor-patient relationships.

Education into practice

In patients presenting with painful periods or pelvic pain, how often do you directly inquire about pain with intercourse, defecation, or rectal pain?

Do you consider endometriosis in a patient presenting with painful periods, infertility, or pelvic pain? Does patient age influence your clinical suspicion?

When do you consider referral to secondary care for a patient with suspected endometriosis?

This is one of a series of occasional articles highlighting conditions that may be more common than many doctors realise or may be missed at first presentation. To suggest a topic for this series, please email us at practice{at}bmj.com .

Within this article, we use the terms “women” and “women’s health.” However, we acknowledge that all people assigned female at birth, including those whose gender identity does not align with the sex they were assigned, need access to evidence based care in order to maintain their gynaecological health and reproductive wellbeing.

Advisers to this article series are Anthony Harnden, professor of primary care, Department of Primary Care Health Sciences, University of Oxford, and Kevin Barraclough, School of Social and Community Medicine, University of Bristol.

Competing interests: The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: none.

Further details of The BMJ policy on financial interests is here: https://www.bmj.com/sites/default/files/attachments/resources/2016/03/16-current-bmj-education-coi-form.pdf .

Provenance and peer review: commissioned and externally peer and patient reviewed

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Obstetrics and Gynecology

• A promising abdominal wall endometriosis treatment emerges at Mayo Clinic through teamwork

May 13, 2023

Tatnai L. Burnett, M.D., a minimally invasive gynecologic surgeon at Mayo Clinic in Minnesota, indicates that a common complaint of women with abdominal wall endometriosis (AWE) is the substantial pain experienced when they bump against the kitchen counter.

AWE is rarer than cystic, superficial or deep endometriosis. One in 10 women has endometriosis, but of women who visit Mayo Clinic for endometriosis, approximately 1 out of 30 has AWE , says Dr. Burnett. This type of endometriosis also forms uniquely from other endometrioses.

"It's unrelated to other types of endometrioses," says Dr. Burnett. "We definitely know it's a different disease process. There's a lot of room for research on abdominal wall endometriosis."

Dr. Burnett indicates AWE is usually iatrogenic, likely related to prior surgery — especially C-sections — and resulting endometrial translocation. However, in rare cases women are diagnosed with AWE with no preceding surgery.

"In a C-section, there's a lot of pulling and cleaning," says Dr. Burnett. "Any little bit of tissue could end up elsewhere."

With the growth of C-sections — now representing 32% of all deliveries — Dr. Burnett expects AWE will grow to affect greater numbers of patients.

Though AWE may start at a C-section, patients with this disease are often delayed in diagnosis, seeking help many years following their deliveries, explains Brian T. Welch, M.D. , an interventional radiologist at Mayo Clinic in Minnesota.

AWE's seriousness depends on one's definition of the word "serious," says Dr. Burnett. Though it can result in significant symptoms, AWE rarely develops into cancer. He says he's seen only one case in the last eight years in which malignancy developed.

In AWE , a patient's disease becomes a palpable mass. Symptoms arise differently among patients. Some find their pain is cyclic, following their menstrual cycles. For others, the pain is noncyclic. Pain intensity can range from mild to significantly bothersome.

"Many patients have debilitating pain — at times causing them to stay home and out of work," says Dr. Welch.

Mayo Clinic gathers a team around AWE, begins cryoablation

Dr. Burnett partnered with Wendaline M. VanBuren, M.D. , a diagnostic radiologist based in Rochester, Minnesota, to develop Mayo Clinic's Complex Endometriosis Clinic. This clinic focuses on AWE plus cystic, deep or superficial endometriosis.

As the team started seeing larger AWE areas, treatment needs became more complex.

"With larger disease areas, you have to move the muscle and fascia and put it all back together," says Dr. Burnett. "This becomes more challenging with more AWE ."

To address the growing complexity of AWE requiring treatment, Dr. VanBuren pointed Dr. Burnett to Dr. Welch and fellow interventional radiologists, who have used ablation for benign and malignant lung, kidney, bone and soft tissue tumors for over 20 years.

"Talking with Dr. Burnett, we realized what we've been doing with cryoablation for tumors could be applied here in abdominal wall endometriosis," says Dr. Welch.

The new partners discussed the use of heat-based thermal ablation versus cryoablation, and cryoablation came out the front-runner, an easy decision according to Dr. Welch.

"With cryoablation, you use probes that form an ice ball you can see," says Dr. Burnett. "So, you can map out treatment and see the extent of treatment in real time."

The AWE cryoablation procedure

Before the procedure, the team conducts preoperative imaging with contrast MRI , which provides information on the extent of disease. The MRI is reviewed during a multidisciplinary endometriosis imaging conference with minimally invasive gynecology, interventional radiology and diagnostic radiology team members. This patient-centric, team-based approach helps guide triage and inform treatment decisions.

Cryoablation for AWE is minimally invasive and often utilizes fluid to protect and displace normal structures such as the bowel, bladder or skin, according to Dr. Welch. This avoids creating frostbite or other injuries. The interventional radiologist constantly monitors the cryoablation process for safety as the ice ball forms. During this process, treatment can be sculpted to the patient's individual needs and anatomy.

"One of the nice things about the cryoablation process is it's very tailored to the patient," says Dr. Welch. "We choose among different kinds and shapes of needles to fit each particular individual."

In this process, the endometriosis cells die due to the cold temperatures. Extraction of dead AWE cells is unnecessary, explains Dr. Welch, as the body reabsorbs the cells over time. A local inflammatory response forms on the patient's abdominal wall, which dissipates well.

Advantages of cryoablation for AWE

Dr. Burnett and colleagues now choose cryoablation over surgery for most patients with AWE . Advantages for patients include less pain, reduced abdominal wall damage, smaller incision, less invasiveness and avoidance of complex reconstruction. Minor scarring occurs at the cryoablation site.

"Cryoablation is just a cleaner and less dramatic process for the patient," says Dr. Burnett.

Most patients with AWE are cryoablation candidates, says Dr. Burnett. He sees no benefit of surgery versus ablation if a patient has no contraindications for AWE . These would include AWE involvement with skin or extensive involvement with intra-abdominal processes, such as disease causing the bowel to become stuck under the abdominal wall.

While a larger disease area may take slightly longer to heal, Dr. Welch says most patients recover within 48 hours of AWE cryoablation and can often return to work within the same week.

Next steps for AWE cryoablation

Dr. Burnett says endometriosis specialists need long-term data on AWE cryoablation to determine whether it is curative. He and colleagues studied and published a safety and feasibility study in a 2022 issue of Abdominal Radiology. This study found the cryoablation technique feasible, durable, repeatable and well tolerated by patients.

Dr. Burnett theorizes this therapy is as effective as surgery, though these results must be borne out in a larger patient population followed over multiple years. He is writing an AWE cryoablation versus surgery comparison study currently.

AWE cryoablation education and referral

Currently, few medical centers are applying cryoablation to AWE , according to Dr. Welch. It started at Mayo Clinic five years ago with only a few patients a year, but the number of patients seeking cryoablation for this disease is growing as awareness of the procedure spreads.

Dr. Welch says he and his colleagues can work with external health care professionals to share Mayo Clinic's experience with the AWE cryoablation procedure, offering helpful tips and insights to those desiring to learn. He also suggests referral to Mayo Clinic as an option, especially due to the multidisciplinary team approach in working with patients with AWE , state-of-the-art MRI and excellent anesthesiology.

Drs. Burnett and Welch indicate Mayo Clinic has treated one of the largest volumes of patients with AWE using cryoablation. This experience has strengthened their techniques, allowing them to take more challenging cases and thoughtfully push the envelope for which patients may be treatable.

"Much like in other procedures, volume matters when seeking a place to refer patients who are struggling with AWE ," says Dr. Burnett.

Referring physicians may send patients to Mayo Clinic's Complex Endometriosis Clinic The clinic then sends potential candidates' imaging to interventional radiology for group discussion at a weekly multidisciplinary imaging review. The multidisciplinary team determines whether a patient with AWE might benefit from cryoablation. Then an interventional radiologist such as Dr. Welch sees the patient to make a final determination on whether to pursue the procedure.

"Cryoablation for AWE is a wonderful offering we have here at Mayo Clinic for patients," says Dr. Burnett. "I'm thrilled for them to take advantage of it."

For more information

Smith KA, et al. Feasibility and safety of percutaneous image-guided cryoablation of abdominal wall endometriosis. Abdominal Radiology. 2022;47:2669.

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Endometriosis: Epidemiology, Classification, Pathogenesis, Treatment and Genetics (Review of Literature)

Beata smolarz.

1 Laboratory of Cancer Genetics, Department of Pathology, Polish Mother’s Memorial Hospital Research Institute, Rzgowska 281/289, 93-338 Lodz, Poland; lp.pw@zciwonamor-annah

Krzysztof Szyłło

2 Department of Operative Gynaecology and Oncological Gynaecology, Polish Mother’s Memorial Hospital Research Institute, Rzgowska 281/289, 93-338 Lodz, Poland; lp.2o@ollyzsk

Hanna Romanowicz

Associated data.

Not applicable.

Endometriosis is a “mysterious” disease and its exact cause has not yet been established. Among the etiological factors, congenital, environmental, epigenetic, autoimmune and allergic factors are listed. It is believed that the primary mechanism of the formation of endometriosis foci is retrograde menstruation, i.e., the passage of menstrual blood through the fallopian tubes into the peritoneal cavity and implantation of exfoliated endometrial cells. However, since this mechanism is also observed in healthy women, other factors must also be involved in the formation of endometriosis foci. Endometriosis is in many women the cause of infertility, chronic pain and the deterioration of the quality of life. It also represents a significant financial burden on health systems. The article presents a review of the literature on endometriosis—a disease affecting women throughout the world.

1. Endometriosis—History

Endometriosis is defined as the presence of the endometrium outside the uterine cavity accompanied by chronic inflammation. This disease was first described by Daniel Shroen in 1690 in the work “ Disputatio Inauguralis Medica de Ulceribus Ulceri ”. The symptoms of this disease were presented by Arthur Duff in 1769 [ 1 ].

The first appearances in the literature regarding the pathogenesis of endometriosis appeared in the second half of the nineteenth century. This condition was described by Karl von Rokitansky in 1860, who defined it as the presence of an active endometrium outside the uterine cavity [ 2 ].

In 1882, Von Recklinghausen suggested the name adenomyoma and by the end of the nineteenth century, several more authors had described this disease.

In 1908, a monograph was published by T.S. Cullen on adenomyosis [ 3 ].

Cullen was the first to describe the two main symptoms of adenomyosis: prolonged menstrual bleeding and severe pain. He believed that endometrial tissue came from the remains of Müller’s ducts [ 3 , 4 ].

In 1870, the German anatomist, physiologist and pathologist Heinrich Wilhelm Waldeyer was the first to put forward the theory of metaplasia.

One of the outstanding doctors of the nineteenth century, Iwanhofen in 1898 was the author of the thesis that endometrial tissue arises from metaplasia of the peritoneal epithelium.

According to Meyer’s research from 1903, metaplasia would promote the inclusion of the epithelium into the lining, under the influence of hormonal and inflammatory factors.

In Poland, Leonard Lorentowicz was the first to describe endometriosis in Polish Gynecology in 1937 in an article entitled: “On the pathogenesis of intrauterine adenomatosis in the peritoneal cavity (endometriosis peritonealis). Contribution to the etiology of abdominal pregnancy” [ 4 ].

Until the 1920s, endometriosis was considered a benefactory hyperplasia disease occurring under various names: cystadenoma, cystic fibrosis, adenomyoma.

In 1927, J.A. Sampson was the first to introduce the term “endometriosis” into medical nomenclature. According to the researcher, the cause of the disease is “retrogradea menstruation” or retrograde transport of menstrual blood with the consequent implantation of exfoliated endometrial mucosa cells within the peritoneal cavity [ 5 , 6 ].

Starting from the first theory of J.A. Sampson, as the years passed and research continued, new theories were formed that attempted to explain the phenomenon of endometriosis. Despite the passage of such a long period of time and much scientific research, Sampson’s theory is still dominant among other hypotheses regarding the etiopathogenesis of endometriosis. It has still not been possible to fully explain why the retrograde transport of menstrual blood, which occurs in nearly 90% of women of childbearing age, only leads to the survival of endometrial tissue outside the uterine cavity in a minority of women [ 7 ].

All the theories were sorted out by K. Schweppe in 1984 into three main groups:

• - First group—includes theories of endometrial transplantation by retrograde menstrual blood as well as mechanical transplantation (e.g., during surgery), and transport by lymphatic and blood vessels.
• - Second group—these are theories of the development of endometriosis in situ; that is, from local tissue from the remains of cells or tissues of the fetal embryo or the genitourinary system. The research of Waldeyer, Russell, Reclinghausen, Gebhard and Meyer and Novak contributed to the above theories [ 4 ].
• - Third group—includes Levander’s 1941 inductive theory. According to her, exfoliated endometrial cells enter the peritoneal cavity and stimulate its epithelium to transform into endometrial tissue [ 7 , 8 , 9 ].

Table 1 presents the main theories of endometriosis emerging over years of research on this disease [ 10 , 11 ].

Theories of the formation of endometriosis—a historical outline.

It is worth emphasizing that despite many years of research on endometriosis that tried to explain its etiology and pathogenesis, it still remains an enigmatic disease.

2. Endometriosis—Epidemiology

Endometriosis is characterized by the presence of active foci of the endometrium (glandular cells and stroma) or endometrial tissue (endometrioides; Gr. eides-similar) occurring outside its cavity, that is, in the muscular layer of the uterus, other genitals and their surroundings, and even in places distant from the genital organs of the body [ 12 ].

Endometrial foci outside the uterine cavity may appear, for example, in the peritoneal cavity, ovaries, bladder or ureters [ 13 ]. The ectopic endometrium is functionally similar to the eutopic endometrium.

Endometriosis is a benign, estrogen-dependent, gynecological disease; however, due to the accompanying ailments and chronic nature, it is a very important medical, social and economic problem.

Infertility is a relatively common symptom in patients with endometriosis. Up to 30 to 50% of women with endometriosis may experience infertility [ 14 ]. Endometriosis can influence fertility in several ways: distorted anatomy of the pelvis, adhesions, scarred fallopian tubes, inflammation of the pelvic structures, altered immune system functioning, changes in the hormonal environment of the eggs, impaired implantation of a pregnancy, and altered egg quality. Often, this infertility remains unexplained due to a delay in diagnosis, causing significant levels of stress [ 15 ].

Endometriosis is a common gynecological disease in Poland and in the world [ 16 ]. This disease affects from 10–15% of women of reproductive age and 35–50% of women with pelvic pain and/or infertility. However, it should be noted that there are also cases of patients with endometriosis after menopause, and it also happens in adolescent women [ 17 ].

The vast majority of cases of endometriosis occur in women between menarche and menopause. The peak of the disease falls in the period between 25 and 45 years of age [ 18 ].

Literature data indicate that endometriosis is found in 0.1–53% of women operated on laparoscopically or by laparotomy, of which 12–32% are women after diagnostic laparoscopy due to pelvic pain delays and 10–60% of the patient after diagnostic laparoscopy due to disability [ 19 , 20 , 21 ].

Endometriosis in 7% of women is associated with their genetic predisposition in the family. This disease was found in 2% of women undergoing tubal ligation and 17% of women after surgery to remove the ovaries [ 22 , 23 ].

World literature also reports the occurrence of foci of endometriosis in fetuses [ 24 ].

There have been isolated cases of endometriosis in men around the world who have been treated with hormones for prostate cancer [ 25 ].

The risk of developing endometriosis is the lowest in black women, the highest in Asian women. Caucasian women have a higher risk of getting sick than black women [ 26 ].

Endometriosis is a problem of enormous importance not only from the medical and social angles but also from an economic point of view. The annual costs of endometriosis treatment in Europe range from €0.8 billion to €12.5 billion depending on the country and are comparable to other chronic diseases such as diabetes [ 27 ].

Endometriosis has a significant negative impact on aspects of social life, family, and sexual, educational and professional life [ 27 , 28 , 29 ]. Pain and the associated dysfunction of the body worsen the quality of life and reduce professional productivity. In cases where there is no clear cause or medication, the disease can be chronic and recurrent. Due to its impact on sexuality and fertility, it can have a negative impact on partner relationships.

3. Endometriosis—Symptomatology

Endometriosis-related symptoms can affect a woman’s overall health and mental and social well-being. It causes a significant deterioration in the quality of life [ 30 , 31 ]. In 66% of women with endometriosis, the first symptoms of the disease appear before the age of 20 [ 32 ]. Symptoms of endometriosis include: gradually increasing acute premenstrual pain, pelvic pain, pain in the sacral region of the spine, dysmenorrhea, painful ovulation, pain during intercourse, pain when defecating, pain when urinating, pain radiating to the back, abundant irregular menstruation, blood in the stool, diarrhea or constipation, infertility and chronic fatigue [ 18 , 33 ].

Patients may also experience uncharacteristic accompanying symptoms such as subfebrile conditions, nausea, dizziness and headaches, symptoms of depression, anxiety, hypoglycemia, rectal bleeding, hematuria during menstruation or susceptibility to infections and allergies.

The pain associated with endometriosis most often takes the form of painful menstruation. It precedes the appearance of bleeding; over time it intensifies and its location concerns the lower abdomen and deeper pelvic areas. Pain can radiate to the sacral region. The pain can extend beyond the bleeding period and also be present throughout the menstrual cycle. There is a hypothesis that the intensification of menstruation soreness is associated with the involvement of the Douglas sinus and the formation of adhesions in it [ 34 ].

Sometimes very advanced endometriosis may not cause any symptoms, and, paradoxically, small foci within the peritoneum can cause great pain. Intraperitoneal adhesions or overgrowth of the fallopian gouges are the most common causes of the problem with the treatment of endometriosis. Sometimes foci of endometriosis produce antibodies to the eutopic endometrium, which can induce poor embryo implantation or spontaneous abortions. Increased and profuse menstruation is one of the symptoms of endometriosis, e.g., in adenomyosis (so-called internal endometriosis) [ 34 ].

Adenomyosis is defined as the occurrence of ectopic foci of the endometrium outside the uterine cavity. Their effect is lower abdominal pain and abnormal menstrual bleeding. Due to its significant similarity to endometriosis, adenomyosis has so far been classified as endometriosis genitalis interna, in which endometrial foci are located within the muscle membrane of the uterus. In recent years, the distinctiveness of this disease entity has been proven, indicating differences in symptomatology, pathogenesis and treatment [ 35 ].

The cause of adenomyosis is still unknown. This disease usually resolves after menopause. The only effective treatment for adenomyosis remains surgery.

The range of diagnosis of adenomyosis varies between 5% and 70% of patients. Adenomyosis is more common in multiparous women than in nulliparous women [ 36 ].

The average age of diagnosis of adenomyosis is between 40 and 50 years of age. However, this disease can occur in young women as well as after menopause. The pathogenesis of adenomyosis remains a mystery.

In addition to typical ailments such as menstrual pain, pain during intercourse or pain in the lower abdomen, there are also problems in partner relationships and symptoms of depressed mood [ 37 ].

The time from the appearance of the first symptoms of the disease to the diagnosis is up to 8 to 10 years [ 38 ].

Despite such frequent occurrence of this disease, the mechanism of its formation remains unexplained, and a good marker of this disease has still not been discovered [ 39 , 40 ].

Deep infiltrating endometriosis (DIE) is defined as the presence of ectopic endometrial tissue infiltration under the peritoneum, pelvic structure, and organ walls, including the uterosacral ligaments, rectosigmoid colon, vagina, rectovaginal septum, bladder, ureter, and lateral parametrium (LP). DIE may cause pelvic pain and thus negatively affect the function of different structures. Studies indicate that women with DIE may have dysfunctions of the pelvic floor muscles (PFMs) and lower limb muscles (LLMs). Pain was associated with PFM hypertonia and difficulty in PFM relaxation [ 41 ].

The presence of lateral parametrial endometriosis (LPE) can be considered a reflection of a more severe disease, ureteral stenosis and dilatation, and voiding dysfunctions, mainly because of the involvement of the inferior hypogastric plexus. Patients with LPE reported more frequent constipation and voiding symptoms [ 42 ]. Associations exist between LPE and straining to void, the feeling of incomplete emptying, intermittency, and abnormal residual urine and bladder outlet obstruction. LPE might stimulate sympathetic fibers of the pelvic plexus, promoting an increase in urethral sphincter tone and thus leading to different degrees of outlet obstruction. These findings emphasize the importance of obtaining a focused history and objective evaluations of urinary and rectal function in patients presenting with clinical or instrumental findings suggestive of DIE [ 42 ].

4. Risk Factors for Endometriosis

Risk Factors for Endometriosis Include:

• Early menarche—epidemiological studies analyzing the cycle of women with endometriosis have shown that the early first cycle (before the age of 11) is associated with the risk of endometriosis [ 43 , 44 , 45 , 46 ],
• Shorter than 27-day genital cycles, genital defects, including hymen overgrowth or narrowing of the cervical canal [ 47 ]. The risk of endometriosis is increased in women with short cycles, i.e., lasting less than 27 days, but is unrelated to the number of bleeding days and the volume of menstruation [ 48 ],
• Small number of births,
• Caucasian race,
• Age 25–29,
• Daily consumption of alcohol in the amount of at least 10 g per day,
• Endometriosis is more often diagnosed in infertile women who are active smokers and whose body mass index (BMI) is normal or low [ 49 ].

Interestingly, the latest data indicate that there is generally no association between BMI and the incidence of endometriosis, but there has been a significant increase in the incidence of endometriosis in obese women compared to women with normal body weight. Obesity is also a risk factor for severe dysmenorrhea [ 50 ].

Diet plays a very important role in preventing the development of endometriosis. The consumption of green vegetables and fresh fruits is considered to be the most beneficial [ 51 ]. They contain antioxidants, which play an important role in the proper functioning of the immune system and the removal of free radicals. It is worth noting that the fiber contained in vegetables interacts in the control of the intestinal bacterial flora and affects hormonal balance.

Red meat exerts an antagonistic effect on the development of endometriosis compared to vegetables and fruits. It is characterized by a high content of dioxins, hormones and fat, increasing the concentration of estrogens [ 51 ].

In the latest research by the team of Yamamoto et al., an attempt was made to determine whether higher consumption of red meat, poultry, fish and seafood is associated with the risk of laparoscopically confirmed endometriosis [ 52 ]. The study group consisted of 81,908 women, and the observations covered the years from 1991 to 2013. Diet was assessed using a properly prepared nutrition questionnaire administered every 4 years. It was shown that respondents who reported eating > 2 servings/day of red meat had a 56% higher risk of endometriosis compared to those consuming ≤ 1 serving/week. Women who were classified in the category that consumed the most red meat were more likely to have endometriosis. No association with poultry, fish, shellfish and egg consumption and the risk of endometriosis was demonstrated [ 52 ].

A very important factor in the prevention of primary endometriosis is the maintenance of an appropriate lifestyle, in which a significant part should be occupied by rest, movement and physical activity [ 51 ].

5. Theories of the Formation of Endometriosis

So far, the pathomechanisms of the formation of endometriosis have not been definitively explained. The theory of Samson (“retrograde menstruation”) is more widespread. It says that the foci of endometriosis arise as a result of the displacement of menstrual blood into the peritoneal cavity through the fallopian tubes [ 5 , 6 , 53 ].

Literature data indicate that in 80% of women with open fallopian tubes there is a retrograde outflow of menstrual blood, while endometriosis occurs only in some. This suggests the presence of other factors determining the survival of endometrial cells in the peritoneal cavity and their implantation [ 54 ].

Implantation in the peritoneum is explained by a local disorder of the mechanisms that prevent adhesion. The consequence is an increased production of cytokine macrophages, including tumor necrosis factor α (TNF-α) and interleukin [ 55 ].

Immune phenomena are important for explaining the possible pathomechanisms of endometriosis foci, as studies indicate altered humoral and cellular immunity [ 56 ].

There are literature data on the statistically higher occurrence of certain immune diseases together with endometriosis, for example, rheumatoid arthritis or hypothyroidism [ 57 ]. Another way of creating endometriosis foci was presented by Mayer’s theory, which says that peritoneal cells are transformed into Muller-type cells under the influence of hormones [ 58 ]. This theory is based on the assumption of the existence of cells capable of differentiating in the endometrium and those cells being precursors of the mesodermal epithelium of the ovary and the pelvic peritoneum. This theory is particularly useful in explaining the existence of endometriosis in different regions of the body where there is a mesothelium, e.g., pleural cavity [ 59 , 60 ].

The last theory is, in the light of two previous theories, that endogenous biochemical and immunological factors responsible for the non-functioning of endometrial factors are not being used for endometrial systems [ 61 ].

Endometriosis is also considered a chronic inflammatory process associated with immune processes [ 62 ]. Disorders of the immune system accompany virtually every stage of endometriosis development [ 63 ]. Macrophages are known to participate in recognizing foreign cells and presenting them to T cells. An increased number of activated macrophages with a reduced ability to phagocytose in the peritoneal cavity is characteristic of women with endometriosis.

They secrete pro-inflammatory cytokines, such as IL-6, TNF-α, IL-1β and IL-8, in increased amounts. Peritoneal macrophages in women with endometriosis have increased mRNA expression of the cyclooxygenase-2 (COX-2), which resulted in increased prostaglandin secretion [ 64 ]. Increased release of pro-inflammatory cytokines and reduced production of anti-inflammatory factors from stromal, epithelial, smooth or immune cells contribute to the initiation, development and progression of endometriosis [ 65 ] ( Table 2 ).

Cytokines associated with the development of endometriosis.

Another important factor in the pathogenesis of endometriosis is the disturbed balance between type 1 (Th1) and type 2 (Th2) helper lymphocytes. Activated T cells differentiate into Th1 lymphocytes and Th2 lymphocytes. The main function of Th1 is the production of cytokines and the promotion of cell-type responses, whereas Th2 secretes cytokines involved in the differentiation of B lymphocytes, suppression of cell-type responses, as well as the severity of humoral type responses. According to literature data, Th2 lymphocytes gain an advantage in women with endometriosis [ 79 ].

In women with endometriosis, reduced Natural Killer (NK) cell activity is found. This is the main group of cells of the immune system responsible for the phenomenon of natural cytotoxicity. Impaired function of NK cells reduces their ability to cleanse the peritoneal cavity of endometrial elements after retrograde outflow of menstrual blood [ 80 ].

The formation of new vessels is a necessary condition for the development of the ectopic endometrium, especially in the peritoneal microenvironment. Neo-angiogenesis is accompanied by the formation of nerves, which may explain the pain in patients [ 81 ].

Vascular endothelial growth factor (VEGF) is responsible for the formation and growth of new vessels. In women with endometriosis, elevated concentrations of VEGF in peritoneal fluid and its correlation with the stages of the disease were found [ 82 ].

At the moment, scientists agree that many factors are responsible for the formation of endometriosis, and in particular genetic, immunological and environmental factors [ 83 ].

It has been confirmed that genetic conditions may be factors influencing the development of this disease. Currently, a group of genes that can enable the formation of endometriosis is listed. These include the cytochrome P450 gene, estrogen, progesterone and androgen receptor, as well as the p53 gene [ 83 ].

6. Types of Endometriosis

There are several types of endometriosis:

• Ovarian endometriosis—occurs in the form of superficial lesions and as endometrial cysts,
• Peritoneal—can occur in various forms: white raids on the peritoneum, peritoneal defects, red, brown, black-blue and black foci, colorless bright vesicles and focal dilated blood vessels and petechiae,
• Deep infiltrating endometriosis—DIE,
• Endometriosis of other locations.

The three most typical types of endometriosis are peritoneal endometriosis, ovarian cysts (chocolate cysts) and nodules of deeply infiltrating endometriosis in the gut or vaginal–rectal septum [ 84 ].

Peritoneal endometriosis can occur in the form of intraperitoneal and sub-peritoneal. Foci of endometriosis within the peritoneum are found in 15–50% of all women diagnosed with endometriosis [ 85 ]. The best diagnostic method for detecting these changes is to recognize them during laparoscopic surgery [ 86 ].

Ovarian endometriosis occurs in 2–10% of women of reproductive age and 50% of patients treated for infertility [ 87 ]. Ovarian endometriosis is one of the most common localizations of this condition.

Deep infiltrating endometriosis is characterized by the fact that endometrioid changes can reach deep into the extraperitoneal space and occupy various pelvic organs such as the bladder, ureters, large intestine, sacro-uterine ligaments or the vagina. The pathomechanism of DIE is not clearly defined.

7. Classifications of Endometriosis

In order to assess the location and severity of the disease, many divisions and classifications have been proposed.

According to Sampson [ 88 ], we will divide it into:

• - Internal endometriosis affecting the uterine muscle
• - External endometriosis occurring outside the uterine muscle

Divisions of endometriosis by location were developed according to the classification of Martius and Kistner [ 89 , 90 ] ( Table 3 ).

Types of divisions of endometriosis by location.

Based on the histological classification according to Brosens (1993), we can distinguish types of endometriosis [ 91 ]:

• Mucosal type (occurs in endometrial cysts of the ovary),
• - early, active, glandular or follicular lesions,
• - advanced, black, wrinkled changes,
• - white fibrotic lesions,
• Glandular type (the main element is fibrous-muscular tissue and concerns deeply infiltrating endometriosis).

Among the many divisions of endometriosis according to the extent and severity of lesions, the division developed by the American Fertility Association (AFS) is the most commonly used. The American Society of Reproductive Medicine distinguishes four stages of endometriosis, where stage I and II are fairly mild types, and stages III and IV are advanced disease [ 92 , 93 ]. Currently, there is a division corrected by AFS in 1985.

The classification developed by the American Society of Reproductive Medicine (ASRM), based on the results of laparoscopy or laparotomy, it is the most common system used in clinical practice. The most important goal of classifying and determining the severity of endometriosis is to propose an effective treatment plan for it [ 94 ].

The ENZIAN scale in deeply infiltrating endometriosis is a descriptive scale, considering both the existence of the lesion and the depth of the invasion. In the ENZIAN classification, the location of foci was assigned to separate anatomical compartments [ 95 ].

• - Compartment A—foci located in the vagina and the rectovaginal septum,
• - Compartment B—foci located in the sacro-uterine ligaments up to the pelvic walls,
• - Compartment C—foci located in the sigmoid colon and rectum.

This classification also describes the foci of the ectopic endometrium depending on the place of their occurrence as:

• FA—adenomyosis,
• FB—urinary bladder endometriosis,
• FU—ureter endometriosis,
• FI—endometriosis of the bowel wall above the sigmoid colon,
• FO—infiltration of other anatomical structures, e.g., abdominal integuments.

Endometriosis occurring outside the pelvis is a rare phenomenon. However, literature data provide information on respiratory endometriosis or pericardial endometriosis or endometriosis in a scar after surgery with laparotomy access [ 96 , 97 ].

8. Diagnostics

Histopathological examination clearly allows for the diagnosis of endometriosis. However, a good medical history, gynaecological examination with specula, two-handed examination, additional diagnostic tests using imaging techniques, laparoscopy and biochemical tests are helpful in the initial diagnosis of the disease.

The basic examination in the diagnosis of endometriosis is an ultrasound examination [ 98 ]. Ultrasound examination (ultrasonography, USG) is helpful in the diagnosis of endometrial cysts of the ovary and of congenital defects of the reproductive organs favoring the retrograde outflow of menstrual blood into the peritoneal cavity [ 99 ]. In the case of endometriosis infiltrating the urinary bladder or the large intestine, it is justified to perform cystoscopy, colonorectoscopy and transrectal ultrasound examination [ 99 ].

In the case of deeply infiltrating endometriosis, the Rectal Water Contrast Transvaginal Sonography (RWC TVS) is also appropriate. The water contrast allows us to detect foci in the intestinal area and assess their progression ( Figure 1 ).

Intestinal endometriosis (from Department of Operative Gynaecology and Oncological Gynaecology, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland).

Deeply infiltrating endometriosis is characterized by the infiltration of endometrial cells > 5 mm below the surface of the peritoneum [ 100 ]. Profound lesions mainly affect the posterior pelvic compartment, including the rectovaginal septum, posterior vaginal vault, utero sacral ligaments and anterior rectal wall, causing adhesions and distortions of pelvic anatomy [ 101 , 102 ]. In addition to the classic DIE pain syndrome (characterized by dysmenorrhea, dyspareunia, chronic pelvic pain, dystrophy and dyschesia), profound changes are associated with dysfunction of the pelvic organs and pelvic floor muscles (PFM) [ 103 ]. A series of events or a combination of factors may contribute to the development of non-relaxing PFM in women with chronic pelvic pain, including direct or indirect (neuropathic) pelvic floor muscle injury, pelvic pain symptoms and inflammation. Evaluation of PFM by palpation or electromyography can cause pain, causing pelvic muscle spasm, which can be a confounding factor. Transperineal ultrasound has been shown to be an important, reliable and non-invasive tool for assessing pelvic floor morphometry [ 104 , 105 ]. Women with DIE have a smaller area of the levator hiatal area (LHA), and dynamic maneuvers with three-dimensional (3D) and four-dimensional (4D) transperineal ultrasound suggest they have higher muscle tone and lower strength. [ 106 ] than those without DIE. In a 3D/4D transperineal ultrasound examination, women with ovarian endometriosis and concomitant profound lesions appear to have increased PFM tone and decreased PFM strength compared to women with isolated ovarian endometriosis [ 107 ]. Transperineal ultrasound is a reliable and non-invasive tool for assessing pelvic floor morphometry [ 108 ]. Pelvic floor hypertonic dysfunction is a complex condition, and the specific cause or event that triggers this disorder is often not clearly identified [ 109 ]. A higher tone of PFM is associated with its damage and innervation (i.e., surgery, trauma or endometriosis), musculoskeletal changes (i.e., skeletal asymmetry), chronic pelvic pain syndromes and/or dyspareunia [ 110 , 111 ].

Moreover, this condition can also be attributed to abnormal learned pelvic floor activity or poor activity acquired in adulthood, through constant voluntary urination or defecation, or through sexual abuse [ 112 ]. The relationship between hypertonic disorder PFM and DIE can be explained by two main mechanisms. First, women with ovarian endometriosis alone tend to have less severity of pain symptoms than women with peritoneal endometriosis. In addition, in DIE lesions, increased density of nerve fibers and the phenomenon of perineural and intraneural invasion were clearly demonstrated [ 113 ]. Women affected by DIE showed smaller LHA than women with isolated ovarian endometriosis. Hypertonic dysfunction of PFM may be associated with pain symptoms (myofascial pain) and changes in pelvic organ function in women with DIE. Indeed, the role of PFM is not only to support the pelvic organs, but its contraction and relaxation are necessary for the proper functioning of the intestines and bladder and to enable painless sexual intercourse. While hypotonic pelvic floor disorders, such as pelvic organ prolapse, are often easily identified, symptoms of hypertonic PFM disorders are often not well studied, making these disorders unreported or misdiagnosed as other, better known concomitant conditions [ 109 ]. Because PFM dysfunction can cause pain symptoms and pelvic organ dysfunction potentially resistant to hormonal or surgical endometriosis therapy, transperineal ultrasound may enable a more complete functional assessment in women with DIE, with the goal of achieving tailored therapy, including pelvic floor rehabilitation.

It is also helpful to have a magnetic resonance imaging (MRI) examination, but the ultrasound examination is the basic tool in the diagnosis of this disease.

However, the gold standard in the diagnosis of endometriosis is laparoscopic surgery, with simultaneous confirmation in histopathological examination [ 114 ].

The less frequent areas of endometriosis include the vaginal vault and cervix, which is why examination with a speculum is an obligatory element of the gynaecological examination. Palpation can detect endometriosis in the area of the vaginal-rectal septum and the sacro-uterine ligaments. A characteristic and frequently encountered feature in patients with endometriosis is also uterine retroflexion, often forced by intraperitoneal adhesions.

9. Treatment

Treatment of endometriosis is a big medical problem due to the fact that this disease is difficult to treat and is chronic in nature. Pharmacological, surgical or combination treatment is possible.

Symptoms associated with the presence of foci of endometriosis are the main factor determining the need to start treatment. These symptoms are pain complaints of varying severity and location, and problems with getting pregnant. Women who notice abnormalities in their body report to the doctor, which allows them to apply a selected treatment in advance. A big problem remains patients who, despite the occurrence of pain, report late and therefore the disease, especially DIE, causes the involvement of other organs and the need to perform extensive complicated surgical procedures. Pharmacological, surgical and combination treatments are used to treat endometriosis [ 115 ]. In pharmacological treatment, we distinguish between hormonal and symptomatic treatment. Currently, hormonal treatment is allowed, for three months without histopathological confirmation of the disease. The choice of treatment is made depending on the age of the patient and her procreative desires, the ailments present and the form of endometriosis. Proper diet and lifestyle also play an important role.

9.1. Pharmacological Treatment

Drug treatment is used in women in their reproductive years. The goal of pharmacological treatment is to reduce or eliminate pain, inhibit further development and regression of endometrial foci and restore fertility. Initiation of pharmacological treatment of endometriosis is possible only on the basis of a clinical exam without the need to confirm the existence of the disease in laparoscopic examination (empirical therapy).

Pharmacotherapy may be part of the preparation for surgery, as well as a complementary procedure in the postoperative period. There are certain types of drugs that are used in the treatment of endometriosis ( Table 4 ).

Groups of medicines used in the treatment of endometriosis.

Non-steroidal anti-inflammatory drugs inhibit the synthesis of prostaglandins, contribute to reducing the inflammatory process and resolve pain [ 114 ]. Complex estrogen-progestogen therapy can be used cyclically or continuously.

In hormone therapy of endometriosis, the following groups of drugs are used [ 116 ]:

Danazol—a derivative of the male sex hormone testosterone. It inhibits the secretion of GnRH, causing a decrease in the secretion of LH and FSH by the pituitary gland. Therapy is long-term (6–9 months) and is started on the scond day of the cycle. The drug has many side effects. These include weight gain, fluid retention, breast reduction, oily skin and acne, hot flashes, decreased voice timbre.

Gonadoliberin analogues are substances with a structure similar to GnRH, which “deceive” the hypothalamus, causing a decrease in the production of real GnRH. This results in a decrease in LH and FSH levels and a significant reduction in estrogen levels. Therapy lasts at least 3–6 months. Side effects are caused by low estrogen levels. These include loss of calcium from the bones leading to osteoporosis, vaginal dryness, decreased libido, headaches, insomnia.

Progestogen preparations—contain progesterone derivatives, whose function is to reduce the level of GnRH, and thus the levels of FSH, LH and estrogen. Therapy should be used for at least 6 months. The most common side effects include fluid retention, weight gain, breast tenderness, spotting and irregular bleeding from the genital tract.

Oral contraceptives (estrogen-progestogen preparations)—their action consists in lowering the level of FSH and stabilizing the endometrium, which leads to a reduction in pain.

An intrauterine device releasing levonorgestrel is a progesterone derivative. The effect is the same as progestogen preparations. Recommended especially for women with severe pain.

Aromatase inhibitors—the latest group of drugs used in the treatment of endometriosis. Their action takes advantage of the fact of specific behavior of endometriosis cells. Foci of endometriosis, regardless of the ovaries, produce estrogens that cause an increase in endometrial lesions. Aromatase inhibitors interrupt estrogen production in both endometriosis foci and ovaries, causing a significant reduction in estrogen levels. Side effects are due to low estrogen levels. The most important of these is the significant loss of calcium from the bone causing osteoporosis. Others include loss of libido, vaginal dryness, insomnia [ 116 ].

All recognized methods of pharmacological treatment have similar therapeutic effectiveness. They differ in the scope and speed of the appearance of side effects. There is still an urgent need to develop new types of pharmacological therapies that will guarantee a complete cure of patients without the occurrence of side effects.

The latest drug to be approved by the Food and Drug Administration (FDA) is elagolix, a drug for the treatment of moderate to severe pain associated with endometriosis [ 117 ]. The results of a study in which about 1700 women with moderate or severe pain in endometriosis participated played a part in the above decision. Doses of this drug—150 mg once a day or 200 mg twice a day—significantly reduced the most common types of endometrial pain: pelvic pain and sex-related pain. For a dose of 150 mg, the duration of use of the drug is 24 months; for a dose of 200 mg duration is limited to 6 months, as the drug causes a decrease in bone mineral density. The drug is taken orally [ 117 ].

Elagolix is a non-peptide GnRH (gonadotropin-releasing hormone) antagonist. Elagolix enables dose-dependent reductions in estrogen levels and is effective in relieving moderate to severe endometriosis pain with long-lasting, sustained effects. As a GnRH antagonist, elagolix may also reduce bone mineral density through its estrogen reduction mechanism [ 118 ].

As evidenced by literature data, although there is a risk of bone loss when elagolix is used, the effect of elagolix on the long-term risk of fracture is minimal [ 119 , 120 ].

Results from the final model simulations indicate support for recommendations for the use of elagolix at a dose of 150 mg q.d. for 24 months [ 121 ].

9.2. Surgical Treatment

In the case of surgical treatment, it can be sparing or radical. Sparing treatment applies to adolescent patients and women of childbearing age planning to become pregnant. Radical surgical treatment is carried out in patients who do not plan pregnancy or those who continue to have pain despite the pharmacotherapy used.

Indications for surgical treatment of endometriosis are as follows:

• - pelvic pain,
• - infertility in endometriosis,
• - endometrial ovarian cysts.

Laparoscopy is the recommended surgical technique for the treatment of endometriosis, regardless of its stage [ 122 ]. The best therapeutic effects are achieved as a result of the combination of surgical treatment with pharmacological treatment. Medications are applied both before and after surgery.

Laparoscopy with the assistance of a robot is a viable method of resection of deeply infiltrating endometriosis, especially in the rectal-sigmoid region. In the case of endometriosis, a mini-invasive laparoscopic or laparoscopic approach using a robot is strongly recommended [ 108 ]. The disadvantage of surgery, however, is that when removing DIE lesions, complications that affect the functions of the gastrointestinal, urinary or sexual tract often arise. Complications after DIE surgery include rectal fistula (0.3–2%), intestinal stenosis (2%), and bladder atony (4–6%) [ 123 , 124 , 125 ].

Several studies have compared laparoscopic or robotically assisted methods in the surgical treatment of endometriosis [ 126 , 127 , 128 ].

Laparoscopically assisted robotics are associated with longer duration of relief than laparoscopic surgery, but the results are controversial [ 129 , 130 ].

The results of previous studies on the benefits of robot-assisted laparoscopy compared to conventional laparoscopy are somewhat heterogeneous. However, patients with features of a complex pelvic situation, such as severe endometriosis, increased body mass index, or previous surgeries, may benefit from robotic surgery [ 131 ].

Endometriosis treatment between robot-assisted laparoscopy and conventional laparoscopy was compared in [ 130 ].

This study did not detect any differences in perioperative outcomes of surgery between robotic surgery and laparoscopy.

The results of other smaller studies, mainly retrospective, were heterogeneous. Some of these studies have shown longer surgery times for robotic assisted procedures than for laparoscopy, whereas other studies have shown benefits of robotic surgery [ 132 ].

Laparoscopic rectal nodulectomy with nerve-sparing robots has been shown to be a feasible and safe treatment for isolated sting-rectal DIE [ 133 ].

The latest study suggests that robot-assisted laparoscopy is a possible method of DIE resection [ 134 ].

9.3. Physiotherapy in Endometriosis

Physiotherapy in endometriosis focuses on non-invasive and conservative treatment of pelvic floor disorders in women. It deals with the restoration of the efficiency and function of tissues and organs in the pelvic area, supports the process of surgical treatment, relieves pain, thus improving the quality of life [ 135 ].

In women suffering from endometriosis, pelvic floor structures are very often dysfunctional. Therefore, it is an indication for urogynecological physiotherapy. Inflammation accompanying recurrent endometriosis can cause tissue damage, and thus the formation of scar tissue to heal the affected areas. Unfortunately, a side effect of this process is the formation of adhesions, which, depending on the location, can cause different symptoms. Occurring in the abdominal cavity, they can limit the mobility of internal organs and contribute to the formation of symptoms, i.e., flatulence, constipation, digestive problems, problems with maintaining proper body posture and pain. For such ailments, it is a good idea to use manual therapy and osteopathic techniques to improve the mobility of internal organs and structures of the pelvis and spine. The following types of techniques can be successfully used: mobilization of the lumbosacral spine, needle therapy, pinopressure, visceral therapy (general abdominal maneuvers, therapy of female organs, intestines, liver), if necessary and with the consent of the patient of the technique per vaginum. As a consequence, in combination with the classic treatment of endometriosis and urogynecological physiotherapy, the course of the disease may become much milder and will allow the patient to return to everyday life [ 135 ].

Physical therapy techniques are known to reduce pain and improve quality of life in endometriosis. The overall goal of treatment is to teach the patient to relax the muscles, which in turn helps to break the pain cycle [ 136 ].

Evidence suggests that the symptoms of endometriosis are the result of a local peritoneal inflammatory response triggered by an ectopic endometrial implant that undergoes cyclic bleeding [ 137 ].

Regular exercise, on the other hand, has a protective effect against inflammatory diseases because it induces an increase in systemic levels of cytokines with anti-inflammatory properties [ 138 ].

Regular exercise is thought to promote reduced menstrual flow, ovarian stimulation, and estrogen effects [ 139 ].

Analysis of the available literature data shows that there are no controlled and randomized trials determining whether and to what extent exercise can be beneficial for women with endometriosis. So far, researchers have only speculated on this subject [ 140 ].

Physical exercise has been shown to have a beneficial effect on muscle relaxation in patients suffering from endometriosis, which in turn helps to break their pain cycle [ 141 ].

Progressive muscle relaxation training has been shown to be more effective in reducing pain, anxiety, and depression in women with endometriosis undergoing hormone therapy [ 142 ].

Cardiovascular activity helps endometriosis patients maintain good energy levels. Exercise is one of the most effective strategies for increasing serotonin levels; physical activity and deep breathing exercises can increase the rate of burning serotonin neurons in the brain, which can stimulate the production of mood-enhancing substances. Aerobic exercise, such as walking and swimming, can have a more significant effect on serotonin levels, strengthening the muscles of the whole body and improving overall circulation [ 143 ].

However, there are literature data that draw attention to the possibility of inferring the non-protective effects of exercise in women with endometriosis, which may result from the discomfort felt that prevents physical exercise [ 141 , 144 ].

10. Biomarkers

So far, no specific marker for endometriosis has been identified. The search is underway for a biomarker obtained from serum, plasma or urine, which would allow for a quick and simple diagnosis. In recent years, many substances have been tested that could be potential markers for endometriosis ( Figure 2 ). With peritoneal endometriosis, serum and plasma are not good diagnostic material; attention is paid to the eutopic endometrium. Eutopic endometrial tissue is available by taking the endometrium through a biopsy.

The potential endometriosis biomarkers.

The endometrium comes from the intermediate mesoderm during mesenchymal-epithelial transition (MET) during the formation of the genitourinary system. It is a reversible process, therefore, during the epithelial-mesenchymal transition (EMT, reverse process MET), it is possible to reach the formation of foci of endometriosis [ 145 ]. Foci of endometriosis behave in the same way as eutopic endometrium. There is monthly bleeding within them, which trigger an immune response. This causes the foci of endometriosis to increase [ 146 ].

Pain is a typical symptom of endometriosis, so the conduction pathways were analyzed and the brain-derived neurotrophic factor (BDNF) was found to be elevated in women with endometriosis compared to the control group [ 147 ]. BDNF is a protein that affects sensory neurons. As research shows, BDNF is not useful in detecting peritoneal endometriosis and deeply infiltrating endometriosis [ 148 ].

The marker of endometriosis was sought among growth factors and cytokines, because the development of ectopic implants is accompanied by the processes of invasion, proliferation and angiogenesis. The most promising results were obtained for hepatocyte growth factor (HGF), fibroblasts growth factor (FGF), epithelial growth factor (EGF), vascular endothelial growth factor (VEGF) and interleukin IL-1, IL-6 and IL-8. The most reproducible results were obtained for IL-6. IL-6 is the most characteristic of endometriosis. Its sensitivity is 63% and its specificity is 69% [ 149 ].

YKL-40, a new biomarker of inflammation, is secreted by activated macrophages and neutrophils in various inflamed tissues. Serum concentrations of YKL-40 are elevated in patients with diseases characterized by inflammation. Protein YKL-40 (CHI3L1–chitinase-3-like protein 1, HC-gp-39–human cartilage glycoprotein-39, gp-38k, chondrex) is the subject of scientific research looking for new biomarkers of endometriosis. Literature data suggest that circulating YKL-40 levels may be a new biomarker for diagnosing and monitoring endometriosis. The studies established serum concentrations of YKL-40 in patients with endometriosis compared with healthy people of the same age. It was shown that the level of YKL-40 was significantly higher in patients with endometriosis compared with healthy women [ 150 ].

It is known that in places affected by endometriosis, oxidative stress further intensifies the immune response, as a result of which there may be an exacerbation of the development of endometriosis [ 151 , 152 , 153 ]. Women with endometriosis have increased oxidative stress in the peritoneal cavity. Data indicate that oxidative stress occurs mainly in the peritoneal cavity in women with advanced stage of the disease [ 154 ].

Polak et al. showed that the peritoneal fluid of women with endometriosis is characterized by impaired iron metabolism [ 154 ]. This is most likely related to the increased number of erythrocytes in the peritoneal cavity of women with endometriosis, which leads to a higher haemoglobin concentration in this environment. Impaired iron homeostasis can have a significant effect on the pathophysiology of peritoneal endometriosis through the direct influence of haemoglobin derivatives and/or the creation of a pro-inflammatory and pro-oxidative environment.

Oxidative stress has been shown to activate the transcription factor NF-κB. The NF-kB protein family consists of the proteins RelA (p65), RelB, c-Rel, p50 and p52. The active transcription factor always consists of two subunits and the most common variant of NF-kB is the RelA (p65) and p50 complexes. NF-kB contains a signalling sequence that allows the transport of the active complex to the cell nucleus and binding to a specific DNA consensus. In an inactive form, the NF-kB factor is localized in the cytoplasm of the cell in association with the inhibitor protein IkB. Activation of the transcription factor NF-kB occurs through the interaction with the receptors of the cells of pro-inflammatory cytokines (e.g., TNF-alpha, LPS or IL-1beta), but also such factors as UV rays, antigens or free radicals. Activation of the specific receptor subsequently leads to phosphorylation of the inhibitory IkB protein by IKK kinases followed by proteosomal degradation of IkB. The released complex can be translocated to the cell nucleus [ 142 ]. This pathway of activation of the NF-kB factor is referred to as the canonical pathway. In addition to the canonical NF-kB activation pathway, the action of LPS, CD40 or lymphotoxin (TNFbeta) may lead to the so-called non-canonical NF-kB activation pathway. The transcriptional activity of NF-kB is crucial for cell function and proliferation. The elevated concentrations of TNF-alpha, TNF-beta, LPS, IL-1beta and CD40 in peritoneal fluid in women with endometriosis promote processes such as adhesion, invasion, proliferation and angiogenesis that stimulate the development of the disease [ 155 ].

Unfortunately, despite the passage of years and many studies in which an endometriosis marker was sought, none of the tested substances can be recommended for the diagnosis of endometriosis.

The only markers that have found partial clinical use in the diagnosis of endometriosis are the glycoproteins Ca-125 and Ca-19-9. The sensitivity of Ca-125 is characteristic of the advanced form of the disease, but its specificity is low because it is often elevated in other gynecological diseases [ 156 ]. The concentrations of Ca-125 and Ca-19-9 glycoproteins do not give us definitive answers in the differential diagnostic and therapeutic process, but they help in decision-making and direction of management and therefore remain the recommended complementary tool.

Despite the fact that research on biomarkers of endometriosis are still ongoing, there are still no satisfactory results, which makes it impossible to carry out effective laboratory diagnostics used in the diagnosis and monitoring of the treatment of the disease [ 157 ].

Some hope for the discovery of the endometriosis marker is carried by studies of microRNAs circulating in the blood [ 158 ]. MicroRNAs are small ribonucleic acid molecules about 22 nucleotides long that regulate gene expression by influencing the translation process. MicroRNAs show stability in tissues and can be easily detected in patients’ serum using quantitative methods such as qPCR. Determination of a single microRNA can help distinguish a healthy person from a sick person. However, the greatest prognostic force is the determination of several microRNAs, the expression of which varies in a given disease.

In studies of microRNAs in endometriosis, it has been shown that a certain group of genes is regulated with the participation of short, relatively stable fragments of RNA. MicroRNAs from the let family are among the dominant in endometrial cells.

In the paper of Sahin et al., Let-7b microRNAs have been shown to influence the expression of the ER-α, ER-ß, Cyp19, KRAS 4A, KRAS 4B, and IL-6 genes [ 146 ]. Let-7b has a pleiotropic effect in the pathophysiology of endometriosis, affecting the regulation of estrogen levels and the receptor of these growth factors.

Liu et al. suggested that miR449b3p altered expression in endometriosis affects the development of the disease [ 159 ].

Altered expression levels of miR-139-5p and miR-375 were observed in the tissues of the ectopic endometrium. These microRNAs may regulate the expression of the transcription factors HOXA9 and HOXA10 and the endothelin 1 gene (EDN1) playing a role in vascular homeostasis, which may be related to the development of endometriosis [ 160 ].

Laudański et al. showed that the mammalian target of rapamycin (mTOR) and VEGF pathway genes can be regulated by abnormal miRNA expression in endometriosis [ 161 ].

The protein kinase mTOR regulates the process of cell growth, proliferation and movement, as well as translation and transcription processes, while VEGF factor intensifies the process of angiogenesis in endometriosis. A team of Polish researchers conducted miRNA profiling of the eutopic endometrium from women with endometriosis [ 162 ]. A sample of 667 human miRNAs were studied in patients with endometriosis compared to the control group. Two of the study miRNAs were elevated, while 13 miRNAs had reduced levels of expression in eutopic endometrium in endometriosis patients compared to control. In addition, hsa-miR-483-5p and miR-629 have been shown to be significantly reduced in expression in endometriosis patients [ 163 ].

Gu et al. identified 14 miRNAs that might be involved in the pathogenesis of ovarian endometriosis: hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7d-5p, hsa-let-7f-5p, hsa-let-7g-5p, has-let-7i-5p, hsa-miR-199a-3p, hsa-miR-320a, hsa-miR-320b, hsa-miR-320c, hsa-miR-320d, hsa-miR-328-3p, hsa-miR-331-3p and hsa-miR-320e.Among them, 10 miRNAs were reported for the first time to be associated with endometriosis [ 164 ]. The miRNA hsa-let-7i-5p and hub miRNAs including hsa-let-7a-5p, hsa-let-7b-5p, hsa-miR-320a, and hsa-miR-320d might be potential diagnostic biomarkers [ 164 ].

Recent studies showed that the levels of miRNAs 199b-3p, 224-5p, and Let-7d-3p in plasma are potential diagnostic biomarkers for endometriosis patients [ 165 ]. In addition, miR-146a, miR-149 and miR-499 may have a role in the pathogenesis of endometriosis [ 166 ].

Some miRNAs are associated with genetic, epigenetic and angiogenic factors, hormones, cytokines, chemokines, markers of oxidative stress, mediators of inflammation, hypoxia, angiogenesis, and altered immune systems, contributing to the pathogenesis of endometriosis. Hormonal imbalance occurs by reducing the levels of miRNA-23a and miRNA-23b and increasing miRNA-:135a, 135b, 29c and 194-3p [ 167 ]. Angiogenesis by vascular endothelial growth factor is attributed to an increase in miRNA-126, miRNA-210, miRNA-21, miRNA-199a-5p and miRNA 20A. OS upregulates miRNA-302a by increased levels of tumor necrosis factor (TNF)-α, TNF-β and interleukin-1β. Upregulation of miRNA-199a and miRNA-16 promotes inflammation and cell proliferation in endometrial lesions [ 168 ]. The gold standard in diagnosing endometriosis is laparoscopy; however, miRNA can be validated as a diagnostic tool for detection, progression and prevention of endometriosis in large, independent cohorts of women, with and without endometriosis.

Despite the identification of several miRNAs, the studies are investigatory in nature. To date, no specific miRNA has been validated for diagnostic purposes (systematic review conducted on PubMed ® , Latin American and Caribbean Health Sciences Literature (LILACS), MEDLINE ® and Web of Science databases using the search terms endometriosis (all fields) AND miRNA (all fields), evaluating all publications up to May 2019) [ 168 ].

In conclusion, studies of the diverse microRNA pool in endometriosis have shown that many biological processes are regulated by the above molecules and can have a significant impact on the development of lesions. However, the use of microRNA in the diagnosis of endometriosis is only at the initial stage of research [ 169 , 170 ].

Recently, in the context of endometriosis, long non-coding RNAs (lncRNAs) that cover more than 200 bp and are a subtype of non-coding RNAs (ncRNAs) have become the focus of interest [ 171 ].

Unlike a group of short, non-coding RNAs (sncRNAs) such as microRNAs, long non-coding RNAs (lncRNAs) tend to exhibit greater sequence matching and thus specificity of action relative to the target genes. Non-coding RNA molecules participate in the processes of regulation at virtually all stages of the transmission of genetic information: from DNA to protein. Particularly spectacular is the involvement of certain non-coding RNA molecules in the mechanisms leading to the switching on or off of the expression of individual genes.

Zhou et al. found that 388 transcripts of lncRNA tested showed overexpression and 188 showed decreased expression levels in the ectopic endometrium compared to eutopic endometrium [ 172 ].

Liu et al. showed that LncRNA H19 may be involved in the pathogenesis of endometriosis especially in the mechanism of recurrence and is a novel potential predictor of the recurrence of endometriosis. In this study LncRNA H19 expression in the ectopic and eutopic endometria of endometriosis patients was significantly higher than that in the normal endometrium [ 172 ].

AFAP1-AS1 (AFAP1 Antisense RNA 1) is an RNA Gene, and is affiliated with the lncRNA class. Recent studies have shown that AFAP1-AS1 may be a potential therapeutic target for controlling the progression of endometriosis [ 161 ]. AFAP1-AS1 silencing can inhibit cell proliferation and promote apoptosis by regulating the STAT3/TGF-β/Smad signaling pathway by targeting miR-424-5p in endometrial stromal cells [ 173 ].

A study by the Cui et al. team explains that LINC01116 promotes the progression of endometriosis through the miR-9-5p/FOXP1 axis. This discovery provides a new therapeutic target for endometriosis patients [ 174 ].

HOX antisense intergenic RNA (HOTAIR) is a recently discovered long non-coding RNA (lncRNA) that plays critical role in gene regulation and chromatin dynamics, which appears to be mis-regulated in endometriosis. HOTAIR interacts with key epigenetic regulators such as histone methyltransferase PRC2 and histone demethylase LSD1 and regulates gene silencing.

Research indicates a significant role for HOTAIR in promoting endometriosis [ 175 ]. HOTAIR can be used as a potential target for clinical applications. Higher levels of HOTAIR mRNA have been shown in endometrial patients with severe endometriosis.

It is suggested that lncRNAs are closely related to the process of endometriosis. Nevertheless, the molecular mechanisms by which lncRNAs bind to endometriosis need to be explained in more detail. In summary, lncRNAs show potential as biomarkers of endometriosis [ 176 ]. However, the clinical significance and biological mechanism of lncRNA in the development of endometriosis remain largely unknown.

11. Endometriosis—Genetics

11.1. hereditary genetic polymorphism.

The concept of the genetic basis for the development of endometriosis derives from many years of observations, in which the family occurrence of this disease was indicated. Since the 1940s, a much higher incidence among women from families in which women suffered from endometriosis has been described, as well as a high incidence among siblings, especially monozygotic twins, where the percentage of co-occurrence exceeds 80% [ 177 ]. On the basis of statistical analyses of the family history of endometriosis, it has been proven that a genetic factor is responsible for about 50% of the predisposition to the disease [ 178 ]. It is believed that genetic and epigenetic conditions are rather conducive to the development of endometriosis, which is caused by environmental factors, or genetic and epigenetic changes caused by environmental factors are necessary to move from subtle changes in endometriosis to the disease stage [ 179 ]. The different phenotypic traits observed among humans are conditioned by millions of polymorphisms scattered throughout the genome, of which single nucleotide polymorphism (SNPs) account for about 90% of the total phenotypic variability. Polymorphic variants sometimes occur in a large percentage of the population and are associated with a variety of phenotypic traits, including susceptibility to various conditions. It has been postulated that certain SNPs systems, perhaps related to jointly inherited haplotypes, may promote the development of endometriosis. In a study on coupling analysis conducted on thousands of families burdened with endometriosis (GWAS–genome-wide association study) from different populations, a number of potential regions associated with the inheritance of this disease were indicated.

The epidemiology of endometriosis can be better understood thanks to the work on the human genome, especially the development of the genome-wide association study (GWAS) technique, i.e., associative studies of the entire genome.

The first GWAS study on endometriosis was published between 2010 and 2011—two papers on the Japanese population and one study of European women [ 180 , 181 , 182 ].

Studies of the Japanese population showed the relationship of polymorphism rs10965235, in the CDKN2BAS gene at locus 9p21 and rs16826658, in the area of the WNT4 gene at locus 1p36 [ 183 ].

Extensive GWAS research was conducted by the International Endo Gene Consortium (IEC) in populations of British and Australian women with endometriosis [ 165 ]. On the basis of these studies, loci associated with the development of the disease–7p15.2–was established. This place is among the genes known so far responsible for the development of the uterus and placenta [ 182 ].

Of lesser importance in the mentioned populations was the loci of chromosome 1p36 previously announced by Japanese studies [ 180 ].

In 2012, an international team of scientists conducted the largest genome-wide association study to date, the first among European women comparing DNA from 5586 women with endometriosis and 9331 people free of the disease [ 183 ].

The team identified two regions of the genome associated with an increased risk of endometriosis. The first is located on chromosome 7. This region may be involved in the regulation of nearby genes involved in the development of the uterus and its lining. The second variant is located near the WNT4gene, which is involved in hormone metabolism and the development and functioning of the woman’s genital tract. The important role of the WNT4, CDKN2BAS and FN1 genes was confirmed by the research of the team of Pagliardini et al. [ 184 ].

Research indicates a link between the 2p25.1 region, located near the GREB1 gene, and the risk of endometriosis [ 185 ].

Literature data on GWAS studies suggest that certain genetic variants, significantly more common in endometriosis, appear to be good functional candidates for the genetic factors responsible for the onset of this disease [ 185 ].

GWAS research in endometriosis is still ongoing, providing new results. Literature reports on 998 Belgian patients with endometriosis and 783 controls showed that the polymorphisms rs7521902, rs13394619 and rs6542095 may be associated with this disease [ 170 ].

It is worth noting that three genetic variants in the area of GREB1 (close to rs13394619) and CDKN2B-AS1 (close to rs1537377) also showed nominally significant associations with endometriosis [ 186 ].

In the paper of Mafra et al., it has been suggested that analysis of genetic variants in the WNT4 gene area (rs3820282, rs16826658) may help identify patients at high risk of developing this disease [ 187 ].

Albertsen et al. conducted a GWAS study in the European population of 2019 surgically confirmed cases of endometriosis and 14,471 controls [ 188 ].

Three of the single nucleotide polymorphisms (SNPs) associated with the disease have been identified: LINC00339-WNT4 at locus 1p36.12 (rs2235529) and RND3-RBM43 at locus 2q23.3 (rs1519761 and rs6757804). The meta-analysis identified two additional loci that were associated with endometriosis: RNF144B-ID4 at 6p22.3 (rs6907340) and HNRNPA3P1-LOC100130539at 10q11.21 (rs10508881).

In the work of the Polish team Sobalska et al., GWAS analysis found statistically significant links between new SNPs not previously described in the literature and endometriosis [ 189 ]. In these studies, a relationship was observed between the rs10129516 polymorphism, located on chromosome 14 in the PARP1P2 and RHOJ intergenic region, and endometriosis. Gen RHOJ encodes one of many small proteins of the Rho family that bind GTP (guanosine-5′-triphosphate), which acts as an energy transporter in the cell. Rho proteins regulate the dynamic assembly of cytoskeleton components in several physiological processes, such as cell proliferation and motility. Rho are also involved in cancer transformation and metastasis. The protein encoded by the RHOJ gene is activated by vascular endothelial growth factor and can regulate angiogenesis and also plays an important role in adipocyte differentiation, endothelial motility, and cytoskeletal formation [ 190 ]. Overexpression of the RHOJ gene has been shown in ectopic endometrium [ 191 ]. Endometriosis can be the cause of ectopic pregnancy. The risk of such a pregnancy is therefore increased in women with endometriosis. It can therefore be assumed that the RHOJ gene may be involved in the development of endometriosis.

Genetic analyses of the Bylińska et al. confirm the role of polymorphisms of the HLA-G gene and its receptors LILRB1 and LILRB2 for the development of endometriosis [ 192 ].

Human leukocyte antigen G (HLA-G) is recognized by KIR2DL4, LILRB1 and LILRB2 receptors on NK cells, antigen-presenting cells, T cells and others. Expression of HLA-G molecules in the ectopic endometrium has been demonstrated. The genes for the receptors KIR2DL4, LILRB1 and LILRB2 are polymorphic, which may affect their activity. The study of Polish scientists analyzed whether polymorphisms of HLA-G, KIR2DL4, LILRB1 and LILRB2 genes may affect susceptibility to endometriosis and disease progression. It was shown that the GG genotype of the rs1632947 polymorphism of the HLA-G gene played a protecting role against disease and its severe stages; similarly, the CT genotype of the polymorphism rs1233334 HLA-G played a protective role against disease progression. The AA genotypes of the rs41308748 polymorphism of the LILRB1 gene and AG rs383369 of the LILRB2 gene predisposed to endometriosis and its progression. No association of polymorphism of the KIR2DL4 gene with endometriosis was observed [ 193 ].

The work of another team of Polish researchers showed the relationship of polymorphisms rs12700667 and rs4141819 of the RAF gene with infertility in women with advanced endometriosis [ 193 ].

Recent research points to new genes and their polymorphisms related to endometriosis. Christofolini et al. showed a correlation of the polymorphisms rs10928050 of the KAZN gene and the rs2427284 of the LAMA5 gene with endometriosis [ 194 ].

Genetic studies provide evidence that changes in DNA increase the likelihood of some women developing endometriosis. Genetic contribution appears to be particularly large in more serious forms of the disease. Many years of GWAS molecular studies have resulted in the selection of several candidate genes as potential markers of endometriosis [ 195 ].

The study, which is a systematic review of GWAS studies published by PubMed until December 31, 2019, indicates that variants of the genes WNT4 rs7521902, GREB1 rs13394619, FN1 rs1250248, IL1A rs6542095 and VEZT rs10859871 may affect the development of endometriosis. However, replication and validation of these variants in different populations are essential for a better understanding of endometriosis etiopathogenesis, to optimize diagnosis, and to improve the effectiveness of clinical treatment of the disease [ 196 ].

Quite high hopes were associated with the possibility of determining the operation of polymorphisms of genes responsible for the metabolism of hormones and xenobiotics. Most of the variants described in the context of changes in drug metabolism were found to have no effect on the risk of endometriosis. The few polymorphisms associated with this disease include rs12248560 and rs4244285 that alter the expression of CYP2C19, which is involved in the breakdown of estrogens and xenobiotics. Other significant changes concern the deletion variant of the glutathione transferase (GSTM1) gene and the glutathione transferase (GSTP1) variant rs1695, which as phase II detoxification enzymes participate in the final removal of drugs and toxins. The presence of glutathione transferase polymorphisms combined with significant dioxin exposure was associated with the development of endometriosis [ 197 ].

A recently published meta-analysis showed that in addition to the above-mentioned variants, gene variants for interferon γ (IFNG CA repeat) and variants of rs16826658 and rs2235529 of the WNT4 gene may be relevant. An unknown trend was also confirmed for the progesterone receptor (PGR) gene variant, the rs1799969 variants of the ICAM1 molecule, rs2292596 of the aromatic hydrocarbon receptor repressor gene (AHRR), the CYP17A1 rs743572 gene and the rs1801282 gene for the peroxisome γ proliferator-activated receptor (PPARγ–peroxisome proliferator-activated receptor γ) [ 198 ].

Estrogen receptors, acting as transcription factors, play a significant role in endometrial growth and differentiation, as well as in numerous biological functions in eutopic endometrium and endometriosis. The ERβ receptor encoded by the ESR2 gene is the dominant isoform in those with endometriosis [ 198 ].

A different expression of aromatase in endometriosis foci has been demonstrated compared to eutopic endometrium. CYP19A1 is a gene encoding aromatase–an enzyme involved in the biosynthesis of estrogens. The exact basis of the observed changes is not yet known.

Literature data indicate that studies draw attention to the significant role of estrogen receptor genes, especially the ESR2 gene and the CYP19A1 gene for the susceptibility and occurrence of endometriosis [ 199 , 200 , 201 ]. The study identified statistically significant correlations between the new, previously unseen, two SNPs and endometriosis: rs4986938 and rs928554 [ 200 , 202 ]. In the case of rs4986938, the AA genotype was found to reduce the risk of endometriosis. A similar effect was demonstrated in the presence of the AG genotype of rs928554. The results obtained during the analysis indicate that the polymorphisms rs4986938 and rs928554 of the ESR2 gene are associated with the occurrence of endometriosis. Recent studies have shown that the polymorphisms rs17179740 of the ESR2 gene and rs2899470 of the CYP19A1 gene are associated with the occurrence of endometriosis [ 202 ]. In the studied group of women with endometriosis, a significant increase in the expression of the ESR2 gene was found, which may indicate the participation of this factor in the pathogenesis of endometriosis [ 200 ]. The results obtained in the work contribute to the broadening of knowledge in the subject of molecular mechanisms conducive to the development of endometriosis. Due to the small amount of research on the analysis of CYP19A1 and ESR2 gene expression and polymorphisms in patients with endometriosis, the research makes a significant contribution to expanding the knowledge about the impact of genetic factors on the development of endometriosis.

Understanding the relationship between gene expression and polymorphism and endometriosis may contribute to the development of new therapeutic strategies in the context of this disease. Molecular studies may be a target for personalized therapy in the future.

11.2. Somatic Mutations

The association of endometriosis with cancer, which appears as a result of genetic mutations, contributed to the search for pathogenetic mutations occurring in cells during the development of the disease. The concept of this research is based on the hypothesis that at least some of the changes arise as a result of somatic mutations absent in the germline and occur during the development of an individual organism. The occurrence of de novo mutations in both the endometrial cyst epithelial and peritoneal foci as well as in DIE foci is described. The most frequently noted genes are: ARID1A, KRAS, PIK3CA and PPP2R1A [ 203 , 204 ].

Analyzing samples taken from DIE patients with the help of next generation sequencing (NGS), it was possible to describe 51 new mutations involving a large group of proto-oncogenes. Some of these mutations have previously been described as mutations that have an initiating effect on the formation of tumors. The new mutations can affect both the eutopic endometrium and endometriosis foci, and do not have to occur in the germline cell line. They can also selectively appear only in the foci of endometriosis themselves. The location of the mutation in the genome appears to be specific to the patient and is not repeated in others. It is emphasized that the impact of these mutations on the development of the disease is complex and requires further evaluation. However, it can be assumed that these patients will be burdened with a higher risk of cancer in the future [ 203 ].

12. Summary

Analyzing the research of recent years on endometriosis, it can be seen that the current therapeutic options available are not optimistic. Unfortunately, the treatment of this disease is still ineffective. However, the progress of knowledge, especially at the genetic level, which has taken place in recent years, allows the separation of certain molecular shields for new therapeutic methods. Much hope is associated with new directions of research, such as the use of miRNAs or lncRNAs, which regulate key cellular pathways in the development of the disease, as molecular markers in endometriosis. However, these studies must involve large groups of patients with their full clinical description in order to be able to draw conclusions about the use of these particles as markers of endometriosis. There are reports of the development of the possibility of using ncRNA as diagnostic tools [ 205 ]. It remains to be seen whether genetic research will allow for the establishment of new therapeutic regimens and significantly contribute to improving the treatment results of women suffering from endometriosis.

Author Contributions

Conceptualization, B.S., K.S. and H.R. writing—original draft preparation, B.S.; writing—review and editing B.S.; revision and proofreading B.S. All authors have read and agreed to the published version of the manuscript.

This research has received no external funding.

Institutional Review Board Statement

Informed consent statement, data availability statement, conflicts of interest.

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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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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• Published: 18 January 2024

A thematic synthesis of qualitative studies and surveys of the psychological experience of painful endometriosis

• Amanda C. de C Williams 1 &
• Honor McGrigor 1  

BMC Women's Health volume  24 , Article number:  50 ( 2024 ) Cite this article

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Endometriosis is a widespread problem in women of reproductive age, causing cyclical and non-cyclical pain in the pelvis and elsewhere, and associated with fatigue, fertility problems, and other symptoms. As a chronic pain problem, psychological variables are important in adjustment and quality of life, but have not been systematically studied.

A systematic search of multiple databases was conducted to obtain surveys and qualitative studies of women’s experience of pain from endometriosis. Surveys were combined narratively; qualitative studies were combined by thematic synthesis, and the latter rated for methodological quality.

Over 2000 records were screened on title and abstract, and provided 22 surveys and 33 qualitative studies from which accounts could be extracted of the psychological components of pain in endometriosis. Surveys mostly addressed quality of life in endometriosis, with poorer quality of life associated with higher levels of pain and of distress, but few referred to coherent psychological models. Qualitative studies focused rather on women’s experience of living with endometriosis, including trajectories of diagnosis and treatment, with a few addressing meaning and identity. Thematic synthesis provided 10 themes, under the groupings of internal experience of endometriosis (impact on body, emotions, and life); interface with the external world (through self-regulation and social regulation); effects on interpersonal and social life, and encounters with medical care.

Conclusions

The psychological components of pain from endometriosis only partly corresponded with standard psychological models of pain, derived from musculoskeletal pain studies, with fewer fears about physical integrity and more about difficulties of managing pain and other symptoms in social settings, including work. Better understanding of the particular psychological threats of endometriosis, and integration of this understanding into medical care with opportunities for psychologically-based pain management, would substantially improve the experience and quality of life of women with painful endometriosis.

Peer Review reports

Endometriosis affects about 5–8% women of reproductive age [ 1 , 2 , 3 , 4 ]. Typical symptoms include dysmenorrhea, noncyclic pelvic pain, dyspareunia, fatigue, pain on emptying the bladder or bowels, and heavy bleeding [ 5 , 6 ]. Pain is not only felt in the pelvis, but can be localized to various other parts of the body, such as the lower back. Pain and other symptoms can be felt constantly, cyclically with worsening around menstruation and/or ovulation [ 6 ], or unpredictably, and they vary between and within people with endometriosis. Additionally, endometriosis can be comorbid with other chronic (persistent) pain conditions, including tension headache and migraine, fibromyalgia, myofascial pain, vulvodynia, bladder pain, and low back pain, often referred to as Chronic Overlapping Pain Conditions (COPCs) and attributed to changes in central sensitization [ 3 , 7 , 8 ].

Diagnosis is commonly delayed for several years after symptom onset, and access to imaging or surgical diagnosis may be restricted by social inequalities [ 3 ] as well as by limited knowledge of endometriosis in primary care, with difficulty both for women and for healthcare staff distinguishing endometriosis from putatively ‘normal’ dysmenorrhea [ 1 , 9 , 10 , 11 ]. Following diagnosis, pain reduction sometimes takes second place to treating the condition, but neither size of lesions [ 12 ] nor stage of disease predicts frequency, constancy, or intensity of pain. Finally, pain often persists or recurs after effective surgical, hormonal, or other treatments [ 13 ].

In any chronic pain scenario, psychological variables are important in determining the personal experience of chronic pain, overall adaptation, and prognosis [ 14 , 15 ]. Difficulty living with chronic pain may or may not reach clinical criteria for depression or anxiety [ 16 ], but tends to be focused on pain and its implications for overall health, including fertility, as well as on difficulties in everyday life and in lifetime goals. Intimate and social relationships are disrupted, as is work, with implications for career and financial security. Women can find it hard to communicate their pain and other symptoms, or to find someone who has the appropriate skill to handle their struggle [ 17 ]. Therefore, people with endometriosis may become isolated and distressed [ 1 , 18 , 19 , 20 ]. Overall, quality of life is reduced, although that is not necessarily routinely reflected in studies of natural history or treatment outcome [ 21 ]. Additionally, its association with menstrual bleeding renders it stigmatized [ 19 ], while female pelvic pains in general are at risk of being dismissed as mental health problems (22, 17].

Within the broader biopsychosocial framework, the dominant psychological model in chronic pain is that of fear and avoidance [ 14 , 22 ], whereby overestimation of the threat inherent in pain for physical integrity leads to avoidance of a wide range of activity, which in turn leads both to increasing disability (through deconditioning) and to depression (through losses inherent in avoidance). Both anxiety about pain and damage and losses due to restricted activity contribute to worsening of pain experience (particularly by descending modulation of pain) and to maintaining anxiety and restricted activity. However, this is largely based on studies of musculoskeletal pain, often low back pain, in which people with pain associate that pain with damage to essential joint and vertebral structures, provoking caution around movement; for instance, fewer than 10 of 335 studies of pain-related fear and avoidance concerned visceral pain, and none endometriosis [ 23 ]. It is not clear to what extent the same psychological model applies to visceral pains, where fears of damage may be less prominent, and fears of disease and long-term prognosis where disease is diagnosed may be far more salient; nor is it clear what activities are routinely avoided and how that affects everyday life in both short and long term.

In early studies, very similar mood and social adjustment outcomes were found in women with diagnosed endometriosis compared with those with negative laparoscopy for pelvic pain [ 24 ], and, despite a high level of concern about undiagnosed disease, few gynecology patients with pain endorsed worry about cancer [ 25 ]. No psychological models specific to endometriosis, or to painful gynecological conditions, have developed, and a 2015 systematic review and thematic synthesis of qualitative research in endometriosis [ 26 ] noted the lack of studies of emotional and social wellbeing. One review since has provided more information on psychological impact of endometriosis. A narrative synthesis of 16 qualitative studies [ 1 ] described themes of powerlessness, and of loneliness and isolation, but not of anxiety about pain, and worry only in relation to infertility. A more recent systematic review included meta-analyses showing higher depression and anxiety scores in women with endometriosis when compared with healthy controls, but not when compared with other women with chronic pelvic pain [ 16 ]; the focus of depression and anxiety were not described, although their correlation in at least some included studies with pain levels and fertility problems was noted.

Several mixed methods or combined quantitative and qualitative reviews add a little more detail of psychological problems associated with endometriosis. One, on coping in women with endometriosis [ 27 ], reported catastrophic thinking to be associated with more pain, and “passive” coping and avoidance with poorer mental health. This review [ 27 ] also sought studies of metacognition in women with endometriosis, but found none. The same authors, in a large mixed method study, reported that worry about pain, rumination and catastrophizing, were all associated with more distress [ 28 ], a result consistent with another review of observational studies [ 4 ] and a separate meta-analysis on stress and endometriosis [ 29 ]. The only review to take a social focus was an account of stigma causing distress; family members, clinicians, and others who believed endometriosis to be no worse than period pain represented women who struggled with endometriosis pain as exaggerating or complaining excessively [ 19 ].

Overall, there is little theorising in this area about the nature of distress or about the fit of existing psychological models of pain in women with painful endometriosis. This literature review aims to elaborate the findings on psychological models used in endometriosis pain described in qualitative and survey research, and to outline outstanding areas that need further investigation, using a systematic method of synthesizing the findings of qualitative studies [ 30 ].

This literature review was pre-registered (PROSPERO CRD42022330527), and in preparation for the review, the researchers discussed endometriosis and key literature with expert clinicians and experts by experience, and consulted an academic librarian about the search terms and databases to use. Reporting of the review is in accordance with the ENTREQ statement [ 31 ] (see additional files Table  2 ).

Search strategy

On 6th May 2022, a comprehensive literature search of all years of Medline, Embase, PsycInfo, PsycExtra, ProQuest Dissertations & Theses Global, and LILACs was conducted, aiming to include grey literature and international databases. Broad search terms on endometriosis, pelvic pain, quality of life and experience were employed, and as they returned a large number of results, references of studies retrieved were not further searched. The search terms used are shown in additional files Table  1 .

Inclusion and exclusion criteria

The inclusion criteria were qualitative research or surveys, from peer reviewed journals or publicly available PhD theses, whose participants were adult women (18 and over), not solely concerned with healthcare experience. There were no limitations placed on language or date of publication. We excluded studies unrelated to endometriosis, studies of non-human animals, literature reviews, and conference abstracts.

Study selection

This search returned a large number of records, initially screened using the Endnote X9.3.3 deduplication function, with further duplications removed by hand. Titles were screened to remove theses below PhD Level and irrelevant literature (e.g. male pelvic pain, cancer etc.). The next stage of study selection (see Fig.  1 ) involved one researcher (HM) screening titles and abstracts, removing those that were solely treatment comparisons, that focused on chronic pelvic pain (CPP) with no reference to endometriosis, or that focused exclusively on interactions with healthcare professionals. Another researcher (AW) checked a ~ 15% random sample (300) of the rejected titles plus all 270 studies identified as possibly meeting criteria; decisions were discussed and agreed. Full papers were read for all possibly eligible studies, with further removal of conference abstracts, papers with no reference to psychological models, accounts only of treatment or healthcare experience, or chronic pelvic pain without separate description of participants with endometriosis.

Search and selection of qualitative studies

Quality assessment

The surveys and qualitative research were then analysed and synthesized separately. For the qualitative research, an amalgamation of the CASP and COREQ quality assessment tools (Appendix A) was used to assess the quality of the studies. The CASP and COREQ quality assessment tools were both selected as appropriate after trying several other tools on four studies. Duplicate questions on the two tools were removed, the combined version test run on four further studies, nonessential items removed, and then the entire set split for rating, with an overlap of four studies to check consistency. Lower quality studies were not removed, but the rating was kept in mind during analysis. The researchers both assessed four randomly selected studies, then compared findings. Following this, they split the studies, and individually assessed them.

Surveys: narrative analysis

For the surveys, data were extracted using narrative synthesis methods [ 32 ], suitable for thin data, on the population, sample size, location of study, questionnaire and research tools used, the preoccupation/themes of the survey questions and psychological models discussed.

Qualitative data synthesis

The data was synthesized according to Thomas and Harden’s [ 30 , 33 ] thematic synthesis method using inductive coding. This was chosen after reading around the topic (particularly [ 33 , 34 ]) and discussion with a colleague experienced in the fields of pain and of methods of qualitative synthesis.

First, line by line codes were developed by the first researcher (HM), and used on the Results and Discussion sections of all included papers, recording in NVivo 12 1.6.1. The resulting longlist contained 189 codes. The second researcher (AW) applied these codes to 20% of the sample primary studies, suggesting new ones where necessary. The codes were discussed, agreed, and collapsed or combined. Descriptive themes, staying close to the content of the primary studies, were then generated from the grouped codes, separately by each researcher, then discussed and agreed. Finally, analytic (interpretative) themes were developed jointly using the map of descriptive themes and their constituent codes. Themes were, where possible, given a title that used the words of a participant from one of the primary studies.

Positionality and reflexivity

Given the subjective bias inherent in decisions described above, and of interpretations, we include a statement of position to make our perspectives more transparent. AW is an academic and clinical psychologist, with over 35 years’ experience working in chronic pain, including chronic pelvic pain. While she has used the fear and avoidance model in academic and clinical work, she considers it to capture only part of the chronic pain experience, even in musculoskeletal pain. HM is a research assistant, with experience in qualitative research. This was her first project researching pain, and considers the biopsychosocial model to be the most convincing pain model to date. Throughout the project, the researchers aimed for reflexive processing of reviewed material, considering at each point whether and how their beliefs and concerns might influence their decisions.

Over 2000 records were screened on title and abstract, and 109 selected as possibly eligible. These were read as full papers. Despite help from libraries, and attempts to contact authors, full texts for seven studies could not be obtained. Two studies were discovered in the search as theses, but authors directed us to their published studies, which were included. Three survey studies, all with abstracts but not full text in English, appeared to be unlikely to meet criteria so were excluded. Responses were not forthcoming from two sets of authors. This resulted in the synthesis of 22 surveys and 33 qualitative texts, one of which was translated from Portuguese.

The research literature that used surveys of women with endometriosis (with or without a comparison population) to elicit information about physical and psychological health were predominantly concerned with quality of life and what physical and psychological variables were associated with it. This appeared to be an area of increasing interest: seven studies were published between 2016 and 2019, six studies each in 2020 and 2021, and three in 2022 up to the point of the search. Six studies were from Australia, four from the USA and Canada, one from Brazil, one from South Africa, and the remainder from Europe. All but one, on adolescents up to 25 years old, recruited adults, usually defined as over 18 years, mainly relying on self-diagnosis, with some self-report of medical diagnosis. All studies were cross-sectional, 12 studies describing a single population, eight comparing women with endometriosis with women without, and two making comparisons within a sample of women with endometriosis, one relating to psychological health and the other to diet.

The most common focus of the studies was quality of life and the gynecological, pain and psychological symptoms associated with it (nine studies), with two investigating sexual activity in relation to quality of life. Pain and its relationship to lifestyle problems in endometriosis was addressed by three studies; psychological problems, depression in particular, were the focus of two studies and stigma of one further study. Fatigue was investigated in two studies; and diet and infertility in one each. One study tested the performance of a generic psychological questionnaire in an endometriosis population.

Pain (pelvic pain, abdominal pain, low back pain, menstrual pain, dyspareunia, and pain on defecation) was investigated in relation to quality of life in 10 studies [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ], all of which found more pain to be associated with poorer quality of life (often health-related quality of life), greater impact of endometriosis on life, or poorer psychological health. Two of these 11 [ 35 , 39 ] reported dyspareunia alone to be associated with poorer quality of life. One further study [ 44 ] did not analyse pain separately from a broader physical function score which was associated with poorer quality of life. Two other studies on pain [ 45 , 46 ] investigated characteristics of the pain itself and reported evidence of central sensitization.

The association of endometriosis symptoms with psychological symptomatology was investigated in eight studies [ 37 , 42 , 43 , 44 , 47 , 48 , 49 , 50 ], generally finding greater distress (although Bien [ 34 ] did not) and an association between greater distress, more or more severe endometriosis symptoms and particularly pain, and poorer quality of life. Only one study [ 41 ] was explicit about the psychological model used as a basis for the investigation, describing the fear and avoidance model [ 51 ] and using catastrophizing [ 52 ] as a central variable. They described phenomena related to the fear and avoidance model in terms of pain cognition: hypervigilance to pain, catastrophizing, and fear of pain, all of which they found to be more extensive in women with endometriosis than in healthy controls; avoidance of activity on the basis of fear of pain was inferred, not sampled. Other papers in this sample drew implicitly or explicitly on psychological distress as a common consequence of endometriosis, but for at least one survey psychological distress was assumed to be an antecedent [ 42 ]. (See additional files for surveys not referenced here.)

Qualitative studies

The largest number of studies (11) was conducted in the UK; Australia and the USA provided 5 each, with 3 from Brazil, 2 each from Italy and Germany, and one each from New Zealand, Iran, Puerto Rico, Spain, The Netherlands, Sweden, Hungary; and one sampled from France, Germany, and the USA. They were published from 1995 to 2022, the majority since 2018, with a range of participants from six to 61, a mean of 25 per study. Participants were mainly recruited through advertisements in endometriosis groups and online message boards and social media (19 studies), with 7 studies using patients identified/referred by medical professionals, 7 recruited from outpatient clinics or hospitals, 5 using word of mouth/snowballing alongside those listed above, 4 using a subset of a larger study, and 2 using a medical recruitment company. For the three studies [ 53 , 54 , 55 ] that included healthcare professionals in their sample, we used as far as possible only material from women with endometriosis. Twenty-three of the 33 studies collected data through individual interview, with a mix of face-to-face and online settings; five used focus groups; three used a written response, and two used combinations of these methods. Participants were mainly in their thirties or early forties, with a range of 12–78 years (23 studies provided data) and a mean of 35 years (from 21 studies). The mean age at diagnosis was 27 years (8 studies), with a mean diagnostic delay of 8.5 years (8 studies) and mean age for onset of symptoms 17 years old (2 studies). Ethnic diversity was purposively sampled in just one study [ 56 ]; where ethnicity was reported, there was a general lack of diversity, but this was rarely commented on (one exception was Cole et al. [ 57 ]) (Table 1 ).

Information collected using the combined COREQ/CASP form is provided in full in Additional files, Table  4 , and summarized here. Interviewers identified themselves as academics, students, psychologists or nurses, although about half the studies provided no information, and few described any training in interviewing. Twenty studies (see Additional files Table  4 ) employed only female interviewers, one used both male and female, and one only male [ 59 ]; the remainder did not specify the sex of the interviewer/s. Five researchers identified themselves in their publication as having endometriosis [ 57 , 60 , 61 , 64 , 67 ], but it is not clear whether that information was shared with their interviewees, making it hard to estimate how it might have affected data. Two studies reflected on whether characteristics of the interviewer/s might have biased recruitment or interview content, one [ 57 ] in relation to ethnicity, declaring interviewers to be white academics, and the other [ 81 ] in terms of sociodemographic characteristics. Seven further studies included reflexive comments on the researchers, and six more a very limited statement; others provided none, despite the convention of qualitative researchers attempting to be transparent about possible biases brought to their data.

Four studies described their methods only as qualitative; the remainder elaborated, either identifying a method (such as discourse analysis, or thematic analysis) or an epistemological stance, or both. The most common aim was to describe women’s experience of living with endometriosis (14 studies), including its social impact; the next most common was studies of assessment tools or trajectories of diagnosis and treatment (8 studies); there were 7 studies of meaning and identity; two of language use; and one each of stigma and of fatigue.

Thematic synthesis

Coding of content of results and discussion, both directly reported participant comments and those of the researchers, provided 188 initial codes, which were then grouped and named as far as possible using quoted phrases from the studies. Further grouping produced five themes concerned with the internal experience of having endometriosis; two themes about interface with the external world; two concerned with effects on interpersonal and social life, and one (in three parts) with encounters with medical care (see Fig.  2 ).

Main themes and sub-themes

Internal experience of endometriosis

Pain-endometriosis affects every aspect of life.

This theme addressed the impact of both endometriosis symptoms and pain on all areas of life, loss of identity, of freedom, and of imagined future. It shared several codes with Emotional components and consequences of pain and endometriosis. There was a minor positive component, although this may have been elicited mainly by researchers’ questions about positive aspects.

Endometriosis pain is different

The sense of difference from normal menstrual pain was widely emphasized, perhaps because so many women had historically had their early symptoms dismissed as “just period pain”, and perhaps because interviewers were almost always women who would be expected to have experience of dysmenorrhea. Pain was described as qualitatively and quantitatively different, often in very powerful terms, and again this shared several codes with Emotional components and consequences of pain and endometriosis .

Endometriosis affects my body beyond pain

This theme particularly concerned unpredictable bleeding, in timing or quantity; effects on the bowel, bladder, appetite, energy and sleep, and comorbidities; and discomfort with sexual activity. Women described a relationship with their bodies that had changed for the worse.

Emotional components and consequences of pain and endometriosis

Self-doubt, anxiety, depression, and a general sense of being unable to function adequately were commonly reported, directly linked to the problems associated with endometriosis and pain. Occasionally this was expressed with some positive sense of managing it: “yes, it’s painful and yes, it’s awful, but you can live with it”.

Fears and worries about pain and endometriosis

Because of our particular research question, we did not subsume this under the previous theme, although that would have been possible. Fears and worries concerned infertility; worsening and recurrence with or without treatment, including the possibility of cancer developing; and concerns that daughters would also have endometriosis. Codes were mainly shared with Pain-endometriosis affects every aspect of life and Encounters with medical care.

Interface with the external world

Self-regulation of pain and endometriosis.

This theme concerned the ways in which women managed their endometriosis in order to be able to live a more normal life, from “hiding from the world”, to taking analgesics, planning carefully, and building understanding of their condition. In that sense many contributions expressed some sense of achievement of controlling the impact of endometriosis.

Social regulation to manage pain and endometriosis

This theme expressed both the scepticism that others in participants’ lives could understand their difficulties, and also help and support received from others in managing endometriosis and pain.

Effects on interpersonal and social life

Endometriosis and pain affect close others.

There was a strong sense, despite self- and social regulation, that family members were negatively affected by the woman’s endometriosis, and in particular, romantic and sexual partners.

Endometriosis and pain affect social life and work

Related to the foregoing theme, and to attempts at social regulation, were many accounts of either avoiding socialising at specific times or in general, and of having to take time off work or struggling to hide symptoms. There were a few accounts of friends and of work colleagues and structures being supportive.

Encounters with medical care

This was a large theme, perhaps partly as a function of being the main research focus of several studies. It shared few codes with other themes, and had three sub-themes. The first described the overall sense of being unpleasantly exposed by diagnostic and treatment procedures: “I think they forget that you’re a person”. The second sub-theme portrayed diagnosis, often many years after the onset of symptoms, as a turning point. Although most accounts described negative experiences of the struggle for validation and diagnosis, there was also a positive aspect when this was achieved, as in, “I was devastated but relieved”. The third sub-theme concerned disappointments with treatment options and with limitations and disadvantages to what was offered, from contraceptives to encouragement to have children as soon as possible, whatever the woman’s situation. There were very few positive comments on achieving some control through treatment.

Psychological dimensions of endometriosis pain

The theme of Emotional components and consequences of pain and endometriosis provided very familiar material from other studies of chronic pain, musculoskeletal, visceral and pelvic, or mixed [ 1 , 14 , 15 , 23 , 85 , 86 ]. Since we are interested particularly in how well the psychological experience of endometriosis pain fits the generic fear and avoidance chronic pain model [ 86 ], we examine here in more detail the content of the theme Fears and worries about pain and endometriosis.

The commonest fears, from almost half the studies, concerned infertility. For younger women, this was anticipation of being unable to conceive or being unable to sustain a pregnancy; for older women, infertility was for many (but not all) a significant loss, or for those who had children, concerns about infertility had interwoven in problematic ways both with their treatment options and with their life planning, and some expressed disappointment that parity had not resolved either pain or endometriosis as they had been led to expect. The next most common fear was of recurrence (12 studies) of endometriosis, of worsening following unsuccessful treatment (11 studies) or without (7 studies), and these were linked to extreme pain (“you’d think you were dying”). This most closely resembled the overly negative predictions and associated distress described in the fear and avoidance model. Two other sources of fear occurred in a handful of studies each: of cancer (the diagnosis having been missed, or developing in future), and of genetic transmission of endometriosis to daughters creating additional responsibilities for their mothers in trying to manage it effectively. Not evident in these studies was women’s fear of damage to their bodies during sexual activity, which unlike most other activities that exacerbate pain (such as digestion, or defecation) can be avoided. Attempts at control for such activities focus rather on the emotional or social aspects.

Taking together the survey findings and the qualitative meta-synthesis, clear associations emerged between endometriosis pain, distress, and reduced quality of life, but not strongly with any definitive psychological formulation of pain and related problems, nor with the predominant sense of threat that contributes to central sensitization [ 14 ]. In the only survey study in which an explicit psychological model was used [ 41 ], that of fear and avoidance [ 86 ] and catastrophic thinking biases [ 52 ], support was found for its application, although methodology was somewhat weak (comparison with pain-free population, and avoidance not directly sampled). Several surveys used outdated models of ‘somatization’, somatic expression of psychological distress, that constitute an unsatisfactory model of endometriosis. The qualitative synthesis combined a relatively large number of studies; they showed substantial common ground in the experiences of women with painful endometriosis, across continents, population samples, and research questions.

No previous review has combined women’s perspectives on the experience of endometriosis pain in such an open-ended way. Our findings describe women’s sense of being let down by and alienated from their bodies, at the same time as needing to attend to and attempt to regulate, or at least predict, their bodies’ vagaries, to function in the outside world, on a daily level, and on a level of life plans. This uses normal rather than psychopathological terms in a coherent framework that combines findings of various other reviews, and is entirely compatible with central sensitization maintaining pain whatever the level of disease [ 3 ].

A narrative synthesis of qualitative, quantitative, and mixed method studies [ 1 ] described concerns of women with endometriosis about fertility and planning and having children, medical management, information and support, emotional distress (although without any description of anxieties), and feelings of powerlessness. A more recent systematic review [ 27 ] of nine quantitative and qualitative studies reported few differences between women with endometriosis pain and people with other chronic pains in metacognitions, including ‘catastrophic thinking’, and coping strategies, noting that more emotion-focused coping and avoidance was associated with poorer mental health. Similar findings are reported in a recent review that distinguished ‘catastrophic thinking’ as the main predictor of pain intensity from anxiety, depression and stress, associated with poorer quality of life [ 4 ]. A thematic synthesis by Young et al. [ 26 ] noted the gaps in the study of emotional and social wellbeing, and recent studies go some way towards filling this gap [ 19 ]. Many reviews of endometriosis note its deleterious effects on quality of life (e.g. [ 87 ]), and a few link this directly to pain [ 16 ] and, therefore, to the need for psychological support or treatment [ 88 , 89 , 90 ].

Limitations & strengths

Our search was broad and not limited to English language papers, although to those abstracted in English. Nevertheless, there are likely to be studies of endometriosis and associated problems inaccessible to our searches, narrowing the cultural range of studies, and we did not screen references of eligible studies for any missed by the search strategy. Two papers focused predominantly on fertility problems, from Iran and Brazil [ 53 , 83 ]. We focused only on the experience of women; there is a substantial research literature on the experience of their sexual partners which we excluded. We annotated the studies using a previously untried combination of two established (and somewhat overlapping) scales; this may have increased the arbitrariness of what is taken as a marker of ‘quality’, and contributed to our decision not to assign scores to annotations. We were interested particularly in the extent to which researchers intentionally or unintentionally elicited particularly content in interviews, but reporting of most studies, even the small minority with a reflexive statement, did not comment on this except in the case of a male interviewer [ 59 , 78 ]. It is hard to summarize quality other than with the narrative provided. We did not double-code and double-rate studies, relying instead on doing so for a sample and proceeding with frequent discussion and consensus, but ideally a larger team would have worked on this review [ 91 ]. Finally, the survey data were hard to interpret given that many respondents were self-diagnosed; we have therefore commented more on survey authors’ models than on their outcomes, nor did we attempt any quantitative analyses.

Clinical and research implications

Many studies recommended better education about endometriosis for clinicians, emphasizing, in particular, the role of nurses in providing information to patients. We would hope that such education fully integrated the problem of pain and involved all relevant healthcare professionals; our search returned many qualitative studies of women’s experience with endometriosis where pelvic pain was barely addressed, or was represented as one symptom among many, disregarding the extent to which pain itself is a significant cause of distress and difficulty managing everyday life (see [ 12 , 29 ]), requiring attention and efforts to mitigate pain in its own right, not just secondarily to treatment of endometriosis.

There is a broader need for psychological care to be better integrated into health services for many diagnosable conditions, including endometriosis. Although we found some common ground for understanding psychological problems that can be extrapolated from chronic pain in general, the focus on fear of physical damage and avoidance of physical demands predominant in some psychological interventions is not supported by our findings. Although it is too early in these explorations to suggest specific psychological interventions, information and support, not least from other women with endometriosis and resources created and maintained by them, may meet most needs, with skilled psychological intervention for those women who are more distressed and limited by their pain. Discussion with a clinical specialist about attention to symptoms and when to seek expert healthcare can support self-management in women concerned about recurrence of adhesions; discussion about possible triggers and systematic ways to test them can be helpful to those seeking greater control. Multimodal pain management interventions based in psychological understanding are widely recommended for chronic pain of all sorts (e.g. NICE [ 92 ]), but ideally is personalized to the particular problems and priorities of the patient and recognition of specific concerns associated with the disease or type of pain [ 3 ].

Several research gaps were noted by As-Sanie et al. [ 93 ] at a US meeting of clinicians of various disciplines, women with endometriosis, researchers, and members from industry and government. Among them were the need for mental health professionals attached to endometriosis clinics; the contribution of physiotherapists and others to pain-relieving strategies; the lack of accurate information on relief from different types of hysterectomy, and on pain recurrence following surgery. A priority setting partnership in the UK included in the top 10 priorities, alongside better and less invasive diagnosis and improved education of healthcare professionals, the need to determine the most effective ways of managing the emotional and psychological impact of living with endometriosis [ 94 ]. Both effective management and the more routine involvement of mental health professionals proposed by As-Sanie and colleagues [ 93 ] require a better understanding of the content of women’s distress about endometriosis, and the particular areas of impact; this review provides a step towards that understanding. There seems little need for repetition of descriptive studies of the impact of endometriosis on women’s lives, given the number and breadth we found. We would recommend investigations with clearer theoretical roots in psychology, particularly but not exclusively the psychology of pain, to establish a solid basis for developing effective psychological interventions, with more of a focus than is characteristic of psychological models to issues of social disclosure, difficulties in social situations, and stigma, affecting both work and personal social situations.

Endometriosis has widespread impact on women: on their relationship with their bodies; their psychological and social wellbeing; and on life plans and lifestyle. This is similar to the situation of people with other chronic pains, musculoskeletal, neuropathic, or visceral. However, the dominant psychological model of pain, of fear of reinjury and increased pain from avoidable activity, resulting in disability, only partly fits the situation of women with endometriosis. Many factors that exacerbate pain cannot be avoided, nor is there evidence of an overarching fear of physical demands (of everyday life or valued activities) threatening bodily integrity. The psychological component of endometriosis pain requires further exploration with the aim of building psychological models that can underpin targeted interventions for distress and social withdrawal.

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Acknowledgements

Our funding is from the Advanced Pain Discovery Platform, funded by the MRC, Versus Arthritis, ESRC, BBSRC, Medical Research Foundation, Astra Zeneca, and EliLilly: Grant Reference No. MR/W002426/1; Primary Investigator Professor Geoff Woods, University of Cambridge.

We are very grateful for discussion of methodology and initial analysis to Kate Seers, Professor of Health Research and Director of Warwick Research in Nursing, Warwick University; for comments on previous drafts from Emma Cox, CEO of Endometriosis UK; Katrine Petersen, Advanced Physiotherapy Practitioner and Specialist in Chronic Abdomino-Pelvic Pain Management, University College London Hospitals, London UK; from Prof Andrew Horne, Professor of Gynaecology and Reproductive Sciences, University of Edinburgh; and from Dr Federica La Russa.

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HM prepared and conducted the search, scanned all titles and abstracts, selected full texts for inclusion, rated all included studies, prepared tables (including additional files) and figure, drafted the Methods, and commented on all parts of the paper.

AW sampled each of the search and selection above, including full reading of included and excluded studies, did several sample ratings (as described in paper), drafted the paper other than Methods, obtained opinions from colleagues named in Acknowledgements, and completed the paper for submission.

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de C Williams, A.C., McGrigor, H. A thematic synthesis of qualitative studies and surveys of the psychological experience of painful endometriosis. BMC Women's Health 24 , 50 (2024). https://doi.org/10.1186/s12905-023-02874-3

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Time for global health policy and research leaders to prioritize endometriosis

• Linda C. Giudice   ORCID: orcid.org/0000-0002-1677-0822 1 ,
• Andrew W. Horne   ORCID: orcid.org/0000-0002-9656-493X 2 &
• Stacey A. Missmer   ORCID: orcid.org/0000-0003-3147-6768 3 , 4  

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Endometriosis is an incurable, under-diagnosed, systemic inflammatory disease affecting millions world-wide. Common symptoms include life-impacting pain, gastrointestinal/urinary symptoms, excessive fatigue, and infertility. Global public health policies are urgently needed to promote awareness, implement multidisciplinary care, and fund research for aetiology, biomarker discovery, and effective therapies for symptoms associated with endometriosis.

Patient and public health impact of underinvestment in endometriosis

Defined by endometrium (uterine lining)-like tissue outside the uterus, endometriosis is a little known, common, hormone-dependent, inflammatory disorder currently diagnosed by surgical or radiologic visualisation of disease 1 . While mainly associated with life-impacting pelvic pain, painful menstruation and sexual intercourse, infertility, fatigue, and depression, those affected also have higher risk of non-reproductive sequelae, including high blood pressure, cardiovascular disease, autoimmune conditions, gastrointestinal and urologic symptoms, multifocal pain, migraines, and ovarian and breast cancer 1 (Fig.  1 ). Endometriosis affects ~10% of persons with a uterus, commonly striking teens and persisting across the reproductive life span (and sometimes beyond), greatly impacting personal relationships, educational and employment opportunities, and quality of life 2 , 3 . Risk of developing disease is ~50% genetic, with no specific “endometriosis gene” or consistently identified environmental triggers 1 .

Basic research is key to understanding its causes and molecular and genomic underpinnings, leading to novel diagnostics and therapeutics to alleviate symptoms and ultimately discover a cure. Education of professional and lay communities and leaders throughout the world about endometriosis and its intersection with social determinants of health are key components to improve the lives of those affected. Moreover, multidisciplinary care is essential for holistic management of this complex and multi-dimensional disorder.

Reliance on surgery and marginal advances in medical therapies for symptom relief maintain delayed diagnosis and insufficient care for many 1 . Moreover, menstrual stigma, pain in women, sexism, and racism are impediments globally for life-improving care 3 , 4 . Lack of awareness and/or discomfort regarding menstrual health remains surprisingly prevalent among healthcare providers 3 , 4 .

Clinical specialties are commonly siloed, which diminishes recognizing and addressing endometriosis in clinical practices and specialist care outside gynecology 1 , 3 . Siloed structures also negatively impact awareness and applying cutting-edge technologies to multidisciplinary scientific discovery of causes, diagnostics, and treatments for endometriosis 3 , 4 , 5 . Impediments to determining aetiology and pathophysiology, classifying clinically-relevant subphenotypes, diagnosing, and treating endometriosis include socio-cultural factors that continue its obscurity among practitioners and the public 1 , 3 , 4 . Here we summarize challenges in endometriosis care and advancing research in this space.

A primary hypothesis for pelvic endometriosis establishment is through transplantation of endometrial tissue refluxed through the oviducts during menses, attaching to and invading pelvic organs, and eliciting a profound inflammatory response and fibrosis 1 . This is replicated in experimental rodent models that utilize seeding with heterologous or homologous endometriotic tissue 7 . However, this paradigm is insufficient, as nearly all persons with uteri experience “retrograde menstruation” and rodents do not menstruate. Thus genetic, epigenetic, hormonal, immunologic factors, endometrial stem cells, and coelomic metaplasia, have been implicated in establishment/survival of lesions (with pathway-informative somatic mutations)—complementing the theory that retrograde menstruation plays a causal role 1 , 4 . While mechanisms underlying this complex pathophysiology are slowly being elucidated, a comprehensive understanding of disease origins is wanting. This has stalled comprehensive animal models with disease fidelity—hampering research on endometriosis overall 6 .

Mechanisms underlying endometriosis-associated pain are complex 7 . Key to establishing lesions and activating peripheral pain pathways are new blood vessels and nerve sprouting (neuroangiogenesis) 7 . Also, in the central nervous system, brain volume and regional biochemical alterations accompany chronic endometriosis-related pain 7 . Endometriosis is also associated with infertility—attributed to scarred Fallopian tubes, diminished egg quality, and/or disrupted hormone signaling within the uterus 1 , 3 , 4 . Improved understanding of endometriosis pathogenesis and its complex and heterogenous manifestations and physiologic impacts are essential to develop improved diagnostics and patient-centred therapies.

Heterogeneous presentation of endometriosis impedes diagnosis and treatment

Most pelvic endometriosis comprises three subtypes: superficial peritoneal, ovarian cysts (“endometrioma”), and deep disease 1 . Symptom manifestation and severity vary, and underdiagnosis is common due to erroneous symptom normalization and overlap with other diseases 8 . Recently, refined imaging techniques identify, with high accuracy, ovarian and deep disease, but reliance on surgical visualisation for the most common superficial peritoneal lesions continues to impede timely diagnosis 3 , 4 . Surgery or imaging requires access to healthcare services, which varies significantly across socio-economic and racial/ethnically underserved groups and geographies 4 , 9 . Average diagnostic delay is 7 years after symptom onset, with delays >10 years not uncommon 4 , 9 . There remains no reliable non-invasive biomarker of any endometriosis subtype 4 .

Treatment of pain symptoms falls broadly into surgical removal of disease and associated adhesions and hormonal suppressive therapies, including combined oral contraceptive steroids, progestins, gonadotropin releasing hormone analogues, androgens and aromatase inhibitors 10 . Medical therapies that decrease oestrogen (or counter oestrogen action) are prescribed, because steroids play a key role in the pathophysiology of endometriosis 1 . Unfortunately, both approaches are suboptimal. Surgery is associated with recurrence rates up to 50% within 5 years, and contraceptive hormone treatments often have unacceptable side effects and are counterproductive to fertility goals 10 . Geographic and financial barriers to accessing treatment from endometriosis-trained healthcare providers are common 9 . Surveys of patients consistently highlight symptom relief and improved medical therapies that do not limit fertility as a top priority for research 3 . Historically, pharmaceutical companies were reluctant to develop new drugs for endometriosis, and focus has been on variations of hormonal, anti-inflammatory, or repurposed therapies 11 , lacking revolutionary impact. While novel treatment discovery is essential, clinical trials for endometriosis have been plagued by widespread variations in outcome reporting, and only a fraction of completed trials is published 11 .

Emerging chronic pelvic pain-focused therapies that include considerations of neuropathic and nociceptive pathways have not been adequately studied 12 . Those with persistent/recurrent pain have a high rate of hysterectomy 12 which does not eliminate pain recurrence and may heighten risks for multiple conditions later in life 1 , 10 . Further, commonly reported life-impacting concerns including fatigue and impaired sexual functioning have yet to be targeted for treatment among patients with endometriosis. A critical impediment to discovery of novel diagnostics and treatments and personalized approaches is the lack of a prognostically correlated classification of the highly heterogenous presentation of endometriosis lesion types and symptoms, which includes variation and evolution within patients across the life-course 3 , 4 .

Endometriosis funding landscape and the socioeconomic cost of underinvestment

The first economic study (2011) revealed the average cost of endometriosis was ~€9579/woman/year (€6298 lost work-productivity, €3113 direct health care costs)—similar to diabetes, Crohn’s disease, and rheumatoid arthritis 13 . However, unlike these well-known diseases with similar socioeconomic impact and burden but considerably lower prevalence in the general population, there is relatively little investment in research into causes and disease mechanisms of endometriosis 5 . Recent governmental attention has included an increase in NIH funding for endometriosis research to $16 M (0.04% of the total NIH budget) for the year 2022 ($2/person with endometriosis/year), while Crohn’s disease received $90 M ($130/person with Crohn’s/year) 14 . Data consistently demonstrate that female-specific conditions are disproportionately underfunded 5 . Further, female reproductive conditions are largely absent from open access reference databases on which much of advanced biomolecular data science relies (e.g., ENCODE, NIH Roadmap epigenomics, GTEx, TissueNexus), impeding novel discovery, although recent endometrium and endometriosis single-cell transcriptomic data should soon appear in the Human Cell Atlas 4 .

Commitments to endometriosis research and care and moving forward

Despite identification of endometriosis as a chronic inflammatory pain condition with multi-systemic symptoms and co-morbidities 1 , 8 , as a disease associated with menstruation and pelvic pain, it is still generally considered a gynaecologic disorder. This reductive concept has resulted in lowered healthcare system and research prioritization, limited integration, and impeded translation of rapidly developing scientific, multi-omic, genetic, bioengineering, and clinical discoveries in pain and inflammation. Their application would hasten identifying shared and unique features of endometriosis, leading to novel therapeutics and multi-disciplinary approaches to symptom management.

Essential to improving diagnosis and care for endometriosis patients is ensuring they are heard and believed when expressing their symptoms to themselves, their personal support networks, and especially to healthcare providers 4 , 10 . The 2021 WHO Endometriosis Fact Sheet ( https://www.who.int/news-room/fact-sheets/detail/endometriosis ) is a welcome leap forward to increase awareness globally. We posit that education and improved awareness including menstrual wellbeing curricula within schools for students of all gender identities could overcome menstruation taboos, ensure understanding of a ‘normal’ period, and when to seek help for distressing symptoms. Improved medical education regarding menstruation and endometriosis signs and symptoms could be ensured with thoughtful targets, e.g., including questions about menstrual health and non-malignant gynaecologic conditions on medical training board examinations, and larger scale initiatives such as revision of didactic teaching and medical curricula to prioritize menstrual health as critical to patient care.

Once diagnosed, individuals with endometriosis require personalised, multimodal, interdisciplinary treatment across the life-course to meet challenges of the evolving disease and changing patient priorities. First proposed in 2006, this novel care approach is optimally delivered through specialist centres comprised of integrated services including gynaecologists, endometriosis specialist nurses, and experts in imaging, pain medicine, psychology, physiotherapy, fertility, colorectal surgery, urology, and gastroenterology 15 . Whilst specialist centres have been successfully implemented in the UK and a few European countries (e.g., Denmark, Germany, France), this is not standard of care worldwide. Importantly, care delivery models incorporating mobile and digital technologies, and including primary care providers, specialists, pharmacy-based, community-based, and risk-prevention approaches, offer great opportunities and need development and investment 4 . For example, the Australian National Action Plan for Endometriosis launched in 2018 with $58 M additional funding in 2022 supports a 4-year plan to fund research and establish specialist endometriosis and pelvic pain clinics in every state and territory. Restructuring similar models globally could fulfil personalized care in all regions.

As delayed or undiagnosed endometriosis leads to compromised health, promoting awareness, improving access to care, and implementing multidisciplinary care paradigms are urgently needed in global public health policies. Equally urgent and important are prioritizing and committing resources to support fundamental research and biomarker discovery to shorten the protracted time to diagnosis and provide effective, long-term therapies for this chronic and debilitating disorder to the benefit of millions world-wide.

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Acknowledgements

The authors thank Kevin Kuan, University of Edinburgh, for Fig.  1 graphic design and critical content editing.

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Linda C. Giudice

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Professor of Obstetrics, Gynecology, and Reproductive Biology, Michigan State University, Grand Rapids, MI, USA

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Contributions

L.C.G. conceived the topic and wrote the initial draft, which was extensively revised with A.W.H. and S.A.M.. L.C.G. contributed much of the scientific information about endometriosis pathogenesis and pathophysiology. A.W.H. contributed key concepts about public health relevance and endometriosis clinical symptoms, clinical care, and health disparities. S.A.M. contributed key concepts in the epidemiology of endometriosis, status of funding for research and multidisciplinary care models. L.C.G., A.W.H., and S.A.M. each provided references throughout the manuscript and in areas of their expertise and assured accuracy of citations and worked as a team on revising the manuscript resulting in its final form.

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L.C.G. is funded by the National Institutes of Health P01 HD106414, “UCSF Stanford Endometriosis Center for Discovery, Innovation, Training and Community Engagement”. She is co-author of patent filed by the Regents of the University of California, San Francisco, U.S. Application Serial No. 63/149,022, “Endometriosis-Related Methods and Compositions”. She is past-President of the World Endometriosis Society and the American Society for Reproductive Medicine, and is a consultant for Celmatix, Myovant Sciences, and Gesynta Pharma. AH’s institution (University of Edinburgh) has received payment for consultancy and grant funding from Roche Diagnostics to assist in the early development of a possible blood diagnostic biomarker for endometriosis. A.W.H.’s institution has received payment for consultancy fees from Gesynta and Joii. A.W.H. has received payment for a presentation from Theramex. A.W.H.’s instutution has received grant funding from the MRC, NIHR, CSO and Wellbeing of Women for endometriosis research. A.W.H. is listed as a co-inventor on a UK Patent Application (No· 2217921·2). A.W.H. is President-elect of the World Endometriosis Society and co-Editor in chief of Reproduction and Fertility. AH has been a member of the NICE and ESHRE Endometriosis Guideline Groups. AH is a Trustee and Medical Advisor to Endometriosis UK. S.A.M. receives research support from National Institutes of Health, USA Department of Defense, AbbVie, and Marriott Family Foundations. She is President of the World Endometriosis Society, the Field Chief Editor for Frontiers in Reproductive Health and has served on advisory boards for AbbVie, Roche, and Abbott.

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Giudice, L.C., Horne, A.W. & Missmer, S.A. Time for global health policy and research leaders to prioritize endometriosis. Nat Commun 14 , 8028 (2023). https://doi.org/10.1038/s41467-023-43913-9

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The Barriers That Adolescents and Young Adults with Endometriosis Experience in the United States: A Conceptual Review and Model

• Published: 17 May 2024

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• Jenny Niedenfuehr   ORCID: orcid.org/0000-0001-6096-5881 1 &
• Lindsey M. King   ORCID: orcid.org/0000-0002-5986-954X 2  

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Introduction

Endometriosis is a chronic disease that vastly impacts patients’ lives, especially those who do not know how to manage the disease, understand the treatment options, or find specialists who can provide the proper care. The aim of this review and conceptual model is to provide a public health foundation for physicians and health care providers to further understand the barriers to endometriosis treatment that young adults and adolescents with endometriosis (10–25 years of age) experience grounded by theory and constructs.

A search was performed on PubMed with mix of MesH headings and keywords such as “adolescent,” “Adult, Young,” “United States,” Endometriosis,” and “Barrier.” Papers were reviewed through an inclusion/exclusion process to reduce bias. All papers that were excluded had no relevance to endometriosis, young adults, and adolescents, or were not located in the United States.

Our conceptual model presents the individual factors within the social ecological model (SEM), belief model, social cognitive theory (SCT) (outcome expectations, observational learning), social support, theory of fundamental causes (stigma, racism and discrimination, the built environment, lack of health policies, high costs, lack of health literacy among patients, lack of knowledge among providers), experiences, and outcomes.

Conclusions

The conceptual model and critical review highlight the intertwined, multi-faceted barriers that patients face to endometriosis treatment at each level of the SEM and may serve as an excellent starting point for future research.

Policy Implications

There are no existing policies for endometriosis patients. This is the first conceptual model to include multiple public health theories in relation to endometriosis and can best guide policy makers, program development, public health interventions, and researchers in mitigating patient barriers.

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(Adolescent [MeSH] OR Adolescen* OR Youth* OR Teenag* OR Humans[MeSH] OR “Adult, Young” OR “Young Adults”) AND (“Young adult*” OR “Young Adult” [MeSH]) AND (“United States” [MeSH] OR “United State*” OR “United States/Epidemiology”[MeSH]) AND (Barrier* OR "Perceived Barrier*" OR Coping OR "Psychological Wellbeing" OR "Social Stigma" [MeSH] OR "Quality of Life"[MeSH] OR "Adaptation, Psychological"[MeSH] OR "Coping Strategies" OR “Social Stigma*” OR “Stigma, Social” OR “Interpersonal Relations” [MeSH] OR “Interpersonal Relation” OR “Partner Communication” OR “Social Relationship*” OR "Life Quality" OR "Health-Related Quality Of Life" OR “HRQQL” OR “Health Related Quality of Life” OR “Employment/Education”[MeSH] OR Employment [MeSH] OR Education [MeSH] OR “Coping Behavior” OR “Behavior, Coping” OR “Coping Skill*” OR “Burden of Illness” OR “Disease Burden” OR “Cost of Illness” [Mesh] OR “Mental Disorders” OR “Stress Disorders, Traumatic, Acute”[MeSH] OR “Patient Satisfaction” [MeSH] or Physician–Patient Relations* OR “Patient Satisfaction” OR “Perception*” OR "Perception"[Mesh])AND (Therapeutics [MeSH] OR “Treatment Effectiveness” OR Treatment* OR Therapy* OR Laparoscopy OR Laparoscopy [MeSH] OR Excision OR Physician[MeSH]) AND (Endometriosis[MeSH] OR "Endometriosis/epidemiology"[MeSH] OR "Endometriosis/physiopathology"[Mesh] OR “Endometriosis / psychology” OR Endometrio* OR Pelvic Pain [MeSH] OR Endometrio* OR Endometriosis OR Endometrioma* OR Adhesions OR “Peritoneal Endometriosis” OR Endometriosis/Therapy*[MeSH] OR “Deep Infiltrating Endometriosis” OR “Ovarian Endometriosis” OR “Women’s Health” [MeSH] OR “Chronic Pelvic Pain” OR “Gynecological Disease” OR “Gynecologic Disease*” OR “Pelvic Pain” OR “Pains, Pelvic” OR “Pelvic Pain*” OR “Endometriosis.”

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Niedenfuehr, J., King, L.M. The Barriers That Adolescents and Young Adults with Endometriosis Experience in the United States: A Conceptual Review and Model. Sex Res Soc Policy (2024). https://doi.org/10.1007/s13178-024-00972-x

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Perspective article, endometriosis is undervalued: a call to action.

• 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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89. Jiang I, Yong PJ, Allaire C, Bedaiwy MA. Intricate connections between the microbiota and Endometriosis. Int J Mol Sci. (2021) 22:5644. doi: 10.3390/ijms22115644

90. Salliss ME, Farland LV, Mahnert ND, Herbst-Kralovetz MM. The role of gut and genital microbiota and the estrobolome in endometriosis, infertility and chronic pelvic pain. Hum Reprod Update. (2021) 28:92–131. doi: 10.1093/humupd/dmab035

91. Chadchan SB, Cheng M, Parnell LA, Yin Y, Schriefer A, Mysorekar IU, et al. Antibiotic therapy with metronidazole reduces endometriosis disease progression in mice: a potential role for gut microbiota. Hum Reprod. (2019) 34:1106–16. doi: 10.1093/humrep/dez041

92. Chadchan SB, Popli P, Ambati CR, Tycksen E, Han SJ, Bulun SE, et al. Gut microbiota-derived short-chain fatty acids protect against the progression of endometriosis. Life Sci Alliance. (2021) 4:e202101224. doi: 10.26508/lsa.202101224

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

• Condition Center

How Does Endometriosis Impact Fertility?

If you're reading this, the first thing you need to know is: getting pregnant with endometriosis is possible. But it's not always an easy journey. The condition — which means tissue that's similar to that of the inner lining of your uterus is growing outside the uterus — can make it harder to get conceive. In fact, as many as 30 to 50 percent of folks with endometriosis "may experience infertility ," per the International Journal of Molecular Sciences .

You may notice that's a pretty big range — and that "may" doesn't sound very certain. Well, unfortunately, there's still a lot that scientists don't know about endometriosis, says Louise Perkins King , MD, JD, an ob-gyn and surgeon in the division of minimally invasive gynecology at Brigham and Women's Hospital.

Every individual has a different experience with endo, and some women have no trouble getting pregnant while others struggle for years. So, what exactly do we know and not know about how much endo will impact your fertility journey? We asked the experts what to know about fertility if you've been diagnosed with endometriosis (or suspected endo — if you're presenting with symptoms but haven't had a laparoscopy yet). Here's what they said.

Experts Featured in This Article:

Louise Perkins King , MD, JD, is an ob-gyn and surgeon in the division of minimally invasive gynecology at Brigham and Women's Hospital.

Tia Jackson-Bey , MD, MPH, is a reproductive endocrinologist and fertility specialist at RMA New York.

Banafsheh Kashani , MD, ob-gyn, is a reproductive endocrinologist and infertility specialist.

Can Endometriosis Cause Infertility?

It's possible that endometriosis may impact your fertility, but just because you have the condition doesn't mean you're guaranteed to have fertility troubles. While some folks with endo struggle to get pregnant, others have no trouble conceiving at all. Frustratingly, the science on the inconsistency — and on how and why endo even impacts your reproductive health — is a little murky, Dr. King says.

"We don't fully understand how endometriosis causes infertility nor do we really understand if it always causes infertility," she says. "We only know about endometriosis-related infertility when patients present as infertile. Many endometriosis patients have no pain and many never present as infertile — these cases of endometriosis without infertility are thus not captured by studies."

However, there are a few theories as to why the condition might impact fertility. "Our best guess is that endometriosis causes infertility because it's a disease of chronic inflammation," Dr. King notes.

When endometrial tissue is growing outside of its usual home in the uterus, it creates an issue because the cells that make up that tissue are responding to your normal hormonal cues as though they're in the uterus. The endometrial tissue grows and proliferates through a certain portion of your cycle and then begins to die when your period starts, explains Tia Jackson-Bey , MD, MPH, a reproductive endocrinologist and fertility specialist at RMA New York. Normally, this tissue would be expelled through the vagina during the menstrual process, but in this case there's nowhere for it to go. "As the cell death-like process happens in other places in the body, it creates inflammation because your body's like: 'hey, um, what are you doing here?'"

Your body doesn't like it so it may start to "wall the endo cells off," sometimes causing cysts or scarring to appear, Dr. Jackson-Bey explains. "You have the creation of new tissue, which almost looks like cobwebs or connections between organs that shouldn't be there, and the main ways that it impacts your fertility is by, one, creating blockages in the fallopian tubes."

In order for an egg and sperm to come together and grow an embryo, the fallopian tubes have to open "like a highway or a tunnel," Dr. Bey explains. The scar tissue and cobweb-like blockage can get in the way of this making it hard for the egg and sperm to come together and grow an embryo that makes its way to the uterus. Scarring can prove problematic if it's impacting the ovaries or the ovarian egg quality or reserve, which can happen if endometriosis remains unchecked or treated Dr. Jackson-Bey says.

Finally, she explains, endo is often associated with chronic pain . When you don't feel good — whether you're having pain with intercourse, trouble moving your bowels, or just general, no-good, very bad pain — it can cause stress and potentially impact your chances of getting pregnant in ways doctors don't fully understand.

Again, there's a lot we don't know about endometriosis — partially because the research is underfunded (though the Biden Administration has recently set aside more money for research into endo and fertility) and partially because this research is incredibly hard to do well. "The way that you get to a scientific answer is to have two individuals in front of you and subject one to an intervention that you don't give the other person — and you see which one does better. In the setting of infertility, it's hard — and you could argue, unethical — to ask people to delay their childbearing. So we may never have those really good randomized controlled trials to get to these answers," Dr. King says.

Is It Possible to Get Pregnant With Endometriosis?

Yes, it is definitely possible to get pregnant with endometriosis. The outcome varies on a case-by-case basis, and where the endometrial tissue has spread makes a difference. But Dr. King notes that age is actually a statistically bigger issue when it comes to fertility than endo is.

In general, the chance of getting pregnant each month for folks with no endometriosis is about 10 to 20 percent, while people who have surgically documented endo have a chance of about one to 10 percent, per Mass General (again, this isn't everyone — some folks have no trouble getting pregnant). But when it comes to age, your chance of successfully getting pregnant without intervention each month drops to about 5%, per Extend Fertility .

"Whether you have endometriosis or not, the primary driver of any infertility in your life will still be your age," Dr. King adds, so don't let the condition scare you out of trying if you'd like to.

How to Potentially Improve Fertility With Endometriosis

The number one thing both Dr. King and Dr. Jackson-Bey recommended for managing endometriosis to preserve fertility is getting on a hormonal medication that helps control your cycle. Again, from what we know, the endometrial tissue is responding to hormonal changes in your body that can lead to inflammation, so if you can head those off, you can reduce inflammation and pain. Although birth control isn't always right for everyone — some folks will experience side effects or have personal reasons for not wanting to be on it — it can help manage things. If you take hormonal birth control and skip the placebo week, Dr. King says, it may help preserve fertility because you're reducing the inflammation because your body won't be bleeding and effectively having a period. She says the Mirena IUD also allows you not to have a period because you're thinning the endometrial lining of your uterus, although it doesn't have the same systemic effects on fertility because it still allows for ovulation that can cause hormonal changes that cause pain and potential issues.

"Anything you do to decrease inflammation, including using hormonal treatment to stop menses, should help preserve fertility," Dr. King says. " Studies support this."

If birth control isn't your thing or you want to take other steps, generally, you can reduce inflammation by eating a balanced diet, getting regular exercise, and generally doing what you can to reduce stress. "Meditation and psychological therapy is actually proven to be anti-inflammatory," Dr. King says. One JAMA review notes that psychosocial interventions may improve your immune system function and help in general with immune-related health. "That's not to say your pain is in your head at all," Dr. King adds.

She adds that acupuncture (from a well-trained specialist) may also help. All of this can help reduce pain, which may in turn help with fertility.

Again, these things aren't foolproof, and, not to be a broken record, there's a lot we don't know. But these strategies can't hurt. And, if you've already tried to get pregnant for six months to a year with no success, it's probably time to speak to your doctor (more on that below!).

When to Speak to Your Doctor Regarding Fertility and Endo

It's never too soon to talk to your doctor about endometriosis or fertility — whether you suspect you have endo symptoms or you have a confirmed diagnosis. Dr. King recommends seeking out a specialist with experience treating endo.

"The biggest thing for women with endometriosis is being diagnosed because the vast majority of women go undiagnosed for an average of 10 years before someone connects the dots and their symptoms," Dr. Jackson-Bey says. "If you are having painful intercourse , pain with periods that makes you change your social schedule, or painful bowel movements, it's not just 'normal.' You deserve to be provided an answer for why it's happening. Proactively ask your physician: Could I be someone who has endometriosis? Make sure that they explain to you the reasons why or why not, and how they're going to screen for endometriosis."

When it comes to endo and fertility, you don't have to wait until you're "ready" for kids (or have to even know you want them) to discuss the possibility. "Be proactive," Dr. Jackson-Bey says.

If you want to get pregnant or are considering freezing your eggs, ask questions about that too. Dr. King notes that the only way to truly know if your fertility will be affected by endo is to start trying. If you've already tried to get pregnant for six months to a year with no success, that's a sign to speak to your doctor or a fertility specialist. "Infertility" is typically defined as not being able to get pregnant after trying for one year, but Dr. King notes: " If we suspect infertility from a specific cause like endometriosis, we suggest shortening the time frame to try on your own," she notes. "Insurance will accept endometriosis as a diagnosis that supports payment for IVF in states in which it's mandated."

Best Fertility Treatment For Endometriosis

If your endometriosis is impacting your fertility, there are options. For starters, you can consult a fertility doctor, who will likely do some testing to assess your condition, says EndoFound medical director Dan Martin , MD. A hysterosalpingogram is common, which involves inserting dye into your fallopian tubes to confirm they're not blocked by endometrial tissue and scarring.

Your doctor will also look at your partner's fertility abilities if sperm is involved, and may suggest a few routes. Your doctor may suggest first trying a procedure known as intrauterine insemination (IUI) , which involves placing the sperm directly into the uterus to achieve pregnancy. This procedure is cheaper than In vitro fertilization (IVF) .

With IVF, sperm and eggs are combined in a lab outside of the body and they're later implanted into the uterus to grow. This process "gives the highest success rates in terms of treatment options for women with endometriosis," says Banafsheh Kashani, MD , ob-gyn, a reproductive endocrinologist and infertility specialist. "Alternatively, some women may take medications (pills or injections) to help them ovulate more than one egg and combine that with an IUI and this can help increase the success of getting pregnant in women with endometriosis." If you're going through insurance, many insurers require you to have multiple failed IUIs before they'll pay for IVF. However, Dr. Jackson-Bey says, if you have an endometriosis diagnosis and can show that the fallopian tubes are impacted, your doctor may be able to help you override starting with IUIs, so your insurance will let you proceed right to IVF, to increase your chance of pregnancy.

Meanwhile, the more you try, you may also end up getting pregnant on your own, Dr. King adds, so don't rule that out. "Don't assume you are infertile simply because you have painful periods or even documented endometriosis," she says.

Pregnancy is possible for many people with endometriosis — remember that stat we mentioned that about 30 to 50 percent of people with endo potentially having fertility issues — that means 50 to 70 percent don't struggle with fertility. And, with any luck, as the science catches up, we'll learn more about how to best treat the condition help those with endo live with less pain and have an easier fertility journey.

Molly Longman is a freelance journalist who loves to tell stories at the intersection of health and politics.

• Health Explainers

Credit: Shutterstock

Academy of Medical Sciences elects eight Oxford researchers as new Fellows

The Academy of Medical Sciences has elected eight University of Oxford biomedical and health scientists to its fellowship in 2024.

The new Fellows have been elected to the Academy in recognition of their exceptional contributions to the advancement of biomedical and health science, cutting edge research discoveries, and translating developments into benefits for patients and wider society.

This year Fellows were chosen from 365 candidates and will be formally admitted to the Academy at a ceremony on Wednesday 18 September 2024.

The new Fellows are:

Professor Ivan Ahel FMedSci , E.P.A. Professor of Chemical Pathology at the Sir William Dunn School of Pathology. He is a member of EMBO and was awarded the Biochemical Society GlaxoSmithKline Award in 2022.

Professor Constantin Coussios FMedSci , Director of the Institute of Biomedical Engineering, Statutory Chair of Biomedical Engineering and Professorial Fellow of Magdalen College.

Professor Catherine Harmer FMedSci , Associate Head of the Department of Psychiatry, Professor of Cognitive Neuroscience and Research Fellow at Corpus Christi College.

Professor Julian Knight FMedSci , Professor of Genomic Medicine at the Nuffield Department of Medicine, Principal Investigator, Deputy Director of the Centre for Human Genetics, Honorary Consultant Physician, Tutor and Fellow at Merton College, Director of the Medical Sciences Division Graduate School, Genomic Medicine Theme Lead at the NIHR Oxford Biomedical Research Centre and Research Director of the Central and South NHS Genomic Medicine Service Alliance.

Professor Teresa Lambe OBE FMedSci , Calleva Head of Immunology at the Oxford Vaccine Group, and Principal Investigator at the Pandemic Sciences Institute.

Professor Lambe said: ‘It is a huge honour to be elected as a Fellow of the Academy of Medical Sciences. I have been fortunate to work with incredibly talented colleagues over the course of my career both in the UK and worldwide, and I’m incredibly proud that this work has been recognised.’

Professor Lambe’s research focuses on delineating the protective immune response post infection and using these findings to rationally design vaccination strategies to prevent disease. Her group is currently developing and testing vaccines against a number of outbreak pathogens including Crimean-Congo haemorrhagic fever, Ebola virus, Marburg virus and Coronaviruses. A number of these vaccines have progressed to clinical trial assessment, including vaccines against Ebola and Marburg virus.

Professor Jane McKeating FMedSci , Professor of Molecular Virology at the Nuffield Department of Medicine.

Professor McKeating said: ‘Delighted to be nominated and for our research to be recognised! A big thanks to current and ex-team members who have made scientific discovery a joy.’

Professor Adam Mead FMedSci , Professor of Haematology at the Radcliffe Department of Medicine, Consultant Physician and CRUK Senior Cancer Research Fellow.

Professor Mead said: 'I am delighted and honoured to have been elected as a Fellow of the Academy of Medical Sciences. Credit goes to the wonderful mentors as well as the talented scientists and clinicians I have had the pleasure to work with over the years. I feel very lucky to be able to work at the MRC Weatherall Institute of Molecular Medicine in Oxford which is an immensely enjoyable and motivating environment to study the molecular basis of blood diseases.'

Adam Mead is a Professor of Haematology at the University of Oxford and leads a team of researchers at the Weatherall Institute of Molecular Medicine focused on a group of blood cancers known as myeloproliferative neoplasms (MPN). These conditions affect over 40,000 people in the UK alone, causing intractable symptoms, blood clots and increased risk of leukaemia. Professor Mead also oversees patient care and clinical trials in this area at Oxford University Hospitals NHS Foundation Trust. Professor Mead and his team are investigating how normal blood cell production becomes disrupted during the development of MPN, with the ultimate goal of improving the diagnosis and treatment of these largely incurable forms of blood cancer. His laboratory have pioneered new techniques to analyse the genetic information contained within individual cancer cells, providing multiple key conceptual advances in the field.

Professor Krina Zondervan FMedSci , Head of Department at the Nuffield Department of Women’s and Reproductive Health, Professor of Reproductive & Genomic Epidemiology, Co-Director Endometriosis Care Centre and Fellow, St Edmund Hall.

Professor Andrew Morris PMedSci, President of the Academy of Medical Sciences, said: ‘It is an honour to welcome these brilliant minds to our Fellowship. Our new Fellows lead pioneering work in biomedical research and are driving remarkable improvements in healthcare. We look forward to working with them, and learning from them, in our quest to foster an open and progressive research environment that improves the health of people everywhere through excellence in medical science.'

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