Endometriosis

Etiology

There are several developed theories about the etiology of endometriosis based on the logical sequelae relating the severity of symptoms to the stage of the disease. However, none of these proposed models can fully explain the range of clinical manifestations of the disease.[3] The most widely plausible theory is Sampson's assumption, stating that the viable cells in the peritoneal fluid with retrograde menstruation can implant, grow, and infiltrate the peritoneal cavity.[3] Retrograde menstruation is a term used to describe the reflux of the blood backward from the Fallopian tubes to the peritoneum during menstruation. It is a phenomenon quite common in a large proportion of women of reproductive age.[3] An alternative to Sampson's theory is the coelomic metaplastic theory suggested by Meyer. This theory relies on the ability of parietal peritoneum epithelium to differentiate into endometrial tissue, probably under the stimuli of cytokines and growth factors of the endometrial stroma.[4] The hypothesis of metaplasia could justify the occurrence of endometriosis in women without a uterus or a lack of endometria, such as female patients with Mayer-Rokitansky-Küster-Hauser syndrome or the rare cases of males who have endometriosis.[5][6]

To explain the occurrence of endometriosis in the cul-de-sac and uterosacral ligaments, the main used theory is the Müllerian remnant theory, suggesting that atypical migration or differentiation of these remnants could imitate endometriotic tissue in the poster pelvic floor.[7] Another theory developed to explain endometriosis is the lymphatic and vascular metastasis theory. This theory proposes that endometrial tissue can infiltrate the lymphatics and vasculature and, through them, get transferred to remote foci like the brain or the pleura or retroperitoneal locations.[8] The stem cell theory could also partially explain the pathogenesis and establishment of endometriosis. Growing evidence has supported that the endometrial stem cells might be responsible for the development and progression of endometriosis. Endometrial progenitor cells have not only been recognized in menstrual blood but have also been identified as clonogenic cells in the endometrial lesions. The mechanism of generation and establishing endometriosis might be by the retrograde discarding of the endometrial stem cells in the pelvic cavity either with neonatal uterine bleeding or with menstruation after menarche.[9]

Moreover, the ambiguous pathogenesis of endometriosis led the investigators to research the role of oxidative stress, inflammatory elements, and reactive oxygen species as long as genetic and epigenetic factors. Oxidative stress is caused by the imbalance between the reactive oxygen species and the body's antioxidant ability. Reactive oxygen species can damage several components of the cell's nucleic acids and proteins. If the enzymatic and non-enzymatic cellular antioxidant capacity is decreased, reactive oxygen species are not eliminated from the cells and can be the leading cause of endometriosis.[10] Besides, the inability of just 1 theory to explain the pathogenesis of endometriosis could be ascribed to the complex interaction between the expression of genes involved in endometriosis, inflammatory reactions, and the disrupted hormone response to these stimuli.

Endometriotic lesions present as a chronic local inflammatory disease and involve alterations in cellular immunity and the expression of inflammatory cytokines. According to previous research, patients with endometriosis have elevated serum levels of many pro-inflammatory cytokines like IL-1, IL-6, and IL-8, resulting in chemotaxis, recruitment, and activation of peritoneal macrophages and proliferation of monocytes. The surgical excision of the endometriotic lesions leads to a decrease in the serum levels of the interleukins, providing evidence that their local production is the reason for the systematic inflammatory reaction. Tumor necrosis factor-alpha (TNF-a) in the peritoneal fluid, produced by the peritoneal macrophages, amplifies the inflammatory response.[11]

The role of steroid hormones in the pathogenesis of endometriosis is also indisputable. Estrogen is the main hormone responsible for the propagation and expansion of the endometrium. The increased action of aromatase, mainly in the deep infiltrating endometriosis, leads to locally increased estrogen activity.[10] On the other hand, the inability of progesterone to have an antagonistic action with estrogen in the endometrial tissue is a determining factor for establishing endometriosis.[12] The epigenetic changes are also an undeniable factor in the pathogenesis of endometriosis, and this is demonstrated by the fact that not only women of reproductive age suffer from the disease but also adolescents and younger women with a family history.[13] Specific genetic loci have also been identified for the initiation of the disease, making some women more prone to the disease than others. However, the genetic profile is not yet fully understood.[10]

Epidemiology

The determination of the epidemiological measurement features sometimes becomes very difficult since a lot of women often remain asymptomatic and go undiagnosed. The exact prevalence cannot be easily defined since the definitive diagnosis of the disease requires a laparoscopic examination. Endometriosis is estimated to affect approximately 10% to 15% of women of reproductive age, whereas this prevalence increases by up to 70% in women with chronic pelvic pain.[14] In the U.S., according to a more recent survey of the National Hospital Discharge Survey, 11.2% of all women between 18 and 45 years old hospitalized for genitourinary causes were diagnosed with endometriosis, and approximately 10.3% of the women who have undergone gynecologic surgeries have endometriosis.[15] Endometriosis is a disease with a high burden in Europe, and it has been shown that in Europe, the average annual cost for every patient, including health care and loss of productivity, was approximately €10,000, whereas, in the U.S., the health care cost is 63% higher than the average woman.[7]

The diagnosis of endometriosis in the majority of women is often delayed. Thus, women unavoidably suffer from the pain and the long-term effects of this debilitating disease, including infertility. In women with infertility, endometriosis is up to 50%, whereas, in adolescents, the incidence of endometriosis is reported to be 47% of those who have experienced laparoscopy for pelvic pain.[15][14] Several predisposing factors have been linked with the risk of developing endometriosis. Early age at menarche (age below 11 years old), shorter duration of menstrual periods(less than 27 days), heavy menstrual bleeding (menorrhagia), and nulliparity increase the risk for endometriosis, indicating and ascertaining the hypothesis that endometriosis is closely linked with the hormonal status of a woman(high estrogen levels and low progesterone).[14]

On the contrary, there are protective factors against endometriosis, mainly by lowering the inflammatory process or decreasing estrogen levels in the body. Parity, protracted breastfeeding, current oral contraceptive use, tubal ligation, and smoking are related to a decreased risk for endometriosis.[14] Tubal ligation has been assumed to decrease the risk of endometriosis by hampering the menstrual reflux to reach the pelvic cavity.[14] Prolonged breastfeeding seems to suppress the development of endometriosis through postpartum amenorrhea but also with other mechanisms.[16] Contraceptive use and parity hamper the occurrence of ovulation. Whenever ovulation occurs, it is followed by inflammation and release of pro-inflammatory cytokines, including TNF-a, interleukin 1 (IL-1), and interleukin 6 (IL-6). These cytokines enhance cell proliferation and oxidative stress and lead to increased production of leukotrienes and prostaglandins.[17] Additionally, primary amenorrhea, physical activity, and other dietary and lifestyle habits such as increased intake of omega-3 fatty acids and smoking are associated with a decreased risk for endometriosis. The fact that smoking has an inverse association with the risk of endometriosis attracts a lot of attention. Smoking has a catastrophic effect on almost every aspect of health, but this is not the case with endometriosis.

Pathophysiology

The understanding of the pathophysiology of endometriosis remains incomplete in many aspects, and there is not a coherent suggested theory to explain all different types of endometriosis, integrating the epigenetic, genetic, immunological, and environmental data. Of the proposed pathogenic theories, the most plausible is Sampson’s theory, suggesting that with retrograde menstruation, viable cells, and menstrual fragments can migrate through the Fallopian tubes, infiltrate into the peritoneal cavity, and then proliferate and cause chronic inflammation.[3] The fact that retrograde menstruation is a phenomenon caused in a large proportion of women of reproductive age, but not all of them suffer from endometriosis, indicates that retrograde menstruation is not enough by itself to cause endometriosis, indicates that there are also other factors contributing to the generation of disease. Other theories, such as the coelomic metaplastic theory and the vascular and lymphatic metastatic theory, are necessary to explain some forms of endometriosis. The role of oxidative stress and ROS, together with genetic, epigenetic, and environmental factors, must be integrated for a more complete picture of the pathogenesis of endometriosis.

History and Physical

The peak of the disease incidence is greater in women between 25 and 29 years old and lowest in women over 44 years old, whereas the prevalence in whites is higher than in African-Americans.[18] The clinical presentation of the disease differs in women and may be unexpected not only in the presentation but also in the duration. Clinicians usually suspect and are more likely to diagnose the disease in females presenting with the typical symptomatology such as dyspareunia, namely painful sexual intercourse, pelvic pain during menstruation (dysmenorrhea), pain in the urination (dysuria), defecation (dyschezia), or infertility.[14] The pain is usually characterized as chronic, cyclic, and progressive (exacerbating over time).[19]

Furthermore, some women suffering from endometriosis experience allodynia, a phenomenon when, even with the application of a nonpainful stimulus, an intolerable painful reaction is released. This condition indicates neuropathic pain. In the case of deep infiltrating endometriosis, the neural damage is caused by the invasion of endometrial stromal cells and mediators such as serotonin, histamine, prostaglandins, and nerve growth factor. These agents are released from mast cells, activated macrophages, and leukocytes, directly damaging the sensory nerve fibers and circulating in the peritoneal fluid.[7] Three subtypes of endometriosis often overlap with each other. These are the superficial peritoneal lesions, the ovarian endometrioma, and the deep infiltrating endometriosis.[20] Notably, the degree of clinical manifestations of the patient is not directly associated with the extent of the disease or the size of endometriosis lesions.[21] Patients with bowel endometriosis often present with a wide range of gastrointestinal symptoms like diarrhea, constipation, abdominal pain, or bloating and could mimic other clinical conditions like inflammatory bowel disease or irritable bowel syndrome.[22] Rectovaginal endometriosis is a very severe deep infiltrating form of the disease involving the vagina, the rectum, and the rectovaginal septum. Most often, it can be presented with bowel irritation, dyspareunia, dysmenorrhea, dyschezia, and rectal bleeding coinciding with menstrual bleeding.[23] Finally, a symptom with great concern is infertility, which often leads clinicians to suspect endometriosis, even in asymptomatic patients.

The endometriotic lesions in ovaries are described as ovarian endometriomas or as pseudocysts. The frequency of ovarian endometriomas accounts for approximately 17% to 44% of women with endometriosis, are bilateral in 50% of the cases[24], and are twice more frequent in the left than in the right ovary due to anatomic variables.[25] They differentiate from the common ovarian cysts by the fact that the endometriotic tissue bleeds inside of the endometriotic cyst, is a well-defined extra ovarian hematoma, and is surrounded by a duplicated ovarian parenchyma, lined by endometrial stroma, epithelium, and glands.[7] Chocolate fluid accumulates, covering the wall and filling in the cyst, containing old degenerated blood products, like hemosiderin-filled macrophages and pigmented histiocytes, resulting in a chocolate-like appearance in laparoscopic imaging.[24] Deep infiltrating endometriosis refers to endometriotic lesions that infiltrate the peritoneum more than 5 mm and cause severe symptomatology.[26] Deep endometriosis can involve additionally the bladder, the ureter, and the bowel, more frequently the rectovaginal septum, and less commonly the sigmoid.[26] Superficial peritoneal lesions are, in most cases, an accidental finding. Still, they sporadically can cause a thickening or hemorrhage of the mucosa or even be the reason for a pathological cervicovaginal smear. The histologic diagnosis of endometriosis could be hindered or obscured by a non-typical appearance of the endometrial glands or even the stroma caused by inflammation, edema, or hemorrhage.[27]

Evaluation

The disease diagnosis is usually delayed an average of 4 to 11 years from the onset of symptoms. This phenomenon occurs in low- and middle-income countries and wealthy societies with universal healthcare access.[19] This delay is attributed to the non-existence of a pathognomonic test or biomarker to detect the disease but also to the diversity of symptoms that could be considered physiologic responses during menstruation (like pain and discomfort), and the wide range of reported symptoms overlap with other gastrointestinal or gynecological causes. To diagnose endometriosis properly, the physician should start by taking a detailed history and performing a gynecological physical examination. Positive family history, pelvic pain, benign ovarian cysts, pelvic surgeries, and infertility issues enhance and alarm physicians to diagnose endometriosis.[19] Physical examination reveals variable findings, depending on the location and size of the endometriotic lesion.[28] Tenderness on vaginal examination, palpable nodules in the posterior fornix, adnexal masses, and immobility of the uterus are diagnostically indicating findings of endometriosis.[29]

Nevertheless, the absence of physical findings cannot exclude the diagnosis of endometriosis. The gold standard diagnostic tool remains laparoscopy, combined with an abdominal cavity exploration and a histological biopsy.[30] The lesions can differ in size and color. They can appear as red, white, or clear vesicular. Black "powder burns" or "gunshot" lesions are brown or black endometriotic tissue.[31] The role of histological confirmation is a bit controversial since macroscopically detected endometriotic lesions cannot always be verified histologically, and vice versa, namely in a macroscopically normal peritoneum, can be detected endometriosis tissue.[30] Direct visualization of the endometriotic lesion alone without a histological confirmation lacks enough diagnostic value since, to a great extent, it relies on the surgical skills and capability of the physician. Because diagnostic laparoscopy is an invasive procedure, it entails risks associated with any invasive process and could lead, albeit rare, to severe complications. Hence, there is a need for a diagnostic transition from surgical to non-surgical options, which could also contribute to a decrease in the time between the onset of symptoms and the diagnosis.

Several other low-invasive diagnostic methods have been evaluated regarding their diagnostic value, including magnetic resonance imaging and transvaginal ultrasound. Transvaginal ultrasound is a diagnostic tool with high sensitivity and specificity for ovarian endometriomas and permits a wide exploration of the pelvic cavity. Endometriomas appear as homogenous formations with a classic ground-glass appearance and low-level internal echoes.[24] Transvaginal ultrasound could moreover facilitate the diagnosis of deep infiltrating endometriosis located in the rectovaginal septum, uterosacral ligaments, pouch of Douglas, and vaginal wall.[30]

To assess whether specific serum, tissue, and urine biomarkers could assist diagnostically for endometriosis, CA125 is elevated in patients with endometriosis. Still, this test could not stand as a single diagnostic test. This is because CA125 can be increased in several pathological conditions except for endometriosis and cannot define the location of endometriotic lesions.[30] Various miRNAs have been found to upregulate or downregulate specific genes and play a significant role in the pathogenesis of infertility and endometriosis. Still, since many results are contradictory, more research is necessary to elucidate these agents' role further.

Treatment / Management

The treatment of endometriosis is broadly categorized into 2 main categories: pharmacological and surgical. Currently, there is no specific drug that could inhibit the progress of the disease other than hormonal and non-hormonal agents used to alleviate the symptoms and increase fertility rates.[32] An empirical medical therapy can be instituted for women with endometriosis symptoms (ie, pelvic pain) even without histological confirmation of the disease[31]. It should be highlighted that since endometriosis is a chronic disease, the treatment is mainly used to alleviate symptoms and not ultimately for the cure.[31] Providers should always remember that response to the therapy does not verify the diagnosis of endometriosis.[31] Many physicians treat women who suffer from persistent pain empirically after taking a detailed history, conducting a thorough physical examination, and excluding other pathologies, even though medical treatment does not improve fertility.[33](B3)

The first-line pharmacological therapy proposed for the management of endometriosis consists of non-steroidal anti-inflammatory drugs, progestins, or combined hormonal contraceptives.[31] Combined hormonal contraceptives can be administered either cyclically or continuously, and they exert their effect by inhibiting follicular development, lowering the levels of LH and FSH, and leading to decidualization and atrophy of the human endometrium.[31][33] Oral contraceptives are generally well-tolerated, affordable drugs, but in case of discontinuance, they have a high possibility of endometriosis-related pain recurrence.[31] Progestins are another option for the medical treatment of endometriosis. Progestins demonstrate their therapeutic action by inhibiting ovulation and creating a hypoestrogenic milieu. By binding directly to the progesterone receptors in the endometrium, they cause decidualization and atrophy of endometriotic implants. They can also relieve symptoms by decreasing peritoneal inflammation[34]. Weight gain and acne are potential side effects associated with the administration of progestins.[34] Lastly, non-steroidal anti-inflammatory drugs have been evaluated as very effective against endometriosis-related pain. They are supported as first-line medical therapy due to their easy accessibility as over-the-counter drugs and the low adverse-effect profile.(A1)

A second-line medical empiric treatment is a 3-month trial of gonadotropin-releasing hormone analogs for the suppression of endometriosis-related symptoms.[31] The continuous administration of the gonadotropin-releasing hormone acts by binding to pituitary receptors and downregulating the pituitary-ovarian axis. This results in pituitary desensitization, a fall in the levels of LH and FSH, anovulation, hypoestrogenism, and endometrial atrophy. The only concerns regarding this therapy are related to the side effects of hypogonadism, including bone loss, hot flashes, vaginal dryness, and headache.[35] Danazol, an androgen used to alleviate endometriosis-related symptoms, leads to atrophy of endometriotic implants by hindering LH surge and lowering estrogen levels. On the other hand, testosterone levels increase, and side effects like hirsutism, irreversible deepening of the voice, or acne can appear.[31]

Surgical treatment could also be adopted as a potential management option, even though it entails several risks related to the complications.[36] The major advantage of surgical treatment compared to pharmaceutical options is the ability to enhance fertility capability, but it can also provide pain relief simultaneously [7]. Surgery should be considered in cases of superficial endometriosis unresponsive or with contradictions to medical treatment.[7] When laparoscopic surgery is performed, the recommendation is to excise all the endometriotic lesions and adhesions. By the ablation of the endometriotic tissue, the local inflammatory milieu decreases in the pelvic cavity, thus increasing the chances of conception.[36][7] On the other hand, the management of ovarian endometriomas is still challenging and poses a dilemma to clinicians. The reason behind this is the cumulative research evidence that shows that the removal of the capsule of the cyst can result in a decrease in ovarian reserve and follicular loss.[36] However, cystectomy is preferable to cyst drainage or ablation due to its greater effectiveness in pain relief and the lower recurrence rate.[36] The final decision about which treatment approach should be followed should be taken collaboratively with the patient after a detailed explanation of all the possible risks and benefits related to each treatment option.[7]

Differential Diagnosis

The most common symptoms of endometriosis are infertility and chronic cyclic pelvic pain; therefore, other conditions should be ruled out from the differential diagnosis. Chronic pelvic pain is a usual symptom derived from pathologic conditions of the urologic, reproductive, and gastrointestinal systems. Pelvic inflammatory disease, adhesions, endometritis, primary dysmenorrhea, and second dysmenorrhea due to adenomyosis, myoma, and cervical stenosis should be excluded from the pathologies of the genital system.[33] Other diseases that should be excluded come from the gastrointestinal system, like irritable bowel syndrome, constipation, inflammatory bowel disease, and the urinary system, such as interstitial cystitis or chronic urinary inflammation.[37] Finally, the physician should also rule out neurologic and psychosomatic causes leading to chronic pelvic pain.[37]

Prognosis

Patients with endometriosis have fewer chances for childbearing and a higher risk for miscarriages and ectopic pregnancies than those without the disease.[38] Additionally, endometriotic lesions can spontaneously regress in approximately one-third of affected women who are not receiving any treatment.[39] According to different estimates, endometriosis recurrence rates after surgery vary between 6 and 67%.[40] Potential risk factors predicting a possible recurrence have not been completely clarified, but the recurrent endometriotic lesions may arise from de novo cells or residual endometriotic tissue.[40] Medical treatment can be proven effective, but in 5% to 59% of patients, the pain continues to exist at the end of the therapy.[41] Even in cases of treatment cessation, pain recurrence has been reported in a percentage of 17% to 34%.[41]

Complications

The main complications of endometriosis include infertility or subfertility, chronic pain, and other debilitating persistent symptoms. These are wide in range, including dysmenorrhea, dyspareunia, and dyschezia. Still, endometriosis can also cause a decrease in the quality of life of patients, complications of surgical procedures, anatomical abnormalities due to possible adhesions, bowel or/and bladder dysfunction, but in the case of ovarian endometriomas could even lead to the development of cancer. The role of endometriosis in infertile women has been debated for a long time, with literature research showing that infertile women are 6 up to 8-fold more likely to suffer from endometriosis than fertile females.[42] Even though several mechanisms have been proposed to explain this phenomenon, no consensus has been reached in the scientific community about the exact mechanism behind infertility in endometriosis.[42]

Chronic pelvic pain is closely associated with endometriosis since endometriosis has been the cause in 71% to 87% of women suffering from chronic pelvic pain.[43] This disease can negatively affect the health-related quality of life and crucially hinder social, emotional, and sexual well-being as well as other domains like daily routines, family planning, efficacy, or productivity of patients in the working environment.[44] Additionally, patients with endometriosis have higher stress levels, report worse quality of sleep, and lower physical activity compared to healthy women.[44] Bowel dysfunction like constipation or other digestive problems can appear in females who have endometriosis as a result of the inflammatory process of irritation of the gastrointestinal system rather than due to the involvement of endometriotic nodules affecting the rectum since patients undergoing surgical treatment for rectal endometriosis might continue experiencing those displeasing symptoms.[45] Although primarily endometriosis was considered a benign condition, later research findings showed a higher risk for ovarian cancer in patients with endometriosis.[46]