What is endometriosis?

Endometriosis is a medical condition in which endometrial 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 levels of the hormone estrogen and primarily affects pelvic tissues such as the ovaries.ⁱⁱ Research suggests that endometriosis affects 5 to 10 percent of reproductive-age females,^iii,iv which means that up to 190 million females worldwide may live with this medical condition. Endometriosis can also affect adolescent girls, and symptoms may even persist in post-menopausal individuals.^v

The development of endometriosis involves interactions between the immune system and the endocrine system (which produces and regulates 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 endometriosis:

• ‍Ovarian: Ovarian endometriosis occurs when cells that are similar in function to the endometrium (the lining of the uterus) 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: Peritoneal endometriosis is a condition in which endometrial cells or tissue are found in the abdomen (peritoneal cavity) or on the surface of the abdominal wall. It occurs in 15 percent of patients diagnosed with endometriosis.^vii
• ^‍Deep infiltrating: 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?

Approximately 2 to 11 percent of females who have endometriosis do not experience any symptoms.^ix However, among patients with an endometriosis diagnosis, 83 percent have one or more of the following possible symptoms:^x

• 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. However, there is only a weak correlation between the patient’s perceived pain intensity and graded severity of the disease.^xi Research suggests that 5 to 21 percent of females hospitalized for pelvic pain have endometriosis, and one third of females who undergo abdominal/pelvic surgery (laparoscopy) for chronic pelvic pain are found to have endometriosis.^xii,xiii

Here are some other endometriosis pain symptoms:^xiv

• 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 symptoms such as anxiety, nausea, headaches, depression, or susceptibility to infections or allergies.^xv

Endometriosis symptoms first appear before the age of 20 in about 66 percent of females diagnosed with the disease.^xvi Over time, debilitating menstrual symptoms can increase in severity as inflammation persists and the nervous system is recurrently stimulated by the endometriosis tissue. Overstimulation can lead 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.^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 why endometrial tissue grows outside of the uterus. There may be multiple mechanisms which can separately cause this disease.^xviii

Here are some suggested origins of endometriotic tissue:^xix

• ‍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 retrogradely in this manner may implant in the abdominal cavity and develop into endometriotic lesions. Retrograde menstruation is the most frequently proposed mechanism.
• ‍Coelomic metaplasia of the peritoneal lining: Cells from other tissues/organs outside of the uterus (for example, the lining of the abdomen, called 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 tissue and organs including the lungs, brains, bones, and peripheral nerves, among others.

Certain factors can put an individual at a higher risk of developing endometriosis. Based on the current research, here are some possible risk factors for endometriosis:^xx

• Low birth weight
• Menstrual periods beginning at an early age
• Short menstrual cycles
• Heavier menstrual flow
• Low body mass index
• Nulliparity (never having given birth)

It should be noted that having “risk factors” for a disease indicates a higher chance of developing the condition but does not mean that the individual will definitively develop the condition.

Is endometriosis inherited?

Research studies on twins suggest that the inheritability of endometriosis is approximately 50 percent.^xxi In other words, about 50 percent of the variation in risk between individuals can be explained by genetic factors (the other 50 percent is due to environmental factors). To be clear, this connection does not mean that if someone has a parent with endometriosis, they have a 50 percent chance of getting the condition too.

Genetic studies have identified various genetic risk locations for endometriosis. A recent global genome-wide associated meta-analysis conducted at the University of Oxford included 60,674 endometriosis cases and 701,926 controls to assess the genetic causes of endometriosis.^xxii The study identified 42 genetic locations linked to endometriosis risk and several of these genes are known to regulate pain perception and maintenance. The size of the genetic impact was largest for individuals with stage III or IV endometriosis. Interestingly, the researchers also found that there were genetic differences between ovarian endometriosis and other types of pelvic endometriosis.

The study also indicated that there are genetic correlations with co-existing chronic conditions, such as headaches and back and joint pain, suggesting that certain females are genetically susceptible to experiencing pain with endometriosis.^xxiii

How is endometriosis diagnosed?

There is often a delay in endometriosis diagnosis, and, on average, it takes about seven years from the time a patient first experiences symptoms before they are diagnosed.^xxiv The condition is definitively diagnosed when a doctor observes endometriotic lesions during abdominal surgery, most commonly via laparoscopy. A laparoscopy involves inserting a camera through a small incision in the abdomen, most commonly through the navel. The physician then examines the pelvis and abdomen for endometriosis and extracts a tissue sample biopsy if needed. The biopsy is sent for histological analysis, meaning that the tissue will be examined under a microscope for structural abnormalities. This analysis is used to confirm the endometriosis diagnosis.^xxv

Endometriosis typically appears as “powder burn” or “gunshot” lesions on the surfaces of the peritoneum (the lining of the abdomen); these lesions are black, dark brown, or blueish nodules or small cysts. Endometriosis can also appear as subtle lesions, called atypical lesions, characterized by 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.^xxvi

Stages of endometriosis

Endometriosis is categorized into four stages according to the severity of disease at the time of surgery. The revised American Society for Reproductive Medicine (ASRM) scoring system is currently the best-known and most widely used system for classifying the four stages of endometriosis, but other scoring systems also exist.^xxix 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,xxxi

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

The revised ASRM classification system has limited ability to predict pregnancy outcomes in patients diagnosed with endometriosis. Another staging system, the Endometriosis Fertility Index (EFI), was developed in 2012 to predict a patient’s ability to achieve pregnancy without advanced reproductive technology after endometriosis surgery.^xxxii,xxxiii The EFI has since been proven accurate for this purpose.^xxxiv

How does endometriosis impact fertility?

Approximately one third of females 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 females with unexplained or tubal factor infertility.^xxxv

In mild cases (stage I and II), endometriotic cells and tissue may stimulate a localized immune and inflammatory response, which has the potential to impact follicular development, endometrial development, or embryo implantation.^xxxvi Inflammatory cells have been identified in the peritoneal fluid of females with endometriosis, which could also impair egg fertilization and transport of eggs and sperm through the fallopian tubes.^{xxxvii,xxxviii}

In patients with moderate to severe endometriosis (stages III and IV), pelvic adhesions (fibrous scar tissues) may form in the ovaries and fallopian tubes. These adhesions can create a barrier that prevents eggs and sperm from travelling through the fallopian tubes. Endometriosis can also impair normal egg development and ovulation.^xxxix Inflammatory reactions due to endometriosis may also impact fertility in patients with severe cases, as described above.

What treatments exist for endometriosis and how successful are they?

Treatment options for endometriosis are targeted toward pain reduction, infertility treatment, or both. These treatments may include medication, surgery, or a combination of the two. If pain is the main problem, patients can try medication before turning to surgery for diagnosis and treatment.

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. Here are some examples:^xl,xli

• ‍Hormone treatments: These treatments can lower estrogen levels and suppress disease activity. Treatments include progestins, which are synthetic progesterone drugs (e.g., dienogest and Sayana^® Press), GnRH agonists (e.g., Trelstar^®), GnRH antagonists, hormonal contraceptives (e.g., birth control pill, vaginal ring, IUD, or transdermal patch), or aromatase inhibitors (medications to stop the enzyme that produces estrogen).
• ‍Pain relievers: Analgesics such as NSAIDS (non-steroidal anti-inflammatory drugs, e.g., Advil^®) are recommended to reduce pain and inflammation.^xlii
• ^‍Non-hormonal treatment: A non-hormonal medication, dichloroacetate, which has previously been used to treat metabolic disorders, is currently being investigated as a potential endometriosis treatment. Clinical trials are underway and are reporting promising results including a significant reduction in menstrual cycle–related pain.^xliii
• ^‍Surgical treatment: When endometriosis is surgically diagnosed in a symptomatic patient, doctors 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 severe cases. However, drug treatment often prevents conception, since the drugs prescribed are generally contraceptive; therefore, this type of medical treatment for endometriosis symptoms does not improve fertility.^xliv

When hormonal therapy is not effective, patients can consider surgery to diagnose, stage, and treat endometriosis. When endometriosis is surgically diagnosed in a symptomatic patient, doctors 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 (ART) 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.^xlviii This cohort study was followed for two years and a pregnancy rate of 55 to 65 percent was observed.

There appears to be a recent trend in endometriosis fertility treatment toward an “ART first” therapeutic approach, unlike the historical approach of surgery.^xlix This trend follows several reports indicating that prior laparoscopic surgery for endometriosis does not improve ART outcome.^l,li

What happens if endometriosis is left untreated?

Although most females report that their pelvic symptoms began during adolescence, it is unlikely that they will receive timely diagnosis or treatment. This delay 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.^lii

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.^liii Other co-existing conditions and subsequent disorders are more likely to occur in females with endometriosis:^liv

• ‍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^lv

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

Conclusion

While endometriosis can often be a chronic medical condition, there are treatment options that can help patients 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 experienced with this disease and its available treatment options.