What is endometriosis?

‍

Endometriosis is a medical condition in which tissue resembling the uterine lining is located outside of the uterus. Often chronic, this condition is commonly associated with cyclic pelvic pain as well as infertility. Approximately 30 to 50 percent of patients who have endometriosis also have fertility problems.ⁱ

Endometriosis is a complex clinical syndrome characterized by chronic inflammation that is dependent on estrogen (ovarian hormone) levels, and primarily affects pelvic tissues such as the ovaries.ⁱⁱ Research suggests that endometriosis affects 5-10 percent of reproductive age females.^iii,iv This means that up to 190 million women worldwide have this potentially devastating medical condition. Endometriosis can also strike adolescent girls and symptoms may even persist in post-menopausal women.^v

The development of endometriosis involves interactions between the immune system and the endocrine system (hormones). The main cause of endometriosis is difficult to determine. More recently, it has been suggested that the definition of endometriosis be expanded to include more diverse symptoms aside from those related to the pelvis, such as systemic inflammation, altered pain sensitization in the brain, and mood disorders.^vi

There are three main types of endometrioses: ovarian, peritoneal, and deep infiltrating. Ovarian endometriosis occurs when cells that are similar in function to the endometrium are found in the ovaries. They can be on the surface of the ovaries (superficial lesions), or inside of the ovary, forming a lump or cyst, called an ‘endometrial cyst’ or ‘endometrioma’.  

Peritoneal endometriosis is a condition whereby endometrial cells or tissue are found in the abdomen (peritoneal cavity) or on the surface of the abdominal wall. It occurs in approximately 15 to 50 percent of patients diagnosed with endometriosis.^vii  

Finally, patients suffering from deep infiltrating endometriosis (DIE) have endometrial tissues that invade deep under the abdominal pelvic organs and walls. The infiltrations may include the small intestine, colon, rectum, vagina, bladder, and/or ureter.^viii

‍

What are the symptoms of endometriosis?

‍

Of women with an endometriosis diagnosis, 83 percent can have one or more of the following possible symptoms:^ix

• Infertility
• Chronic pelvic pain
• Severe and/or frequent cramps during menstrual periods (dysmenorrhea)
• Pain associated with sexual intercourse (dyspareunia)
• Painful bowel movements and/or constipation

‍

Pain symptoms can increase with more significant injury to the endometrium (endometriotic lesions). However, there is only a weak correlation between pain intensity as stated by the patient and graded severity of the disease.^x Five to 21 percent of women hospitalized for pelvic pain have endometriosis,^xi and one third of women who undergo abdominal/pelvic surgery (laparoscopy) for chronic pelvic pain are found to have endometriosis.^xii

Other symptoms of endometriosis include the following:^xiii

• Pain when urinating
• Pain radiating to the back
• Irregular menstruation
• Increasing premenstrual syndrome (PMS) pain  
• Pain at ovulation
• Blood in the stool
• Diarrhea or constipation
• Chronic fatigue

In addition, some patients may experience unusual symptoms such as anxiety, nausea, headaches, depression, or susceptibility to infections or allergies.^xiv

Endometriosis symptoms first appear before the age of 20 in about 66 percent of women diagnosed with the disease.^xv Over time, debilitating menstrual symptoms can increase in severity as inflammation persists and the nervous system is recurrently stimulated by the diseased tissue. This leads to a phenomenon called central sensitization, defined as pain that occurs when the central nervous system is not processing pain signals properly, leaving the patient hypersensitive to stimuli.^xvi

It should also be noted that some women who have endometriosis do not show symptoms (estimated 2 to 11 percent).^xvii

‍

What causes endometriosis?

‍

Endometriosis is characterized by the growth of endometrial-like tissue, called endometriotic lesions, outside of the uterus. Their growth requires estrogen, which is a hormone produced naturally in the ovaries. Researchers have yet to definitively uncover the etiology of endometriosis, in other words, understanding what causes the tissue to grow outside of the uterus. There may be multiple mechanisms which can separately cause this disease.^xviii,xix

Postulated origins of endometriotic tissue may include the following:^xx

• Retrograde menstruation: During menstrual periods, blood and tissue can travel backward from the uterus into the fallopian tubes and/or into the abdominal cavity. It is hypothesized that cells that travel retrograde in this manner may implant in the abdominal cavity and develop into endometriotic lesions. This is the most frequently proposed mechanism.  
• Coelomic metaplasia of the peritoneal lining: Cells from other tissues/organs outside of the uterus (for example, in the peritoneal mesothelium) transform and become like cells of the endometrium.
• Lymphatic and vascular metastasis: Cells of the endometrium travel through lymphatic and blood vessels to develop on distant tissues and organs including the lungs, brain, bone, and peripheral nerves among others.

Risk factors for endometriosis include the following:^xxi

• Low birth weight
• Menstruation/periods beginning at an early age
• Having a short menstrual cycle
• Heavier menstrual flow
• Low body-mass index
• Nulliparity  

Research studies on twins suggest that the heritability of endometriosis is approximately 50 percent (meaning that approximately 50 percent of the disease is due to genetic risk).^xxii Genome-wide association studies have identified 27 genetic risk locations associated with endometriosis.^xxiii

Genetic correlations with co-existing chronic conditions, such as headaches and back/joint pain, suggest that certain women are genetically susceptible to experiencing pain with endometriosis.^xxiv

‍

How is endometriosis diagnosed?

‍

From the time of the appearance of the first symptoms to disease diagnosis is on average seven years.^xxv Endometriosis is definitively diagnosed through direct visualization of the endometriotic lesions at the time of abdominal surgery, most commonly via laparoscopy. A laparoscopy involves inserting a camera through a small incision in the abdomen, most commonly through the umbilicus. The physician then examines the pelvis and abdomen for endometriosis, and if needed, extracts a tissue sample biopsy. The biopsy is sent for histological analysis, meaning that the tissue will be examined under a microscope for structural abnormalities. This is used to definitively confirm the endometriosis diagnosis.^xxvi

Endometriosis typically appears as “powder burn” or “gunshot” lesions on the surfaces of the peritoneum; these lesions are black, dark brown, or blueish nodules or small cysts. Endometriosis can also appear as subtle lesions that are also called “atypical” lesions, characterized as red or clear clumps of cells or tissues. These cells and tissues additionally occur with bleeding or white fibrous plaques and yellow-brown discoloration within the abdomen.^xxvii

Occasionally, physicians are able to non-surgically diagnose endometriosis by ultrasonography or magnetic resonance imaging (MRI) if an ovarian endometrioma or deep infiltrating endometriosis is noted.^xxviii However, most peritoneal endometriosis lesions are too small to be identified on imaging.^xxix

Endometriosis is staged according to the severity of disease visualized at the time of surgery. The revised American Society for Reproductive Medicine (rASRM) scoring system is currently the best-known and most widely used system for classifying the four stages of endometriosis. Values are assigned according to the size and location of the endometriotic lesions. Points are also assigned based on the presence and severity of scar tissue in the pelvis. All points are added, and the resulting total score is classified into four grades of severity.^xxx

• Stage I, Minimal, 1-5 points
• Stage II, Mild, 6-15 points
• Stage III, Moderate, 16-40 points
• Stage IV, Severe, greater than 40 points^xxxi

Unfortunately, the rASRM classification system has limited ability to predict pregnancy outcomes in patients diagnosed with endometriosis. A new staging system, the Endometriosis Fertility Index (EFI) was developed in 2010 to predict a patient’s ability to achieve a non-ART pregnancy (unassisted pregnancy or IUI) after endometriosis surgery.^xxxii,xxxiii The EFI has since been well-validated for this purpose.^xxxiv

‍

How does endometriosis impact fertility?

‍

Approximately one-third of women with endometriosis have infertility. The presence of endometriosis can negatively affect the chance of spontaneous conception. In vitro fertilization (IVF) pregnancy rates are also decreased in patients with endometriosis when compared to women with unexplained or tubal factor infertility.^xxxv,xxxvi

In mild disease (Stage I-II), endometriotic cells and tissue may stimulate a localized immune and inflammatory response which has the potential to impact follicular development, endometrial development, or implantation.^xxxvii Inflammatory cells have been identified in the peritoneal fluid of women with endometriosis which could also impair oocyte fertilization and tubal transport of the gametes.^{xxxviii,xxxix}

In patients with moderate to severe endometriosis (Stages III-IV), pelvic adhesions (fibrous scar tissue) may cause anatomical distortion of ovaries and tubes. This can create a barrier that prevents the egg and/or sperm from traveling through the Fallopian tube. Endometriosis can also impair normal egg development and ovulation.^xl Inflammatory reactions due to endometriosis may also impact fertility in patients with severe diseases as described above.

‍

What treatments exist for endometriosis and how successful are they?

‍

Treatments options for endometriosis are targeted towards pain reduction, infertility treatment, or both. These treatments may include medication, surgery, or a combination. If pain is the main problem, medication may be tried before surgical diagnosis and treatment by laparoscopy. Clinicians should consider patient preferences, side effects, efficacy, cost, and availability when deciding on treatments.

‍

Both the European Society of Human Reproduction and Embryology (ESHRE) and the American College of Obstetricians and Gynecologists (ACOG) guidelines have similar recommendations for treatment, which may include the following:^xli,xlii

‍

• Hormonal treatments: these can lower estrogen levels and suppress the activity of the disease. Treatments include progestins (synthetic progesterone drugs) GnRH agonists (e.g., Trelstar®), GnRH antagonists, hormonal contraceptives (e.g., birth control pill, vaginal ring, IUD, or transdermal patch), or aromatase inhibitors (stop the enzyme that produces estrogen).  
• Pain relievers: analgesics such as NSAIDs (non-steroidal anti-inflammatory drugs, i.e., Advil®) are recommended to reduce pain and inflammation.^xliii‍
• Surgical treatment: When endometriosis is surgically diagnosed in a symptomatic patient, doctors will recommend laparoscopic destruction (surgery via the abdomen) of the endometriotic lesions to reduce endometriosis-associated pain or to improve fertility.

Drug treatment, as noted above, is used to prevent the recurrence of pain symptoms and ovarian endometriosis and may also be used as an alternative to surgery for patients without extensive disease. However, drug treatment often prevents conception since the drugs prescribed are generally contraceptives and therefore medical treatment (using medications) of endometriosis symptoms does not improve fertility.^xliv  

When medical therapy is not effective, surgery to diagnose, stage, and destroy endometriosis can be considered. When endometriosis is surgically diagnosed in a symptomatic patient, doctors will recommend surgical ablation or excision of the endometriotic lesions to reduce endometriosis-associated pain or to improve fertility. Laparoscopic excision and ablation are associated with improved clinical pregnancy rates. ^xlv,xlvi

Following surgery, most patients will experience a reduction in their pain symptoms, however recurrent symptoms are common.^xlvii Repeat surgery should be avoided when possible, due to the risks of the surgical procedure and limited data regarding the benefit of repeat surgery. However, for patients with severe pain who do not tolerate or respond to medical treatment, repeat surgery may be considered. For patients with infertility who are unable to conceive after surgery, assisted reproductive technology (i.e., IVF) may be an option. One clinical trial of 450 patients showed that three months of hormonal treatment (GnRH agonist), surgical treatment, or both treatments combined were all effective to treat symptoms. This study cohort was followed for two years and a pregnancy rate of 55-65 percent was observed.^xlviii

‍

What happens if endometriosis is left untreated?

‍

Although most women report that their pelvic symptoms began during adolescence, most do not receive timely diagnosis and treatment. This is because the varying symptoms can be attributed to other conditions and imaging has low sensitivity to detect the presence of endometriosis. Surgery, the gold standard for diagnosis, is only appropriate when symptoms reach levels of severity that justify the risk of surgical complications. For patients with pelvic pain due to endometriosis, the long interval between symptom onset and diagnosis can result in prolonged pain, decreased quality of life, and psychological stress.^xlix

‍

What are other endometriosis risks and complications?

‍

Pelvic pain may be inflammatory as well as neuropathic (impaired nervous system), resulting in persistent pain even after endometriotic lesions are removed.^l Other co-existing conditions and subsequent disorders are more likely to occur in women with endometriosis. These include:^li

• Gynecologic – uterine fibroids, adenomyosis
• Pain – fibromyalgia, migraine
• Central sensitization
• Gastroenterological – irritable bowel syndrome, ulcerative colitis
• Genitourinary – interstitial cystitis
• Mental health – depression, anxiety
• Immunologic – rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, allergies, asthma
• Cancer – ovarian cancer, melanoma, thyroid cancer
• Cardiovascular disease^lii

Chronic pain that is unresponsive to conventional treatments develops in about 30 percent of patients with endometriosis. Women with endometriosis are also at high risk for cross-organ sensitization (pain perception from adjacent structures due to convergence of neural pathways).^liii This explains the poor post-surgical pain relief in many affected women.

‍

Conclusion

‍

While endometriosis can often be a chronic medical condition, there are treatment options that can help women manage their endometriosis symptoms and improve their quality of life. Treatment options depend on whether the endometriosis symptoms are related to pelvic pain, infertility, or both. Patients with endometriosis related symptoms should seek care from a physician that is experienced with this disease and the available treatment options.