Every woman should read this! | Endometriosis
-About 6-10% of women during the reproductive phase are affected by endometriosis.
Overview:
Endometriosis is a chronic, neuroinflammatory disorder characterized by debilitating chronic pelvic pain or excessive menstrual cramps (dysmenorrhea); however, it can be asymptomatic. About 6-10% of women during the reproductive phase are affected by endometriosis. Diagnosis of endometriosis is based on evaluation of symptoms, and there is not a specific test that can be used to diagnose the condition. The definitive diagnosis of endometriosis is the presence of endometrial-like tissue (“lesions”) outside the uterus (mostly on the ovaries, fallopian tubes, and pelvic peritoneum), which is confirmed with surgery or laparoscopy. However, endometrial-like lesions can also be found in the liver, lungs, limbs, pericardium, central nervous system, and surgical scars. Recently, non-invasive methods are used for staging and classification of most forms of endometriosis without surgical intervention, including transvaginal ultrasound and magnetic resonance imaging (MRI). Even these imaging techniques cannot exclude endometriosis despite improvements in imaging leading to a high rate of missed diagnosis of (peritoneal) endometriosis.
The hormone responsiveness of these endometrial-like lesions is maintained because they act just like the normal endometrial tissue, leading to cyclical bleeding inside these abnormal sites, chronic inflammation, and progressive scarring of the normal tissue surrounding the endometrial-like lesion. About 50% of women who suffer from infertility are diagnosed with endometriosis. Most endometriosis cases are missed, as the pelvic pain is associated with other conditions and due to other various clinical presentations, including infertility, dysmenorrhea, pain during intercourse, abnormal or heavy menstrual flow (menorrhagia), and being asymptomatic. Other symptoms are based on the site affected by endometrial tissue, including gastrointestinal symptoms and painful urination. The course and clinical presentation of endometriosis depend on the site of ectopic tissue, the tendency of lesions to invade neuronal structures or to form scars, and the depth of infiltration.
Studies showed that endometriosis is associated with a higher risk of breast cancer, ovarian cancer, melanoma, cardiovascular disease, rheumatoid arthritis, and asthma.
Unfortunately, endometriosis cannot be cured, and treatment mainly controls symptoms only. Treatment of endometriosis includes suppressing ovarian hormone production through medications (progesterone-based therapy) and surgical removal of endometrial-like lesions, which can be extensive. About 40% of endometriosis patients are progesterone resistant. Other treatment options include synthetic androgen therapy or gonadotropin-releasing hormone (GnRH) agonists to induce a hypoestrogenic state. Unfortunately, the medications used have a lot of side effects. About half of women undergoing surgery require other surgical interventions 5 years later.
Further research is required, and global attention should be paid towards relieving the suffering of millions of women worldwide.
Endometriosis over history:
Despite many years of research on endometriosis, the exact etiology and pathophysiology of endometriosis are still unclear. In 1690, endometriosis was first described in “Disputatio Inauguralis Medica de Ulceribus Ulceri” by Daniel Shroen. In 1769, the symptoms of endometriosis were presented by Arthur Duff. In 1860, Karl von Rokitansky defined endometriosis as "the presence of an active endometrium outside the uterine cavity." In 1882, the name "adenomyoma" was suggested by Von Recklinghausen. In 1908, a monograph on adenomyosis was published by T.S. Cullen, who was the first to describe the two main symptoms of adenomyosis: severe pain and prolonged or heavy menstrual bleeding, believing that the remains of Müller’s ducts are the source of the endometrial tissue. In 1870, Heinrich Wilhelm Waldeyer, who is a German physiologist, pathologist, and anatomist, was the first to establish the "metaplasia" theory. In 1898, Iwanhofen established the theory of endometrial tissue arising due to metaplasia of the peritoneal epithelium.
From 1903, Meyer’s research put forth the theory that hormonal and inflammatory factors lead to metaplasia that promotes the inclusion of the epithelium into the lining. In 1937 in Poland, Leonard Lorentowicz wrote the article “On the pathogenesis of intrauterine adenomatosis in the peritoneal cavity (endometriosis peritonealis)," being the first to describe endometriosis in Polish gynecology. Endometriosis was described under several names, including adenomyoma, cystadenoma, and cystic fibrosis, as a benefactory hyperplasia disease until the 1920s. J.A. Sampson was the first person to introduce the term “endometriosis” into medical terminology in 1927. J.A. Sampson established the theory of “retrograde menstruation” or "retrograde transport of menstrual blood" leading to implantation of exfoliated endometrial mucosa cells within the peritoneal cavity as the cause of the disease. The "retrograde menstruation" occurs in about 90% of women of childbearing age, but endometrial tissue survives outside the uterine cavity in some women. Other theories have emerged over the past years; however, Sampson’s theory is still dominant.
In 1984, K. Schweppe classified all the theories of endometriosis into three groups:
1-Theories of endometrial transplantation, whether by retrograde menstruation, transport by lymphatic and blood vessels, or mechanical transplantation as during surgery.
2-Theories of the development of endometriosis in situ that were established by Russell, Reclinghausen, Waldeyer, Gebhard, Novak, and Meyer. This development is from the remains of cells of the fetal embryo or the genitourinary system.
3-Theories of endometrial cells being exfoliated, entering the peritoneal cavity, and stimulating its epithelium to transform into endometrial tissue, including the "inductive theory," which was established by Levander in 1941.
How common is endometriosis?
Approximately 10% of women worldwide are affected by endometriosis. According to the World Health Organization (WHO), infertility is defined as the "inability to achieve pregnancy after regular unprotected intercourse for ≥12 months." Infertility is a serious problem, as it affects nearly 48.5 million couples globally. About 15-30% of infertility cases remain unexplained. About 30 to 50% of infertility causes in women are due to endometriosis. Infertility in endometriosis is due to adhesions, scarred fallopian tubes, hormonal changes of the ova (eggs), altered quality of ova, altered immune system functioning, distortion of pelvic anatomy, inflammation affecting the pelvic structures, and impaired implantation of a pregnancy. A delay in diagnosis causes a high level of stress, and the infertility remains unexplained for a long time. Diagnostic delays last up to years.
About 10–15% of women of reproductive age and 35–50% of women with pelvic pain and/or infertility are affected by endometriosis, which makes it a common and challenging gynecological disease worldwide. Not only the reproductive age but also adolescence and menopause can be included in the age groups affected by the disease. The peak incidence of the disease is between 25 and 45 years of age. About 0.1–53% of women undergoing laparoscopy (a diagnostic and therapeutic technique using a camera (laparoscope) inserted through small abdominal incisions) or laparotomy (a major surgical procedure used to examine and treat abdominal organs) are diagnosed with endometriosis.
About 7% of endometriosis cases are associated with genetic predisposition in the family. Nearly 2% of women undergoing tubal ligation (a surgical sterilization procedure for women that cuts or blocks the fallopian tubes to prevent pregnancy) and 17% of women undergoing oophorectomy (surgery to remove the ovaries) were diagnosed with endometriosis. In the UK, endometriosis is the second most common gynecological condition. Some studies found the foci of endometriosis in fetuses. Some cases of men who have been treated with hormones for prostate cancer also had endometriosis. The highest risk of endometriosis was found in Asian women. Only 6-10% of cases become symptomatic with pelvic pain, and most cases are asymptomatic.
Unfortunately, endometriosis negatively impacts the quality of personal life of affected individuals, including professional, educational, social, family, and sexual life, due to the severe pain and dysfunction caused by the disease. It also leads to mental health issues, including anxiety and depression.
What are the risk factors of endometriosis?
0-The peak age is 25-45 years.
-Early menarche: according to several studies, early menarche before the age of 11 is associated with a higher risk of endometriosis.
-Nulliparity (a woman who has never given birth to a live child).
-Genital defects, including narrowing of the cervical canal or hymen overgrowth.
-Genetic factor: heritable genetic factors may explain the different types and clinical presentations of endometriosis. Since the early 1950s, familial risk was noted as contributing to the etiology of endometriosis. Studies showed that a positive history of a first-degree relative woman who has histologically confirmed endometriosis leads to a five-to-seven times greater risk of developing endometriosis in women. Familial endometriosis is also associated with a severe course of the disease and earlier onset of symptoms. In addition, monozygotic twins have a greater risk of developing endometriosis compared to dizygotic twins.
-Short genital cycles: genital cycles shorter than 27 days are associated with higher risk of endometriosis according to research unrelated to the number of bleeding days or the volume of menstruation.
-Active smoking and daily consumption of at least 10 g of alcohol per day.
-Low body mass index (BMI) may be a cause, but obesity has a higher risk for severe dysmenorrhea.
-Fewer consumption of food that is rich in vitamin D, long-chain omega-3 fatty acids, and omega-6 polyunsaturated fatty acids.
Diet is an important factor; for example, consumption of green vegetables and fresh fruits, which contain antioxidants, is really beneficial for improving the function of the immune system, improving hormonal balance, and controlling the intestinal bacterial flora. On the other hand, red meat contains fat, hormones, and dioxins that increase the concentration of estrogens, increasing the risk of developing endometriosis. A study from 1991 to 2013 including 81,908 women aimed to determine the effect of red meat, poultry, fish, and seafood in relation to endometriosis being confirmed by laparoscope. A nutrition questionnaire was used every 4 years to assess diet. Women who had more than 2 servings/day of red meat were 56% at higher risk of developing endometriosis compared to those consuming ≤ 1 serving/week, according to the study. The highest consumption of red meat was associated with a higher risk of endometriosis, with no association with poultry, fish, shellfish, and egg consumption. An appropriate lifestyle (regarding physical activity) is also an important factor in preventing endometriosis.
Any condition that may lead to prolonged exposure to estrogen, like early menarche, late menopause, or conditions that are associated with variation in estrogen levels, such as heavy menstrual bleeding, short menstrual cycle length, or uterine outlet obstruction, or taking an exogenous source of estrogen for any reason, also increases the risk of endometriosis. Studies have shown that estrogen and estrogen receptors (ER) play an important role in the pathogenesis of endometriosis, which is considered an estrogen-dependent disease.
Types of endometriosis:
-Superficial peritoneal type: represents about 80% of endometriosis
-Ovarian type
-Deep endometriosis
Note that endometriosis can also be found in extra-pelvic sites, including abdominal visceral organs, abdominal wall, pleura (“thoracic endometriosis”), diaphragm, peripheral and central nervous system, and urinary system. The most commonly used staging system for endometriosis is the revised scoring system of the American Society for Reproductive Medicine (ASRM). Stages of ASRM range from I to IV, representing minimal and severe endometriosis depending on the location, appearance, type, depth of invasion, adhesions, and extent of the disease. Staging and diagnosis are confirmed and definitive using surgical laparoscopy; however, transvaginal ultrasonography and magnetic resonance imaging (MRI) may be used to detect ovarian and deep endometriosis but are not as accurate compared to surgery.
What are the symptoms and signs of endometriosis?
-Women, including those under 17 years, presenting with infertility and one or more of the following should be considered as having endometriosis:
-Cyclical and non-cyclical chronic pelvic pain
-Painful period (dysmenorrhea), which increases in intensity over time
-Heavy irregular menstruation (menorrhagia)
-Pain in the sacral region of the spine
-Pain radiating to the back
-Cyclical gastrointestinal symptoms (particularly dyschezia, which is painful or difficult defecation), diarrhea or constipation, blood in stool or rectal bleeding, nausea
-Cyclical urinary symptoms (particularly hematuria (the presence of blood in the urine) or dysuria, which is pain, burning, or discomfort during urination)
-Dyspareunia (genital pain occurring before, during, or after sexual intercourse)
-Fatigue, dizziness, depression, anxiety, headache
-Hypoglycemia (low blood sugar level)
Endometriosis is considered a "syndrome" diagnosed only when both visible lesions and symptoms are present. The first symptom of the disease appears in about 66% of women before the age of 20. About 8-10 years is the time between the appearance of the first symptoms of endometriosis and the diagnosis of the disease. Antibodies against foci of endometriosis may also attack eutopic endometrium (endometrial tissue lining the uterine cavity in women with endometriosis), leading to spontaneous abortions.
Other guidelines include cyclical cough, hemoptysis (coughing up of blood or blood-stained mucus), and/or catamenial pneumothorax (a rare, recurrent lung collapse (spontaneous pneumothorax) occurring in women of childbearing age, usually 72 hours before or after the start of menstruation). Thoracic endometriosis, despite being rare, is associated with pelvic endometriosis in up to 55% of cases.
How to diagnose endometriosis?
There is no specific test to diagnose endometriosis.
-Biomarkers:
Most endometriosis biomarkers have poor diagnostic value, as biomarkers have poor sensitivity or specificity. Micro-RNAs that may be involved in the genetic expression of endometriosis may be beneficial.
-Clinical examination:
A normal clinical examination cannot exclude endometriosis. However, it is an important initial step for patients with undifferentiated pelvic pain. Some clinical examination findings include tender pelvic nodularity, palpable tethering of pelvic organs such as uterine immobility, and visible vaginal lesions mainly in the posterior fornix.
-Imaging:
For detection of endometriomas and deep endometriosis, high-quality transvaginal USS (TVUSS) and magnetic resonance imaging (MRI) have sensitivity and specificity. For detection of superficial endometriosis, laparoscopy remains superior. When involvement of the bowel, bladder, and ureter is suspected, in Australia, MRI is performed for surgical planning. Transabdominal USS has low diagnostic accuracy.
-Diagnostic laparoscopy:
For histological confirmation, diagnostic laparoscopy is considered the gold standard for the diagnosis of endometriosis. Normal clinical examination and normal imaging cannot rule out endometriosis, and further laparoscopy with biopsy taken should be considered. Even a negative histological result does not exclude endometriosis.
-Classification of endometriosis:
The revised American Society of Reproductive Medicine (rASRM) staging system of endometriosis cannot predict the severity of symptoms or prognosis. Endometriosis is divided into three categories: superficial peritoneal disease, ovarian endometriosis, and deep infiltrating endometriosis (DIE), which is defined as "endometriotic lesions invading >5 mm beyond the surface of the peritoneum." In addition, pelvic organs, including the bowel, bladder, pelvic wall, and retroperitoneal structures, are often infiltrated with endometriosis.
Is endometriosis treatable?
Unfortunately, there is no complete cure for endometriosis; however, there are treatment strategies used to manage the symptoms. Treatment methods include medications and surgery. There is no medication that could prevent the disease from progressing or prevent its recurrence. One of the reasons is the difficulty of diagnosing the disease and detecting its recurrence through the non-invasive techniques.
1-The role of surgery:
The international guidelines recommended laparoscopic removal of endometriosis lesions, as it may improve the associated pain and correct the distorted anatomy caused by adhesions and scar tissue. In the case of ovarian endometriosis, surgical excision with biopsy is considered the optimal treatment in addition to using medications to control the pain. A biopsy is obtained to exclude ovarian malignancy. Surgical excision of deep endometriosis is also considered the standard treatment. Guidelines recommend cystectomy of endometriomas to reduce the pain and risk of recurrence and increase the rate of spontaneous pregnancy compared to ablation. However, risks and benefits should be weighted carefully before making the decision.
Surgery does not cure endometriosis. It removes any visible lesion only, and according to research, relapse of symptoms following surgery occurs in about 40–45% of women. About 30% of women require another surgery within 5 years following their first surgery.
Surgery may even exacerbate the pain in certain subtypes of endometriosis. Chronic post-surgical pain (CPSP) occurs in up to 15%–20% 3-6 months post-surgery. Factors contributing to CPSP include comorbid stress symptoms, other chronic preoperative pain conditions, and acute postoperative pain. For secondary prevention of pain and disease recurrence following surgery, hormonal suppression via levonorgestrel-IUD (LNG-IUD) or continuous COCP may be used.
Hysterectomy (removing the uterus) is considered if women do not seek pregnancy and if previous surgical and medical interventions have failed with concurrent heavy menstrual bleeding and/or adenomyosis. If bilateral oophorectomy (surgical removal of ovaries) is performed, women become at increased risk of diminished bone density, dementia, and cardiovascular disease due to depletion of ovarian hormones, and further supplements may be prescribed.
2-Medical management:
*Hormonal treatment:
When endometriosis is suspected in young women, treatment is usually started even before surgical confirmation of the disease. Some studies showed that steroids contribute to the pathophysiology of endometriosis, so hormonal suppressive therapy is routinely prescribed. Hormonal treatment acts by suppressing ovarian activity or by a direct action on steroid receptors and enzymes found in the endometrium and lesions. This can help reduce the menstrual bleeding or suppress the inflammatory pathways related to the disease and lead to atrophy of the endometriotic lesions. Medical agents used include combined oral contraceptives (COCP), gonadotrophin-releasing hormone agonists (GnRH agonists), GnRH antagonists, progestogens (oral, intramuscular, and intrauterine system), anti-progestogens, or aromatase inhibitors. Recurrence of symptoms occurs after stopping medical treatment. Moreover, medications cause multiple side effects, including weight gain, mood swings, acne, nausea, and breast tenderness. GnRH agonists can induce temporary menopause, causing hot flashes, vaginal dryness, and bone density loss.
These therapies can reduce the dysmenorrhea and non-menstrual pelvic pain, and the choice of therapy depends on the tolerance and priorities of the patient. Guidelines recommend prescribing COCP or progestogen to individuals suspected of having confirmed or recurrent endometriosis. GnRH agonists are considered a second-line therapy according to the ESHRE (European Society of Human Reproduction and Embryology) guideline, whereas the RANZCOG (the Royal Australian and New Zealand College of Obstetricians and Gynaecologists) guideline recommended using GnRH agonists as an adjunct (an additional treatment used alongside a surgical procedure to improve patient outcomes) to surgery for DIE involving the bowel, bladder, or ureters.
Some studies showed that mifepristone, which is a progesterone-receptor modulator, can relieve the pain associated with endometriosis. Danazol, which is a synthetic androgen, is no longer used due to its androgenic side effects, including hirsutism, weight gain, acne, and adverse effects on blood cholesterol levels. Some of danazol's side effects are irreversible.
*Analgesia:
Most women use paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) to reduce the pain. Using NSAIDs or other COX-2 inhibitors may inhibit ovulation, which would be a problem if a woman wants to be pregnant, especially with chronic use. A short trial of paracetamol or NSAIDs is recommended according to the guidelines.
*Neuromodulators:
Neuromodulators act through central nervous system (CNS) modulation of pain, and many of these agents are also used as antidepressants or anticonvulsants. Some agents that may be used are selective serotonin uptake inhibitors (e.g., duloxetine), tricyclic antidepressants (e.g., amitriptyline and nortriptyline), and anticonvulsants (e.g., gabapentin and pregabalin).
3-Non-pharmacological treatment:
Non-pharmacologic treatment includes herbal medicine, exercise, physiotherapy, nutrition, and acupuncture. These methods are not effective alone to manage endometriosis. Some individuals may benefit from pelvic floor physiotherapy if they have concurrent pelvic floor dysfunction. Psychological support is crucial. Cognitive behavioral therapy (CBT) can help individuals with anxiety and depression that occur due to the chronic pain and/or infertility associated with the disease.
4-Management of associated infertility:
Endometriosis is responsible for about 50% of infertility/subinfertility causes in women. Endometriosis may increase the risk of first-trimester miscarriage and ectopic pregnancy. Management of infertility includes surgical methods and assisted methods of reproduction (ART).
-Surgical methods:
Surgery may improve fertility outcomes. However, ovarian surgery in the case of ovarian endometriomas may affect ovarian reserve. The decision of surgery is cautiously made, and the benefits and risks of fertility preservation should be weighed. Guidelines recommend that surgical management of rASRM stage 1 and 2 endometriosis may improve fertility outcomes. If fertility is a priority, hormonal suppression should not be offered postoperatively, according to the guideline.
-Assisted methods of reproduction (ART):
Intrauterine insemination (IUI) with ovarian stimulation may be performed with rASRM stage 1 and 2 endometriosis according to the ESHRE guideline. If other treatment methods failed, or if tubal function is affected, or if a male cause of infertility presents, in vitro fertilization (IVF) is recommended.
Note that pregnancy may affect endometriosis lesions, whether by regression or growth. Becoming pregnant is not a treatment for endometriosis.
Menopause and endometriosis:
About 2 to 5% of individuals after menopause will experience endometriosis-related symptoms, according to the ESHRE guideline. Pelvic pain postmenopausal should be differentiated as it may be malignancy or other causes of pelvic pain. A systematic review found that treating menopausal symptoms with menopausal hormone therapy may cause reactivation of endometriosis in patients with a history of endometriosis in addition to the increased risk of malignant transformation of the lesions. To avoid this risk, according to the ESHRE guideline, it is recommended to use combined estrogen–progesterone formulations even in individuals who had a hysterectomy.
Remember that endometriosis is a common disease. A delay in diagnosis and management of endometriosis affects the quality of life of thousands of women.
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